CLEAR/VNCE TESTS IN' CLINICAL MEDICINE Puhtteatkm Kumber S39 AMERICAN LECTURE SERIES® A Afonogntph in the B\NNEnSTONC DIVISION of AMERICAN LECTURES IN LmNC CHEMISTRY Edited by I. NE\VTON’ KUCELMASS, M.D, PhD.. Sc.D. Connltenl to the Departments cf Dcalth and llospilals Nftc VofJt, Kew Yorl: CLEARANCE TESTS IN CLINICAL MEDICINE By FRANgOIS C. REUBI, M.D. Trofcstor of Medicine Vntcersily of Bern (Medical Polichnie) Bern, S\iitzcrland CHARLES C THOMAS • PUBLISHER Sprin^eld • Jlhnois • U.S.A. 35^3 Fubhfhed and Distributed Throughout the World bij CHARLES C THOMAS • PUBLISHER BAJfNERSTOS'K HOVSE 301-327 East LawTence Avenue, SpringGeld, lilioois, U.SA. This boolc Is protected by copyright. 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Printed in the United States of America rORLWORD Oim LI^'I^G CiiE\usTRY Series was conceived bj Editor and Publisher to advance the newer knowledge of cliemical medicine in the cause of climcal practice Tlie mterdependence of chem istry and medicme is so great that physicians are turning to chemistry and chemists to medicine in order to understand the underlying basis of hfe processes m health and disease Once chemical truths proofs and comictions become sound founda tions for chnical phenomena ke> hjbnd investigators clanfj the bevvaldenng panorama of biochemical progress for apphca tion m everydaj practice stimulation of experimental research and extension of postgraduate instruction Each of our mono graphs lluis unravels the chemical mechanisms and chnical man agement of many diseases tliat have remained relabvel> static in the minds of medical men for three thousand years Our new JTenes is cfiargecf vvitli the iiisws elan ot* cfiemicaf wisdom su preme in choice of international authors optimal m standards of clienucal scholarship provocative m imagmation for experi mental research comprehensive in discussions of scientific med icine and autliontative in chemical perspective of human disorders Dr Reubi of Bern, Switzerland evaluates the abihty of the kidney to perform its function in health and disease Detailed assessment of renal function involves many different tests in view of the multiplicity of renal activities Fortunately the overall renal efficiency can be estimated sufficiently accurately for diag nostic and prognostic purposes by a few simple function tests The nephron utilizes four major mechanisms for maintaining homeostasis of the internal milieu since the formation of urme is determined by adequate flow of blood to the nephron filtra tion of plasma tlirough the glomerular membrane resorption of filtrate components and secretion by tubular cells The renal pro- cedures— GFR RPF and Tm are measurable by clearance tests vi Clearance Tests in Clinical Medicine revealing qualitatively complete or partial remo\'aI of a sub- stance from blood during its passage througli the kidneys; and quantitatively, the least volume of blood or plasma which con- tains all of a substance excreted in the urine in one minute. It is this so-called virtual volume, the result of arithmetical calcu- lations, that provides a measure of the glomerular filtrate and of renal efficiency. Clearance techniques have supplied a w’ealth of accurate in- formation in Dr. Reubi’s Clinic, well adapted for routine clinical use. The facts did not blunt his ardor. An infant’s urea clearance is one-fourth, sodium clearance one-fifth, and phosphate clear- ance one-tenth of the adult range when proper correction by surface-area measurements are made for differences in size. In- fant GFR gradually attains nonnal levels as the total volume of body ^^’ate^ becomes the standard of comparison with adult values. Renal function tests at any age detect possible renal dam- age in a patient suffering from some disorder winch involves tlie kidneys or determines tlie degree of functional damage of kid- neys knovTi to be diseased. Clearance thus unravels the differ- ential diagnosis of perplexing renal problems, i.e., lipid neplirosis from clironic glomerulonephritis with accompanying neplirosis; nephrosclerosis from chronic glomerulonephritis with sympto- matic renal hjpertension; glomenilonephritis in remission or progression; and renal function reser\’e in medical and surgical disorders. Early functional deviations in nepliropathy are di- rectly correlated with the progress of kidney disease by the tests more than the chemical concentration of some blood component or urinary e.xcretion rale of some extraneous substance; as in the end-results of marked renal dysfunction where non-\’alid predictions pre\'ail that PAH e-xtraction may be almost complete or that inulin is not resorbed tiuough tlie tubule. The progressive abnormalities of various clearance measurements tlius interpret the course of events in chronic renal failure, i.e., inulin and PAH clearance and Tm decrease progressively as the underl)'mg dis- ease responsible for renal failure advances. Richard Bright (1836) considered it “a humiliating confes- sion that although much attention has been directed to this dis- ease for nearly ten years, little or nothing has been done toward Forctund Ml devising 'i method of permanent relief It inspired Schmidt (1850) to mitnte biochemical analysis of bod> fluids \\hich led to the chmcal development of anal>tical methods The con cepts of the laboratory were thus adapted to tlie bedside for detecting disease unravellmg mechanism and planning ther apy The resulting quantitative biochemical methods give us the understandmg necessary to fulfill Brights dream Once we understand action is easj But chemical vision is needed in medicine more than methods Ambatd (1912) initiated the em pineal kidne> coefiieient Richards (1934) muhn clearance Addis (1925) physiologic clearance formulae lanSlyke (1935) urea clearance and Homer Smith (1945) renal function tests offenng statistical evaluation of tlie nephron population but not the state of the individual nephron let the authors effective correlation of clearance for quantitatmg clinical problems is a practical achievement well worth embodying in our laboratory armamentaria Function tests for every organ m the body have come into tlieir own m this medical era as a result of the pro longed human hfe span which increases the incidence of chronic diseases the phenomenal advancement in medical teclmology which provides sensitive tools for accurate measurement of liv mg mechanisms m the human body and the newer knowledge of pathophysiology which enables quantitation of biochemical changes I Newton Kucelmass MD PhD ScD Editor PREFACE The elaboration of clearance methods by D D van Slyke H W Smitli and their groups undoubtedly represents one of the most fascinating contributions to renal physiology that has been made during tlie first half of this century These metliods have since been widely used by physiologists and clinical in vestigators But surprisingly enough only a few clinicians have attempted to mtroduce them into clmical practice This is per haps because they uere considered to be too elaborate for gen eral application Fifteen years ago I became acquamted with these techniques and was much more impressed by their potential interest m clinical medicine than discouraged by the technical problems raised by their use as routine diagnostic tools I started my work iMth the hope that these methods would finally prove more satis factory m the diagnosis of renal diseases than tlie usual semi quantitative tests I am now convinced that this is so Many interesting contributions to the clinical use of clearance methods published so far are concerned with a single disease These papers arc scattered throughout the world literature Only a few attempts have been made to review the whole subject It IS hoped therefore that tins monograph wall fill a gap and prove of some value to those who are interested in renal diseases Al though considerable space has been devoted to the description of the methods lliemseivcs and to their critical mterpretation emphasis is definitely placed on the clinical sections ACKNOWLEDGMENTS I AM INDEBTED TO niosE ^^ho lia\e preceded me in this field and whose names are mentioned m the hst of references I should hke to express mj gratitude to my past and present assistants for their help in collecting the clinical material presented in tliese pages and to the technicians who performed se\eral thousands of clearance determinations I am speciall) indebted to Mrs E Gautier who read cnticall) llie manuscript and whose ad\ice was most helpful m improving m> English I wish to thank Mrs D Pauli and Mrs A L Jeanneret for their unfailing secretarial assistance I am also obliged to vanous journals and particularlv to tlie pubhshers Huber (Bern) Masson (Pans) and Springer (Berlin) for permitting me to reproduce man> of the illustra tions used in this book CONTENTS Page Foreivord v Preface ix AcknouAcdgments xi PART ONE THEORETICAL CONSIDERATIONS METHODS AND INTERPRETATIONS Section I DEFiNmov and Theory of Renal Clearances 7 I Definition 7 II Glomerular filtration rate 8 III Renal blood flow 16 IV Filtribon fraction 24 V Tubular reabsorpbon 26 VI Osmolar clearance free water clearance and free water reabsorption ‘*8 VII Tubular secretion 29 Section II Clinical Methods 33 I Simultaneous delerminabon of glomerular filtration rate and PAH clearance 34 II Clearance of certain physiological constituents of the unne 36 III PAH estraction rMvo 41 IV Glucose reabsorption and glucose Tm 4“’ Section 111 Intebpretatiov of Clearance Results 49 I Introductory remarks 49 II Normal values ^9 III Changes due to aging 50 xm xiv Clearance Tests in Clinical Medicine Page IV. Values in renal disease 51 V. Validity and limitations of clearance methods in the dis- eased kidney 58 PATIT 'nvo CLEARANCE PATTERNS IN RENAL DISEASE Section IV. GLOMEnuLONEPimms 73 I. Acute diffuse glomeniloncphrilis 73 II. Acute focal glomerulonephritis S4 III. Chronic glomerulonephritis 84 Section V. The NErirncmc SiTsDnoME 95 Section V7. OniEn CtOMEnuLAn Diseases Ill I. Amyloidosis Ill II. Diabetic glomerulosclerosis HI III. Toxemia of pregnancy 116 Section VII. Vasculab D;se:»ses 121 I. Essential hypertension and renal arteriosclerosis 121 II. Unilateral renal artery lesions 132 Section VIII. PYELo-NEPimms 137 Section IX. Acute Renal Failuhc 147 Section X. Tubular Syndromes 157 I. Renal glycosuria 158 II. Fanconi syndrome, hjiwraminoaciduria, hyperphospha- turia 164 III. Hyperparathyroidism and hyiwparalhyroidism 168 IV. Renal functions in hypokalemia 167 V. Diabetes insipidus IH VI. Renal functions in gout 172 Section XI. Funchonal Distobb-anck of Re-val Hemo- dynamics 177 I. Renal functions in acute hypotension and shock 178 Contents x\ Page II Renal disturbances following dvseIectrol>temn 180 III Renal functions in dnbebc coma 181 IV Renal functions in heart failure 186 Bibliography 191 Index 211 CLEARAjNCE tests IN CLINICAL MEDICINE DEriNITION AND THEORY OF RENAL CLEARANCES I DEFINITION Xhe word “clearance was introduced into renal physiology thirty years ago as an empincal means of describing the excre- tion of urea Van Style and hts associates (207) called “urea clearance” the volume of blood cleared of urea by one minute's excretion Expressed in terms of the analytical values, urine urea concentration U, urine volume V and blood urea concen- tration B, the clearance corresponds to formula clearance = Unfortunately, the urea clearance is dependent on the urine flow At flow rates below 2 ml/min, van Sl>he and his collab orators (207) found that the urea clearance fell approximately in proportion to the square root of the urme volume and there- fore proposed a second formula clearance ~ U\/V UV The clearance was called ‘maximal clearance and the ex- l5 uvv ^ B standard clearance” Obviously, the “standard clearance is not a “clearance” in tlie proper sense of the definition, and this term should no longer be used But the concept of the maximal clearance’ lias proved extremely useful, becoming a generalized notion applicable to all aspects of renal excretion (298) Thus, tlie kidneys clear the blood of a large variety of substances, and these different opera- tions may all be expressed in terms of clearance As it is more convenient to use plasma llian whole blood for the analytical determinations, the plasma clearance is noxx generall> emplojed 7 8 Clearance Tests in Cltnical Medicine Indicating the plasma concentration of the substance as P, the clearance formula becomes: where C = clearance (ml/min) V = urine flow (ml/min) U = urinarj' concentration (mg/ml) P=: plasma concentration (mg/ml) Tlie clearance of any substance is the virtual volume of plasma completely cleared of this substance per minute, or more simply, the excreted amount of this substance divided by its plasma concentration. The calculation of the clearance does not involve any consideration of the mechanism by which the sub- stance is cleared. The clearance values obtained for the various constituents of the urine differ considerably, depending on how they are excreted. Tlie glucose clearance is normally zero, be- cause all tlie glucose filtered is reabsorbed. Tlie inulin clearance is equal to the glomerular filtration rale (i.e., about 125 ml/min), if we assume that inulin is neitlier reabsorbed nor excreted by the tubules. The PAH clearance is the highest clearance so far recorded (i.e., about 650 ml/min), because the plasma is almost completely cleared of its PAH content by tubular secretion. The upper limit of any clearance is obviously the plasma flow through the kidneys (i.e., about 700 ml/min). n. THE GLO.NfERULAR nLTRATION RATE Tlie glomerular filtration rote can be determined by measur- ing the plasma concentration and the urinary e.xcretion of a free filtrable substance X wliich is neither reabsorbed nor metab- olized nor actively secreted by tlie renal tubules (300, 301). Let GFR = glomerular filtration rate (ml/min) V = urine flow (ml/min) Px = plasma concentration of the substance X (mg/ml) Us = urinary concentration of tlie substance X (mg/ml). If tlie above mentioned requirements are fulfilled, the excreted amount of the substance X equals its filtered amount: Definition and Tliconj of Renal Clearances 9 U^V^P^GFR therefore GFH = UxV but -p— = Cj = clearance of the substance X In other ^\ords the gJomemJar filtration rate ts equal to the clearance of a free filtrabJc stihstance which ts neither rcah sorhed nor metabolized nor actively secreted by the tubidcs The search for such a substance began forty years ago In 1926 Rehberg ( 244 ) proposed tlie use of creatinine on the grounds that it was concentrated in the unne to a greater extent than any other identified substance Later ssork showed how e\er that in man the creatinine clearance could not be con sidered a rehable method of measuring the glomerular filtration rate (see below) In 1933 H W Smith (300) started working with muhn and was soon able to show that this polysaccharide was a suitable substance for this purpose At the same time but independently Richards (273) had come to the same conclusion Inulm lias since been widely used as the best standard of refer ence Mannitol sodium thiosulfate and allantom have also been recommended With the exception of sodium thiosulfate how ever they did not prove to be satisfactory According to H W Smith (300 301) the evidence that mulm fulfills the requirements for measunng the glomerular filtration rate in man may be summarized as follows 1) Inulin IS not bound by plasma proteins it is entirely filtrable from human plasma and has been shown to pass mto the capsular fluid of frogs and Necturi in the same concentration as was present in the plasma 2) Inulin IS not excreted by tlie aglomerular fish kidney 3) The rale of urinary excretion of muhn is proportional to its plasma concentration over wide ranges of the latter indicating no tubular participation (166 201 290) 4) The creatmine/inuhn clearance ratio is equal to 1 00 m the dog and tlie rabbit Tins ratio is vanable and greater than 1 00 in man where independent e\ idence demon strates the tubular secretion of creatinine 10 Clearance Tests in Clinical Medicine 5) Other relatively inert substances (sorbitol, mannitol) have clearances approaching that of inulin in man. 6) In the case of a substance which is reabsorbed, or alter- natively secreted by the tubules, elevation of the plasma concentration causes the clearance of the substance to increase or decrease, respectively, and to approach asymptotically the inulin clearance. 7) Administration of phlorizin raises the glucose/inulin clearance ratio to 1.00 in all animals studied and to 0.91 in man. 8) Inulin is not excreted in the dog or rabbit when the blood pressure is reduced below the les’el conceived to be necessary’ for filtration. We should like to add two more arguments in favor of the suitability of inulin: 9) The thiosulfate/inulin clearance ratio is equal to 1.00 in man, despite the very dissimilar chemical structure of tliese two compounds. 10) Both in human patients and e.xperimental animals, acute and subacute glomerular nephritis reduces tlie inulin and the sodium thiosulfate clearance much more than the excretion of sodium paraaminohippurate. Thus, it seems to be clear that inulin is a reliable test sub- stance for measuring the glomerular filtration rale in normal man. Nevertheless, its use has raised several objections. The pro- portionality between urinary' excretion and plasma concentration has been questioned by Ferguson et al. (116), who found that the clearartce was lower al low plasma levels, suggesting some tubular reabsorption. But Kennedy and Kleh (166), who reex- amined this problem carefully, were unable to confirm the results of the British investigators and obtained clearance values which were identical at all plasma concentrations. Further objections to the use of inulin iiave been raised by Frey (121) and Gayer (131). Under certain experimental con- ditions these authors found after a single injection of inulin in the rabbit relatively high concentrations of this substance in the 11 Definition and Theory of Renal Clearances renal tissue Frey (121) expressed the opinion that tins finding \\ould be consistent with a tubular secretion of inulm, wliereas Ga}er(131) believed that some uiulin \wis diffusing back from the tubular lumen into the tubuhr cells Other mvestigators (151) usmg the same technique, failed, however, to reproduce Frey’s findings Concerning the axpenments performed by Gayer (131) m normal rabbits, it is reasonable to assume that the back diffusion, if any, took place after removal of the clamped kidney or during its subsequent perfusion with sahne On the other hand, some back diffusion of muhn is likely to occur in animals whose tubules have been damaged b} mercury or tar- trate poisonmg (130) But we feel that such experimental re suits do not invalidate the overivhelming evidence that inulin is a suitable substance for delenmmng the glomerular filtration m man, with the exception of patients with tubular damage The fact that commercial inulm is not a homogeneous prod- uct might represent a source of theoretical and analytical difB culties Inulin contains two major fractions m variable proper tion a) a portion of relatively large molecular weiglit resistant to heating in alkah (alkali stable imdin), and b) a portion of smaller molecular weight which is alkah labile (81, 330) A companson of the clearances of the two fractions has been made by several mvestigators, who came to different conclusions While two groups ( 149, 314 ) reported higher cleirance values (about 10 per cent) for the alkali stable fraction, suggesting some tu bular reabsorption of the fraction of smaller molecular weight, Cotlove (81) and Walser et al (330) found both clearances to be identical withm analytical error In their study, Walser ct al (330) used imprmed analjtical methods and this fact strongly suggests that their conclusions are vahd On the other hand, most commercial solutions available at present consist mainly of alkah stable inulm (at least 905f), so that even the differences reported by some imestigators %vould be of no practical signifi- cance The inulm solutions formerly used often contained pyrogenic material As an) pyrexial reaction produces serious hemodynamic changes within the kidney (300,301), pyrogenic inulm cannot be used for measuring the glomerular filtration rate under basal 10 Clearance Tests in Clinical Medicine 5) Other relatively inert substances (sorbitol, mannitol) have clearances approaching that of inulin in man. 6 ) In the case of a substance which is reabsorbed, or alter- natively secreted by the tubules, elevation of the plasma concentration causes the clearance of the substance to increase or decrease, respectively, and to approach asymptotically the inulin clearance. 7) Administration of phlorizin raises the ghicose/inulin clearance ratio to 1.00 in all animals studied and to 0.91 in man. 8) Inulin is not e.^icrcted in the dog or rabbit when the blood pressure is reduced below the level conceived to be necessary for filtration. We should like to add two more arguments in favor of the suitability of inulin: 9) The thiosulfate/inulin clearance ratio is equal to 1.00 in man, despite the very dissimilar chemical structure of these two compounds. 10) Both in liuman patients and e.xperimental animals, acute and subacute glomerular nephritis reduces the inulin and the sodium thiosulfate clearance much more than tlie excretion of sodium paraaminohippurate. Thus, it seems to be clear that inulin is a reliable test sub- stance for measuring the glomerular filtration rate in normal man. Nevertheless, its use has raised several objections. The pro- portionality between urinary excretion and plasma concentration has been questioned by Ferguson et al, (116), who found that the clearance was lower at low plasma levels, suggesting some tubular reabsorption, But Kennedy and Kleh (166), who reex- amined this problem carefully, were unable to confirm the results of the British investigators and obtained clearance values which were identical at all plasma concentrations. Furtlier objections to the use of inulin have been raised by Frey (121) and Gayer (131). Under certain experimental con- ditions these authors found after a single injection of inulin in the rabbit relatively high concentrations of this substance in the 11 Defintiion and Theory of Renal Clearances renal tissue Frey (121) expressed tlie opinion that this finding would be consistent with a tubular secretion of inulin whereas Gayer (131) believed that some inulm was diffusing bach from the tubular lumen into the tubular cells Other investigators (151) using the same technique, failed, however, to reproduce Frej’s findmgs Concerning the experiments performed by Ga>er (131) in normal rabbits, it is reasonable to assume that the back diffusion, if any, took place after removal of the clamped kidney or dunng its subsequent perfusion wntli sahne On the other hand, some back diffusion of muhn is likely to occur in animals whose tubules have been damaged by mercury or tar- trate poisonmg (130) But we feel tliat such experimental re- sults do not invalidate the overwhelming evidence that muhn is a suitable substance for determining the glomerular filtration m man, with the exception of patients with tubular damage The fact that commercial muhn is not a homogeneous prod- uct might represent a souice of theoretical and analjtical diffi culties Inuhn contains two major fractions in variable propor- tion a) a portion of relatively large molecular weight resistant to heating in alkah (alkali stable muhn), and b) a portion of smaller molecular weight winch is alkah labile (81, 330) A companson of the clearances of the two fractions has been made by several investigators, who came to different conclusions While two groups (149,314) reported higher clearance values (about 10 per cent) for the alkah stable fraction suggesting some tu bular reabsorption of the fraction of smaller molecular weight, Cotlove (81) and Walser et al (330) found both clearances to be identical within analytical error In their study, Walser ef al (330) used improved analytical methods and tius fact strongly suggests that their conclusions are valid On the odier hand, most commercial solutions available at present consist mainly of alkah stable muhn (at least 9055), so that even the differences reported by some investigators would be of no practical signifi cance The muhn solutions formerly used often contained pyrogenic material As an> pyrexial reaction produces serious hemod>mamic changes within the kidney (300,301). p>rogemc muhn cannot be used for measuring the glomerular filtration rate under basal 12 Clearance Tests in Clinical Medicine conditions. Fortunately, all commercial preparations now avail- able are phannaceutically certified as free of pyrogenic activity. Assuming that the intilin clearance really measures the glo- merular filtration rate, we are in position to find out whether other substances can be used for the same purpose. Tliis can be done simply by comparing their clearance with the inulin clearance under various conditions of plasma concentration, urine flow and glomemlar filtration. Tlie sodium thiosulfate clearance has been showai to be prac- tically identical with the inulin clearance in the dog (136) and man (215). In 203 observ-ations on healthy men and women, we obtained an average sodium thiosulfate clearance of 126 ml/min per 1.73 sq.m. (261, 262). This figure does not differ sig- nificantly from the normal inulin clearance values of 124 ml/ min/1.73 sq.m. and 123 ml/mln/1.73 sq.m. reported by Goldring and Chasis (139) and Smith (300) for mcred sexes. A thiosul- fate/inulin clearance ratio close to unity has also been found in twenty-five children with kidney disease by Matter et al. (192) and in forty-eight patients with low glomerular filtration rate by Brun (49). TJie slight deviation from 1.0 observed in smaller series (24,27) is likely to be accidental.* \Vlien, however, the plasma concentration of thiosulfate is very low (10 mg per cent or less), the thiosulfate clearance is higher than the glomerular filtration rate (89, 178, 182). The reasons for this are not entirely elucidated. It might be that a small fraction of the sodium thio- sulfate is secreted by the tubules and that this phenomenon can- not be detected unless the filtered amounts are extremely small. It might also be due to an inaccurate determination of the rela- tively high plasma blank. This blank usually varies between 2 and 4 mg?, but occasionally values up to 7 mg? may be found. A small analytical error miglit result in too large an estimate of the blank and falsely low thiosulfate levels, increasing the appar- ent clearance. It is therefore important, if sodium thiosulfate is to be used, to ensure that the plasma concentrations lie between 20 and 35 mg?. At plasma levels higher tlian 40 mg? the patient • The thiosulfate/inulin clearance raho of 1.38 reported by Bucht (57) at thiosulfate plasma concentrations of about 18 mg* is so far out of hne wth other obsersations that some analytical error may be suspected. 13 Definition and Theory of Renal Clearances ma) experience some discomfort (nausea) At any case, only freshly prepared solutions of sodium thiosulfate should be in jected, as stored solutions show increased toxicity If these pre cautions are observed, we feel that sodium tluosulfate is quite suitable for measunng the glomerular filtration We have been usmg it now for almost fifteen years and still use it for routine clearance determmations It was m 1926 that Rehberg(244) proposed the exogenous creatinine clearance for the measurement of glomerular filtration rate In order to improve the reliabihty of the analytical methods, a certain amount of creatinine (3 5 gm) was administered by mouth Tins technique, however, was shovvn by all subsequent investigators (205, 287, 300) to yield, in man, clearance values considerably higher than the filtration rate (m tlie dog the exog enous creatinine and inulin clearances are identical) Accord mg to Smith (300) there are two lines of evidence that a fraction of creatimnc is excreted by the tubules (a) The creatinine/ inuhn clearance ratio which is always greater than 1 0, falls with increasing creatinine plasma concentrations (b) This ratio be comes close to unity after the administration of carmatnide, phlorizin or sodium paraamuiohippurale The endogenous crcrtfimnc clearance w’as proposed m 1937 hy Popper and Mandel (236) and independently by Miller and Dubos (202) as a measure of the filtration rate It was soon real- ized, however, that especially m patients wath reduced filtration, tlie endogenous creatinine clearance was much higher than tlie muhn clearance, the clearance ratio values showing a wide scat- ter (150, 192,202, 203, 205, 284, 300) This phenomenon can be observ-ed with any analytical method used, even with the “spe- cific” enzymatic method developed by Miller and Dubos (202) In a large series of patients witli kidney disease, whose tliiosul- fate clearance ranged from 3 1 to 179 ml/mm, we obtamed (261, 262) an average creatinine/tliiosulfate clearance ratio of 1 47 (range 073 to 2S5) ^VIle^ Uie clearance ratios were plotted against the thiosulfate clearance values (Fig 1) a rough inverse relationship could be demonstrated For thiosulfate clearance values ranging from 120 to 179 rol/min, the Cr/T ratio averaged 1 07, for thiosulfate clearance values between 60 and 119 ml/min, 14 Clearance Tests in Clinical Medicine Cc/Ct J 2.6 J 2J! J ^ 1 1 1 1 I I - I 1 0 60 tio tSO ml/min Cr Fig. 1. Behavior of Ihe ereatlnme/lhiosiilfale clearance rah’o (Ccf/Cr) at various levels of glomerular BUtation rale (Ct). The sjmbols @ refer to the average ratios corresponding to each of three groups of subjects (Cp 0-59 ml/min. 00-119 ml/min and 120-180 ml/min). 1.37, and /or thiosulfate clearance values between 3 and 59 ml/ min, 1.75. This phenomenon may be e.xplained on the basis of a tubular secretion of creatinine wliich becomes relatively impor- tant at low levels of filtration rate (132, 150, 192), Our data con- firm the unreliability of the creatinine clearance in patients vviTh reduced renal functions. On the other hand, unexpectedly low creatinine clearances liave been observed in patients with con- gestive heart failure and edema (7,203). This seems to support the view that the creatinine clearance depends to some extent on the urine flow (132). In normal subjects, a rather close agreement between inulin and creatinine clearances has been found by some investigators (47,98,192). But again, the great variability of the clearance ratio in individual cases has been emphasized by otlier work- ers (99, 203). Therefore, it seems that in a large group of nor- mal subjects the average clearance ratio does not differ sig- nificantly from unity. In a given case, however, the ratio is un- Definition and Theory of Renal Clearances 15 predictable and the creatinine clearance cannot be considered a precise measure of the glomerular filtration rate. Mannitol has been widely used during the war for measuring the glomerular filtration rate, because at this time pyrogen-free inulin was not available. While many investigators reported mannitol/inulin clearance ratios close to unity (109, 298, 306), other Laboratories came to the conclusion that the mannitol clear- ance was lower than the inulin clearance ( 13, 76, 148, 248 ) . The question whether this difference is due to analytical difficulties or to mannitol reabsorption by the tubules has remained unan- swered. According to our own experience, the mannitol clear- ance is lower than the inulin and the thiosulfate clearance. In a small series of she normal subjects we obtained an average mannitol clearance of 104 ml/min/173 sq.m. (248). When the average mannitol/PAH clearance ratio (“filtration fraction”) was calculated in this series, it was found to be 0.146 ( 248), while the inulin/PAH and Ihiosulfate/PAH clearance ratios average 0.195 in normal subjects (139,261,262). In a larger series of hypertensive patients, we also found, when mannitol was used, lower values for tl\e glomerular filtration rate and the filtration fraction than with inulin or thiosulfate (248). For these reasons, most investigators no longer consider mannitol to be suitable for clinical measurement of the filtration rate (300, 301). Exogenous alUmtoin has been proposed by Friedman et al. (123) as a substitute for inulin. These authors found an average allantoin/inulin clearance ratio of 1.04 in five normal subjects (range 0.88 to 1.20) and of 0.99 in elev’en hypertensive patients. Therefore, they concluded that allantoin was excreted solely by filtration in man. On the other hand, a comparison of the allantoin and inulin clearances in the diseased human kidney has been made by Miller et at (204) who found considerable deviations. These deviations were not related to renal function. While in some patients the allantoin/inulin clearance ratio was close to unity, it was definitely lower in most of them, the lowest being 0.64. This suggests tubular reabsorption of allantoin. If both tlie tediousness of the analytiol procedure and the erratic, unpredictable deviations from the inulin clearance are taken into account, there is little justification for the use of allantoin in clinical clearance studies. 16 Clearance Tests in Clinical Medicine lU. THE RENAL BLOOD FLOW In man, the renal blood flow can only be measured by in- direct methods, based either on the Stewart principle (313) or the Pick principle (117). Tliey can be divided into three groups: —The dye dilution methods. —The gas diffusion methods, using NjO or radioactive Kryp- ton. — Tlie methods based on the urinary' excretion of substances like sodium paraaminohippumte, Diodrast or radioactive Diodrast. A. The Dye Dilution Methods According to the Stew'art principle, the amount of a dye in- /ecled into the renal artery' is equal to iJie amount vvliich leaves the kidney by the renal vein, if no recirculation occurs during the time of sampling. If recirculation of the dye does occur, the amount of dye entering the kidney is equal to the sum of injected plus recirculating quantities. Different equations have to be used depending on tlie techinque employed. All techniques require catheterization of the renal artery and of the renal vein. Cath- eterization of the renal artery is performed with a Oedman catheter inserted into the femoral artciy' (221) and the renal vein is calheterized with a Coumand catheter from tlie ante- cubital vein. a) Single Injection Technique {2S7) An acairately measured quantity' of d>'e is injected within one to two seconds into the renal artery’. Renal venous blood is drawn at a constant rate through a photoelectric cell and the concentration of the dye is recorded using a modified oxyTnefer during the time of its first circulation. Let I = quantity of dye injected (mg) Qii = quantity’ of dye leaving the organ (mg) F = renal blood flow' (ml/min) R = concentration of dye in the renal vein (mg/ml) If I = Qr and Qr = F R dt, ^ R dt 17 Definition and Theory of Renal Clearances For practical purposes, Hamilton’s equation (171) is used F (ml/min) • in which S = area under the recorded dye concentration cur\’e. For tlie calculation of F, the area S is measured and compared with the area under tlie curve obtained after a known quantity of dye has been injected directly into the recording system (307). With this technique it is also possible to determine the mean transit time through tlie kidney (MTT) and therefore to cal- culate the effective renal vascular volume from equation. V„(ml)=-^ - MTT (sec) b) Technique xoith Constant Rate of Dtje Infection (267) A solution of dye is injected by a constant speed injector (1 ml/min) into the renal artery. After equilibrium has been reaclied, simultaneous blood samples of 10 ml are taken from a needle in the femoral artery' and from the \'enous catheter. Let A = tlie concentration of dye in arterial blood (mg/ml) Qi=:the quantity of dye entering the kidney (mg) Qn = Q. But Qx = I + F J‘ A dt and Qr = F R dt therefore F — I J‘(R-A)dt or in differential form F = D R- A where D = the constant rate of dye injection (mg/min). This formula has been used by Gibbs et at (135) for the measure- ment of cerebral blood flow. Tliese teclmiqiies liave been developed in our department for the last few months (2ff7). Our preliminary results are more than encouraging, but further work is needed before the re- liability of the dye methods can be definitely established. So far we have gained the impression that the single inj'eclion tech- nique yields better values. 18 Clearance Tests in Clinical Medicine B. The Methods Based on the Fick Principle Tlie Fick principle postulates that the quantity Q of any sub- stance taken up in a given time by the kidney from the blood, which perfuses it, equals the amount carried to the kidney by arterial inflow less the amount Qr removed by the renal vein during tlie same time period, so Q (1) but Qa = FaA and Qr = FrR, where Fa= arterial blood flow Fr = venous blood flow A = arterial blood concentration of the substance R = renal venous blood concentration of the substance Therefore Q = F^A - FrR ( 2 ) While in most organs the outflow equals the inflow, this is not entirely true in the case of tl>e kidney because of tlie forma- tion of urine, so that Fa^Fr + V (3) where V = urine flow In most cases, however, V is very small as compared with Fr and can be neglected. Tlierefore let Fa = F„ = F so that equation (2) becomes Q=F(A-R) (4) There are two groups of methods based on the Fick principle. We shall discuss them separately. 1. The Gas Diffusion Methods The kidney, like the brain, is able to absorb by simple solu- tion an inert gas which readies it by way of the arterial blood. The gas is administered to the patient by inhalation in an open system. From the start of inlialation and tliroughout a ten minute period, the blood gas concentration cur\’es in a peripheral artery 19 Definition and Theory of Renal Clearances and in the renal \em are drawn on the basis of four to fise pairs of blood samples The arterial concentration nses rapidl), the venous concentration more slowly, owtng to the quantity of gas taken up b\ tlie kidney tissue After about ten mmutes, satura- tion and equihbnum are reached, and the concentration m the arterial blood in the venous blood and in the kidney tissue are approximately equal The renal blood flow can be calculated from equation (4), but as the blood concentrations are \ranables with respect to time Q = F (J‘Adt-J-‘Rdt) Qr F — Q or m terms of unit weight of kidney y - Q/W ^ J‘ (A-R) dt where W = weight of the kidney Q/W represents tlie renal concentration of the inert gas After equihbnum has been reached at time t it may be taken as q/W = R, k where k represents a partition coefficient between kidney tissue and renal V enous blood By substituting appropriately we obtain for the renal blood flow 100 R, k F/lOO gm mm = (5) k mav be taken as 1,0 R, can be determined in the renal venous blood at time t For the calculation of the denommator, a graph real conslmction is used Smooth curves are dravm through tlie artenal and the venous points From these curves tlie integral of tlie artenovenous difference can be obtained by means of the trapezoid rule This technique was originally devised by Kety and Schmidt (16S) for tlie determination of cerebral blood flow These au thors used nitrous oxide Tlie mtrous oxide metliod has been later adapted by Galmier et dl (129, 195), Conn et al (69,72) 20 Clearance Tests in Clinical Medicine and Crosley et al. (86) to the measurement of tlie renal blood flow. A similar technique has been employed by Bnm cf al. (51), the inhalated gas being radioactive Krj’pton Kr*^ The main in- terest of the method lies in the fact that it makes it possible to determine the renal blood flow even in cases with anuria. Two disadvantages of the methods are that it is rather troublesome to perform and that it yields only relative values. For these rea- sons, it is not widely used. 2. The Excretion Methods As long as the e.xcrctor)’ functions of the kidney are not too severely impaired, these methods are quite reliable (70). Tlicy were first used in animals by Sheelian and his co-workers (10-1) and van Slyke and his group (296). From equation (4), F = ^ ^ and since Q = lA', where U = urinary concentration of the excreted substance and V = urine flow', F= -HI- (6) Provided that tlie concentrations can l>c measured in the whole blood, the renal blood flow (RBF) can be calculated from equa- tion (6). It is the case if, for instance, radioactive Diotirast-I'*' (D*®*) is used. Tims: RBF = V Ao“< — Bp"* (7) Tlie concentrations of D'®' arc measured by means of a scintilla- tion counter. This method was devised in 1959 by Bergstrom et al (17), but has not so far been used by other investigators. Most substances suitable for the determination of the renal blood flow do not, however, penetrate into the red cells, or do it verj' slowly. It is, therefore, necessarx' to measure the concen- tration in the plasnm samples. But under these circumstances the values obtained from equation (6) refer to the renal plasma DefintHon anil Theory of Kcnal Clearances 21 flow (RPF) If sodium pamimnolnppurate (PAH) is used as die test substance (300, 303), RPF = UpAll ApAH — RpAH (8) The renal blood flow (RBF) may be calculated from RPF and hematocrit values (He) RBF = Ui^nV (ApA„-RpAn) (l-Ilc) (9) Up to this point it has been assumed that the venous out flow IS equal to the .arterial inflow which is not exacllj true (equation (3)) If the blood flow is markedly reduced and the urine volume veo high the difference between Fa and r,{ ma) become significant (343), so tint equations (2) and (3) have to be used If Q = FaA - F„R. UV = FaA- (Fa- V)R, or UVsFa (A-R) + nv, , ,, UV-RV whence Fa = If PAH IS used as the test substance tlie renal plasma flow which equals the arterial plasma flow, can be calculated from the following equation HPF= (Ur«i-n,«n) (10) ApAll RpAll Of course, all methods reviewed so far involve calhetenzation of the renal vein It was lliercforc a considerable achievement v.l\cw K \V SwwUv and Uvs group (303) found that the PAll clearance (Cpah) was almost equal to the renal plasma flow Tins means that under nonnal conditions of tubular aclivit) and at low artcnal levels tlic PAH concentration in the renal vein is small, averaging about 9 per cent of the arterial concentration If this concentration is neglected equation (8) becomes npr= in 20 Clearance Tests in Clinical Medicine and Crosley ct al. (86) to the measurement of the renal blood flow. A similar teclmique has been employed by Brun cf al. (51), tlie inhalated gas being radioactive Krypton Kr®^. The main in- terest of the method lies in tlie fact that it makes it possible to determine the renal blood flow even in cases uith anuria. Two disadvantages of tlie methods are that it is rather troublesome to perform and that it yields only relative values. For these rea- sons, it is not widely used. 2. The Excretion Methods As long as the excretory functions of the kidney are not loo severely impaired, these methods are quite reliable (70). They were first used in animals by Sheehan and his co-workers (104) and van Slyke and his group (296). From equation (4). F= ^ ^ and since Q = UV, where U = urinary concentration of the excreted substance and V = urine flow, F = UV A-R ( 6 ) Provided that the concentrations can be measured in the whole blood, the renal blood flow (RBF) can be calculated from equa- tion (6). It is the case if, for instance, radioactive Diodrast— (D*®‘) is used. Thus: RBF = V AdW — Rd*” ( 7 ) Tlie concentrations of are measured by means of a scintilla- tion ccftiniei. This tnellTOd vras devised in 1959 by Betgstrotti et al. (17), but has not so far been used by other investigators. Most substances suitable for the determination of the renal blood flow do not, however, penetrate into the red cells, or do it veiy' slowly. It is, therefore, nec«sary to measure the concen- tration in the plasma samples. But under these circumstances the values obtained from equation (6) refer to the renal plasma 21 Definition aiul Theory of Renal Clearances flow (RPF). If sodium paraammoliippurate (PAH) is used as the test substance (300,303), RPF = ( 8 ) The renal blood flow (RBF) may be calculated from RPF and hematocnt values (He): RBF- UpAH V (ApAn-RpAn) (1-Hc) ( 9 ) Up to this point, It has been assumed that the venous out- flow IS equal to the arterial inflow which is not exactly true (equation (3)) If the blood flow is markedly reduced and the urine volume very high, tlie difference behveen F^ and Fr may become significant (343), so that equations (2) and (3) have to be used If Q =FaA-FrR, UV = FxA-(Fa-V)R. or UV=Fa (A - R) -HRV, UV-RV A-R whence F^ If PAH is used as the test substance, the renal plasma flow which equals the arterial plasma flow, can be calculated from the following equation: RPF=: (UpAB — Rpah) ( 10 ) ApAK — RpAn Of course, all methods reviewed so far involve catheterization of the renal vein. It svas therefore a considerable achievement when H. W. Smith and his group (303) found that the PAH clearance (C„„) was almost equal to the renal plasma flow Tins means that under normal conditions of tubular activity and at low arterial levels, the PAH concentration in the renal vL is small, averaging about 9 per cent of the arterial concentration If tins concentration is neglected, equation (8) becomes KPF: UrsnV Clearance Tests in Clinical Medicine Obviously, the PAH clearance measures only approximately the renal plasma flow. The fraction measured has been referred to by Smith as “effective renal plasma flow” (300) and may repre- sent under certain circumstances the “cortical plasma flow.” As the term “clearance” is wdcly used in renal physiology and clinical nephrology as well, it is convenient to calculate the PAH clearance in every case, even if the true plasma flow is to be determined, by means of renal vein catheterization. If both the numerator and the denominator in equation (8) are divided hy ApAu> this equation becomes (Ap^ii — But the numerator - -represents the clearance CpAn. and A — R the denominator — may be defined as the PAH e.\- Apan traction ratio or E^^q. The true renal plasma fiow is therefore g/cen by the PAH clearance dicUlcd by Us extraction ratio, or RPF=^ (12) For renal blood flow, the following equation may bo used: Thus, it appears that renal circulation in man may be ex- pressed as “effective plasma flow” (or PAH clearance), as “true (total) plasma flow” or as “tnie (total) blood flow.” Only the PAH clearance which is quite eas>’ to determine and does not involve catheterization of the renal vein, represents a clinical method of diagnosis. Tlie validity of the PAH clearance under pathological conditions wH foe dfseassed later. But perhaps «'e should briefly examine wliat the PAH clearance exactly measures in normal subjects wtbout renal disease under conditions of normal tubular activity. In normal man, the PAH extraction ratio usually lies around 0,91 (33,38,248,300,333). Tliis means that tlie PAH clearance corresponds to 91 per cent of the total renal plasma flow Cnu/ EpAH- There is some indirect evidence that CpAu might represent DcfiniUon and Theory of Renal Clearances 23 the pHsma flow tlirougli the renal cortex Thus the uptake of PAH from the peritubular blood by tlie tubular cells and its se cretion into the tubular lumen seem to be an exclusive property of the renal cortex When kidne> shces are suspended in a solu tion containing PAH the accumulation of this substance is con fined to the cortex shces of medulla are completely inactive (315) Exidence that PAH is secreted at a very proximal site of the tubules presumabl) in the proximal con\o!uled segment IS also guen bj the results of slop flow expenments (188) In the normal dog the renal extraction ratio of PAH usually lies around 0 85 (231) According to TIuirau (323) who performed photoelectric measurements m situ the cortical blood flow in the dog is about 85 per cent of the total blood flow while 10 15 per cent flows through the outer zone of the medulla and 1 2 per cent through the inner zone (papillary zone) These figures seem to support the hypothesis that under normal conditions the blood flow mg through the renal cortex is entirel) cleared of low con centrations of PAH while tl e PAH content of the medullary blood remains unchanged (258 259) Tins would mean that under normal conditions of tubular actnity the PAH clearance corresponds m man as m the dog to the cortical plasma flow and that the extra cortical plasma flow may be calculated by sub traction Presumabl> this extra cortical flow is mamly a medul lary one the flow through the renal capsule and the upper part of the pelvis being negligible Thus CpAH PAH clearance = cortical plasma flow CpAu/I “ He = cortical blood flow Cpab/Epah ~ total renal plasma flow CpAn/P'r\n (1 “ He) = total renal blood flow ^ (CpAn/CpAn) — CpAB = extra cortical (“medullar)”) plasma flow (CpAn/HpAn) ~ CpAo = extra cortical (“medullar) ) 1 — He blood flow If tlus assumption is correct xxe may consider that in normal man with normal tubular function tlie measured PAH extraction ratio depends on tlie ratio between cortical and medullary flow An increase in medullary flow without change m cortical flow 24 Clearance Tests in Clinical MaUcine or a greater increase in inedullai>' flow will decrease the extrac- tion ratio. Similar changes in the extraction ratio will be elicited by a decrease in cortical flow wthout change in medullary flow or a greater decrease in cortical flow. An increase in the PAH extraction ratio will be produced by inverse hemodynamic changes. As a matter of fact, such changes may be produced by certain vasoactive drugs, like epinephrine, hydralazine and ergot alkaloids (263,269,270). We also believe that the decrease in tlie PAH extraction ratio obser\’ed by Pappenlieimer and others (172,173,174,228,322) in animals made severely anemic and by our group (263,270) in anemic patients, is related to this phenomenon. There is some evidence, that in the medulb, auto- regulation of flow does not operate with the same efficiency as in the cortex (324). Therefore, tlie decrease in the PAH extraction ratio obsen'ed at very low hematocrit values might be due to cortical vasoconstriction elicited by a decrease in blood vis- cosity (263, 270). We should like to emphasize, however, lliat this assiunpUon is no longer \'alid in most patients ^vith renal disease and re- duced PAH clearance. If certain nephrons are destroyed, the scarred tissue will still be perfused with blood. Tliis blood will not be cleared of its PAH content Under such conditions the PAH extraction ratio will be decreased and the PAH clearance will probably measure the amount of plasma perfusing the in- tact functioning units (“effective” renal plasma flow’). IV. THE FILTZIATION PTiACllON Assuming that the PAH clearance corresponds to the amoimt of plasma flowing through the glomeruli, it is possible to cal- culate the fraction of fluid removed from the blood stream by glomerular filtration. Tliis can be done simply by dividing the inulin clearance (or thiosulfate clearance) by tlje PAH clearance. Thus, F.F. = where F.F. = filtration fraction CiB = inulin clearance CpAH = PAH clearance Definition and Theory of Renal Clearances 25 The BItration fraction, which lies around 0^0 in normal sub- jects, may increase or decrease under certain conditions of al- tered renal hemodynamics. Epinephrine in small doses does not influence the inulin clearance but reduces the PAH clearance, and therefore increases the filtration fraction. According to Smith (302) tills may be explained on the basis of efferent arteriolar constriction, if it is assumed that filtration equilibrium is neces- sarily reached in the glomerulus. The resulting increase in filtra- tion pressure fully compensates for the decrease in plasma flow, so that a greater fraction of the circulating plasma is extracted by glomerular filtration. If the assumption of a filtration equilib- rium is not correct, this hemodynamic pattern must be the result of efferent and afferent constriction as well (300). Pyrogenic sub- stances may do the reverse: an increase in plasma flow is not accompanied by augmentation of the glomenilar filtration rate, so that the filtration fraction decreases. This is turn may be ex- plained by pure efferent vasodilatation or, alternatively, by ef- ferent and afferent vasodilatation (300,302). On the other hand, a pre-glomemlar vasoconstriction (or a fall in systemic blood pressure) leads to a decrease in both PAH and inulin clearances, the filtration fraction showing at first little change. At very low levels of filtration pressure, however, the glomerular filtration rale can be expected to fall abruptly to zero, as soon as the hydrostatic pressure in the glomerular capillaries has reached the level of Uie oncotic pressure of the blood. Under these circumstances the kidney will still be perfused with blood, but, in the absence of urine flow, PAH cannot be extracted and the PAH clearance will also fall to zero. Under pathological conditions, a decrease in filtration frac- tion usually indicates a reduction of the filtering surface (glo- merulo-nephritis ) or an increase in urinary pressure (hydro- nephrosis). The behavior of the filtration fraction is therefore of considerable interest in clinical medicine (261,262). The question arises, whether it would not be more accurate to relate the filtration rate to the real plasma flow CpAn/Ep^,i. and to calculate a “corrected" filtration fraction from equation “corrected" FJ*. — '-'PAn 26 Clearance Testa in Clinical liiedicine This does not seem to be the case, liowever. In normal subjects the available evidence indicates that die PAH clearance prob- ably measures the cortical plasma flow. As there are no glomeruli in the medulla, an attempt to correlate the glomerular filtration rate with the total renal plasma flow would seem to be rather meaningless. In the diseased kidney, it is very likely that PAH is only extracted by tubules supplied with glomerular filtrate. Tlius, the PAH clearance conesponds to the “effective” plasma flow through the functioning glomeruli, while the total plasma flow also includes the flow through non-filtering areas. There- fore, only tlie uncorrected F.F. is of clinical interest. V. TUBULAR REABSORPTION If the clearance of any sxibstance is smaller than the glo- menilar filtration rate, it is likely that this substance is reabsorbed to some extent by the tubules. But t!ie calculation of tlie re- absorbed amount involves some necessary assumptions: a) the substance is entirely filtmble from tlie plasma, b) tliere is no additional tubular secretion of the substance. Tliese two assumptions do not hold good for many urinary constituents. In the case of calcium, for instance, the filtered amount cannot be determined accurately, as a great fraction of the blood calcium is bound to proteins. In the case of potassium, the available evidence indicates that this electrolyte is entirely reabsorbed from the proximal tubular urine, only to be actively secreted (or better said: exchanged for sodium) in the distal part of the tubular system (20,32). A mechanism involving glo- merular filtration, tubular reabsorption and tubular secretion has also been suggested in the case of uric acid (144), phosphate (134,154,320) and magnesium (276). Under such conditions any calculation of the reabsorbed amoimt is illusory and mean- ingless. If tlie necessary requirements are fulfilled, however, the re- absorbed fraction T of the filtered amount can be calculated verj’ simply from the glomerular filtration rate and the clearance of the substance: Defmilion and Theonj of Renal Clearances 27 T - ~ - 1 _ T F.n C,.p^ UA This formula can be used, for instance, for sodium, chloride, amino acids and urea. In the ease of water, \se can write: ThjO If the substance is reabsorbed to a great evtent, like sodium and chloride, it may be more convenient to record the “rcjeclcd fraction of the filtered amount”. rejected fraction = U cryoscopic methods If the unne is isosmotic with the plasma C<,n„ = During waiter dm resis however, tlie urine is h>potomc and V is greater than C«,n Under such conditions the urine ma> be considered to con sist of a mixture of osmoticall) obligated water equal to admixed with solute free water Ci *0 Thus C is equal to the free tvater clearance Dunng antidiuresis on the other hand the unne is hj’per tonic and is greater than V We mav assume that tlie urine IS concentrated by the subtraction of solute free water from an isosmotic tubular urine Tins volume of reabsorbed water is given h} the following equation T^io = a™- V In clinical medicine these expressions have some implications for the studv of pol)airic stales VII TUBULAR SECRETION If the clearance of any substance is greater than tlie glomer ular filtration rate we have to assume that this substance is ac tivcl) secreted b> llic tubules While some unne constituents are e\clusivel> secreted (for instance ammonia) others are fil tered and secreted (for instance PAH) and still others are filtered reabsorbed and secreted (for instance potassium) In the case of a substance w Inch is filtered reabsorbed and secreted the clearance mav of course be smaller than the filtration rate The calculation of Uie secreted amount of an> unne con stituent involves two neccs5ar> assumptions a) there is no glomenilar filtration of tins substance or if any its rate can be exactly determined b) tlicre IS no tubular rcabsorpUon of tins substance or if any it may be assumed to be essentially complete These requirements seem to lx, fulfilled in the case of ammonia The tubular secretion of ammonia equals the quantity excreted in tlic unne UvhjV expressed in mg/mm In the case of by drogen ions the excreted amount can be taken as the sum of 30 Clearance Tests in Clinical Medicine titratable acidity and NH^-ions appearing in the urine over a period of one minute, but the total amount of hydrogen ions formed in the kidney is considerably greater, a large fraction being expended in bicarbonate reabsorption (19). In the case of PAH, which is partly filtered and partly se- creted, the rate of secretion is given by the difference between the total rate of urinary excretion Un^nV and the rate of PAH filtration 0.83 C{„Prxii (the factor 0.83 expresses the fraction of free, fillrable PAH in the plasma). Thus, TpAit = Up,^„V ~ 0.S3 Pp^n In the case of potassium, the available evidence indicates that the quantity filtered is entirely reabsorbed by the proximal tu- bule. If this assumption holds true, the secreted amount is iden- tical with the quantity appearing in the urine over a period of one minute, UkV. Maximal rate of ttibular secretion for PAH. Like the reab- sorptivo mechanism for glucose, the tubular secretion of PAH seems to be quantitatively limited (140, 304). Therefore, pro- gressive elevation of the plasma concentration of PAH ultimately leads to saturation of the excretory mechanism in all nephrons. Under these conditions the tubules secrete PAH at a maximal, fixed and more or less reproducible rate (Trap^n)* Instead of PAH, Diodrast can also be used for the study of the maximal secretory capacity. Extremely interesting studies of the correlations between glomerular filtration rate, PAH clearance and Trap^H (or Tm DiodrMt) have been performed by H. W. Smith and his group (140, 305). In clinical medicine, however, the determination of the maximal secretory capacity for PAH had not proved to be of great diagnostic value. SECTION II CLINICAL METHODS Tiie CHIEF INTEREST of the clearance methods m clinical med- icine lies in the fact that they enable tlie physician to measure the glomerular filtration rate and Uie effective renal plasma flow in a varietj’’ of orgamc and functional disorders of the ladney. In special cases the clearance of certain electrolytes (for instance potassium in hypokalemic states) may also be of considerable significance. In renal glycosuria tlie study of the glucose re- absoiplion ma)' give the clue to the correct diagnosis. It is a umque feature of the clearance determinations that tliey yield accurate, quantitative information about the per- turbated kidney function. Obriously, semi-quantitative methods hke van Slyke’s urea clearance or the endogenous creatinine clearance cannot be used for the same purpose Therefore, they wU not be considered in the follo\ving sections For the same reason, "simplified” modrficabons of the onginal methods (clear- ance calculation without urine collection (102, 106) or after a single injection of the test substance (ISO)) should be discarded as maccurate. It should be clearly recognized tliat catheteriza- tion of the bladder is a necessary precondition for obtaining rehable urine volumes Of course, it must only be done by a physician or a well trained nurse m order to avoid infection of the urinary tract. The potential dangers of bladder catheteriza- tion have certainly been o\eremphasi 2 ed (10). If rigidly sterile technique is used, complications do not occur. In order to m- crease the safety of the procedure, a mild antiseptic agent, for instance Phenazopyridme, can be given after completion of the test. Only those metliods wbidi have been used extensively in our department for the last thirteen jears will be described briefly. They are; I. The simultaneous determination of tlie inulm (or thio- sulfate) clearance and PAH clearance. 33 3-i Clearance Tests in Clinical Medicine 11. The simultaneous determination of the inulin clearance and the clearance of some other constituent of the urine (potassium, pliosphate, amino acids, etc.). III. The determination of the PAH e.vtraction ratio. IV. The determination of the glucose reabsorption and glu- cose Tm. I. SIMULTANEOUS DETERMINATION OF GLOMERULAR FILTRATION RATE (INULIN OR TIUOSULFATE CLEARANCE) AND PAH CLE.4RANCE ( 139 , 261 , 262 , 301 ) The lest is performed with the patient lying in bed. No special preparation is required,* but dnigs capable of altering the renal functions or interfering with the analytical procedure should be withdrawn for at least 48 hours. After catheterization of the bladder \vitli an inlying multi- eyed nibber catheter, a urine sample is collected and a Wood sample is drawm from an antccubilnl vein (for urine and plasma blanks). Blood is always collected in heparinized syringes and centrifuged at once. A priming infusion of inulin (or sodium thiosulfate) and PAH in saline is ll^en given intravenously at a rapid rate (15-20 ml/min), followed by a sustaining infusion at a constant rate of 4 ml/miu (an ordinary infusion set carr)’ing a tunnel clamp or an infusion pump maj' be used for this pur- pose). After 15 minutes, the bladder is emptied and rinsed with distilled water and air, urine and wash-out fluid are discarded. The catheter is then clamped with a forceps and the time U#, w’hicli corresponds to the beginning of the first collection period, is accurately recorded. Two minutes later, blood is drawn from the other arm through an indwelling needle inserted into the antecubital vein. The time P, is recorded at the midlime of blood sampling. Towards the end of the period, w’liich should last about ten minutes, urine is collected into a flask, the bladder is rinsed tivice with 20 ml of distilled >vater and some air, and the wash-out fluids are added to tlie urine, Tlie lime Uj is accurate!)' recorded. This corresponds to the end of the first period and to the begin- • Only if inulin is used and analyzed for by tie resorcinol tnetiod(2Sl}, should the patient be in the postabsorpbve stale. Chmcal \fefhods 35 ning of the second period, which is completed usmg tlie same procedure The blood and unne samples are designated as Pj and Uo If the urine volumes V, and Vj do not differ markedl>, onl) two periods are necessarv Infusion fluids Tlie stock solutions from which the infusions are prepared are (a) p)rogen free inuhn m salme, 10 per cent, (b) freshly prepared sodium thiosulfate, 10 per cent, and (c) so dium paraaminohippurate, 20 per cent For a subject with normal body weight, normal bod> surface and presumabl) normal kidnej functions, the infusions may con- tam the following quantities Priming 40 ml of inuhn and 3 m! of PAH, made up to about 100 ml with sahne, or 75 ml of sodium lluosulfate and 3 ml of PAH Surtflinmg 25 ml of mulm and 5 ml of PAH, made up to 200 ml with saline, or 50 ml of sodium thiosulfate and 5 ml of PAH, made up to 200 ml with saline In patients, w hose body surface is less or more than 1 73 sqm, the amount of tlie test substances m both the pruning and the sustaining infusion his to be adjusted in proportion If the clearances are expected to be below normal, the concen tration of the sustaining in/«sion onhj sliould be reduced (the plasma concentrations obtamed after tlie rapid introduction of the pnmmg solution depend chicfl) on Oie magnitude of the extracellular compartment, and little on the renal excre tion) After completion of the test, unne volumes are accuratelj measured For calculation of the urmc flow per mmute, the quan- tity of wash out fluid is subtracted from the total apparent vol- ume Tlie dilution factor, by whicb the analytical concentrations of the test substances m tlie unne are to be multiplied, is gi\ en by the ratio total volume/true unne volume All plasma and iiruie samples are tlien analvzed for inuhn (or thiosulfate) and PAH Xnulin is delemiined by the method of Schremer (281), PAH by the method of Bratton and Mar- shall (41, 139), thiosulfate by the metliod of Gilman et al (136) 36 Clearance Tests in Clinical Medicine Clearances are calculaiecl from the formula C= the filtra- tion fraction is equal to Ci./CrAn or Ct/Cpah (Table 1). The plasma levels of the test substances show little variation during the two clearance periods, if the composition of the in- fusions is adequate. In order to be representative of the mean plasma concentration corresponding to each collection period of urine, the blood samples should be drasvn about five minutes before the midtime of the period (correction for “delay time”). Even if it is not exactly the case, graphical inter- or extrapolation of the Inie concentration is tisually unnecessary, unless the plasma levels differ markedly in the two periods. All clearance values are corrected for the body surface and expressed per 1.73 sq.m. The actual body surface of the patient may be estimated from his height and weight and read on a nomogram (286). n. DETERNUNATION OF THE CLEARANCE OF CERTAIN PHYSIOLOGICAL CONSTITUENTS OF THE URINE, WITH OR \VITHOUT SIMULTANEOUS MEASURE- MENT OF THE GLOMERULAR FILTRATION RATE During the course of a conventional inulin clearance deter- mination, it would be easy to measure at the same time the clear- ance of any constituent of the urine. But, wth few e.xceptions, the various clearances values obtained in this way are of little clinical interest. The electrolyte clearances depend so much on the intake, that they have to be determined under rigidly stand- ardized conditions. Even so, balanw experiments usually yield more valuable information. Therefore, there are only a limited number of indications for the deteimination of the clearance of physiological urinary solutes. In certain tubular syndromes, it may be helpful to measure the renal excretion of potassium, phos- phate or amino acids and to compare their clearance with the glomerular filtration rate. Again, the excretion of these substances depends on so many factors, that it is rather difficult to give nor- mal reference values, unless they are studied under well-defined experimental conditions. I x.^urL> or CALctKTiON or TiiioMtrATi as» 1*\II Ci CUmcal Methods 37 3S Clearance Tests in Clinical Medicine It should be remembered lliat if electrolyte clearances are studied, only inulin can be used for the simultaneous measure- ment of the glomerular filtration rate. Sodium thiosulfate would alter the excretion of sodium and chloride and markedly increase tJie potassium clearance (264). Neither should PAH be infused at the same time for similar reasons (108). We shall now describe briefly and comment on the technique of three clearance detenninafions which may be used clinically. A. Fotnssium Clearance In hypokalemic states the potassium clearance maj’ be per- formed to differentiate renal wastage from extrarenal potassium losses. We use the following technique: Tlie test is performed in the morning with the patient having fasted overnight. Inulin in saline is infused, the sustaining in- fusion is given at a rate of 8 ml/min. In normal subjects on nor- mal potassium intake \vith plasma potassium concentrations be- tween 3.5 and 4.8 mEq/1, the potassium clearance ranges from 8—24 ml/min. In potassium depletion from extrarenal causes (for instance diarrhea) it is usually lower. If renal losses account for the hypokalemia, the clearance is within or above the normal range, despite a low' plasma potassium (187). B. Phosphate Clearance Tlie behavior of the phosphate clearance is of interest in parathyroid dysfunction and osteomalacia, where it may be ab- normal. As the phosphate excretion shows considerable diumal variations (96,225), the lest should be performed in the morn- ing with the patient having fasted overnight. Several techniques have been described; a ) Kyle et al. ( 175) have simply measured the phosphate clearance alone under fasting conditions. In normal subjects they reported clearance values ranging from 6.3—15.5 ml/ min. The phosphate clearance was elevated in most patients with Iiyperparathyroidism or osteomalacia and reduced in hypo- parathyroidism. But the phosphate clearance is also markedly Clinical Methods 39 depressed in patients with impaired glomerular filtration rate, so that, if the latter is not known, it may be difficult to draw any conclusions as to the handling of phosphate by tlie tu- bules. b) Other investigators have compared tlie phosphate clearance «7th the ghmeruhc Sltcatian rate, or, in other words, calculated the reabsorbed fraction of the filtered phos- phate load (84, 293). For this purpose, a conventional inulin clearance may be performed. The per cent reabsorption of phosphate, however, largely depends on the rate of glomer- ular filtration. In normal subjects it ranges from 78 to 97 per cent (66, 134) and may decrease markedly in patients with renal impairment. The wide scattering of the individual values renders the comparison with stales of parathyroid dysfunc- tion difficult. Furthermore, the reliability of any reabsorption value may be questioned, as tubular secretion of phosphate is by no means e.xcluded (134, 154, 320). c) Phosphate clearance under phosphate loading and Tmpo*. In man, tubular reabsorption of phosphate at high plasma levels seems to be quantitatively limited, as a maxi- mal reabsorptive capacity (Tmpo 4 ) can be demonstrated (280). The range of the normal Tmpo 4 values, how’ev’er, is so large as to overlap the results obtained in l)ypoparath>TOid subjects (321). Only in h)'perparalhyroid states and familial hypophosphatemia may the Tmpo, be depressed (238, 321, 342). Therefore, the determination of the Tmpo 4 seems to be of limited value in clinical medicine, and should be performed only if detailed information on phosphate e.xcretion is needed. The following technique may be used (321): A priming and a sustaining infusion containing inulin in saline are infused as for conventional clearance determina- tions. After tw'o collection periods a 0.5 M buffered sodium phosphate solution (pH 7.40) is added to the sustaining in- fusion in a sufficient amount to provide for the deliver)’ of 0.4-0.8 mM P per minute. After sixty to ninet>’ minutes clear- ance determinations are performed over two more collection 40 Clearance Tests in Clinical Medicine periods at elevated plasma pliospliate levels. The Tmpo^ is calculated from the equation Tmpo* — Gin Ppo^ — Upo* V A somewhat different technique has been proposed by Lam- bert (177) who measured the per cent phosphorus reabsoip- tion during phosphate loading at increasing plasma levels of phosphorus. C. Clearance of Amino Adds Aminoacidura may result from increased formation of amino acids in the body or from diminished tubular reabsoq>t/on. Jn tlie case of increased formation (in liver disease, for instance, or in certain 'mbom errors of metabolism”), the increased excre- tion is related to elevated blood levels, On the other hand, in renal aminoaciduria the blood leveb are low or normal. It is Uierefore necessary to compare the renal excretion with the blood levels, or, in other words, to measure the clearance of the amino acids. A normal clearance indicates normal tubular func- tion. In tubular defects, the clearance may be greatly increased. The total clearance of amino acids can be simply measured as the a-amino-nitrogen clearance. It is, however, significantly in- creased only in cases with generalized aminoaciduria. In many tubular syndromes, the increased excretion is limited to certain amino acids, so that tlie but the procedure is somewhat easier on the right side Two different techniques can be used for the measurement of the PAH extraction ratio (261 262) a) If only the extraction ratio IS to be determined a blood sample for the plasma blank is drawn from a contralateral arm vein and 4 6 ml of a 20 per cent PAH solution are m jected mtravenousl) After ten minutes three pairs of blood samples are collected simultaneously from the catheter and from a peripheral artery at time intervals of about three minutes Since the extraction is determined at falling blood concentrations only artenal blood can be used as peripheral venous samples would yield falsely high plasma levels As no unne is collected there is no delay time problem For the measurement of the extraction ratio the plasma levels of PAH should lie between I and 5 mg% Higher levels might depress the extraction ratio while too low peripheral concentrations would render the determination in the renal vem inaccurate The quantity of PAH injected (4 6 ml) will ensure adequate plasma levels in subjects with normal body weight and normal kidney ftmction In patients w’_ Clearance Tests in Clinical Medicine reduced renal function, this amount lias to be adjusted ac- cordingly. The lieparinized blood samples are centrifuged at once after they have been collected, and the plasma is separated. Plasma filtrates are analyzed for PAH by the method of Bratton and Marsliall (41). For the determination in the renal venous blood, a known quantity of a standardized PAH solution is added to the filtrates. Otherwise, the very low concentrations could not be estimated with sufficient ac- curacy by the colorimetric procedure. b) If extraction ratio and clearance are to be determined at the same time, a procedure has to be used similar to that of the conventional PAH clearance, with priming and sus- taining PAH infusion. Since the blood level of PAH remains almost constant, peripheral venous blood can be .used instead of arterial samples. The renal venous samples and the periph- eral samples are collected simultaneously. Calculation of the extraction ratio is not dependent on the leclinique used. It is based on the equation: — o tpAn where Pp^n = peripheral plasma concentration and RpAn = renal venous plasma concentration. If the single injection technique is used, it is important that all blood collections should be accurately timed. If arterial and renal venous sampling is not exactly simultaneous, the analytical \’alues should be interpolated graphically on semilogarithmic paper. DETERMINATION OF GLUCOSE REABSORPHON AND GLUCOSE Tm (Tmc) This procedure is extremely helpful in differentiating renal glycosuria from true diabetes mellllus as well as the different types of renal glycosuria from each other. It requires simul- taneous determination of the glomerular filtration rate and of the urinary excretion of glucose under glucose loading. We use a simplified "titraUon” tecimique (298), with determinations at Chntcnl Methods 43 three or four different glucose plasma levels Tlie use of sodium thiosulfite IS preferable to mulm because of the high blood glucose le\els The test should be performed on fasting patients In all cases of renal glycosuria it is necessary to start at low glu cose plasma levels in order to measure the renal threshold The test is performed m three or four steps corresponding to different plasma levels of glucose Two urine collection periods are carried out at each level Between two steps the urine is always discarded Tlie plasma glucose concentration has to be raised stepwise not continuously as it must vary but little dur mg a given urine collection period Otlierwise the dead space would become an important source of error and it might be diffi cult to obtain rehable To values Procedure Step 1 (No loading) Two conventional thiosulfate (and if desired PAH ) clearance penods are carried out The only van ation from the standard technique is that orfenal plasma samples are drawn for the glucose determinations If the first two urine samples already contain glucose Step 2 can be omitted and glu cose loading is performed according to Step 3 If Ui and Uj do not contain sugar Step 2 is earned out Step 2 (slight loading) 10 ml o! a 40 per cent glucose solu tion are mjected intravenously and a small amount of this so lution is added to the sustaining thiosulfate saline infusion (about of the remaining volume) After ten minutes the bladder is emptied The urine is now allowed to dram into a flask and IS repeatedly checked for the presence of glucose If no glyco suna appears more glucose is injected and also added to the sus taming infusion As soon as the urine is found to contain measur able amounts of sugar the bladder is emptied and rinsed with water and two clearance penods (lliiosiilPale and glucose) are earned out Step 3 (moderate loading) 30*40 ml of 40 per cent glucose are injected inlravenousl) The sustaining infusion is changed so os to contain b> volume V* of 10 per cent sodium thiosulfate Vi of sahne and % of 40 per cent glucose After ten minutes the bladder is emptied and rinsed Two clearance penods are per formed 44 Clearance Tests in CUnical Medicine Step 4 (lieavy loading). A solution containing 25 ml of 10 per cent sodium thiosulfate and 175 ml of 40 per cent glucose is given at a rate of 8 ml/min for twenty minutes. The infusion rale is then slowed down to 6 ml/min and 10 ml of 10 per cent thiosulfate are added. After ten minutes, the bladder is rinsed and the last two clearance periods are started. During Steps 3 and 4 the urine flow increases markedly (os- motic diuresis). It is important to prevent excessive dehydra- tion, which might disturb both the systemic and the renal cir- culation. The patient is therefore allowed to drink water freely during the whole procedure. After completion of the test, all urine and plasma samples are analyzed for thiosulfate and glucose (for glucose the method of Shannon and Fisher (289) may be used). The tubular re- absorption of glucose is given at any plasma level by the formula Tc = CxPo-UcV The maximal reabsorption capacity or Tmo is taken as the aver- age of the last two periods (normal values: 300-450 mg/min). The ratio Tc/Ct is also calculated for each period. It is im- portant to correlate tlie To values wth the glomerular filtration rate, the latter being subject to unpredictable changes (increase or decrease) during glucose loading. For tlie ratio Tmo/Cr, Govaerts (142) found a normal value of 2.41 ± 0.35. The renal “threshold" can be estimated approximately from the values obtained during the two periods with tlie low’est glu- cose excretion (i.e, periods 1-2 or 3^, depending on whether glycosuria was present from tlie beginning or not). It is equal to or lower than tlie figiue given by the equation: glucose threshold (mg55) = Tc • 100 Cr In renal glycosuria, interpretation of the data is simplified if the individual To values are plotted on a graph against the corre- sponding “load” (CtPg)' More details can be found in the sec- tion on tubular syndromes (Section X). Cbntcal Methods 45 Ilcnal threshold 235 mg% gliicosc SECTION m INTERPRETATION OF CLEAR/VNCE RESULTS I. INTRODUCTORY REMARKS For TiiE LAST TinRTEEN YEARS we Iiave used clearance methods extensively in clinical medicine, and we are convinced that the routine determination of the glomenilar filtration rate and effec- tive renal plasma flow constitutes an important diagnostic pro- cedure. The use of special methods, like Tmr. or electrolyte clear- ances, however, should be restricted to particular conditions. The chief advantage of tlie inulin (or thiosulfate) and PAH tech- niques over simpler methods like the phenol-red excretion test, lies in their quantitative reproducibility, which enables us to make reliable comparisons. First of all, tlie clearance values obtained in renal disease can be compared with the normal values, thus allowing an accurate quantitative estimation of the functional impairment. Secondly, comparison of the results of several tests performed on the same patient at convenient time intervals during the course of any renal disease gives extremely valuable information about its prognosis. Tliirdly, the behavior of the filtration fraction, i.e., of the clearance ratio inulin/PAH, may enable us under certain conditions to differentiate glomer- ular from tubular-interstitial or N'ascular changes. For liiese reasons, the clinical chapters of this monograph will deal mainly with the behavior of the inulin (or thiosulfate) and PAH clearance in N’arious renal diseases. This section will be concerned exclusively with these techniques, whereas the other clearance procedures will be briefly discussed in the correspond- ing clinical sections. II. NOR.MAL VALUES Inulin clearance. Goldring and Chasis{139) have reported normal values of 131 ml/min in men and 117 ml/min in women. The standard deviations w’cre 21.5 and 15.6 respectively. Smith (300) has summarized the data rcairded by numerous investi- ng 50 Clearance Tests in Clinical Medicine gators and obtains an average normal value of 123 ml/min for the mixed sexes. Thiosulfate clearance. In a series of 203 subjects of mixed sexes with presumably normal renal functions, we found an aver- age value of 126 ml/min, with a standard deviation of 16.5. The normal range may be taken as the mean ± 2 v, i.e., from 93 to 159 ml/min (261,262). PAH clearance. In the same series of normal subjects we foimd an average value of 646 ml/min with a standard deviation of eighty-four. Tlie normal range may be taken as the mean — 2 «r, i.e., 478-814 ml/min (261, 262). Tlie data recorded by other investigators have been analyzed by Smith (300) who obtains a normal value of 634 ml/min for the mixed sexes. Filtration fraction. For the filtration fraction calculated as the inulin: PAH clearance ratio. Smith (300) gives an average normal value of 0.197. In our series of 203 normal subjects the thiosulfate: PAH clearance raUo was 0.195, with a standard de- viation of 0.019. Tlie norma! range of tlie filtraUon fraction, taken as the mean s: 2 er cent. The filtration fraction is normal in 65 per cent of Uie cases. It is moderately decreased 55 InlcrpretaUon of Clearance Rcsitlls in 5 percent of tlie cases which all belong to the group of chronic liydroneplirolie p) eloncphnlis It is elected in acute tubular necrosis and advanced pyelonephntis with h>T;>ertension The PAH extraction was measured m fifteen cases It is normal in two cases and reduced in thirteen In the oligunc stage of tubu jar necrosis it is extremely low (007) but improves rapidly at a (ml ffi n) IiR 4 Onipansoii of Cpah “"*1 Cr m 2JS subjects with renal vascular disivscs InterjjTetaUon of Clearance Restilfs 57 0 100 200 300 400 SCO 600 700 800 CpAM (ml/min) Fig 7 EpAu w relation to Cp^H seventeen subjects with tubular and/or interstitial diseases (A = p>elonephntis, ^ = tubular neaosis V - renal diabetes) In tascular renal diseases (245 cases) the glomerular filtra tion rate is normal m 34 per cent of llie cases (most of \\hom are suffering from early essential hypertension ) It is reduced m the remiimng cases The PAH clearance is usual!) reduced (84 per cent of the cases) but may also be normal The filtration fraction IS normal (44 per cent of tlie cases) or more often increased (56 per cent) The PAH extraction ratio was measured m thirty five cases It IS normal in twenty-seven patients (77 per cent of the cases) and only moderately reduced in the remammg subjects, ranging from 0 61 to 0 81 For the wliolc group the PAH extraction ratio correlates roughly with the PAH clearance (cases of acute renal ischemia due to s)stemic hypotension, m which Ep^n may drop markedly, are not included m this senes) Several tentative conclusions may be drawm from tlie entire data, which are in man) points supported b) similar obsenaUons made by other in\ estigators 1 In most renal diseases, lliere is a roughl) parallel decrease m glomerular filtration rate and PAH clearance, so tint in 53 Clearance Tests in Clinical Medicine many cases tlie filtralion fraction remains within normal limits. 2. An increase in the clearance values above the normal range rarely occurs and can be seen only in early diabetes, in lipoid nephrosis and in acute glomerulonephritis. 3. The filtration fraction is usually low* in glomerular dis- eases; it is normal in most cases with tubular-interstitial diseases and often increased in vascular r>cphropathics. Therefore, the behavior of the filtration fraction is useful in differentiating nosological entities. 4. Tlie PAH extraction ratio is often normal in vascular renal diseases; thus showing the PAH clearance to be a reliable measure of the effective plasma flow under such con- ditions. The extraction ratio is often significantly de- creased in glomerular and tubular-interstitial diseases; this observation is consistent with the existence in sucli cases of perfused, non-functloning tissue. V. VALIom* AND LIMITATIONS OF CLEARANCE METHODS IN THE DISEASED KIDNEY The limitations of the clearance techniques in renal disease have been emphasized by II. W. Smilli himself (297, 300) and also overemphasized by some other w’orkers. Our opinion is that the clearance methods arc still of great value in these conditions, even when the "effective blood flow” is no longer a measure of the whole cortical blood flow, or a small fraction of the filtered imilin diffuses back tlirougli the damaged tubules. We feel that this view is supported both by clinical evidence and tlieorclical considerations, but this needs a short comment. According to Smith, a diseased kidney may consist of nor- mal nephrons, aglomcrular tubules, impotent nephrons and inert tissue (297,300). But obviously, the x*arious renal diseases be- have quite differently in this respect. I. Normal Nephrons There is little doubt that normal nephrons exist in cveiy (> 7)0 of diseased kidney. Tlieir number, bowcicr, is c.vlrcincly s-arLnble. Interpretation of Clearance licstiUs 59 In focal glomerulonepliritis, over 90 per cent of the neplirons are normal. In the advanced stages of clironic glomerulonephritis or chronic pyelonephritis, only a few function normally. We may assume that “normal neplirons” excrete inulin and PAH at a nor- mal or slightly abnormal rate. The tnulin and PAH clearances, therefore, largely depend on the number of functioning neph- rons. For instance, the clearance sulues are within the normal range in focal glomerulonepluilis, but maj' be markedly reduced in chronic sclerosing nephropathies. In chronic renal disease, there may be an increased dispersion in the glomerular-tubular activity ratio (40, 298). Tliis means that among active neplirons, the filtering and/or the reabsorptive function may be increased in some and decreased in other units. 2. Aglomcrular Tubules It is extremely unlikely that, when glomerubr activity is lost, the attached tubule begins to excrete water. And in the absence of tubular flow, neither tubular reabsorption nor secretion are conceivable. Therefore, the term "aglomerular tubule” probably does not correspond to a real enlit>' in man. Admittedly, in glo- merular diseases, glomerular filtration is more impaired than tu- bular functions, and in shock, gfomenilar fihraa’on may be abol- ished, whereas the renal parenclijina is still perfused wath blood. But it should be kept in mind that as soon as the glomerulus becomes inactive, the whole nephron behaves like inert tissue If in a single nephron tlie glomerular filtration rale is reduced, hut still existent, inulin is filtered at a reduced rate, while in tlie attached tubule PAH extraction remains normal. But if filtration is completely abolished, inulin is no longer filtered and PAH is no longer extracted from the peritubular blood. Thus, if the glo- merular filtration is rudaced in some or all nephrons, the tu- bular flow of urine being preserv'ed in all of tliem, the inulin clearance is reduced but the PAH clearance and the PAH ex- traction ratio remain normal. The filtration fraction is low. But if the glomerular filtration is abolislied in some neplirons and reduced in the remaining units, inulin and PAH clearances, filtra- tion fraction and PAH extraction ratio as well are reduced. Clearance Tests in Clinical Medicine 3. Impotent Nephrons If glomerular filtration is a precondition for tubular work, the reverse is not true. There is good evidence that in some dis- eases tubular functions may be partly or completely lost, whereas filtration remains intact or only partially impaired. In congenital tubular defects like renal diabetes, for instance, the tubular reabsorption of glucose is abnormally low, but tlie glomerular filtration rate is normal. In the polyuric phase of acute renal failure tubular functions are abolished at a time where glomeni- lar filtration has been partially restored. In such cases, tlie behavior of the inulin and PAH clearances depends on the nature and the extent of the tubular changes. In renal diabetes, for instance, inulin and PAH clearances, fiUra* tion fraction and PAH extraction ratio are normal, only the glu* cose reabsorption is impaired. In tubular necrosis caused by merctiry poisoning, for instance, PAH secretion is impaired and inulin may diffuse back tlirough (he damaged tubules. Clearances are extremely low (partly owing to renal ischemia) and may actually become almost identical, because specific tubular func- tions are lost. The PAH extraction ratio is also ver)’ low. Tlie fact that the PAH extraction ratio is reduced in advanced chronic renal disease could be similarly related to the inability of the damaged tubules to excrete PAH above a certain rate. Were this interpretation correct, ErAn would vary inversely with the PAH plasma levels at concentrations lower than the normal depression limit. Tlie finding of a low Epin measured at a pl.isma concentration of about 2 mg? would indicate tubular saturation. Therefore, Epin should decrease furllier at higher plasma levels and increase at lower plasma levels. It can be sbouTi, however, that /a most chronSc renal diseases, the PAH extraction ratio does not var>' significantly within the usual concentration range of 1-5 mg? (248). Nor is the PAH clearance dependent on the blood concentration within this range (Table 4). This problem has been recently reinvestigated by Bergstrom et al. (18), In a majority of experiments, their extraction ratios did not fall with increasing load. The few ex- amples recorded in which a decrease was observ’ed include cases Interpretation of Clearance Results 61 TABIE 4 FAII Clear.\sce asd PAII EEm.icriON Uatio in Relation TO P\1I Pla a Pin Eitract on Rat 0 0 43 _ 0 30 0 SI 0 3o4 1 00 4a 5 1 13 43 — 1 ss 4a 7 — •> 4S 5 0 343 3 01 0 311 3 36 30 J , 3 44 41 with Probenecid poisoning where sucli a f^ll could be expected Other cases m which the PAH extraction ratio dropped were examined at relativel) higli PAH levels so tint an increased dispersion of the glomerular tubular activity might well account for this £ndmg Therefore we may conclude that only in tubuhr necrosis *106 a fe\\ instances of degenentne or congenital tubular dis ease does diffuse tubular damage represent the mam factor re sponsible for a reduction of Cpan and Ep^n 4 Inert Tissue This term includes not only fibrolic areas in winch glomeruli and tubules hive been destroyed and replaced by connective tissue but also non functioning nephrons Inert tissue is perfused by blood but does not contribute to the formation of unne If a clironically diseased kidney mamly consists of active nephrons and mert tissue as has been suggested (43 44) inulin and PAH cleamnces will be reduced in proportion to the rela five amounf of inert tissue If the active nephrons haie retained a normal function (for instance in chrome pyelonephritis) tlie reduction of both clearances is roughly parallel and the filtra tion fraction remains within the normal range If the function of the active nephrons is disturbed the filtration fraction may be decreased (for mstance m chronic glomerulonephritis) or in creased (for instance in essential hypertension) 62 Clearance Tests fn Clinical Medicine In our opinion, the PAH extraction ratio in tlie diseased kid- ney largely depends on the quantity of blood perfusing inert tissue. Since non-functioning areas do not extract PAH, the blood flowing through these channels contains the same amount of PAH when it reaches the renal vein, as when it leaves tlie renal artery. But in fibrotic areas resulting from vascular sclerosis, the blood circulation is probably extremely low. This may ex- plain why in essential hypertension (even at an advanced stage of renal sclerosis) the PAH extraction ratio remains normal or becomes only slightly reduced. On the other hand, in clmonic pyelonephritis and glomenilonephritis the destruction of neph- rons does not primarilj’ result from vascular obstruction (except at a late stage). For this reason, non-functioning areas in such kidneys still receive an appreciable quantity of blood, so that in these conditions the PAH extraction is significantly reduced. Finally, if the inert tissue consists of histologically normal non- functioning nephrons (for instance during shock), tlie rates of perfusion of functioning and non-functioning areas do not greatly differ, so that the PAH extraction ratio may be markedly de- pressed. A possible objection to our interpretation is the existence of anastomoses between the peritubukir capillaries, so that blood primarily flowing through inert tissue might be cleared of its PAH content by adjacent nephrons. It cannot be denied that such a possibility exists. But we must also consider, that, under such circumstances, a certain amount of blood primarily flowing through functioning glomerub might in turn escape tlirougli inert tissue channels. The relative amounts of blood exchanged in this way would depend on the rale of circulation through the inert tissue. Therefore, tlie overall effect of such anastomoses seems to be negligible. In summarizing this discussion, we should like to propose to the reader a few illustrative schemes (Fig. 8 a-e). These are over- simplified examples of what may happen in the diseased kidney. On these sketches each nephron represents a third of the renal parenchyma. To make the calculation of the clearances easier, the following values have been taken as normal: Cm 120 ml/min, Cpatt 600 ml/min, F.F. 0.20, Epah 1-6 Interpretation of Clearance Results 63 Changes Due to Renal Ischemia (Fig 8a) The nephrons are histologically nornnl, but in 66 per cent of them, no filtration occurs as a consequence of low systemic blood pressure and/ or marked constriction of the afferent artery Therefore, m these nephrons no PAH can be extracted by the attached tubules, as PAH taken up by tlie tubular cells cannot a Clearances Cm 40 Cf>AK 200 FF 0 20 ^PAH 0 33 Clearances Cm 40 CpAH 400 FF 010 Clearances Cm 80 epAH 400 FF 0 20 ^PAH 1 0 Clearance Tests in Clinical Medicine Fig. 8 a-e. SchemaUc representalion of llie different mechanisms respon- sible for the reduction of clearance values in renal disease (see text). be removed in the absence of tubular urine flow. The remaining nephrons are assumed to function normally. A 66 per cent re- duction of Cjn, CpAB and Er^n can be expected, while F.F. re- mains normal. Such a mechanism may be involved for instance in shock. If an afferent constriction of moderate degree but not suffi- cient to stop filtration is present throughout the kidney. Cm and CpAu will be reduced but Epab 'vill remain nonnal. Such a mechanism probably accounts for the findings in many functional disturbances of renal hemodynamics and in early essential hyper- tension. Changes Due to Glomerular Lesions (Fig, 8b) The filtering surface of all glomeruli is reduced; in 33 per cent of these in such a manner as to make glonieniLir filtration Interpretation of Clearance Results 65 impossible Therefore PAH cannot be extracted m these neph rons while in the remaining tubules it is secreted at a normal rate Assuming a total filtering surface of 33 per cent of normal the following clearance \alues can be anticipated C,B 40 ml/mm Cpah 400 ml/min F F 0 10 Ep^a 066 In the case of a more regular distribution of tlie glomerular lesions glomeRilar filtrabon x\ill take place at a reduced rate m all nephrons so that PAH will be excreted by all tubules As summg the same degree of reduction of the filtering surface as m the foregoing example the clearance values in this case will be Cjn 40 ml/mm Cp^R 600 ml/mm FF 0067 Epah 1 0 TJiese two possibibbes may expbm the dearance changes observed m acute glomerular nephritis C7jangc» Due to the "Presence of Inert Tissue (Fig 8c and d) (c) One third of the nephrons have been destroyed by a vascular process leading to progressive obliteration of tlie glo meruli These nephrons are replaced by fibrotic, non functioning tissue in which tliere are only a few patent vascular cliannels The remaining nephrons are normal Tlie following clearance values can be expected Cib 80 ml/min Cpah 400 ml/min FF 020 Epah 10 Clearances of this t^pe can be observed m many cases of vascular nephrosclerosis (d) One third of the nephrons ha\e been destroyed by an inflammatory process Tliose remaining are normal The de stroyed nephrons are replaced by non functioning tissue which stiU receives appreciable amounts of blood As tins blood is not cleared of the test substances the foUomng clearance values can be anticipated C,B SO ml/min Cpar 400 ml/nun F F 0 20 E, ar 0 66 Many cases of chronic pyelonephntis seem to follow this pattern In most cases of chronic sclerosmg nephropatliies however 66 Clearance Tests in Clinical Medicine clearance patterns between (c) and (d) wiW be observed, de- pending on the rale of perfusion of the inert tissue. Changes Due to Tuhttlar Lesions (Fig. 8e) All glomeuili are histologicalty normal, but two-thirds of the tubules are severely damaged. In lliese tubules the PAH secre- tion is abolished. Furthennore, a fraction of the filtered inulin diffuses back through the tubular barrier. As renal ischemia is also present, it is assumed in our example that no filtration occurs in one-third of the glomeruli. If back diffusion of the glomerular filtrate amounts to 50 per cent of the quantity formed, the fol- lowing clearance values will result: C,B 40 ml/min, Cp^n 40 ml/min, F.F. 1.0, Epin 0,10 Clearance patterns of this 1 ) 7)6 may be seen, for instance, in acute tubular necrosis. To conclude, we are well aware of the limitations of the clearance methods in tlie diseased kidney. But Nvith a few ex- ceptions, such as acute anuria or tubular damage of any origin, the difficulties encountered do not impair the clinical usefubess of these techniques. Apart from the few exceptions mentioned, intriin does not appear to be reabsorbed to an appreciable extent in most renal diseases. This assumption is supported by the iden- tity of the inulin and thiosulfate clearances and by the relative constancy of the ratio between either one of these two clearances and tlie clearance of partially reabsorbed substances. Therefore, the inulin clearance seems to be in most renal diseases a good measure of the filtering surface of the glomeruli. A decrease may be due either to organic clianges in tlie wall of the glomerular loops or to a reduction of the number of tlie filtering units. In the latter there is also a roughly parallel decrease in the PAH clear- ance, while in the former the PAH clearance remains unchanged or is affected in a lesser degree. If significant tubular damage can be ruled out, the PAH clearance seems to be in most cases a good measure of the quan- tity of plasma perfusing functioning tissue. In tliis sense, the PAH clearance corresponds to the “effective renal plasma flow.” Interpretation of Clearance Restihs 67 While in the normil kidney the effecti%e flow is probably iden tical with the cortical flow in the diseased kidnej it includes only a part of it The PAH clearance does not reveal liow mucli blood flows througli inert tissue But for clinical purpose the effective flow is much more important than the real flow The real floio can be estunated onl> if the PAH extraction ratio IS koiown We have learned a great deal about the fate of PAH in the diseased kidney from studies involving cathetenza tion of the renal vein Our present interpretation of the clearance data is based on the results obtained from such experiments performed in a great vanet> of pathological conditions The dc termination of the PAH extraction ratio however is somewhat too troublesome for use as a routine chnical method Moreover the information gained from this procedure is only of clinical value in a few selected cases The filtralion fraction is a good measure of tint fraction of fluid which IS removed by glomerular filtration from the plasma effectively flowing through the active glomeruli Unless tlie tu biilar secretion of PAH is markedly impaired a filtration frac- tion calculated from the total plasma flow is of less value In acute tubular necrosis where tlie ratio C ./Cpjti mi> increase almost to unity a progressive fall m ibis ratio usually indicates recovery of the tubular functions No conclusions concerning renal hemodynamics can be drawoi in these cases Much emphasis Ins been laid in tins countr) on tlic com panson of the clearance values with transfer maxima that is on the ratios Cio/Tmo and CrAn/Tmi ui (300) The opinion that these ratios say more than the clearances alone rests upon the assumption that the latter represent variable functions whereas the transfer maxima depend solcl> on the mass of active paren chyma It is evident however that this assumption does not hold good in man> pathological conditions In ren il diabetes Tm^ maj be markedlv reduced despite an enlirel) normal filtration rate In tubular necrosis the transfer maxima ina> drop to zero and even become negative In chronic nephropathies the replace menl of active nephrons bj inert tissue results in a roughlj parallel fall of C,„ Cpaii Tm^ and Tm^An Mbile in glomerular nephritis a decrease in Cia relative to Tmc maj point out to the 68 Clearance Tests in Clinical ifedicine glomerular nature of the lesion, the same information may also be obtained by simply relating Ci« to Cp^n. In essential liyper- tension the ratio CpAn/Tmpxn is decreased, indicating a reduc- tion of flow through functioning tissue. But in these cases the filtration fraction Ci„/CpAn is generally increased and tliis finding leads to tlie same conclusion. It should also be kept in mind tliat the experimental errors in determining Trap^n considerable, and that the high PAH concentrations needed for saturation of the tubules may produce profound hemodynamic changes (194), As for obvious reasons, CpAii £trid Tmp^n cannot be determined simultaneously, the re- liability of the ratio Cp^n/TnirAn remains entirely open to ques- tion. For all these reasons, we feel that the routine determination of the transfer maxima in clinical medicine is neither necessary nor verj' useful. Tliese tests are no longer performed in our de- partment, except for Tm^ in renal glycosuria. But, paradoxically enough, in this special case Tm© may vary, while the filtration rate remains normal. PART TWO Specific deimnce jpatlems m rena) chsease SECTION IV GLOMERULONEPHRITIS I. ACUTE DIFFUSE GLOMERULONEPHRITIS Most cases of acute diffuse glomcnilonephnlis are rehted to a group A streptococcal infection of tlie tonsils Infections \Mth t>'pes 12, 4, 1 and ‘’red lake" are especially likely to be followed by an attack of diffuse glomerulonephntis (240, 241,268, 339) Acute glomeniloneplmlis may also be due to infection with vmises and nckettsias, subacute bacterial endocarditis, anaphy* Lctoid purpura, disseminated lupus erythematosus and hyper- sensitivity to certain drugs Evidence suggests tint the glomeru- lar alterations arc produced through the mediation of altered tissue reactivity (allergy) It is of interest that in animals acute glomerulonephritis can be elicited by the repeated administra- tion of gamma globulin or by the use of renal antibodies (Mas ugi nephntis [191]) The histologic changes consist essentially of a diffuse capil- hritis of the glomenilar loops (2, 11, 114) There is at first widen- ing of the capillary walls with swelling and proliferation of the cellulir elements, and also acciimulalion of polymorphonuclear leucocytes Only ui the more severe cases is there partial ob- stniction of the capillaries due to marked endothelial prolifer- ation, thickening and fibnnoid degeneration of the basement membrane and glomerular thrombosis Tlie epithelium of the proximal tubules may show hydropic vacuolization and cloudy swelling Most of these changes arc entirely reversible The chnKtl syviptafns of the post streptococcal \anety in- elude albuminuria and hcmalum (m 90? of the cases), ohguna and edema (80?), hypertension (75?), lumbar pain (50?), car- diac enlargement wath pulmonary crepitations, dvspnea and pleural effusion, and headache A significant azotemia occurs in less than 10 per cent of the patients with acute glomerular nephritis (201,262) The clinical evolution is variable Death dunng the acute pliasc is quite unusual In about 20 to 30 per 74 Clearance Tests in Clinical Medicine cent of the cases, tlie disease may progress to subacute or clironic nepliritis. In a majority of patients recovery is complete, but the process of liealing may take several months, even years (1). Clearances in Acute Diffuse Qlotnerulonephrilis Tlie determination of the glomerular filtration rate and of the PAH clearance is, both from a theoretical and from a practical point of view, of great interest in this disease. A. Theoretical Considerations a) In order to explain the rise in blood pressure seen in most cases with acute glomendonephrilis, Volhard (327) had postu- lated the existence of a primary renal ischemia due to arteriolar spasms. Even the glomenilar alterations were considered to rep- resent a cellvdar reaction to ischemia. This hypothesis has been W’idcly accepted in Europe. It was, lljerefore, of considerable interest to investigate the renal blood flow at a very early stage of the disease. Later during the course of an acute glomerulo- nephritis, cellular proliferation might alter renal hemodynamics and the finding of an ischemia at that time would neither prove nor disprove llie ralidity of Volhards hypoUiesis. In 1043, Hildcn (156) published the results of Diodrast clearance determinations performed in seven patients with acute glomenilonephritis between tlie 9th and 150th day from the supposed onset. Tlie initial values ranged from 274 to 721 ml/min; they cannot, however, be considered to be entirely re- liable, as the clearances were measured on falling plasma con- centrations and witliout catheterization of the bladder. Tlie first complete clearance studies in acute glomenilone- phritis were performed in 1944 by Earle, Taggart and Shannon (109). Their cases all had normal blood pressure and none were in the early weeks of the disease. In 1948, Black et al. (25) re- ported on three patients, in whom inulin and Diodrast clear- ances had been determined on the twelfth, fifteenth and twenty- fourtli day', respectively, after onset. The published data indicate normal or moderately reduced values for Co, a marked reduction of Cin and a low filtration fraction. In 1949, we reported on four patients (246), two of whom had normal PAH clearances on the Chmerulonepltnlls 75 third and tentli da> respecti\el> after onset The other t«o had reduced \alues (273 ml/mm on the eighth day and 254 ml/mm on the sixth day ) but in one of these cases the PAH extraction ratio XV as depressed to 0 60 The glomerular filtration rate and the filtration fraction were reduced in all The blood pressure was normal m one case with normal Cp^n and in one case watli reduced CpAn it was moderately increased m the other two The same year Bradley (34) repotted a senes of twelve cases five of whom had been examined between the seventh and the fourteenth day after onset In these five cases the Cnn between 62 and 653 ml/min Tlie PAH extraction ratio was de termined only m a case w ith normal Cp^n and found to be some what reduced (076) There was no correlabon between Cpah and blood pressure Subsequent studies bv vanous investigators have on the whole confirmed these findings (453 107 122 217,248) Since our first publication we had Uie opportunity of examining nme additional cases within the first ten days of the disease Tlie data are summarized in Table 5 From tliese findings it can be concluded that some degree of renal ischemia may occur at an early stage of tlie disease It is however by no means a rule and tiie blood pressure may rise markedly in tlie absence of renal ischemia On tlie other liand TIBIE 5 TiiiowLrvTE Clfvkance I \II Clfvrvnce Filtration Erection anp PU l Extraction Ratio in TiiiRTtrN Patients at tiil E.\rlt Stagf Ord TO lOni Day Xrrrn Onset) or Vccri Dirnsr Glov ratLONFriiRms AtJ j III i ' ml/rr n 1 t'pAR 1 f /A R i f f liloal 1 PrfMUTt 1 f mllg Fln-i 1 3 SO ■\ s __ 0 IBS 1 0/90 4 1 11 •16S 0 sss i 0 ira 1 0/110 ■> Jl’ u G13 0 is .1 1 T 9 “N 0 Ml 0 €0*1 0 St 0 133 ICVlOO 0 — 0 0 ) + SO — 0 I ) IBO/SO + lOS ~0 0 14 1 0/100 0 GO 0 0 s no/Go + a >0 0 ri 0 loG 100/100 ; + S" " 0 a 0 113 lio/a ! + SIS 0 s 0 1 4 ij /m + C3^ 0 ”2 0 1 u IS /no + 13 10 c- — 0 OSS + 76 Clearance Tests in Clinical Medicine cases w-itli reduced CpAu may exhibit normal blood pressure values. Thus, Volhard’s hypothesis is no longer acceptable. b) In an attempt to explain the edema of acute glomerulo- nepliritis, tlie liypotliesis of a glomcrular-tubukr imbalance has been advanced (107,234). According to this interpretation, tlie retention of sodium and water might be due to the reduction of the filtration rate in the absence of any impairment of the tu- bular reabsorplion. This would suppose a good correlation be- tween glomerular filtration rale, oliguria and edema. It can be showi, however, that such a correlation does not exist (261, 262). Serial clearance measurements clearly demonstrate that: (1) Al a time wliere w-ater and salt retention are maximal, the glomerular filtration rate may be almost normal or only slightly reduced (Fig. 9). Tlu's is particularly true in patients svith the so-called "post-infectious Jiypertension with edema,” in whom practically no urinary sj’mptoms occur and renal function remains normal (254). (2) In some patients no edema develops despite marked re- duction of the filtration rale. (3) In most patients the lowest x’alues for the inulin clear- ance are recorded two to four weeks after onset, at a time where edema is no longer present (Figs. 9 and 12). ■\Ve may conclude that the obserx'cd facts give no support to the hypothesis that a reduction of the glomerular filtration rate per se is responsible for the development of tlie nephritic edema. c) Two main types of clearance patterns can be encountered in acute glomerulonephritis (261,262), The first type is charac- terized by a normal or sligliUy elevated Cpin. a normal Epah. and decreased glomerular filtration rate and filtration fraction. The second type is accompanied by a reduction of Cpah and Fig 9 Renat hemodynamics, yenal excretion of vrater and salt, body weight, plasma volume and Wood pressure in a case with acute diffuse glomerulonephnlis. At the time of the first clearance determination Epah svas 0&4. GlomeruhnejihrtUs 78 Clearance Tests in Clinical Medicine EfAH. a marked decrease in glomerular filtration rate and a de- crease in filtration fraction. The first pattern is seen in the exudative type of the disease, and results from the combination of two factors: (1) Inflamma- tory hyperemia of tire Malpigliian tufts, and (2) exudative changes of the capillary walls which tend to reduce the filtering surface. The second type is observed in more severe cases of the obstructive-proliferative group. The organic changes produce an overall reduction of the glomerular plasma flow and an even greater reduction of the filtration rate. It can be assumed that in many glomeruli filtration is no longer performed. Tims, PAH cannot be extracted by the corresponding tubules and Ep^n decreases. It has been suggested that a certain degree of tubu- lar damage could also contribute to tlie decrease in Ep^n (107). d) The clearance values obtained in acute glomerular nephri- tis depend on the severity of the glomerular lesions and vary during the course of tlie disease. At a very early stage, C|a, Cpin and F.F. may still be normal. A few days later, there is a progres- sive decline in the filtration fraction, no matter whether it is due to a slight decrease in Cjb with a concomittant rise in Cpab* or to a decrease in both clearances, Ci# being more affected. The lowest filtration fraction is often observed a fortnight to a month after onset. In the following weeks or montlis there is in most cases a progressive improvement in all clearance values. In pa- tients who recover completely, clearances are later found to be entirely normal. It is of interest that in tlie experimental glomerulonephritis produced in rabbits by anlikidney duck serum, the filtration fraction can be sho\vn initially to follow the same pattern (Fig- 10 ). B. Practical Use a) Differential diagnosis between acute diffuse glomerulo- nephritis and other renal diseases. An unequivocal diagnosis of acute diffuse glomerulonephritis can easily be made when tlie classical signs and symptoms are ChmcrtihnqyhrUis 79 present. But in the absence of edema. l)>'pertcnsion and azotemia, it may be difficult to differentiate clinically diffuse from focal glomerulonephritis. Tliis can be done, ho\\c\er, by measuring the inulm and PAH clearances. In focal glomeniloncphnlis both clearances are vsathin the normal range In diffuse glomcnilo* nephritis the PAH clearance may also be normal, but glomerular filtration rate and filtration fraction are significantly decreased h) Following the course of the disca'sc hy serial clearance tests. Tills is the most valuable application of the mclliod A few weeks after the onset of the disease, clinical examination rexeals m most patients a normal blood pressure, no edema and only discrete iirinar)' sjmptoms But no statement regarding the prog* nosis can yet he made on the b.ists of these findings alone On the other liand, clearance measurements performed at tins stage may reveal profound differences in the functional bchaxior of individual cases Pcco\cr>' may be effected after six weeks, six months or sexcral >oars, or in less fortunate instances, the disease takes the fonn of progressixe glomcniloncphntis. Accordmglj, serial clearance tests enable us to measure qiinntJtatixel) sliglit improx'cmcnts, or, on tlic contrar>’, a sloxv deterioration in renal 0 * 8 12 16 » 24 Days np 10 . Bctiaxi'orof (he fiJtnilfen fraelion In four ntibifs «itJi RlonUTiilonrTjIintu Tlie ano\x-s indicate injections of nntiLklncx tlncL smim so Clearance Tests in Clinical Medicine function. Comparison of the results of successive tests is ex- tremely useful in evaluating both the outcome of the disease- recovery or progression-and the rate of evolution-rapid or slow. In order to illustrate this short comment, we should like to report a few examples of acute glomendoncphrilis examined on several occasions b)* the clearance technique. 1. Diffuse, poststreptococcal glomerulonephritis. In a m.i- jority of patients, normalization of the clearance values is effected within two to three months (261, 262). Data showing the charac- teristic behavior of the filtration fraction in thirteen cases are given in Figure 11. Complete data including Ct, and F.F. in four cases are reported in Figure 12. In these cases, the glo- merular filtration rate was normal or slightly reduced, hut a Filtration I Fraction \ QOS' 0 10 20 ICO iw Daira Fig. 11. Serial >-aIues of the flltratiorj fraction in thirteen patienU «itl» acute diffuse glomerulonephritis in die early stage of the tlisexsc. transitory rise in Ci..,ij cottid be noted, resulting in a significant decrease in the filtration fraction. Data obtained in a case wtli rapid improvement are also reproduced in Table 6. In other patients, the rale of recover)* is slower. The l)ehavior of the filtration fraction In four cases of this Utic is shown in Figure 13. Table 6 also illustrates a case with slow recover)*. Finally, patients may not recover. Table 6 shows the clear- ance values recorded in a case uith rapid deterioration and death from renal failure within four months. Further cases with pro- gressive deterioration of renal function will I>c reported in the pages tlcvotcd to chronic nepfiritts. Glomerulonephrilis 81 2. Diffuse glomeridonephrifis accompanying disseminated lupus erythematosus. Renal lesions are very frequent in dissemi- nated lupus erythematosus (5). In favorable instances, the glo- menifar alterations are of the focal type (“m're-loops”) and can- not be detected by clearance methods. In more severe cases, the nephropathy corresponds to a diffuse glomerulonephrilis. The onset may or may not be acute, but the course is progressive in 0 10 20 40 60 BO 100 Fig. 12. Serial clearance values in four cases wth acute diffuse glomerulo- nephritis. Recovery ii’ithm three months. Flllrttlen Fraction S » ‘ i« ») 0*>* Fig. 13. Serial values of the filtration fraction in four patients with acute diffuse glomcniloncphrilts. Slow recovery. 82 Clearance Tests in Clinical Medicine TABLE C Clearaj^e Patteev^ ijt Three Patievts wmi Diffuse Poststreptococcal GtOMERutovEPimms Palienl E B., 27 year old. Acute elomeniioRcphritia after infection »ith ^hemr>. ly-tic str^tococci Rapid improvement. Xormslization of clearances within 0 weeks. Complete recoverj-. „ Blood d/'cr Ct CpAH Allfumi- Ilema- l^etsvrt Vnuet ml/imn mi/mttt F. F. nuna tuna mm.Ifg Eiit-ma on 10 59 5 072 o.oss c.o ++ + 135/SO 95 5 793 0 121 1.5 + + 125 /SO 005 0.103 traces + 110/70 0 6.50 0.172 0 0 120/7.** 0 .1/. 5 , 2S year old. Acute elomeruloncmhritis after infection with ^hemo* Irtlc streptococci. Slow improvement. Normalization of clearanee*i sithin C months. Complete recover)-. Day Blood Afler Ct Pretsvre ti itrui nvi'jjii Ontel ml/min ml/mtn F.F. PpAn mm.Hg 0/1 i-O 8 93 099 0.13.3 0.84 1C5/IOO 1 0 03 16 75 5 703 0.107 no/so 0.4 56 32 57 5 524 0.11 110/63 0 5.3 til 78 5 040 0 123 no/75 0 51 84 $0 5 533 10.'./70 traces 106 84 5 700 0 121 125/.SO traces 140 101 TC9 0 132 110/70 0 175 119 736 0 IC2 100/00 0 ISO 113 C6i OBJ 105/.50 0 Pahent 5. // , 1 1 year old. Acute elomerulonephrilia fproliferativc form) Rapid deterioration. Death from renal fauurc after 4 months. AfiHmi- Blood nuna Ct Preiture liana- On»el ml/min ml/min F.F. mm Ha luna Edema m?7e 44 ZOO 0 140 120fS0 +A- + 23 J2.5/S5 ■h+ -h 23 100/110 ++ ++ 32 IIS 1 — — 135/03 + + nearly aiJ patients. As already pointed out by Earle (105), ex- tremely low filtration fractions are encountered in these cases. A marked, dense tliickening of the glomenilar walls probably accounts for this feature (261,262). In the example reported in Table 7, a low PAH extraction ratio was found at a time where Cpio was 322 ml/min, indicat- ing a nearly normal total blood flow. Ghmenilonephnits 83 TABLE 7 Patient E L 2o\earOld Acute Disseminated Lupts Erythfmatoscs ■mm GLOMERULONEPHsms Onsetwith Peter and Skin Rash Fiat. Weees Before Admission ALBUjnNUHiA Discoaered Three ^\eeks Later Death from Renal Faillrb WmiiN Three Months Time A//er Ct ml(min F F ^PN Albumi Blood PreMure mmHg 5 weeks 10 2 322 0 032 0 386 73 5 0 150/100 6 ^eeks 11 8 310 0 038 64 4 0 140/90 7 Aveeks 6 3'>0 0 03 6o C 0 130/85 10 weeks 1 54 5 0 (k>7 97 4 0 140/105 11 weeks 2 3 48 5 0 047 160 2 0 150/11'’ 12 weeks — — — 3S0 2 0 llo/~o 3 Acute glomerulonephritis accompanying subacute bac tendl endocarditis In subacute bacterial endocarditis clearance values are often moderately reduced Cp^n more than Ci„ as they are in most patients with valvular disease of the heart If focal glomerulonephritis (Loehlein) develops no significant further decrease needs to occur But a sharp fall may be observed if the lesions are of the diffuse type This usually happens onl> in un treated, or inadequately treated cases and not earlier than sls Meeks after onset (155) The course is \anible and depends on whether or not treatment of the underl>ing endocarditis is sue cessful Recovery is not uncommon as m the case reported in Table 8 Interpretation of the clearance data is rendered difficult by tlie fact that m cardiac patients Cm and Cp^n are alread> re duced, and the filtration fraction is high (see Section XI) In T \BLE 8 Patient E I 29 Year Old aimiAL Di^^ba'^b Mithout Heart Failcbe Normal Pregnancy ^oon After Delivery Feafb Lassitude Dyspvfa ANT) Palpitations The Patient atas Adautted to the Policlinic Sin W EEKS After the Onset op the Disease Positive Blood Clltcre (Stbep- TOCOCCIS VlRJDANS) PeMCILLIN TREATMENT RECOVERY AfTEB ThREE aiONTHS Tune After Onset of Subacule Bader xal EndocarlUts Daj After Onset of Hemaluna Cl mlfmm CpAB ml/min F F Hen a illnnt 3 46 26“ 0 172 ++ + 11 3J 215 0 ISl + + + + + 42 89 400 0 223 + traces <8 »1 510 0 1C.5 traces 8 months C montlia 100 40i 0 •’17 0 0 84 Clearance Tests in Clinical Medicine our case E.I., both clearances low during the nephritic epi* sode but the filtration fraction was normal. That it had been depressed to normal by the glomerular changes was indicated by the later rise occurring after healing of the renal lesions ( com- plete recovery of the nephritis was confirmed by renal biopsy). It may be mentioned that neither hj-perlension nor edema were obser\’ed, despite the low clearance values. II. ACUTE FOCAL GLOMERULONEPHRITIS Acute focal glomerulonephritis may accompany a great va- riety of infectious diseases and is not due to a specific agent. Tiie symptoms are usually confined to urinary’ findings (slight to moderate albuminuria, hematuria). Hypertension, edema and azotemia are never seen in such cases. In the acute form, re- covery is usually complete within a few weeks. In subacute cases, recovery may be delayed up to several niontlis. Histologi- cal examination of biopsy specimens reveals inflammatorv’ lesions limited to certain glomeruli, and in any one glomenilus to cer- tain segments of the glomerular tuft. Tlicse lesions reduco the filtering surface to some extent, but tliey are not sufficient to depress the clearance values in a significant manner. Therefore, Ci„, Cp^n 2 od F.F. remain normal, or low normal, so that focal glomerulonephritis may be distinguished on tin’s basis from dif- fuse glomerulonephritis. In a series of thirty recorded cases, wc found inulin clearances ranging from 102 to 152 ml/min, PAH clearances from 561 to 860, and filtration fractions from 0.15 to 0.248. in. CHRONIC GLOMERULONEPHRmS Chronic glomenilonephrifis may follow acute diffuse glo- merulonephritis or develop slowly- without previous history* of acute onset. The course is v’ariablc. A rapidly progressive form causes death w’ithin one to two years. Histologically, there is a diffuse intense cellular proliferation, not only of the cnpillaiy* walls but also of the Dow’man’s capsule, witli the formation of epillielial crescents (2, 11, 114). In other forms, death from renal failure or hypertension may occur ten to forty years after the onset of tlie disease. In these cases, the histological changes arc Clomerulonephritis 85 irregularly scattered throughout the renal parenchyma \Vliile many glomeruh have been replaced by fibrous tissue others show prohferation and sclerosis of the tufts, and the remaining are h>’pertrophic In a less advanced stage healmg may still occur In such patients renal biopsy reveals essentially normal structure witli the exception of a few hjalinized glomeruh (261 262) Albuminuria may persist for years without furtlier deterioration of the renal function Chronic glomenilonephnlis may also appear with the fea tures of the nephrotic syndrome These forms are discussed in Section V Finally the disease ma> take the form of recurrent hematuna also called benign liemorrliagic nephritis (11) In such cases the prognosis is usually good as there are no pro Iterative lesions of the glomerular tufts There must be of couree circumscript ruptures of the glomerular loops but these can hardly be recognized by light microscopy (2) Clearances tn Chrome Glomerulonephritis A Theoretical Considerations The behavior of the clearances m this disease has been studied by many mvestigalors (4 37 38 53 63 79 105 109 148 157 160 217 234 248 261 262) The observed values largely depend on the se\enty of the organic lesions Super imposed arteriolar spasms related to hypertension or congestive heart failure may also alter the clearance pattern to some ex tent In the absence of definite lesions as for instance in re current hematuna clearance values are normal They are also normal or perhaps shglitly subnormal m healed cases of exuda tive nephritis m which a feiv glomeruh are hyalimzed They are always reduced in the remainmg forms (Table 9) The deter mining factors by which clearance changes are effected are a) glomerular lesions leadmg to a reduction of the filtenng sur face and of the glomerular blood flow b) occlusue vascular changes producing renal ischemia c) replacement of active nephrons by inert tissue d) some degree of renal vasoconstnc tion It is clear that the resulting clearance pattern will \ ar) with the relatwe significance of the single factors At a rather earl> 86 Clearance Te^s in Clinical Medicine TABLE 9 CtE.\nAVCE PATTEnSS rv A IlEPKESIlXTATIVE SfRIES OF TeV PlTlE\T3 wmi CitROMC GiA]McsrLo\criiRm< Cate .Vo. Cl, (Ct) ml/min Cp' low and in severely hjpertensive patients the filtration fraction is frequently in* creased. Tliat this increase is due to arteriolar (efferent) spasms can be easily demonstrated in those cases who respond witlj a fall in blood pressure to conseiA'ativc treatment (for instance bed rest). Such a case is illustrated in Table 10 and Figure 14. On admission, a blood pressure of 240/140 was recorded. C|, was 13 ml/min, Cpau 59 ml/min, F.F. 0.254. On bed rest alone, the blood pressure fell markedly and Cpah rose to 83 ml/min, while C,o remained unclianged. The filtration fraction then was 0.165. A linear relationship between l/Cp^n and diastolic blood pressure can be sIioaati in this patient (Fig. 14), indicating a close correlation between sj'stemic h>’pertension and renal %aso- constriction. TABLE 10 Patient W. W., 20 Ye.m» Old. Cihiontc GLOMCRnANEMnuTK Doy Afler Admission Ct tnl/mtn Cptn F.F. .V/'.V Ffttsnre mm Hg S9 0 25-1 W 210/140 0 16> 92 S4 fo IS 71 0 216 70 190/10.5 GlomeruJonephritis 87 VC^AH ml 100/min 15 J y ’'■I , 90 110 130 1 50 170 mmHg DIAST BLOOD PRESSURE Fig 14 Linear relationship between l/Cp*H and the diastolic blood pressure m a patient with chronic glomerulonephritis The reduction of blood pressure vs as e0ected by bed rest alone For Q discussion of tiie interpretation of the clearance pat terns m correlation \vitli structural changes in chronic glomerulo nephritis, the reader is referred to Section III B Chmeal Use 1 Differenttal diagnosis between chronic g?o;neridoncp/intis and other renal diseases As already pointed out a decrease in filtration fraction is not found with tlie same constancy in chronic glomerulonephntis as in acute diffuse glomerulonephritis (see Table 9) If present it constitutes good evidence in favor of glomerular disease Of the whole group of chronic nephropa thies, in which there is no primary involvement of the glo menih, only bilateral hydronephrosis ma) depress the filtration fraction to a comparable extent (111) If the filtration fraction is walhin the normal range, or in creased the clearance technique is of questionable value m dif ferenlialmg glomerular from non glomerular diseases 2 Following the course of the disease by serial clearance tests A single clearance delemimation m chronic nephntis gives a good measure of tlie actual renal impairment, but does not 88 Clearance Tests in Clinical Medicine enable one to make a prognosis, unless normal values are still found many years after the onset. On the contrary, if the course of the disease has been followed over many j'ears by this tech- nique, much can be learned from the comparison of successive clearance results. On the basis of the clearance values, patients with chronic glomenilonephritis may be classified into three groups: a) Cases with normal clearance values many years after the onset. Tliis group includes cases with normal values througli- out the period of observ'ation, and patients in whom clear- ances w’ere initially reduced. b) Cases with cither reduced values but no convincing evi- dence of deterioration over several years, or still normal clear- ances but no adequate follow-up period. c) Cases with progressive impairment of the clearance values, ultimately leading to renal failure. Tliese clearance patterns are illustrated in Figure J5 (only the glomenilar filtration values are plotted on this graph). Tlio first group consists of thirteen patients wlio had repeated clear- ance determinations during a follow-up period extending up to sixteen years after the onset In most of them there was slight albuminuria and/or microscopic hematuria, all liad normal blood pressure, none had edema. While in some patients clearance values still improved during the follow-up period, in other sub- jects they remained unchanged. In every case the last value re- corded was entirely normal. Renal biopsy performed in a few pa- tients revealed either normal glomeruli or slight focal thickening of the wall of some loops. Thus, we may assiune that these cases had practically recovered at this time. The second group consists of nine cases. In two patients, the clearance values were williin the normal range, but a slight de- crease uxis recorded during the follow-up period. Li the remain- ing subjects, the glomerular filtration rate remained definitely below normal, but there was no distinct tendenej' to further im- pairment. We feel that in this group no statement regarding the prognosis can be made, except tlial in the event of a later de- terioration the progression probably would be extremely slow. Glomerulonephntis 89 ml/min Fig 15 Glomerular filtrabon rale in thirty four patients with “chronic” glomerulonephntis during a follow-up period extending up to sLxteen years A = healed cases, B = latent cases, C = progresswe cases Another possibility is that renal function might remain at this level, indicating stabilization of the inflammatory process. The third group consists of twelve cases, eleven of whom died from renal failure. Six patients were first seen in the ad- vanced stage of the disease and liad glomerular filtration rales below 20 ml/min. In tlie remaining cases the follow-up period 90 Clearance Tests in Clinical Medicine extended over several years. In these patients the progressive impairment of the clearances was indicative of a poor prognosis. Occasionally partial remissions followed by new relapses were observed. A few representative cases are reported in the following tables. TABLE II pATiEvr R. W., J7 Year Old. Recurrext nEM\TCRii xtith N'orjial C lXA&.^NCES In 1952, first attack of gross hematuria, lasting a fev days la 19S3, i atlaels. Betircen these episodes, the urine tonlained only a fete red cells and traces of pro- tnn. The last S altaels tcere obim-td in 1955. In 100 1, the urine still contain^ a small niimler of red cells and traces of albumin. The clearances remained normal throughout (he follovy-vp period, exe^ dunng one hematune episode, irhen they icere slightly increased. }io edema, Hood pressure normal. Date Ct nllmin CpAH mf/mm F.F. Ifema- lima Albumin nuria Blood Pressure tnm Hg 4/ 8/195.3 120 ecu 0 199 <+) traces 115/70 3/29/1953 lOS 557 (+) traces 110/70 0/1 1/1 955 152 S77 + + + + 115/75 1/11/1901 115 541 (+) traces 120/70 TABLE 12 Patiext W. K , 23 Year Old. Chronic GLOiiERCLOVEPHRms irmi l-NStoiors Onset AftumjHuna tras diseorcred «n January 1951. Complete recorery after S years. Cpm normal or slightly eleiated throughout Ike fHlotc-up period inituilly slightly reduced. Slenc progressire normalixalton of Ct and F. F. Blood Ct CpiH Hema- Albumi- Pressure Date ni//»iin Evsn F.F, turia nunavmJIg 5/31/1951 S/31/1951 11/12/1951 5/ 2/1952 2/12/1953 9/ S/1953 4/ S/19W 5/20/1956 0 093 0 133 0 152 0 151 0.14S 0 I&4 0 16 0.17S + traces traces 130/90 I25/S5 130/SO 125/SO 120/SO 125/75 120/70 120 '70 Glomerulonephritis 91 TVBLE 13 Patient J II 33 ‘^ear Old Chhovic Procbessite CLOMERtLOSEnmiTis ^TTii Temporary Partlal Reunion and New Relapse Ao kno ti h story of acute gtan erulanephnti* Onset prcHiably trt 195o Death fro renal failure tn IprllSSO Dale Ct CpAlt F F Ilema tuna ill mi Blood Pressure r !Ig ^FV ’’O c 7/l‘’/19oo 114 S'’! 0 218 + + + lKO/110 20 1/14/I9o0 06 561 0 17 + traces 17o/110 2o 8/15/19o6 45 335 0 135 + + + 1 o/lla 26 10/ 2/19o6 71 390 0 165 + + + 1 5/115 2> iVis/ios? 83 346 0 230 + + 1 0/1‘’0 24 2'/ 9/1960 11 6 42 0 *» 7 + + 100/115 -Q 4/2G/19G0 Death from renal failure — — 3‘’0 SECTION V THE NEPHROTIC SYNDROME The nephrotic syndrome is a cbnical complex consistmg of marked proteinuria, generalized edema, hypoprotememia and hypercholesterolemia In most severe forms, the proteinuria may exceed 20 gm per day, the fluid retention may reach 20 liters, total phsma proteins below 4 gm per 100 ml are not uncommon, and plasma cholesterol concentrations above 1000 mg per 100 ml have been recorded There exist also incomplete forms of the syndrome in which no hypercholesterolemia occurs In ad dition to the features |ust mentioned, there may be, of coarse, other symptoms due to tlie underlying renal disease hematuria hypertension, azotemia The nephrotic syndrome may occur m the following con ditions 'hpoid nephrosis, various types of glomerulonephritis, diabetic glomerulosclerosis, amyloidosis, and tlirombosis of the renal vein As diabetic glomerulosclerosis and amyloidosis will be discussed later, we shall deal in tins section exclusively with lipoid nephrosis and glomerular nephritis The etiology seems to be an infection m most cases, but toxic factors (Inmetliadione) are sometimes involved The nephrotic syndrome is seen only m glomerular chsease or in vascular con ditions mterfering with the permeability of the glomeruli It is bebe\ ed that tlie heavy protemuna is largely responsible for the development of the hypoprotememia, and secondarily of the edema (257) It is not known rvhetlier Jiypercliolesterolemia is due to hypoprotememia or produced by another mechanism (261,262) The structural changes of tlie glomeruli observed m renal biopsy specimens are extremely xariable (2, H, 115, 145, 164,229,262,265) The following types can be seen a) No lesions on light microscop), with the electron micro- scope, changes m the basement membranes and in the foot processes of tlie epilhelia] Ia>er can ahxays be observed 95 THE NEPHROTIC SWDROME XiiE NEiMutoTic SYNDnoNiE IS a cimical complex consisting of marked proteinuria, generalized edema, hypoproteinemia and lijT^ercliolcsterolemia. In most severe forms, the proteinuria may exceed 20 gm per day, the fluid retention may reacli 20 liters, total plasma proteins below 4 gm per 100 ml are not uncommon, and plasma cholesterol conccnlmtions above 1000 mg per 100 ml Iiave been recorded. There exist also incomplete forms of the syndrome, in which no hypercholesterolemia occurs. In ad- dition to tlic features jitst mentioned, tjicre may be, of course, otlior symptoms due to the underlying renal disease; hematuria, liyperlension, azotemia. The nephrotic syndrome may occur in the following con- ditions: "lipoid neplirosls," various t>^es of glomcnilonephritis, diabetic glomerulosclerosis, amyloidosis, and thrombosis of the renal vein. As diabetic glomerulosclerosis and amyloidosis will be discussed later, we simll deal in this section exclusively with lipoid nephrosis and glomcnilar nephritis. The etiology seems to be an infection in most cases, but toxic factors (trimethadione) arc somelimes involved. The nephrotic syndrome is seen only in glomerular disease or in vascular con- ditions interfering with tlic permeability of tlic glomeruli. It is believed that the heavy proteinuria is largely responsible for the development of the hypoprolcmcinia, and secondarily of the edema (257). It is not knoxvn whctlicr hj'percholestcrolemia is due to hypoproteinemia or produced by another mechanism (261,262). Tlie structural changes of the glomenili observ’cd in renal biopsy specimens arc extremely variable (2, 11, 115, 145, 16-1,229,262,265). The following l>*pes can be seen; a) No lesions on light microscopy; with the electron micro- scope. changes in the basement membranes and in the foot procc.sscs of the epithelial layer can always be obscrx-cd. 05 96 Clearance Tests in Clinical Medicine Tliese cases seem to represent trae examples of "lipoid ne- plirosis.” b) Sliglit to moderate diffuse tluckening of tlie walls of tlie glomerular loops ("membranous glomerulonephritis”). c) Lobulation of tlie glomerular tufts due to obliteration and fusion of two to three thickened adjacent loops, with some degree of endothelial proL'feration (“lobular glomenilone- phritis”). d) Lobulation of the glomerular tufts as described under (c) with cellular proliferation of the Bowman’s capsule (“lobular-proliferative glomerulonephritis”). e) Diffuse endothelial proliferation of the glomerular tufts without striking changes in the basement membranes. No involvement of the capsular epitlielium (“acute intrncapil- lary glomerulonephritis with the nephrotic s>Tidromc”). f) Diffuse endothelial and epithelial proliferation of botli the glomerular tufts and the Bowman’s capsule ("subacute proliferative glomerulonephritis”). g) Clironic sclerosing glomcnilonepliritis of the intracapil- lary type. It is not known with certainly whether these different pic- tures represent only various stages of the same disease or rather different entities. Only serial renal biopsies performed over many years could provide an answer to this question. From our limited experience, we are inch'ned to believe that pure lipoid nephrosis in the adult patient does not progress to proliferative nephritis. On the other hand, membranous glomerulonephritis may lemain slabihxed ox progress very sfowly to lobulat nephii- tis. We do not know whether distinct membranous lesions may disappear in certain cases. Mixed lesions of the membranous and lobular type are found in a large number of patients, in many of whom no real progression can be detected even after years, or at most, an extremely slow progression. On the other hand, in all cases with rapid or at least easily measurable deterioration of the renal function, cellular proliferation of the Bowmiaji’s cap- The Nephrotic Syndrome 97 sule IS alread) present at an early stage Fmallj , acute inflamma- tory changes of the tufts may heal completely or progress to sub acute proliferative or chrome sclerosing glomeniloneplmtis Thus, the course of the disease depends on the nature of the organic lesions (1) Complete remission or even recovery ma> be expected in pure Iipoid nephrosis and m some cases of mem- branous and acute mtracapiUar^ nephritis (2) Partial remis- sion, stabilization or very slow' progression are seen m mLxed membranous lobular and lobular types (3) Progression with death from renal failure is to be expected in tlie remaining cases Only the first two groups show a good or at least a satisfactory response to steroid therapy It may be extremely difficult to recognize on the basis of clmical examination alone the exact nature of the underlying disease in the early stages of a nephrobc syndrome (261,262, 265) While a significant hematuna and a marked rise in blood pressure support the diagnosis of proliferative nephritis, a few red cells and a transient hypertension may be found m the mem- branous and lobular ty'pes and m pure lipoid nephrosis as well Clearances fn the Nephrotic Syndrome Numerous studies have been concerned witli clearance de- termmations in the nephrotic syndrome (37, 48, 105, 113, 122 128,164,200,229,257,265,309) The conclusions of these re- ports, however, are not uniform These differences are readily explained by the fact that the patients studied had vanous types of renal disease and were exammed at v anous stages of the ne- phrotic syrndrome The available data indicate that the glomerular filtration rate, the PAH clearance and tlie filtration fraction may be increased, normal or decreased in any one case More recent studies in which clearance determinations were repealed over many years and compared with the results of renal biopsy, have throwTi some light on tins interesting problem ( 164, 229, 265 ) A Theoretical Considerations Cases of nephrotic syndrome m which glomerular lesions are very slight or not delectable by light microscopy may be ex- pected to yield normal cleanmce values Actually, supernormal 98 Clearance Tests in Clinical Malicinc values can also be seen, especially in children (48, 105, 113, 309). Tlje elevation of the glomerular filtration rate may be due to increased permeability of the basement membrane, and/or to in- creased renal blood flow. The elevation of the PAH clearance may represent some kind of inflammatory' hyperemia” or result from the anatomically demonstrable hyTiertrophy of tubular tis- sue (48). Tlie second interpretation is supported by (be finding of an increased Tm^Aii (48). In nephrotic subjects with super- normal clearances, the filtration fraction may be normal, in- creased or decreased. It must be remembered, however, that in cases without de- monstrable glomerular lesions, tJ»e clearance values arc quite often markedly reduced. This phenomenon may' be due In part to the presence of an interstUia} edema interfering with the renal circulation (48, 164, 331), in part to an increase in abdominal pressure related to the presence of ascites. Perliaps a more likely caplanation is iJial tlie impairment of renal homod}7iamics resaUs from disturbances in the systemic circulation (257). An increase in blood volume is often followed by an elevation of tlie clear- ance values in normal and nephrotic subjects (110, 163). Hut the reverse is probably also true, and in nephrotic patients with marked anasarca, tJie blood volume is frequently rctlnccil FoJ- lou'ing diuresis, the reduced clearance values may be restored to normal (257). A representative case illustrating these rela- tionships is reported in Tabic J4. Therefore It appears that in ses’erely edematous patients the clearance results have to be interpreted witli caution, and Uiat low values do not ncccssarjJ>' mean extensive organic changes. T.inu: M Patievt I. S., 23 Ymr Oi.i>. Cieabwct Vaeith tv ItFUL-nos- to .tvwAJict AM} liLOOU VOLVME SS A PATIENT WJTH LirOIt} Ni rilKOSIS ~ JJloof Ct CpAH .4&1IITH- n’rifffll I'ol. Jlfrujl Dale ml/tnin rnl/rnin P. F. nuna f'Jrma kg L Ihitpiy 3/20/1054 OS 74S oTlSJ ++ + CS 5/20/1054 32 5 21S 0 13 © 7 © +++ + + 4- 74 2 0 +•• 9/2S/1054 100 .->60 0.(77 tracw 0 57 5 .5 •DcfcrminiNl with P” W>eled iwl evils. •• No intwlitial edema. INeept for » Tciy sliglit tliiekmins of the Ijivnient membranes, normal Riomcruli. The Nephrotic Symiromc 99 In acute nephntis with the nephrotic syndrome, essentially the same pattern as m difFuse poststreptococcal glomerulonephri- tis can be observed, that is glomerular filtration rale is reduced, PAH clearance is high and filtration fraction is low In mem- branous glomerulonephritis, the clearance \alues depend on the degree of thicl^ening of tJie glomerular loops In most cases tlie glomerular filtration rate and the filtration fraction are reduced, the PAH clearance is high, normal or slightly reduced In lobular nephritis both clearances are reduced, the filtration fraction is normal or low In all proliferative forms, the same pattern as in chronic, sclerosmg glomerulonephritis maj be expected, mclud ing a fall m Ep^n as outhned in the preceding section It must be remembered, however, tint at an early stage of the nephrotic syndrome the glomerular lesions are often ex- tremely discrete, no matter whether they are of the membranous lobular or of the cellular type, so that even in proliferative forms the initial clearance values ma) be quite uncharacteristic On the other hand, m patients with anasarca, a functional reduction of tlie clearances can be observed witli any type of glomerular lesions, exactly as in Lpoid nephrosis It would appear, there fore, that the clearance patterns correlate better with the nature of the underlying nephropathy in a late than m an early stage of the nephrotic syndrome (265) B Practical Use of the Clearances As tlie later course of Uic disease, and also the responsiveness to steroid therapy largely depend on the nature of the glomeru- lar lesions, it was hoped that early clearance determinations might help differentiating 'pure hpoid nephrosis” from other types of nephrotic syndrome (257) Unfortunately, this does not Jjold true for several reasons a) Even inflammatory lesions of the exudative proliferative or lobular type are imtiilly rather discrete b) A functional reduction of the clearance values may occur even in cases without detectable glomerular lesions c) In elderly patients, other lesions may exist at the same time (arteriosclerosis, pyelonephntis) and influence the clear- ance results Clearance Values Recorded Within One Year After Onset op the Nephrotic Syndrome 100 Clearance Tests in Clinical Medicine I The Nephrotic Symlronic ' 101 In Table 15 we present clearance \ allies obtained in 16 pa tients witlnn one >ear of onset of the nephrotic s>Tidrome The patients hive been classified according to the results of renal biopsy It can be seen that m each group the glomerular filtration rate is eitlier normal, reduced or increased Witli three excep tions the PAH clearance is normal or mcreased The filtration fraction is low in thirteen cases, normal in t\\ o and increased in one On the whole, these values are similar to those found m acute glomemlonephntis There is no specific pattern for the nephrotic s>’ndrome, wnth one possible exception the increased filtration rate found in some cases But e\en this feature may be obsened m different t)pes of glomenilar lesions In a later stage, ho\\e\er, serial clearance determinations are ver) useful in followmg the course of tJie disease, and the) may enable us to draw certain conclusions concerning the nature of the organic lesions In Table 16 we present clearance values obtamed up to fifteen >ears after onset in eighteen nephrotic subjects Most of these patients had senal determinations per- formed over many months or years The cases have been chssi fied into several groups according to the behavior of the clear ance values and these have been compared with the results of renal biopsy In the frst group, clearance values were found to be normal several years after the onset of the disease These subjects en ) 0 )ed complete remission and renal histology revealed onl> a slight thickening of the basement membrane (“hpoid nephrosis ) In the second group, clearance values were also normal and renal biops)' showed only lesions of the membranous type A slight alhumimma persisted, however, at the time of the last clearance determination In tJie third group, clearance v'llues were initiali) high or normal and remained during the follow up period within the nor- mal range Nevertheless, a slow decrease became evident after several )ears These patients had persistent albuminuria On renal biopsy they showed a picture consistent with tlie diagnosis of membranous lobular nephritis without capsular proliferation In the fourth group, clearance values were markedly de pressed, but no further decrease could be observ ed ov er man) NEprmoTic Syndkomb 102 Clearance Tests in Clinical Medicine The Nephrotic Sijndrome 103 Clearance Tests in Clinical Medicine years. The patient enjoyed a complete remission of tlie nephrotic sjTidrome. Renal histolog)' revealed mcmbranous-lobnlar lesions without capsular proliferation. In the fifth group, clearance \'alues were definitely reduced and tended to decrease further. All patients had persistent ne- phrotic sjTidrome. Tliere were hvo membranous-lobular nephritis and one chronic sclerosing intracapillar>' nephritis in this group. In the sixth group, tlje recorded clearances ^\•ere low but the further course could not be predicted, as previous or later clear- ance values were not available. All patients had persistent albu- minuria. Two suffered from membranous-lobular nephritis with arteriosclerosis and the third had a thrombosis of the renal vein with glomeruli of normal morphologic appearance. In tlie last group, clearance x'alues were found to decrease steadily. The first patient died from renal failure within two and ihree-fourtljs years and was found to have lobular nephritis with capsular proliferation. The second died within a few months and post mortem examination, confirming biopsy findings, showed a subacute glomerular nephritis with inlracapillary’ and capsular proliferation. From these data, it appears that in “pure lipoid nephro- sis” or membranous glomerulonephritis with slight anatomical changes the clearance \’alucs normalize and remain normal fol- lowing remission. During an episode of nephrotic syndrome they may be normal, increased or decreased. This clearance pattern should enable us to recognize a nephrotic s>Tidrome with no or only slight residual lesions. An illustrative case (I.S.) is pre- sented in Table 17. A practically complete remission of the nephrotic s>Tidromc can also be achieved in cases with a permanent reduction of the clearance values. In these cases a further decrease is unlikely. The lesions seem to be stabilized. If another cause of renal impair- ment can be ruled out (arteriosclerosis, pyelonephritis), the re- duction of the clearance values can be related to marked mem- branous-lobular changes with complete hyalinization of some glomeruli but no tendency to proliferation. A representative case (M.W.) is recorded in Table 17, CiRAnASa Nalufs avd Otiifii Data is Tiirff pAnrNxs hith Dju'hirnt Tyiis op tii> The NepJwoitc Stjnilromc J05 Clearance Tests in Clinical Medicine (autopsy). The Hephrotic Syndrome 107 If no complete remission can be effected the clearance ^ alues ^\lll, as a rule, show a progressive decline If the decrease is ex- lremel> slow, the under]>ing glomerular disease is in most cases a membranous lobular nephritis with shglit mtracapilhr> pro lifention or perhaps a chronic sclerosing glomenilonephnlis These processes lead to a progressiie h)ahnization of the gJo- menili and to renal failure and/or hy’pertension but the last stage of the disease may not be reached before thirty to forty years If the decline is rapid death from renal failure mn be ex peeled within a few montlis or years In tliose cases marked pro liferation of the glomerular tufts and of the Bowmans capsule IS the rule Clearance data from a represenlatwe case (F H ) are given in Table 17 Therefore, in cases walh the nephrotic syndrome the clear ance technique represents a good method of evaluating the prog nosis It also gives some indications as to the nature of the glo merular lesion, but m this respect renal biopsy offers many ad vantages over the clearance tests We feel that botli methods should be used in the diagnosis of the nephrotic syndrome SECTION VI OTHER GLOMERULAR DISEASES 1 AMYLOIDOSIS In renal amyloidosis, the localization of the amyloid deposits IS rather variable (2) In many cases the glomeruli are the site of the pnncipal changes Amyloid is deposited on tlie endothehal or epithehal side of tlie basement membrane In advanced forms there is an extreme focal thickenmg of the Nvalls of the capil lanes leadmg to the formation of homogeneous splieres Amy loidosis also tends to involve the afferent arterioles, the mter- lobuhr arteries and the arcuate arteries Am>loid thickening of the tubular basement membranes occurs m some cases The chmcal picture of renal amyloidosis depends on the type of histologic involvement In glomerular amyloidosis a nephrotic syndrome IS frequentlj found Vascular am> loidosis may produce only a shglit albummuna, while tubuhr deposits are occasionally accompanied by pitressin resistant polyuna (64) In cases with extensiN e deposits throughout the kidney, h>’pertension and azo temia ma) ultimately develop In view of the vanabihty of the histologic picture, it is not surprising that clearance values do not follow a single pattern in this disease On the whole there is alwa> s a reduction of both the glomerular filtration rate and the PAH clearance Ep^n also he depressed (16) If there is a marked involvement of tlie glomerular loops, the filtration fraction may be decreased (16) To summarize The clearance technique does not make it possible to differentiate renal amyloidosis from other renal dis eases, but it gives \ aluable information about the functional state of the kidneys n DUBETIC GLOMERULOSCLEROSIS In 1936, Limmelstiel and Wilson described in diabetic sub jects a peculiar ty'pe of renal lesion which the> called ‘mter- capillaiy glomerulosclerosis’ Hie fnlly developed lesion consists ill 112 Clearance Tests in Clinical Medicine of a hyaline mass in the central portion of the glomenilar lo- bules (170). Subsequent investigations confirmed the specificity of this nodular alteration, but also revealed the frequent occur- rence of other changes in diabetes mellitus. Tliese include a dif- fuse thickening of the glomerular basement membrane, a “diffuse type” of intercapillarj' sclerosis and a significant arteriosclerosis (2, 12, 15, 80. 93, 103, 133). In tlieir original paper, Kimmelstiel and Wilson noted a marked correlation between the obser\*ed glomenilar changes and a clinical sjmdrome characterized by nephrotic edema, gross albuminuria, lij’pcrtension, diabetic retinopathy and renal fail- ure (170). Later work did not, however, entirely corroborate this statement. Specific nodular lesions are often found in pa- tients who never presented the clinical sjTidrome outlined by Kimmelstiel and Wilson. Conversely, a nephrotic sjmdrome with hypertension may occur in diabetic patients whose kidneys arc the site of diffuse changes only (133, 261, 262). At the present time, most investigators agree that glomerulo- sclerosis is quite a freqvient renal disease, developing during tlic course of diabetes mellilus earlier than was formerly thought. Early changes are not specific, however, and e\-en at a later stage, hyaline spheres may be absent Clinically, the symptoms may extend from slight albuminuria with or without hypertension to the full picture described by Kimmelstiel and Wilson (169, 170). The complete sjmdrome is seen more often in young patients than after the fourth decade of life. In elderly subjects the clin- ical picture may be indistinguishable from essential h>’perten- sion, except for the presence of diabetic retinopathy (261,262, 274,277,308). Clearances in Diahelic Glomerulosclerosis A. Theoretical Considerations Several factors are responsible for the behavior of the clear- ances in diabetic glomenilosclerosis: 1. The diabetes per sc. Diabetic kidneys are often en- larged and in the absence of secondary lesions, high clearance Olher Glomerular Diseases 113 \ alues ( Cin CpAn and also Tnic ) y. ill result from tissue hj'per trophy (275 309 310) 2 Tlie tluckening of tlie glomerular basement membrane reduces the filtering surface leading to a disproportionate fall m glomerular filtration rate relative to Cp^n In cases with gross albummuna (he filtration fraction may be low as in many cases of nephrotic syndrome of unlaio%vn ongm (160) 3 Progressive sclerosis of the afferent arterioles and m vasion of the glomerular tufts by hyaline deposits lead to complete sclerosis of the glomeruli with secondary atrophy of the attached tubules The resulting reduction of the num ber of functioning units is responsible for a parallel decrease in C,n CpAn and Tmc the filtration fraction remaining nor mal (52 79 159) Tlie PAH extraction ratio is somewhat re duced m these cases 4 In cases svath marked hypertension arteriolar spasms produce as m severe essential hj-pertension a greater fall in Cp^ir than in Qb thus raising the filtration fraction In Table 18 clearance values are presented whicli ha\e been obtained in twenty four patients with diabetic glomeruloscle rosis veriSed hy reus] hiopsy or post mortem exammatioo These data seem to roughly support the theoretical considerations In most patients mixed diffuse and nodular changes were found on histologic examination In a few early cases only shght diffuse changes were seen The extension of the lesions correlated well with the level of the glomerular filtration rate if allowance was made for the fact that in uncomplicated diabetes tlie values are usually above normal Thus m case eiglit distinct nodular and diffuse alterations could be observed but the glomerular filtra tion rate was still 91 ml/min It can be seen from Table 18 that the filtration fraction was below the lower normal limit of 0157 in eleven cases seven of whom had gross protemuna It was normal in eleven patients and increased onl> in tw o instances Previous investigators have reported either low (160) or normal (52 79 159) filtration frac tions It IS clear from our material that both may occur 114 Clearance Tests in Clinical Medicine TABLE 18 Clearakce Values ih Twehtt-^cr Cases or Diabetic GUtMEBULOSCLEROSIS I'alicnt Age Cr mt/min epAtt ml/min F. F. Albums- inirio Blood Pre^'SHTC mm Ilg Early stage 1 . r. M. 35 175 1135 0.154 20 161 1060 0 152 56 157 819 0 192 St! 4 R W. Gi KM 719 0 145 63 KM 5S0 O.IS (-1-) GO 95 592 0 16 20 92 5 770 0.119 ++ 160/100 H. Li A. 91 C6S 0 137 170/110 150/S5 9. 0. Z 31 91 416 0 218 -f- Late stage 10. M.II. CG 79 500 0.159 203/110 11 G. G. 22 70 5 555 0.127 +++ 235/125 W 62 319 0.195 155/110 13. E, L. 67 Cl 360 0.170 195/80 14. A. n 37 60 430 0.139 +++ 180/110 IS K Z. 47 57 430 9 132 lQO/105 16. L.8 20 52 252 O.lSl 220/120 17. M. K. 48 50 387 0.129 -l"t- 100/100 Terminal slage 18. n. B. 24 39 156 0.25 170/135 10. A. 11. 3S 36 5 270 0.202 -1'+ 200/116 20. G. 0, 23 26 4 203 0.13 170/100 21 K. 2. 4S 25 209 0.12 +++ 205/123 22. L.S. 30 10 63 0.30 190/110 23. G. 2. 38 16 5 75 245/110 24 G 60 12 4 00 0.207 + 215/103 We may conclude that in diabetic glomenilosclerosis it is not possible to define a specific clearance pattern, except for a con- stant decrease, as the disease progresses, and a tendency for the filtration fraction to be low in cases with marked proteinuria. B. Practical Use Whereas a single clearance determination is of little help in making a correct diagnosis of diabetic glomenilosclerosis, serial tests performed over many years give quite a true picture of the course of the disease, and are of great prognostic value. It is beyond any doubt that diabetic glomerulosclerosis results in a progressive impairment of the renal function, but the rate of de- terioration is variable. It depends on the age of the patient, on Other Glomerular Diseases 115 the duration and severity of diabetes, on the presence of associ- ated pi’elonephritis and on se^’eral additional foctors. In certain cases the deterioration is rapid, in other patients the clearance x-alues maj' remain stabilized at a low level for many years. In Table 19 serial clearance values recorded in three patients with the mixed type of glomerulosclerosis are presented. In case G.G. renal deterioration was accelerated: the clearance values were still above normal in 1953 and the patient died from renal failure in 1956. In case L.S. die course w’as less dramatic. The first clearance determinations, performed in 1955, were already marVedly reduced. Nevertheless, die patient survived for five years. In Patient M.K., the values recorded in 1953 were already reduced, but subsequent determinations shou'ed no further im- pairment behveen 1955 and 1958. Tims, temporary' stabilization may occur in flu's disease. Tire patient died, however, in 1961, from renal failure. To summarize: Serial clearance detenninations are of great value in appreciating the course of diabetic glomerulosclerosis. TABLE 10 ScRUL Cleounce Valves am> Other D'ta is Three Patients WITH Diabetic Glouervlo^clerosis Patiml Dale Ct tnl/min mf/rwin F F. nunn Blood PrtMnre mmJIff Relin- opalh^ 2/20/53 iGi lOCO 0 152 + 125/SO ++ old.— 3/30/53 158 914 0 173 130/S5 Diabetes known 8/ 8/55 70.5 0 127 150/90 ++ 9/26/55 02 2 319 0 195 160/9.1 -H- 1/ 9/58 40.2 270 0 107 ++ ■M-l- 2/20/56 2S 4 210 0.135 ++ I95/II0 +*++ 3/ 5/56 6/ 6/56 26 4 203 0 130 Death from renal failure 170/100 ++-H- 4/30/55 52 2M 0 isi + 190/100 old.— 7/ 9/56 31 7 159 ++ ++ Ifisbetes known ti;26;5& 37 110 y 1/ 7/57 194 + +++ 6/ 4/57 33 15S 12/ 5/57 29 4 156 0 iss + 210/100 1/2S/59 1/31/60 19 2 C3 2 0 30 Death from renal failure * lSO/120 +++ 7/ 2/63 SO 357 0 129 ++ lOO/IOO ++ 47 193 + +++ 4/11/50 42 220 0.19 ++ +-H-+ since 193G. 2/24/5S S/15/61 43.5 236 0 17 Death from renal failure + ++++ 116 Clearance Tests in Clinical Medicine Tlie clearance patterns, however, show little speciBcity and do not enable us to difFerenliate with certainty this disease from other renal affections. in. TOXEMIA OF PREGNAXCY The renal disorders of late pre^ancy may be classified as follows: 1) Specific toxemia, occurring in previously healthy women. 2) Toxemia superimposed on preexisting renal disease or hypertension. 3) Preexisting renal disease without toxemia. Only specific toxemia will be considered in this section. Clin- ically, it is characterized by a progressive rise in blood pres- sure accompanied by edema and proteinuria but without azo- temia. In severe forms, convulsions may occur (eclampsia). After delivery edema and proteinuria subside rapidly. In the majority of cases, blood pressure also falls to normal levels. Tliere is no convincing evidence that toxemia of pregnancy is due to renal dysfunction. It is most likely tJiat renal involve- ment is a secondar)' phenomenon. The nepluopathy of toxemia consists of at least three different renal disturbances; a) a specific glomerular lesion presenting as a thickening of the basement membrane (11) and/of a swelling of the en- dothelial and epithelial cytoplasm (235); b) superimposed arteriolar spasms without anatomical changes. Only in very severe eclampsia may renal ischemia produce cortical necrosis; c) an increased tubular reabsorption for sodium and water, probably due to extrarenal influences. Except for cortical necrosis, which may cause death from renal failure, the renal alterations are entirely reversible after delivery. Clearance Tests in Toxemia In evaluating the results of clearance tests in toxemia, we have to remember that during normal pregnancy, there is a con- Olhcr Glomerular Diseases 117 si'derable rise in glomerular filtration rate and PAH clearance as well (58,67,291). The highest values are observed by the fourth month. Buchl (58) indicates average \'alues of 170 ml/ min for inulin and 800 ml/min for PAII. Other investigators report an increase of 50 per cent for inulin and 25 per cent for PAII above the control values (291). In late pregnancy, the PAII clearance gradually returns to normal, while the glomerular fil- tration rate remains elevated until deliver)’, althouglr at a lower level than in early pregnane)'. Clearance tests in toxemia have been performed by numerous investigators (3,67,75, 167,325,337). The PAH clearance is often within normal limits or slightly reduced. As lij’pcrtension is a constant sj'mptom of toxemia, it seems, therefore, tliat it is not caused by a renal circulator)' disltirJxince. On tl)c other band, tlie glomerular filtration rate lias been found to be signifi- cantly depressed in most cases, resulting in a decrease in filtra- tion fraction. The clinical usefulness of clearance tests during specific tox- emia is somewhat questionable, as the ultimate prognosis often boars no relation to the degree of renal involvement. After deliver)', however, clearance determinations may liclp in making a correct diagnosis, \\nicreas after specific toxemia the renal lesions usually disappear and clearance values return to normal, in preexisting renal disease they do not. If several weeks after delivery a significant depression of the clearance values persists, it is likely that the patient suffers from an organic nephropathy not related to pregnane)’. SECTIOxV VII VASCULAR DISEASES I. ESSENTIAL HYPERTENSION AND RENAL ARTERIOLOSCLEROSIS Essential hypertension is a vascular disorder of unknown Origin characterized by a sustained elevation of blood pressure and the progressive development of organic changes of the ves- sels, especially nephrosclerosis. In the early stage of the disease, renal biopsy shou’s practically no vascular lesions (63). After several years, arteriosclerosis becomes manifest and an increas- ing number of glomeruli show partial or total hyalinization. In “benign hypertension" tlie progression of tlic vascular changes is very slow. But in “malignant forms" (tliat is in severe hyper- tension with high diastolic blood pressure, grade III-IV retinal changes and marked alteration of the general condition), more rapid and even acute changes develop; they appear as a fibrinoid necrosis of tlie arteriolar walls and some glomerular loops. The affected glomeruli also show hypercellularity (114,283). There is still some controversy as to tlie real nature of the relationsliip between essentia! hypertension and the renal vas- cular changes. Personally, we do not share Goldblatt’s view ( 138 ) that organic renal ischemia initiates the blood pressure rise. Nor can a functional ischemia be demonstrated in the early stage, as we shall see below. But if nephrosclerosis or functional renal iscliemia are not responsible for tlie elevation of blood pres- sure, the reverse might be true. Actually, there is a considerable body of evidence to indicate that high arterial pressure partici- pates to some extent in causing arteriolar necrosis in the malig- nant cases (190, 232), In beniga hypertension with nephroscle- rosis, no statement can be made regarding priority. We would rather suggest that high blood pressure and vascular sclerosis mi^t represent two symptoms of the “hypertensive disease” (261,262). 121 122 CJearancG Tests in CUniail Medicine The renal symptoms of benign nephrosclerosis are a slight to moderate albuminuria and, in advanced cases, impairment of the ability to concentrate urine. Excessive diuresis and saluresis in response to water and salt loading have also been reported (82). The renal symptoms of malignant or accelerated hyper- tension include moderate to marked proteinuria, hematuria and progressive azotemia. Deatli from renal failure is quite frequent in this condition. Clearances in Essential Hypertension A. Theoretical Considerations Studies of renal plasma flow in essential hypertension are of considerable interest for the understanding of the pathogenetic mechanisms operating in this condition. Such studies have been performed during the last two decades by a large number of in- vesUgators (31, 68, 85, 119, 124, 139, 148, 158, 227, 248). It is well established that during the initial stage of the illness, the glomerular filtration rate and the PAH clearance may be essen- tially normal. As tlie disease progresses, however, they become gradually impaired. In many cases the fall in Cr^n antedates tlie decrease in glomerular filtration rate, so that the filtration frac- tion increases (139, 300). Even later, Cr^n may be relatively more reduced Aan C,n, but sometimes the per cent decrease in both clearances is similar. It has been shown that these changes in renal hemodynamics can be related to an increase in both afferent and efferent arteriolar resistance (300). This increase, in turn, may result from organic changes (arteriosclerosis) and/or arteriolar spasms. The significance of these two factors can possibly be appreciated from the renal response to anti-hyper- tensive tlierapy. If functional vasoconstriction alone is involved, one would only expect a transient drop in clearance values to occur when blood pressure is reduced. If organic obstruction of the arterioles exists, blood pressure reduction as a rule, would be followed by a permanent decrease in tlie clearance values. From the behavior of most hypertensive patients, it appears that both factors play a role. But it is of interest that Talbott and his associates found a good correlation between renal vas- Vascular Diseases 123 cular disease and renal plasma flow (317) On tlie otlier Innd tliere is a rough inverse relationship between the level of the diastolic (or mein) blood pressure and Cpah in untreated hyper tensives Usually, Cpao decreases as blood pressure increases, but the scatter of values is considerable so that no satisfactory matliemitical correlition can be demonstrated between these two vambles (Fig 16 and Table 20) It must be emphasized tliat in subjects with early hyper tension the PAH extraction ratio is normal and becomes only slightly impaired as the disease progresses (33, 38 261 262) Thus tlie PAH clearance remains a reliable measure of the renal plasma flow as long as it is more than 150 200 ml/min (Fig 5) This peculiar behavior of tlie PAH extraction ratio m hyperten sive subjects is probabl) due to a low rate of blood perfusion tlirough the areas of inert tissue (see Section III) B Chucal Use 1 Differential diagnosis betiveen essential hypertension and other hypertensive nephropathies AltJiougli the differentiation of essential hypertension from chronic glomerulonephritis or pjelo Fig 16 Glomerular filtration rate in relabon to d astoLc blood pressure m essential hypertension (H) diroiuc glomerulonephritis (G) and chronic pyelonephritis (P) Average \alues taken from Table 20 m Clearance Tests in Clinical Medicine ^MPABI^ON or Cix.\B»,\ct VAiras WlTJl TT/E UlEt Or Vustriur litjoott rRKSSl-RElV 1 ATIEXTS wrm liUsENTItL I jrrERTEMi>!OV, Ol^MI RL'UlsmmfTU Axn Prt.toNEpHRrrt» Ilon^ of Glomerular Ftl- Iralton haU ! P.ll! cleoranfT FiUto- pMIffnoAM Ca»fa Pnuurr mn,Mg Atrragt Rii/min Itange ml/mtn Itongf »n(/,nin F nirtion Essential 12 S5-TO lOlt 77-144 449 31G-0T1I hi-pertension 100 -ttn M .394 12 12-:, To (UO case?) 110-119 1)0 55-1 12 300 223-OJ3 120-129 95 1I-U0 407 130-139 30-1.51 '.■JS ll'Wl- 140- H9 GO 25-IOS 210 *.«-350 5 ]50-|.9>l 05 20-100 an 101-,51.5 0 215 > ICO OS IS-lIl) 249 00-4.50 0 273 Oironie 3 CO- 09 92 01-12S 41.5-rjO plomenilo- C 70- 79 9S .50-131 .5.39 .Tv34;70 0.1S3 nephntLi (55 cases) 9 SO- .<9 M Ov-IOS .520 3n3-S07 0 It.2 10 IK)- 09 T5 2:{-i{n 4.52 210 0 lOR 0 1(10-109 50 7-ion 2.50 4')-4S.S 0 2ir> 9 110-119 41 12- W 219 42-.50I 0 177 A 120-129 14 51 lO-HXl 0 3.V) 130-139 27 13- 40 1.51 0 179 2 > 140 14 12- 15 49 39- 09 0 2N.5 2 GO- 09 5'f 27- on 2S3 on-47.5 0 2m pvelonepJiritu to 70- 79 04 2S-120 302 121 -.51 5 0 '211 (5S eas<.-s) 21 99 7-11.5 273 30-590 0 209 15 t«0- 1»9 4.5 9- >.*•'> 219 37-»'J2 0 '2015 0 m-m as IS- 01 107 50-2NN « 227 2 0 U0-II9 120-129 32 8- .55 HI 4.5-212 0 221 2 130-139 27 14- S'* no 35-1 ((7 0 233 nephritis mainly rests upon clinical examination, this problem may sometimes be solved more easily if clearance results arc taken into account. No single clearance pattern can be considered to be specific for essential Ii>’pcr(cnsion, but comparison of the clearance values n-ith the blood pressure level may give a clue to tbe correct diagnosis, tn Table ^ and Figure 10 we base re- corded the clearance \-alucs obtained in 110 patients with es- sential h>-pertcnsion, fifty-two vx-ith chronic glomeniloncpliritis and fifty-eight with chronic pyelonephritis. The clearance results liave been compared witli llie level of the diastolic blood pres- sure. From these data it appears that within a given range of blood pressure the clearance values are extremely xariable. If, Vascular Diseases 123 however, the average clearance \alues corresponding to each blood pressure level are considered, the tliree nosological en titles show some distinct trends The highest clearance \ allies are observed m essentia! hypertension, the lowest in chrome pyeloneplmtis Even if allow’ance is made for the wide scatter of the data, the difference appears to be significant at least in the blood pressure range between 100 and 120 mm Hg where practically no overlapping occurs In chronic glomerulonephritis, the data occupy an intermediate position There is a marked de crease m the mean clearance values wnth increasing diastolic blood pressure Therefore, clearance \alues are almost as high as in essential hypertension in the relabvely low range of blood pressure, and as low as in chronic pyeloneplmtis at a high level of blood pressure Overlapping is here quite evident, so that when the blood pressure is moderately elevated, a clear-cut dif ferenliation between chronic glomerulonephritis and essential hypertension is not possible on this basis In tins range of blood pressure, however, the behavior of the filtration fraction may be helpful, as this ratio is usually low er in glomerulonepiintis than m essential hypertension From a clinical point of view, the following conclusions may be drawn A marked elevation of the diastolic blood pressure associated with a discrete reduction of the clearance values is strongly sug- gestive of essential hypertension In cases with shght to moder- ate hypertension, relatively high clearances are found, not only in essential hypertension, but sometimes ako m chronic glo- merulonephritis Under these circumstances, an elevated filtra tion fraction suggests, but does not prove, essential hypertension The behavior of the clearances in the separate kidneys is also helpful in differentiating essential from secondary h>q)er- tension due to unilateral renal disease This wall be discussed later 2 rolhtinng the course of the disease and assessing the value of anti hypertensive treatment Follow-up studies of the renal function in essential hypertension indicate that in benign forms the progressive deterioration is extremely slow (209,260) 126 Clearance Tests in Clinical Medicine On the other hand, in untreated cases of mah'gnant or accelerated hypertension, renal impairment develops fast, but can be slowed dowTi or ev'cn arrested by appropriate antihj'pcrtcnsis'c treat- ment (77, 209, 230, 260). Serial clearance measurements are therefore of great interest in e\'aluating the prognosis of the dis- ease. We should like to summarize briefly the results of a study performed two j’ears ago, which may be taken as standard of reference for the interpretation of individual cases (260). Seventy-two patients \rilh moderate to verj' severe essential hypertension were followed over one to five years. Thirty-three cases had no effective treatment during this period. In the re- maining thirty-nine, the blood pressure had been significantly reduced by drug therapy. All patients were under ambulator)’ medical super\’ision. The renal functions were controlled re- peatedly in ever)' patient during the follow-up period (204 de- terminations of tlie thiosulfate (or inulin) and PAI! clearances), According to the severity of Ii)’pertcnsion, these patients were divided into three groups: Group I: supine diastolic blood pressure < 130 mm Ilg, retinal clianges of grade I-II (Wagencr-Keitli); Group II: supine diastolic blood pressures between 120-150 mm Hg. retinal changes of grade ll; Group HI: supine diastolic blood pressure > 130 mm Ilg, retinal changes of grade III-IV. In each group the renal functions of the trcatctl and un- treated patients were compared (Table 21 ). Tlic average changes at tlie end of tlie follow-up period were calculated per year in per cent of the control values. The t-tcsl was used to determine the significance of the differences. Restths (Table 21 and Fig. 17) Group I. In the untreated patients the mean duration of follow-up was two and three-fourth years. There was an as’cragc decrease of 1.6 per cent per year in Cj and 1.3 per cent in Cp;»ii. In the treated patients the mean duration of follow-up was two and onc-half years. Tirerc ww an average decrease of 3.1 per cent per year in Cr and an increase of 1.2 per cent in C,.an. The 128 Clearance Tests fn Clinical Medicine Vascular Diseases 129 Eraup I Group JT Group JH Fig 17 Changes in renal functions of treated and untreated hypertensive patients during a followup period of one to five )ears The seventy two cases have been divided into three groups according to the sev erity of the disease The changes are expressed in per cent of control values per year (Courtesy of Springer Ber! n ) differences observed between untreated and treated patients are not significant (p>01) Group II In tlie untreated patients the mean duration of follow up was two and three fourth years There was an average decrease of 1 7 per cent per > ear in Ct and 5 0 per cent in In tlie treated patients the mean duration of follow up was two and one half years Tliere was an average decrease of 3 6 per cent per year m Ct and 1 5 per cent in Cpao Tlie differences between untreated and treated patients are not significant (p>01) Group III In the untreated patients the mean duration of follow up was eighteen months On the average there was a decrease of 28 6 per cent per year in Ct and 36 5 per cent in CpAU In the treated patients the mean duration of follow up wois two years On the average there was a decrease of 74 per cent per > car in Cf and 2 7 per cent in Cpah 130 Clearance Tests in Clinical Medicine The differences observed between untreated and treated pa- tients are significant (p<0.0o for Ct and p<0.01 for Ci-^n). From these results, it appears that in Group I the average decrease per year observed in untreated patients is very small and does not differ significantly from the figures obtained by Watkin and Shock (335) for tlie agewise decline in normal indi- viduals. Treated patients of this group behave similarly. In Group II, tlie changes in glomendar filtration rate are comparable to the corresponding figures in Group I. With respect to Cp^n. un- treated patients show a somewhat greater decrease than treated subjects. The difference, however, is not statistically significant (p>0.1). A few examples are listed in Table 22. In Group III, the differences between treated and untreated patients become significant. In untreated cases, the renal de- terioration is obvious, but its rate is variable. It is most rapid in patients witli high diastolic pressure together witli Grade IV retinal changes, and ma)' be slower in less severe cases. If such '* TABLE 22 Serial Observatio.ns or Reval F^^c^o^•s iv a Pew Treated and Untreated Cases wmi Moderate to Severe HypERTEvaioN Sunns Blood Pressure Cr Crkti Dale mm Hg fnj/min mllmin F. F. Treatment a) Stable rcpal functioos in an untreated case ol group 1 (E. P., ISDl). 2/1955 200/115 74 3J0 0 240 none 3/1956 205/103 G4 303 0 210 none 7/1959 193/105 08 294 0.233 Done b) Stable renal functions in a treated case of group I (F. K., 1900). 0/1955 205/120 ItO 6/1956 190/100 119 2/1958 190/103 119 2/1960 210/93 101 540 0 204 none 527 0 226 Ecolid 473 0.251 Chlorothiaiide 533 0.188 Chlorothiazide, Ilescrpbe. c) Stable renal functions in a case both with and without treatment of group 11 10/1955 240/140 1/1959 230/125 2/1969 200/100 67 261 0.256 73 264 0 278 62 290 0.214 none none; therapy startcil Hydrochlorothiazide, Hydralazine. d) Slow deterioration 10/1955 6/1937 9/1959 160/130 160/125 170/125 an untreated case of group H E., 1922). 151 517 0.290 none I'm 502 0.238 none US 418 0.2S3 none Vascular Diseases 131 patients receive adequate h>'potensivc drug tlierapj, the renal deterioration generally comes to a halt (Figs 18 and 19), at the beginning of the treatment, however, a further decrease in Ct and Cp^n is usually observ cd Later on, the renal functions mav remain at this level for months or years (Fig 18), or they may improve gradually (Fig 19), on rare occasions they will increase over the control values In very severe cases, the progression is only partly inhibited In cases vvath sev crely impaired renal function and v er> high M nntig KO US Htt nopstSf Croat iv jr ° ffss ffsr ffft ffsy aso Ywrj Fig 18 Climcnl course In a patiinit with malignant hypertension (case AM) Marletl dttenontiOTi of renal functions before therapv Under hypo- tcnsi\c treatment there is first a further drop m thiosulfate and PAIl clear anccs Tliereafter, renal functions remain stabilized at a low level (Courtesy of Spnngtf Dtrlm ) irearistnf 132 Clearance Tests in Clinical Medicine Albminuf'fa: -H- + ^ 5 . Fig. 19. Clinical course In a patient with very severe hypertension (ease M. 6 .). Renal functions show a marked deterioration before therapy and improve gradually under treatment. (Courtesy of Spnnger, Berlin.) diastolic pressure, the acute depression of renal hemodynamics produced by hypotensive therapy usually results in an increase in blood urea (Fig. 18). This nitrogen retention may gradually subside after a couple of weeks, but in certain cases, slight azo- temia persists for months, e\'cn years. rr. enSTLATEKAL RENAL ARTEKl' LESIONS ASSOCIATED WTHl HYPERTENSION It has been recognized over the last ten years that unilateral stenosis of the renal artery occurs more frequently than wtis formerly thought and may eliat secondary • (237). Since in many cases the blood pressure will drop after surgical repair of the \’ascular lesion or Vascular "Diseases 133 detection of the arterial changes has become an important diag- nostic problem Wliile most investigators agree tliat the defect can be demonstrated only by renal angiography, an indirect ap- proach to the diagnosis lies In the functional comparison of the separate kidneys. Sei’eral tests based on the clearance technique have been worked out in various laboratories (23,73,242,311). In a majoritj' of cases, a definite functional disparitj' can be demonstrated between the ischemic kidney and its unaffected partner. On the ischemic side, there may or may not be a re- duction of the muhn and PAH clearance. A more constant find- mg is a sharp reduction of the urine flow and sodiiun excretion, due to increased tubular reabsorption As some disparity exists, however, in patients with essential hypertension (6) and even in normal subjects (161), only clear-cut differences are sugges- tive of unilateral vascular obstruction Even so, false-positive as well as false-negative results have been recorded in most pub- lished series of cases. There is no general agreement on the rebabibly of the test originally proposed by Howard and his group (73), and there- fore, numerous modifications have been worked out by other investigators. Witli the origmal technique, the patient having been placed on a diet of normal sodium content, receives 800 ml of water one hour before the beginning of the test. After local anesthesia, cystoscopy and ureteral catheterization are per- formed, using large diameter catheters to prevent leakage, urine flows and sodium concentration of tlie urine samples are meas- ured. If on one side the urine volume is reduced by at least 50 per cent as compared with Uie opposite kidney, and tlie so- dium concentration by at least 15 per cent, arterial obstruction is considered to be probable If sodium concentrations are equal, the existence of sectorial ischemia is assumed Other authors are o£ the opinian that, one should simultane- ously determine the clearance of endogenous creatinme or inulin and calculate the tubular rejected fraction of sodium, which is found to be decreased in unilateral renal obstruction (23,242). Tlie most elaborate procedure has been recently devised by Stamey and his associates (311). These authors use a constant infusion of sodium chloride, muhn and PAH. Urea and antidiu- 134 Clearance Tests in Clinical Medicine retie homione can also be added to the infusion fluid in order to make the differences between botli sides more evident. Tlie spe^ cific clearance pattern of unilateral arterial disease is believed to be characterized by a reduction of CpAii "‘ith increased tubular reabsorption of water and sodium. At the present lime, no statement can be made regarding the reliability of the Howard test and the advantages of the \'arious techniques. It would appear from the most recent reports that the information yielded by these procedures is useful, altliough not entirely conclusive. On the other hand, percutaneous cathe* terizalion of the femoral artery' which has been recently intro- duced (221) makes renal angiography very easy. Therefore, we feel that angiographic techniques should be preferred, as they are by no means more inconvenient or troublesome than ureteral catheterization and offer distinct advantages. SECTION VIII PYELONEPHRITIS PvELONEPimiTis may be defined as a non-specific inflammation of bacterial origin, involving the renal parenchyma. The infec- tion is beh'eved to reach the Ic/dney by tlie hematogenous route in most instances, at least in primary pyelonephritis (or inter- stitial nephritis). In those cases where urinary stasis is present (congenital anomalies or obstruction due to inflammatory changes, tumor or calculus) an ascending infection (perhaps through lymphatic channels) probably also plays a role. Under such circumstances, inflammation of the pelvis, the ureter and the bladder is common, but this does not necessarily occur in the hematogenous form. Among the organisms causing pyelonephritis, Escherichia coH, Staphylococcus aureus, Aerobacter aerogenes, Pseudomonas aeruginosa, Proteus vulgaris and Streptococcus faecalis are most frequently found in urine cultures (256, 261, 262). In most cases, pyelonephritis is a bilateral disease, but it may affect each kid- ney to a different extent. Several forms may be distinguished on the basis of their clinical course: a) acute pyelonephritis b) recurrent pyelonephritis c) chronic pyelonephritis with insidious onset d) papillary necrosis The pathological changes depend on the stage of the dis- ease ( 11, 220, 346). In acute pyelonephritis, there is a rather dif- fjjse infexsfJtial ij^traiisxa with leucocytes; the tubules also con- tain leucocytes. Acute pyelonephritis may heal completely or leave scars of connective tissue. In recurrent pyelonephritis, patchy areas with acute inflammatory cells are seen in addition to more chronic changes, consisting of fibrous scars infiltered witli lymphocytes and plasma cells. As a consequence of the in- flammatory process, there is a progressive sclerosis of the func- 137 13S Clearance Tests in Clinical Medicine tioning units. The tubules are involved first and become atrophic. The glomeruli may remain unchanged for a long time, but later they become surrounded by a thick collar of fibrous tissue and ultimately undergo complete fibrosis. Arteriosclerosis and ar- teriolosclerosis are comirion, tlie extent of the vascular changes depending on whether the blood pressure is normal or elevated. In chronic pyelonepliritis with insidious onset, the changes are more diffuse and consist of a marked interstitial sclerosis with tubular atrophy and relatively discrete glomerular changes (137). In papillary necrosis, the necrotic area may be confined to the lip of one or more papillas or extend to the w’hole medulla. The lesion is sharply demarcated from the remaining parenchjTna, which shows cluonic pj'elonephritic changes. The diagnosis of acute or recurrent pyelonepliritis is not a real problem. But the detection of the chronic, hematogenous, nomobstructive form may be e.xtremely difficult, as this disease usually takes an insidious course up to the point where uremia appears. At the time Haaschou (239) published his monograph (1948), a correct diagnosis Iwd been made cbnlcally in only one-sixtlx of his cases. Today, early recognition of this condition lias been greatly facilitated by the use of the clearance tech- nique (256). Clearances in Pyelonephritis A. Theoretical Considerations Raascliou w'as the first to perform clearance tests in a large series of patients with chronic pyelonephritis, using inulin and Diodrast (239). He found a reduction in C,n, Co and Tm©- Usu- ally, the decrease in Cp and Tmo w’as more pronounced than lliat in C,n, so tliat the filtration fraction was sliglitly above nor- mal. In our owTi material we find thiosulfate (or inulin) clear- ance values comprised between 2.0 and 120 ml/min, and PAH clearances ranging from 6.9 to 545 ml/mtn. The filtration fraction is not altered in a characteristic manner, ranging from 0.15 to 0.375 and being in most cases nonnal or slightly elexated (261, 262). Similar results have been recorded by others (37, 79). The PAH extraction ratio shows a marked reduction in cases with decreased PAH clearance (Fig. 7). pyelonephritis 139 In wew of the nature of the organic lesions wlncli character ize pyelonepliritis a relatn ely greater impairment of the tubular secretion of PAH might have been expected resulting m a sharp increase in tlie filtration fraction This is not so however for several reasons (a) PAH secretion is a function of the cortical tubules and these are less affected than the medullary ones (b) The inflammatory process ultimately leads in a certam num her of neplirons to the total destruction of the whole unit so that filtration and secretion are both abohshed (c) Interstitial infiltrabon and thickening of the arteriolar walls result in a cor responding decrease in blood flow and filtration rate (d) Com pression of intact tubules by tlie surrounding infiltration and edema may reduce the glomerular filtration rate more tlian the blood flow o\vmg to the increased intratubular pressure (e) A similar phenomenon may contribute m lowering the filtration fraction if pyelonephntis is associated with hydronephrosis (111) Therefore the overall effect of these various factors is a virtually parallel reduction of the glomerular filtration rate and the PAH clearance In chronic pyelonephritis however there may be a marked impairment of otlier tubular functions such as concentrating abiUty acidification of urme synthesis of ammonia excretion of potassium etc (46) These disturbances must be related to changes m tlie distal tubules and collectmg ducts They will be discussed m Section X Calculation of the total renal plasma flow from the PAH clearance and tlie PAH extraction ratio is not always vahd m pyelonephritis because both kidneys may not be affected to the same extent If the extraction ratio is only measured on one side erroneous values for Cr^u/ErAa result from such differ ences To summarize pyelonephritis produces in most cases a pro portional decrease m glomerular filtration rate and PAH clear ance In acute pyelonephritis these changes are reversible In recurrent pyelonephritis each exacerbation is followed by a new drop in clearance values which is only partly reversible In chronic pyeloneplintis the reduction is eitJier steadily progres sive or more often episodic so that stabilization o\ er many years may follow an acute detenoration The PAH extraction ratio de 140 Clearance Tests in Clinical Medicine creases with decreasing PAH clearance. This plienomcnon prob- ably results from the replacement of active nephrons by connec- tive tissue. B. Clinical Use 1. Differential diagnosis between pyelonephritis and other renal diseases. At first sight, it would seem tliat the finding of reduced clearance values with normal or slightly elevated filtra- tion fraction is of little assistance in making tlie differential diag- nosis of a renal affection. The same pattern can be found not only in pyelonephritis but also in many cases of essential hyper- tension, a few cases of adv'anced glomerulonephritis and still other nephropathies. Furthermore, it must be remembered that a low filtration fraction, suggestive of glomerulonephritis, may be seen in rare instances of pyelonephritis complicating hydrone- phrosis ( 111 ) and tliat in hy'pertensive cases of pyelonephritis, the filtration fraction may be as high as in essential h>'perlension (79). Nevertheless, comparison of the clearance values with tlie clinical picture, the grade of proteinuria and the level of blood pressure may still be of great diagnostic interest. We liave al- ready mentioned in tlie preceding section tliat, in evaluating the nature of a nephropathy of unknown origin, persistently low clear- ance values wtli little or no elevation of the blood pressure are at least suggestive of chronic pyelonephriUs, especially if pro- teinuria is slight. The clearance technique is even more useful in the detection of certain oligosymptomatic forms of hemato- genous pyelonepliritis, where reduced values of C,, and Cpin are the only evidence of a renal disease. This wall be illustrated by the following e.xample: Patient H.B., 50 year oW.— This patient, who had had a cholec>’stectomy 18 years before, was always complaining of lassitude. She had occasionally episodes of d>-suTia. At the time of e.tamination we found a normal blood pressure (120/65), a normal blood count, a slightly eles-ated blood sedimentation rate (11 mm) and a normal urinal>'sis (no albuminuria, no leucocj’turia, sterile cultures). A clearance determination dis- closed marked renal impairment: Cr 59 ml/min, C,.^ji 2-iO ml/min. Renal biopsy confirmed the e.xistence of chronic pyelo- nephritis. Ptjehnephntis 141 2 ileasttnng the degree of functional imfmirment and fol- lowing the course of the disease The mam factors affecting tlie behavior of the clearance values in pyelonephritis are the inflam- matory changes per se (cellular infiltration, edema) and the rela- tive amount of mert tissue (destroyed or damaged functional umts ) \Vlnle the inflammation may actually subside, destroy ed nephrons cannot regenerate From repealed clearance measure roents, we may tlierefore gam valuable information regardmg the nature and extension of the pyelonephntic changes We shall discuss briefly four typical situations occurring in this disease a) Acute Pijelonephnlis In this form, changes are almost entirely reversible, so that even m severe cases, acute renal failure may be followed by a prompt mcrease and even normahzalion of the clearance values Here is an example Patient LA, 22 year old — Acute pyelonephritis during the sixth month o£ pregnancy No adequate treatment progressive detenorabon On admission, 3 weeks bter the pabent was se verely ill, her NPN was 170 mg?, her plasma potassium 64 mEq/i Hemodialysis and anbbiohc treatment Rapid improve ment, as shown by the clearance values recorded 1 and 5 months later The last values were shll somewhat reduced, indi cabug the persistence of (piesumahiy inactive) renal Jesjons (Table 23) b) Acute Exacerbation m Chrome Pyelonephritis In tins form, clearance values are persistently reduced be- cause of the presence of inert tissue Every acute exacerbation table 23 \P\ AI.D CLEULV.VCE VAttES U* A pATlEXT WITH ACCTE PrELOVEPHRms (L.A ) Clearanee* Date of Ezamtrwilttm Ct (C,J ml/mtn CriB vtlfmtn F F APV Pressure mmHg 1/22/1958 l/31/19oS 2/11/195S 2/17/1958 6/12/195S 71 81 810 3S3 0 209 0 219 167 85 24 26 25 145/60 140/50 130/85 130/90 140/95 142 Clearance Tests in CImical Medicine will be followed by a further drop in llie clearance \’alues, wlucli in certain cases leads to death from renal failure. In more favor* able instances, the acute changes are partly reversible and after their initial fall, the clearance values will rise again, sometimes almost to their previous level. Here arc two e.xamples illustrating these hvo possibilities: Patient P.G., 52 ijcar old. — ^This patient suffered from es- sential h>'pertension for many years. In 293S antih>pertcnsive treatment was started and the blood prcssiue sliow^ a good response to Chlorothiazide. Signs of renal infection were noted, however, and renal functions declined progressively (Tabic 24). The patient died of renal failure in 1959. Post mortem e.'Cimination revealed vascular nephrosclerosis and superim- posed pyelonephritis with papillary necrosis. Patient A.S., 35 year old. — First attack of pyelonephritis in 1933, and probably chronic pyelonephritis since. In November 1935 acute exacerbation with fever, severe lumbar pain, dys- uria, oliguria and leucocyiuria. NPN 201 mg7. After hemo- dialj’sis and antibiotic treatment, progressive improvement. In 1960, the only complaint \vas lassitude and occasionally a dull lumbar pain. The clearance values seemed to be stabilized at about 502 of the normal range (Table 25). c) Chronic, Stabilized Pijeloneplmtis Many cases of chronic pyelonephritis may remain for years stabilized at a reduced level of renal functions, especially if they are treated with antibiotics on a long term basis. It is, of course, an important fact in evaluating the prognosis, if it can be shown that the clearance values do not vary’ significantly during the follow-up period. We should like to report briefly an example: Patient I.H., 46 year ohL — First pjelonepliritic episode re- corded in 1952. In 1954 the urine contained numerous leuco- cytes and traces of proteins. Tlie BSR was markedly cle\ alcd, the clearances w'erc reduced to ^4 of the normal values. Tlie patient has since been treated repeatedly with antibiotics and her general condition has much improved. Today (1962) the urine contains only a few leucocytes and the blood scdimenla- Pyclonephntis 143 tion rite IS nomnl During the last eight jcars cleirance \alucs have remiined at the sime !c\el Tliere is, ho\%e%er, some m crease in blood pressure (Table 26) TVniF 24 NFS AM) ClEAnANCE \aLLLS> IN A PATIEVT WITH LmLNTIAL llTrt.KTtN'eloneplintis) and in rare in- stances, acute glomenilonephnlis More often, it results from acute tubular necrosis caused by circulatory disturbances or toxic influences The term shock-kidney' mcludes all instances of acute renal failure due to hemorrhagic or traumatic shock, se- vere bums, crush syrndrome, septic abortion, peritonitis mis- matched blood transfusion, idiopatliic myoglobinuria anaphy- lactic reaction, surgery of the biliary or unnary tract, etc In “acute totic ncphropathij' the tubules are damaged by exogenous poisoning ethylene glycol, sublimate, sulfonamides, carbon tet- rachloride, oxalic acid, phenylbutazone, etc In both groups, the clinical picture is very much tlie same and consists essentially of an acute anuna, lasting from a few days to several weeks (261,262) Tile patient may die during the anunc phase from uremia or extrarenal compbcalions In less severe cases, or if renal failure has been treated successfully by hemodialysis, amma is followed by a stage of marked polyuria, during which the blood urea begins to decrease slowly In a later stage, the urine volumes fall to normal values and renal functions improve pro- gressively. Complete clinical recovery is common, although some degree of functional impairment may persist for years The histological picture depends on the etiology’ In toxic nephropathies there are widespread areas of severe tubular ne- crosis, with marked interstitial edema and infiltration In renal failure resulting from shock, the changes are less conspicuous Oliver (223) has described two types of lesions the “tubulo- rhexis,” consisting of circumscnpt ruptures of the tubules with a random distribution m any part of the nephron, and the “lubulo- necrosis,” aHeclmg all nephrons equally but confined to the prox- imal segment Other investigators have also observed tubular 147 1*^8 Clearance Tests in Clinical Medicine dilatation {29, K). There are small foci of interstitial infiltra- tion, and pigmented cast may be seen in tlie tubules (53,90). But on the whole, these changes are of moderate degree and contrast sharply with the severity of the clinical picture. In renal failure due to poisoning, several factors are believed to account for the development of anuria: (a) The tubular le- sions may result in a back-diffusion of glomerular filtrate, as shown by Richards in the frog (272). (b) A rise in intralubular pressure due to obstruction of the tubules by epitlielial casts or compression by interstitial edema may cause cessation of glo- merular filtration, (c) Circulatory disturbances may reduce the renal blood flow* and the glomerular filtration rate (71). These changes probably result from arteriolar spasms and/or compres- sion of the capillaries by the interstitial edema. In renal failure due to shock, the factors leading to anuria are less clearly understood. It has been assumed tliat a severe renal ischemia could entirely account for the functional break- down (59, 295). Recent investigations indicate, however, that the renal blood flow, measured in anuric patients either by the gas diffusion techniques or the dye dilution metliod, is not as markedly decreased as was formerly believed. Actually, some of the flows recorded so far in a few patients were equal to or greater than one-third of the normal valuesf (51,196,214,267). If the primary disturbance leading to anuria is purely hemody- namic in nature, one has to assume that filtration ceases because of a lowering of the hydrostatic pressure to the level of the on- cotic pressure of the plasma, that is about 25 mm Hg. This figure represents approximately one-third of the normal hydrostatic pressure and would correlate well with the observ’ed decrease in blood flow. A parallel decrease in pressure and flow of such a magnitude could he achieved by afferent vasoconstriction. In addition to circulatory disturbances, or alternatively, other fac- tors, like those involved in renal poisoning, might play a role. • Using the dye dilution technique, we have recently obtained In one anuric subject with mercury poisoning a whole blood flow of 106 ml/min for one kidney, while in a second patient the recorded values were almost normal, averaging 539 ml/min (264, 267). f With the dye diluUon technique we have recorded in tliree anuric with shock kidney blood flows of 345, 316 and 215 ml/min for one kidney (26-1. 267). Acute Renal Fathrc 149 F g 20 Concentration index U/P for PAH (A) and for urea (B) and creatinme/urea clearance ratio (C) in a case with shock kidney The lowest values are observed on the eleventh day after onset Clearances m Acute Renal Fatlure A Theoretical Considerations In complete anuna clearances are of course not measur able If small amounts of unne are still bemg formed for in stance 20 to 50 ml daily clearance measurements are possible but of limited value Under such circumstances it is of interest to compare the urinary concentrations of vanous substances with their plasma concentration and to calculate tlie concentration mdex U/P This may give some information of the degree of tubular damage (50 59 141 248 249) While it is obvious that the PAH clearance does not correspond to the renal plasma flow and uncertain whether the inuhn clearance still expresses the amount of filtrate actually fonned llie clearances remain a good measure of the rate of excretion of all substances considered and therefore of the overall renal activity 150 Clearance Tests in Clinical Medicine If various clearances are delemiined at tins stage, tlic v-alues obtained are extremely small, for instance 1 ml/min or less (14, 50, 59, 78, 141, 189, 243, 292). But in tlie early days of a shock kidney the U/P ratios may remain nearly norma! (248). For in- stance we found on the third day in a case of acute renal failure after abortion the following ratios; U/Pp.,,,,: 21; U/P„,„; 5; crcati- nine/urea clearance ratio: 3; PAH/urea clearance ratio: 4.2 (the urine volume was 38 ml/24 hours, the urea clearance 0.25 ml/ min). On the eleventh day there was a marked tendenc>' for the clearances to become equal to each other and for the ratios to drop to unity; JJ/Frxa- 3; U/P„,„: 2; creatinine/urea clearance ratio: 1; PAH/urea clearance ratio; 1,5. At that time the urine volume \vas 2050 ml per 24 hours, the urea clearance was 2.9 ml/min. From this point tliere was a slow but progressive im- provement of tlie above mentioned ratios, wbich ultimately reached normal values (Fig. 20). These data seem to indicate that in the early stage of the shock-kidney, tubular function is still preserved. After a few days, how'ever, secretory and reabsorptive functions are prac- tically lost, except for the rcabsorption of glucose and possibly the secretion of potassium. In tubular necrosis due to poisoning, loss of function takes place earlier (141). In this stage, plasma and urine have about the same osmolality and the urine is in many respects like a plasma filtrate. It is of special interest that the Tmr^n niay be found to be zero or even negative (243, 292) and the PAH extraction ratio is so small (59,214,292), that it can no longer be measured with accurac>\ Tims, even if diuresis is satisfactory, no blood floxv estimation can he made on the basis of CrAi! £>nd Ep^n x'ahies: Assuming, for instance, a real plasma flow of 200 ml/min (this assumption is based on results obtained by other methods), an observed PAH clearance of 4 ml/min would correspond to an extraction ratio of less than 0.02, if allowance is made for a urine volume of 1.5 ml/min. From our experience, we are inclined to believe that reliable blood flow measurements can be performed only if the PAH ex- traction ratio is greater than 0.10, This does occur as recover)’ progresses, so that at the end of tljc polyuric phase clearance methods can be used for Uiis purpose, provided the calculations are made from equation: Acute Renal Failure 151 RPF (renal phsma flow ) — ^ ^ ApAii — Rr\n During com alescence, Ep^u nses rapidl> For example, we found m one case an extraction ratio of 0 75 on the nmeteentli day, in anotlier case a ratio of 066 on the thirty fifth day (249) In a case of carbon tetraclilonde poisoning Sirota (292) found on the Uiirty sexenth day a ratio of 0594 Therefore it is very liXelj that in most cases the PAH extraction ratio has returned to normal xxathin tw o months after the onset of anuna, and tliat the PAH clearance alone can be taken as a reliable measure of tlie effective renal plasma flow for evaluating the rate and de gree of recover) B CUrucal Use Acute renal failure can be observed in prevaously healthy sub jects as well as in patients suffering from chronic renal disease After recovery from tlie acute episode, renal functions may im prove great!) and even become normal m the first group of pa Fig 21 Rale of recox ery in ten cases wth acute renal failure, as shoxvn b> the behaMor of the glomerular fiffraUon rate dunng the first few months after the onset of anuna 152 Clearance Tests In Clinlcol Medicine TABLE 27 TuKcnoKAL REcorenv ix Ttx Case^ with “Pcrk” Accte rcxal FAiLtJiE Time Afltr FiUrntion PA II Pn( Onset Bate oj Anurut tnl/min tnl/min Fraetum 1. E. S., 39 year old. Shock'kidiiey post 3 days 20 days 0.4 10.0 1.2 47. .5 0.35 patlum. 40 davs 27.8 IM 90 days 7! 282 10 months 75 5 349 0.217 2. H. B., 24 year old. Shock-kidney after 4 yeara SI 495 ^0 daya 4.*i 37. S 247 operation. 03 day's 49 300 O.lOt SO days 93 S5.5 O.KW 3. H. U., 27 year old. Shock-kidney after 115 520 13 day-s 3 8 5 22 days 33 204 0.162 operation. 35 dava 85 414 0 20.5 4. F. I., 43 year old. Bhoek^kianc)' atter 105 days 123 D31 0.193 <1.0 55 days 61 309 0.108 myelography. 9 months 85 412 0.206 2 years 93 0.210 3 years M 425 0.208 6. L. G.. 2S vear old. 5 years 92 442 0.209 0.5 Shoek-kidney post 12 days 21.7 93 0.22S partum. 48 223 0 215 72 days 81 303 0.232 0 months 70 335 0.27 C. II. A., £0 >ear old. 4 years 103 458 S days <1 0 Sbock-kidney after angiocholitia. 190 days 119 629 0.190 7. A. H., 47 year old. Sbock-kidney after 7 days <1.0 30 days 99 4 SO 0.200 pentomtu. S. E. I.. 51 year old. Shock-kidney after 2 0 lOi days 78 308 0 251 operation. 9. A. K., 60 year old. 3 days <1.0 _ _ Carbon tetracWo- tide tKiisoninit lQ2daya 134 <1.0 10. M. A., 42 year old. 4 days Shock-kidney after myeloRTaphy. 4G days 95 tients (50), whereas lliej' remain more or less reduced in ihe second group. Therefore, clearance determinations are of great value at this stage in differentiating “pure” acute renal failure from renal failure superimposed on chronic renal disease. In Tables 27 and 28 we present clearance values recorded in sixteen patients up to five years after the onset of anuria. In the first group (Table 27) complete ftmcOonal recover}' had oc- Acute Renal Failure 153 curred m six patients uitliin six montlis or so In two otlier pa tienls the values were not quite noimahzed after three months, but no subsequent determination could be performed in one and in the second subject low normal values were obtained after four years In tw o patients the clearances were still somewhat reduced after four and five years These data suggest that m pure acute renal failure complete recovery occurs m a majonty of eases The improvement is rapid during llie first three months, but subse quenti) slows dowm (Fig 21) Among the patients of the second group (Table 28) two imderwent nephrectomy at the time anuna developed and a third two years before Therefore values recorded after recovery were lower than normal They indicate however that m the remaimng ladney, renal functions were practically noimahzed The behavior of the clearances is different in cases wnth pre existing renal disease (Table 28, cases 4 6) After initial improve meat the values remam stabilized at a reduced level or may even TABLE 2S FocnosAt Recoitkt rnou Acrre Ren vl Fajlcee e. Three NEPUtiEcrouTZED Patievts aad Thbee Patients wttb Chrovic PrELOVEPimms 154 Clearance Terfi in Clinicol Medicine show a tendency to further deterioration. It lias been stressed by several investigators that after acute renal failure, functional recovery is not complete (118, 185,331). It is possible that cases willi pree.xisting renal disease have been included in these au- thors’ series. This might explain why their results are less favor- able than ours and those reported b>' Bnm (50). SECTION X TUBULAR SYNDROMES Specific tubular defects may occur m pitients \Mth normal mulin and PAH clearances and whose kidne>s are histologicall) intact Disturbances in tubular function can also be obsened in organic renal diseases, especially in chronic p>eIoneplmtis In these cases, the glomenilTr filtration rate and the renal plasma flow are frequently impaired, so that figures expressing the changes in tubular reabsorption and/or secretion are of little interest unless the> are related to the glomerular filtration rale Let us consider, for instance, the case of an impairment of (he concentrating ability This defect ma> be produced b> several mechanisms (a) Replacement of a certain number of active nephrons bj inert tissue Under such circumstances ( for instance m clironic glomerulonephntis ), the concentrating abililv appears to be limited only b) tlic filtered solute load (43) (b) In ni>e* loma and m many cases of pyeloneplintis the decrease m glo- merular filtration rate alone cannot account for the reduction m the concentrating abiht> This is probabl> due in part to spe- cific tubular damage (“water losing nephritis”) (c) In a third group of patients, the kidnc>s are luslologicTll> intact, inulm and PAH clearances are normal, but the tubules do not respond to antidiurelic hormone ( nephrogenic diabetes insipidus”) (d) rinally, in central diabetes inspidus the kidne>s are m every respect normal, hut the defect in ADH production results in marked polyTina For those reasons, a diagnosis of ‘tubular insu/Sciencj ” can- not be made without tlio determination of tlic glomcnilar filtra- tion rate, which constitutes the basis for the calculation of tlic reabsorbed amounts of water and solutes Depending on the na- ture of the tubular disorder, special examinations have to be performed simultaneousl> (Tim-, osmolar clearance, phosphate clearance, etc ) In the following pages onl> a few tubular svm- dromes will l>c discussed in some detail 157 158 Clearance Tests in Clinical Medicine I. RENAL GLYCOSURIA Renal glycosuria results from an Imbalance between glomeru- lar filtration and tubular reabsorption of glucose. Two forms have to be distinguished. (a) A congenital form without anatomical changes in the kidnej', characterized by a normal filtration rate and an im- paired reabsorplion of glucose. This form is called “renal diabetes,” and includes a type with normal Tmc and a type with reduced Tmc. (b) An acquired form with organic changes in the kidney (tubular necrosis, pyelonephritis, etc.), characterized by a reduced filtration rate and a greater reduction of the glucose reabsorption. Clearance determinations are very useful in differentiating the various forms of renal glycosuria. Clearances in Renal Glycosuria A. Theoretical Considerations 1. Renal Diabetes During the last twenty years, various studies have indicated that glomerular filtration rate Is normal in these cases. But until recently, there was some disagreement as to the ma.ximal glu- cose reabsorption, as several authors had observed normal Tma (125,146), while others had found exclusively low TmQ(120, 142, 216, 312). Subsequent studies, however, have clearly shown tliat both types exist (35,74,210,250,255). Our ovTi studies were started in 1949 (250). All patients were e.xamined by means of the titration procedure devised by H. W. Smith (298), i.e., glucose reabsorplion was determined for levels of blood glucose varying over a wide range. Since our first publication our material has increased to a total of eighteen cases. Data of these ei^ileen cases are presented in Tabic 29. They include glomendar filtration rate, PAH clearance, filtration fraction, glucose Tmc and Tme/Cr ratio. It can be seen that the Tubular Syndromes 159 T\BU 20 Clearancis i\ Ligutle> C\se^ 'RiTii Renal Diasetfs Ao j Sex Patient Ct ntl/mtn CpAH ml/n tn F } Tiks mg/mtn Pme Ft* 1 M XI L 111 443 0 2? 201 1 74 X M H F 152 031 0 24 220 M P *5 131 210 1 50 M 1 F L 1 126 710 0 17S 144 1 22 M R *' 1 116 6^ 0 19 G M 1 P K 1 90 4S4 0 >o-> 151 1 55 M \X K ; 10> 53.3 0 19" 1^6 1 51 S XI A s; 91 53 2;3 1 16 M H II I2f 580 0 217 ’00 2 iS 17 XI 0 F no < 0 0 m SCO 2 14 1 16 M H 0 lie 515 0 2o2 212 2 00 •In this ratio Ct nia tikcn as the \jlue ohiaincnl during miNimil loading with gluemc Tmr/CT ratio, normally equal to 241 * 035 (142), is (lefinilclj below normal in cases 1 12 and normal m cases 13 18 Analysis of the incliNidual titration curves shows tint in the first group srmll changes in T^/Ct occur during progressive loading with glucose (Figs 22 and 23) On the contrary, in the second group, the ratio Tq/Ct vvhicli is low at normal and inodentely elevated blood glucose levels increases progressively under loading to reach ultimately normal Tme/Cr values (Figs 22 and 24) We have found it convenient local! iJic l>'pe with reduced Tnv ‘‘l>pe A” and tile 1)^10 vvntli nontial Tmc type B (250 255) In the twelve cases belonging to t>’pe A, glomerular fillra* tion is normal, except in one (A S ), where it is slighllj reduced The PAU clearance vs normal m all but one (M L ) Hie fihra tion fraction is normal m most of them, being slightlj elevated m only three cases In two cases, PAH extraction ratio and TmpAii were found to be xvithin normal limits Tins means that discrete renal functions other than glucose rcabsorption arc prac- tically unaltered in this group As the glucose rcabsorption is im 160 Clearance Tests in Clinical Medicine Fig. 22. Glucose titration cur\'es in normal subjecti and patients with the two types of renal diabetes. The schematic drawings represent the corre- sponding tubular acthity: 1: normal total activity, ph>'Siological dispersion: Hi reduced total activity, physiological dispersion; 111: normal total ac- tivity, greatly increased dispersion (two types of nephrons). Fig 23. Tc/Cr ratio in relation to tlie glucose filtered load CrPo in 10 patients with 1)^6 A renal diabetes. Tubular Syndromes 161 paired at any level of blood sugar, this t>'pe of gUcosuna seems to be due to a relati\e unpotencj of all proximal tubules The defect IS limited to glucose, since excretion of ammo acids and phosphate remains normal In all cases examined so far b> needle hiops> the structure of the proximal tubules has been found to be entirely normal (except m two cases reported b> Monasterjo (208) ) Therefore, the disturbance must be functional in nature As the normal mechanism wnderljing glucose reabsorption is still unknown, nothing can be said about the nature of the biochem- ical defect In the second group (Type B), the data are less homogene ous, as this senes includes two cases wath nephroangiosclerosis and reduced PAH clearance, the glomerular filtration rate being also reduced m one In all patients, Tmc/Cr is normal, despite a constant gl>cosuna at low blood glucose levels This means that glucose i^absorption increases «alh llie loading of the tu bulcs At least (wo mechanisms could possibl) account for this remarkable finding The first was suggested b> Shannon (288) to explain the increase in To observed m normal dogs when Tg/Ct Us 21 To/Cy in relation to CtPa m six patients nitli l>pe B rtnal ’mptoms of hypoglycemia. Glomerular filtration rate is nor- mal (130 ml/min). At a blood sugar concentration of 67 mg7, there is a glycosuria of 70 mg/min. Tlierefore, the rate of glu- cose reabsorption is e.Ttremely low and equals: Tq = (130 • 0.67) — 70 = 17 mg/min. Tlie tlieoretical threshold would be ^ = 13 mg? blood sugar. Under loading there is only a slight increase in Tq. At a blood glucose concentration of 600 mg?, only 26 mg/min are re- absorbed (Tmg). This case undoubtedly belongs to t>pc A renal diabetes. Patient K.B., 42 year oW.— No familial history of glycosuria. The patient feels perfectly healthy, despite an intermittent gly- cosuria. Glomerular filtration rale is normal (109 ml/min). At a blood sugar concentration of 120 mg?, the glycosuria 1$ only 2 mg/min. Therefore, the theoretical tJjreshold equals 118 mg? blood glucose. Under glucose loading there is a marked increase in T^. At a blood sugar concentration of 718 mg?, 304 mg/mln are reabsorbed (Tmg). Both the Tm^ and the Tmo/C^ ratio are normal. This case is an example of type B renal diabetes. n. FANCONI SYNDROME, HYPERAhUNOACIDURU, HYPERPHOSPHATURIA These sjmdromes presumably result from tubular disturb- ances localized to the proximal segment. In most cases, a con- genital defect, with or without organic lesions, is responsible for the tubular inability to reabsorb glucose, amino acids and/or phosphate at a normal rale. In the remaining instances the symptoms can be related to an acquired renal disease. Tlie behavior of tlie glomerular filtration rate and the PAU clearance depends on whether there are organic lesions or not. Surprisingly, the PAH secretion does not soem to be specifically impaired in these s>'ndromes, so that the level of the PAH clear- ance remains rou^ily parallel to the number of functioning Tubular Syndromes 165 nephrons* Both clearances ma> be normal in cystinnna (100), familial glycogljciniina (165), and m earl} cases of idiopathic Fanconi syndrome More frequently the> are both reduced, for mstance m Wilson’s disease (9) and most advanced cases of Fanconi s}7idrome (329) In cases with glycostma, the Tmr and the Tm^/CiB ratio may be either normal or depressed Therefore, it would appear that, as in renal diabetes, two different mechanisms are responsible for the gljcosuna In the Fanconi syndrome Tmr./Ci„ is usually low (217,177,294,329), indicating generalized involvement of the tubules (tj-pe A) In one case we found tlie following clear- ance values Ct 65 ml/min, Tm^ 90 mg/min, Tm^/Cr 111, CpAR 233 ml/min In another case these values were 88 ml/min, 20 mg/min, 0 19 and 492 ml/mm, respective!} In Wilsons dis ease and in famihal glycoglyciniina, normal Tme/Cr ratios have been recorded (9,163), suggesting type B glycosuria (increased dispersion in glomerular-tubular activit} ) In cases with generahzcd eininonctdunn the clearances of most individual ammo acids arc increased (177) Owing to con siderable technical difficulties, however, individual clearances are seldom determined m such conditions Most investigators simply prefer to measure the daily excretion of n-ammo nitrogen Ammo acid clearances are of interest only in cystinuria and related dis- orders Dent et al (97) foimd, for mstance, m cases with cys tinuna, cystine and mulin clearances which were identical In tlie same condition, Dowlan ct al (100) observed that the lysine clearance w as also markedl} increased, av eragmg 50 per cent of the glomerular filtration rate and approaclung the inuhn clear- ance under loading with amino acids In a case with cystmuria pubhshed by Fnmpter ct al (126) the cystine clearance was greater ^fra^ the rmrfnt cfestrrflce, saggestirtg teiwiar of c>stine In familial glycmuna, a 70 per cent tubular rejection of glycine has been reported (328) In cases with bone lesions (osteomalacia, vitamin D resistant rickets), the phosphate clearance is often increased, but as we • W'e are auare of only one pubhshed case of raoconi syntlrome, in ^vhlch ihe PAH cTCretion was stnJangly inqiaired (294) In this case the following clear ance values were recorded Cj. 37 iQl/nun Cmr 44 ml/min Tbifah 5 9 mg/nun, fmo 26 mg/min 166 Clearance Tests in Clinical Medicine have already pointed out, considerable difficulties in interpreta- tion may arise. They are due to tlie fact that even in normal individuals, tlie urinar>' e.xcretion of pliosphate is subject to large diurnal variations. Therefore, the diagnosis of h)'perphos- phaturia can only be made if Uie phosphate clearance is found on repeated occasions to be definitely above tlie normal range. In one case with the Fanconi s)'ndrome we ha\’e recorded a fasting phosphate clearance of 32 ml/min (normal range 4-20 ml/min), corresponding to a tubular reabsotption of 50 per cent (normal range 78-972). In a similar case, Lambert ct al (177) found on loading with phosphate a tubular rejection which xvas distinctly above the normal range at any blood level of phosphate. In five subjects with osteomalacia, tliree of whom had multiple tubular defects, Kyle et al. (175) found Cpo, rang- ing from 26-38 ml/min. In familial hj^pophosphalemia, low TmK>< values have been reported (238, 342). m. inTERPARATHYROIDISM AND HYPOPARA- THYROIDISM Since parathjToid hormone is known to decrease the tubular reabsorptlon of phosphate, the behavior of the phosphate clear- ance should enable us to recognize easily most states of para- thyroid dysfunction. This is not quite so, liowcx-er, because fac- tors other than p3rath>Toid d\-sfunction may influence the results of the phosphate clearance: phospliate concentration in the blood, phosphorus intake, level of the glomerular filtration rate, etc. Satisfactory results have been reported by Kyle ct al (175). These autliors found consistently low phosphate clearance x-alues in h>’poparath>Toidism (between 1.7 and 7.3 ml/min). In hjper- parath>Toidism the phosphate clearance xras high, unless the glomerular filtration rate was markedly reduced. A decrease in Cpo 4 following operative remoral of a parth>Toid adenoma has been obser\’ed by several investigators (175, 184, 293). In one case \vith nephrocalcinosis and markedly reduced glomerular filtration rate, we found no significant change in Croi following parathyroid surgeiy, despite a striking drop in blood calcium. Measuring the mxxima! reabsorplive capacity for phosphate Tubular Syndromes 167 (Tmpo^), niompson and Hiatt (321) found Ion \alues m a sub- ject \vitli hyperparathjToidism, while the TmrOi \alues in lij-po- parathyroid patients fell within the broad range of nonnal All investigators who have measured tlie tubular reabsorption of phosphate in parathyroid hyperfunction agree tliat clear cut deviations from tlie normal range are observed only in cases whose glomerular filtration rate is not depressed below 50 per cent of die nonnal (66, 134) It lias been suggested that in sub jects with a low glomerular filtration rate the response to para- thyroid extract might he of diagnostic value In patients with renal impairment but without h>’perparathyroidism parathjTOid extract reduces the tubular reabsorplion of phosphate, while hyperparathyroid subjects do not respond (134) As the tubular reabsorption of phosphate vanes with the blood phosphate concentration, it has been suggested that one should consider the two variables together Nordin and Fraser (218) have proposed the calculation of a 'phospliatc excretion mdex” (PEI) as follows PEI = _ 0 035 Proj + 0 07 t-'Cr This index has been found to be 0 009 m normal subjects, increased in hyperparalb>'TOjdism and osteomalacia and de- creased in hypoparathyroidism In tlus formula the ratio is calculated without measunng the urine \ olumo from equation UP04V CpO^ Pp04 UpQi Fcf ■qT ~UrrV~ “ Ucr Pr04 Pc But as Cc, IS not determined, nothing is known about the functional state of tlie kidne> Since cases with renal impair- ment ma> behave like liyperparalloToid patients, calculation of the PEI under sucJi circumstances is rather misleading TV. KENAL function IN HYPOKALEMIA In most instances, h>’pokalemia results eitlier from enteral losses or from renal wastage of potassium In the first group of 168 Clearance Tests in Clinical Medicine cases potassium depletion is a consequence of chronic diarrhea, vomiting, abuse of laxatives or ureterocolostomy. In the second group, it may be due to a defective tubular meclianism for hand- ling potassium (potassium-losing nephritis) or to functional tu- bular disturbances secondary to diseases of the endocrine glands (for instance hyperaldosteronism) or to the use of diuretics. But as potassium depletion per se leads to functional and anatomical changes in the kidney (224, 245), renal disturbances are encoun- tered in every case of severe low potassium syndrome. Early recognition of the causative factors involved in potas- sium depletion is extremely important. Wlrile in many cases a correct diagnosis can be made from the clinical data alone, there are still a few patients in whom differentiation is difficult unless the urinary excretion of potassiiun is measured. In such cases it seems to be most convenient to determine the potassium clear- ance, the glomerular filtration rate and the PAH clearance. In evaluating the usefulness of t])e potassium clearance, it must be remembered that it depends on several factors. Tlie degree of depletion, the daily intake and the blood concentra- tion of potassium, the degree of renal impairment and the rate of urine How may all inSuence the potassium clearance. But on the whole, hypokalemia resulting from extrarenal losses is char- acterized by a low potassium clearance, whereas in cases with primary renal wastage the potassium clearance remains normal or high despite a very low blood potassium concentration. Of course, if hypokalemia results from previous hyperkaluria related to the use of diuretics, the picture, after withdrawal of the drug, may resemble low potassium syndrome of enteral origin. In normal individuals on normal intake who have fasted overnight before performing the lest, the potassium clearance ranges from 8 to 24 ml/min. In Table 30, clearance data are presented, which were obtained in a forty-three year aid ^vomart who had suffered from diarrhea for several months. On admis- sion, the plasma potassium was very low (1.7 mEq/1), but after potassium administration, it could be normalized within a week. The potassium clearance remained extremely low during the first seven days, despite the high potassium intake and the progressive rise in the blood concentration. Tliis strongly suggests that the Tubular Syndromes 169 level of potassium clearance is regulated, m part, by the body pool of this cation Only after replacement of the potassium deficits could the clearance nse to low normal values It can also be seen from Table 30 that on the day of admis Sion, the NPN rose to 99 mg2 so that the glomerular filtration rate was presumably less than 20 ml/min On the sixth day the NPN had dropped to normal values but on the fifteenth day the inulm and PAH clearances were still reduced These data con- firm that a transient impairment in renal hemodynamics and tu- bular function can be elicited by potassium depletion Compre- hensive data obtained in a similar case have been published by Reiman and Schwartz (245) They are reproduced m Table 31 In this case Cm, CpAu, Tmp^n ^nd maximum specific gravity of unne were determined on three occasions and Ep^n "as meas ured three weehs after potassium therapy had been started Be- fore treatment there was moderate unpairment of Cm, Cpah and TmpAn. while the concentratmg ability was almost entirely lost During potassium therapy a slow but progressive nse m all values was recorded Ep^n ^vas still somewhat reduced when it was determined \Vhjle in the conditions of acute potassium depletion, the secondary renal changes appear to be reversible, a permanent TADJ F 30 P 0 TV 8 MVM ClEAKVSCF IV Ill-L-iTIOV TO Serim Coscentratios AVD D^IET Intake xn a Patipnt with Lo" roTAxwicM SrvDSows Die to hsrytuL Lo‘«SFS (PvTirNT M K 43 ^ e-ab Old) 170 Clearance Tests in Clinical Medicine TABLE 31 CLEAILiSCX D\Ti I.V A PaTIENT WfOl POT»SSItiI DErLETTOV OF E-TnURESAL Oiucrs- (Froai Reuiak and Schr-arti [215]) Date Polaiexutn mEq/l Inutin Cltarante ml/min PAfl Ctfaraner ml/miit EpAR o/T-nV 1/10/52 1.0-2. 3 43 31.5 — 4» 2/ 5/52 4 5 72 370 0 71 55 1 015 3/21/52 4.4 103 — 71 1.023 impairment due to organic tubular lesions is obsen'cd in many cases of chronic or recurrent In-pokalemia. In potassium losing nephritis, the inulin and PAH clearances are also reduced, but they show little or no tendency’ to improve on potassium replacement. More important for the diagnosis is the beha\ior of the potassium clearance, which is always mvich higher than in conditions of hypolcalemia due to cxlrarena! losses. In a case 5vith chronic pyelonephritis and renal wastage of po- tassium, Mahler and Stanbury’ (187) obser\ed a normal potas- sium clearance (ranging from 10 to 20 ml/min) despite low serum potassium values (between 2 and 3 mEq/1), In a case with low potassium S)’ndrome, due to chronic nephritis, Earle et al (lOS) found a normal or increased potassium clearance (Table 32). In this case C,. was 43 ml/min, Cp.ui 293 ml/mh) and TmpAn 21 mg/min. It can be seen from Table 32 that on a low potassium intake, serum potassium was extremely low while the potassium clearance was within the normal range. On a verj’ TABLE 32 PoTA^ICU ClEAE-INCE |V UeLATIOVToFeRCM PoTAV«IlH AND PoTA^«IL-U InTAKB IS “POTASMtM LoAINCT XmiBITta" (FbOU KaRLE ft ol. |H)S!) SeruPi P<>laMium PS 0 Tubular Syndromes 171 higli mtike, the serum potassium rose but remauied below the normal range, \\liile the potassium clearance was greatly m creased If die %alues listed m Table 32 are compared wth the data recorded m Table 30, a clear cut difference can be noted between tlie tw o conditions Obviously, the beha\ lor of the po lassmm clearance is of clinical \alue in differentiating the two chief mechanisms of potassium depletion V DIABETES INSIPIDUS Diabetes insipidus is a condition characterized by the e'^cre tion of large volumes of hypotonic or at best isotonic urine When it IS not due to potomany (compulsive water drinking), it results either from lack of antidiuretic hormone (central diabetes in sipidus) or to impaired abih^ of the renal tubules to respond to antidiuretic hoimone (nephrogenic diabetes insipidus) Tlie nephrogenic ty'pe may be due to a congenital tubular defect or to secondary changes related to tubular necrosis pyelonephritis, nephrocalcinosis, amyloidosis, polyarteritis nodosa or hypokale mic nephropathy Nephrogenic diabetes insipidus is always pitressin resistant In central diabetes msipidus and in the hmihal nephrogenic type, the glomerular filtration rate and the PAH clearance are usually normal (336 341) Especiall) in clnldren who develop severe dehydration both clearances may he transiently reduced (functional nephropathy) but avjII be restored to nonrnl values following administration of large amounts of \vater On the other hind if pitressin resistant polyuna is due to renal organic changes, both clearances are permanently reduced Therefore, the determination of the glomeruhr filtration rate and of the PAH clearance is helpful ui differentiating these conditions In most cases, the urine flow is larger than the osmolar clear- ance, so that tlie calculated free water clearance can be taken as an indev of the tubular dysfunction (Cii*o = V— Co.„) In central diabetes msipidus, the situaUon can be re^ ersed by pi tressm The urine tlien becomes hypertonic, ow mg to the reab soiption of solute free water, the amount of which can be calcu- lated from the equabon Clearance Tests in Clinical Medicine In nephrogenic dialxites insipidus, tlie patient docs not respond to pitressin. It has been shown recently, howe\er, that in die familial type the free»water clearance can he substantially reduced by the administration of thiazide diuretics (83,87, 183. 336). A similar response can also be obsei^ed in central diabetes insipidus (83, 152). The mechanism of this antidiurctlc effect is not clearly under- stood. As a reduction of the glomenilar filtration rate per sc has been shown to increase urine osmolality in polyuric states (21), the effect of chlorolliiazide in diabetes insipidus might be due to a similar mechanism (87, 152). But if it is true that thiazide diuretics produce in most patients a sliglit fall in the inulin clear- ance, the magnitude of indindual responses is unpredictable. Moreover, an anlidiuretic effect has been notctl by some inves- tigators in die absence of a significant fall in the glomemlar filtradon (183). RENAL FUNCnO.V IN GOUT In most patients with gout, a slow but progressive impair- ment of the renal functions occurs during tlic course of the dis- ease. The observed fall in glomentbr filtration rale and PAIl clearance is attributable to die development of organic lesions. These lesions consist of N-ascuIar nephrosclerosis, urate deposits and interstitial infiltration (319). It is of great interest to loiow whether or not the hjpcniri- cemia of gouty patients without marlccd impairment of die glo- merular filtration rate is due to an abnormality in the renal excretion of uric acid. Extensive investigalions have been carried out by numerous authors (143,316). Most agree that there is no essential difference in die clearance of uric acid between nonnal and gouty subjects and attribute the h>'pcruricemia solely to aii overproduction of this mctalx>h’lc. In these studies, however, it has not been considered lltal normal subj'ecls and patients witli gout have different plasma concentrations, so that a similarity in the clearance values docs not prove that there is no almor- malily in the handling of uric acid by the kidney. More recently, Nugent and Tyler (219) have performed sug- gestive experiments. Non-gouty subjects have been given uric Tubular Syndromes acid or its precursors in amounts great enough to elevate tlieir plasma unc acid concentnbons to values comparable to those of patients \vith gout Under these conditions, tlie non gouty sub jects had a unc acid clearance well above the levels observed in gout) patients (Table 33) These authors conclude that abnor mal excretion of unc acid is an unportant cause of hj'peruncemia in gout In our opinion, their evidence is not entirely convincing as the) have compared a state of acute loading with basal con ditions TABLE 33 Lric Acid Clearance in Goity and Non ooctt Slbjects (From Ncgevt and Ttler 1219)) Plasma Unt trie 4cid Inuhn And Clearance Clearanec ms% ml/mm iil/min SECTION XI FUNCTIONAL DISTURB,\NCES OF RENAL HEMODYNAMICS E\ev in the absence of anatomiciil lesions, disturbances of the renal circulation tnaj cause profound alterations m the func- tions of the kidney It was the development of the clearance methods which made it possible to recognize the important role played by renal ischemia m “cxtrarenal azotemn,” which was formerly attributed exclnsitoly to increased urea formation Ad- mittedly, increased breakdown of proteins is followed h\ in- creased s>'nthesis of urea But as long as renal functions are nor- mal, the load of niliogen-conlaining substances can bo excreted without any significant elevation of the NPN in the blood This factor liccomos important only if tlie glomenilar filtration is markedlj impaired We have learned during the last fifteen >ears tint man> dis eases may eventually lead to sccondar> renal ischemia, despite the fact that they do not primarily involve the kidney In these conditions, renal ischemia represents citlier a part of more gen- eralized circulator)' disturlnnccs, or a peculiar reaction to changes in the composition of the body (Imds Doth from tlie clinical and pathogenic points of view, it is desirable to distinguish several forms 1. Renal isclicmia primanlj due to functional iindcquac) of the artenolar blood supplj this ma) result from low bIooC%8» AND IVWTt.B\I. ItrrOTFN'ION 180 Clearance Tests in Clinical Medicine normal clearance values before and after the acute episode. In one patient the blood pressure dropped to 90/50 at the end of the clearance period: was found to be reduced to 379 ml/min but Ep^n remained normal (0.92), In the second case pallor and sweating developed at a time wliere the blood pres- sure was 100/65: Cpjur was reduced to 293 ml/min but again EpAH remained normal (0.904). In the third patient a vaso-vagal syncope was followed by an anuric episode lasting a few minutes. Shortly after diuresis had resumed, the PAH extraction ratio was 0.41, increasing to 0.55 five minutes later. These observations are consistent with the view that in hypo- tension and shock, renal ischemia occurs. As long as all nephrons are still perfused with blood Cp^H and C,8 are reduced but Ep^vn remains normal. In more severe instances of renal ischemia, fil- tration is no longer performed in a certain number of neplirons, thus preventing renal e.xtraction of PAH taking place in the corresponding tubules. This fact may explain the reduced PAH e.xtraction ratio recorded in such cases. If filtration ceases in the whole kidney, Cu, Cp^n and Ep.^n drop to zero despite the fact that the kidneys are still perfused xxith blood. 11. RENAL DISTURBANCES FOLLO\VlNG CIUNGES IN THE ELECTROLYTE COMPOSITION OF THE BODY FLUIDS Since the first description of the "azotemie par manque de seF (Blum (28)), the infiuence of the electrolyte composition of the blood upon renal functions has been studied by many in- vestigators. During the last ten years it lias been sIioAvn that hj'ponatremia, hypochloremic alcalosis, respiratory acidosis, hypokalemia, h)'percalcemia and other disorders are capable of reducing the renal blood flow. While in sev ere cases organic le- sions may develop, this does not ocewr if the electxolyte disturb- ance can be corrected at an early stage. In such cases we are dealing with a pure functional nepluopathy. The mechanism leading to renal ischemia is not clearly understood, but in the absence of significant hyperviscosity and hypotension, arteriolar vasoconstriction must occur (247, 249, 258). It is conceivable that the arteriolar tone depend to some e.xtent on the electrolyte ’Functional Disturbances of Renal llemochjnatnics 181 composition of the blood plasma. Experiments performed on iso- lated arteries seem to corroborate this assumption (30). Another factor could be a swelling of the tubular cells related to h>po- tonicity of the plasma (147). Among possible causes for such disturbances, adrenal insuffi- cienctj and pyloric stenosis deserve a short comment. Tlie former has been extensively studied in the past (278, 318, 334). All in- vestigators report a greater decrease in glomerular filtration rate than in PAH clearance and transfer maxima. Following treat- ment the values tend to increase, but they may remain sub- normal. In pyloric stenosis tJ»ere is a corresponding decrease in C,„ and Cp^n so that the filtration fraction remains normal, or increases sliglitly (61,249,279). While in certain cases, ade- quate treatment results in a prompt rise in the clearance values, this is not true in all instances. In the case reported in Table 35, recovery was slower. The patient, w))o had a duodenal ulcer, began to vomit fifteen days before he was admitted to the hos- pital. At tlie time of admission, clearance values were very low. Following treatment they incre.ised slowly but ten days later, CpAH was still reduced to 192 ml/min. PAH extraction ratio was determined at the same lime and found to be normal (0.86), indicating true renal ischemia. III. RENAL FUNCTIONS IN DIADETIC COMA It Ijas long been recognized that renal disturbances, even azotemia, may develop during the course of a diabetic coma. But only a few attempts have been made to evaluate the nature and the cause of these changes. In a first approach to this prob- lem, McCance and Widdouwn (193) found a decreased inulin clearance and low creatinine/inulin and urea/inulin clearance ratios. In 1950, we reported a case in which the decrease in renal blood flow occurring during coma xvas directly proportional to the increase in blood viscosity (251). In subsequent papers these results were confirmed and oljservations extended to a larger number of cases (253). A study dealing with clearance investi- gations has also been published by Bernstein and co-worfcers (22). Besults obtained in eight patients studied in our department 182 Clearance Tests in Clinical Medicine Functional Disturbancxs of Renal Hemodynamics 183 are presented in Table 36. These patients «’ere submitted to clearance procedures during diabetic coma and several days after the acidotfc episode had been controlled. In three subjects renal extraction of PAH was also measured in tlie acute stage. Tlie ex- traction ratio was assumed to be unchanged after recovery from tlje coma. In all cases in whidi it had not been measured, it was considered to be normal, that is 0.91. True renal blood flow was calculated by tlie formula: RBF = CpAH EpAn (1-Hc) Effective blood viscosity was estimated using Lamport's formulae and charts (179), which required determination of hematocrit readings and plasma protein concentrations. Since in, our cases, the blood pressure remained essentially unchanged during and after the acidolic episode, the Poiseuille law may be simplified as follows; Renal arteriolar resistance = -= — r-u — rr- Renal blood flow X Viscosity That means that, if the product (Renal blood flow X Viscosity) remains constant during and after coma, no change in renal vas- cular resistance has taken place during diabetic acidosis. Tliis product was calculated in all our cases. It appears from the data presented in Table 36 that there M’as a sliarp reduction of urea clearance, glomerular filtration rate and PAH clearance during diabetic coma. Nonprotein nitrogen rose significantly. PAH ex- traction ratio was normal in one subject and slightly reduced in the other two. Hematocrit readings, plasma protein concentra- tions and blood viscosity %vere much higher during coma than after recovery. Renal plasma flow was affected more than true renal blood flow, o\vmg to the marked hemoconcentration. All values obtained after recovery from the acidosis, were virtually normal, except for Cpah hi patient 8, who may have had some degree of pre-existing renal impairment (nephrosclerosis). The values obtained by multiplying the blood viscositj' y by the renal blood flow (tj X RBF) were of the same order of mag- TABLE 36 nKLATTovm.ir n,^oi. Viscosity Beval FuNonoM-, iv Diabetic Subjec 183 Functional Disturbances of Renal Hemodynamics nitude during and after coma for each patient The quotient ) 7 XRBF(coma) jt- non c varied between 0 80 and 1 11 wth an av ■rj X RBF (recovery) erage of 1 01 indicating that renal artenolar resistance remained practically identical during and after coma Thus the azotemia occurring m diabetic coma appears to be largely due to reversible renal disturbances During coma there is a marked reduction in renal blood flow renal plasma flow glomerular filtration rate and urea clearance which may account for the nse in nonprotein nitrogen The role of mcreased production of urea is only contributory As the PAH extraction ratio IS normal or only shglitly reduced the PAH clearance in most cases affords a rebable estimation of the kidney circula tion As no renal vasoconstriction can be demonstrated v-e be heve that increased blood yxscosity alone due to se^ ere dehydra tion accounts for the observed slowing doNvn of the kidney cir culation In all cases improvement of the renal function occurred promptly as soon as blood viscosity had returned to normal values which was readily achieved by parenteral fluid and in suhn therapy Organic tubular alterations which may develop in severe cases can be almost ruled out m our senes because of the rapid improvement in renal clearances followmg rehydra tion and the nearly normal PAH extraction ratio The renal in efficiency in these cases was a consequence of a pure functional nephropathy It IS interesting to note the different behavior of the renal vascular tree in conditions of acutely and cbromcally increased I iscosity It seems to remain quite passive m acute diabetic coma but m polycythemia vera total renal blood flow is usually in creased (252 331) which means that a compensatory drop m arteriolar resistance takes place No such hemodynamic com pensation can be observ ed in diabetic acidosis In contrast to the functional type of renal failure organic tu bular lesions ma> be found in rare instances (253) These are of the type seen in acute renal failure (shock kidney) Their ex istence is strongly suggested b} persistently low clearance values a low PAH extraction ratio and a high urea/thiosulfate clearance ratio 186 Clearance Tests m Clinical Afccficinc RENAL CIRCULATION IN CONGESTIM: HEART FAILURE It has been known For many years that patients witli conges- tive lieart failure are unable to excrete a given load of sodium, and therefore tend to accumulate salt and water, Tlie problem of how the kidney retains sodium in these subjects is still un- settled, altliough a new approach lias been made possible bv the introduction of clearance methods. In patients wth heart disease but without fluid retention and increased venous pressure, the glomenilar filtration rale may be normal at a time where the PAII clearance is already reduced, so that the filtration fraction is increased (153). On exercise the PAH clearance shows a further decrease and the glomerular filtration rate begins to fallflOS). In patients with congestive failure there is already at rest a moderate decrease in Cj, and a marked decrease in Cmu, resulting in an elevation of tlie filtra- tion fraction (197). Transfer maxima are normal or reduced, and the PAH extraction ratio is normal (197), Thus it would appear that we are dealing with pure hemod>mamic disturbances, which become more striking on exercise. It is not known by wliat mechanism cardiac disturbances lead to renal ischemia. Tliere is no significant correlation lielwocn renal blood flow and cardiac output (92), altliough both may occasionally be decreased to a corresponding extent (338). Nor does the reduction of the renal blood flow correlate with the in- crease in venous pressure or the degree of anoxemia. It is be- lieved that efferent arteriolar vasoconstriction is involved and that this is mediated through the ncrxous sjslem or adrenal medullar>' liormones (199). Renal ischemia of such a degree as to result in azotemia is extremely unusual. But it has been claimed that the disturbances in renal Iiemodvmamics might be respon- sible for the sodium retention. In 1946, A. C. Merrill proposed the thcorj' of the “fonvartl failure” ( 197). He suggested that the decreased glomerular filtra- tion rate accompanying congestixe heart failure might Ive re- sponsible for the sodium retention. As the tuhular reabsorplion for sodium and water is not impaiitjd in this condition, a de- Functtonal Disturbances of Renal llcmodtjnamtcs 187 crease m the filtered sodium load should lead to glomcrular- tulnilar imbalance This theor> has been accepted by some imestigaiors Moho- tofT ct al (206) found that the proportion of sodium reabsorbed in normal and decompensated patients svas essentially tlic same and concluded tlial sodium retention in heart failure was a result of the decreased filtration But olniously the rejected fraction of sodium IS so small under .all circumstances, that an almost linear correlation exists o\er a wade range between filtered load and sodium reabsorption (36) This docs not prove that tubular reabsorption is unchanged, os \cr> small changes in the rejected fraction will produce large changes in the unnaty output of sodium Moreover, espenments m animals have documented the role of tubular factors In dogs with Incuspid insulRcicncj Bar- ger (8) was able to demonstrate an increased tubular reabsorp- tion of sodium when the glomerular filtration rate was restored to normal by saLne infusions Finally, it could be sIiowtj in man that during digitalis treatment, diuresis and salurcsis occurred before any improvement of renal hemodynamics (45. 112) An increased tubular rcabsorption of sodium in congestive heart failure seems to be well established An attempt has been made to correlite tins phenomenon will) an increase m tlie renal venous pressure It is true that sodium retention occurs in ani- mals whose pressure in the renal vein is acutely raised (26) But experiments, in which chronic elcvoition was produced, failed to show ail) disturlnnces in salt excretion (162) More recently it has been suggested that the increased tu- bular reahsorption of sodium might be a result of the elevated filtration fraction (326) It is evident tint if a greater fraction of fluid is removed from the pltsma circulating through the glomerular loops, the oncotic pressure will be increased in tlic post-glomenilar capillaries Tins might conceivably explain a high reahsorption of water and electrolytes A serious objection to this view is that m artcrnl hypertension an increased fillra- tioii fraction docs not result m sodium retention, and tint m the nephrotic syndrome fluid retention occurs m spile of a low filtra- tion fraction and low phsina protein concentrations Increased production of aldosterone seems to be an itnpor- 1S8 Clearance Tests in Clinical Medicine tant factor in promoting salt retention (211, 344), altlioiigli it could not be demonstrated in e\'ery case of congestive heart failure. So far, it is not known by what meclianism cardiac de- compensation may elicit secondary hj'peraldosteronism. Recent work suggests that renal ischemia might be one factor (94, 212). According to this view, a reduction of the renal blood flow w’oiild result in an increased production of renin, which, in turn, w’ould stimulate the aldosterone synthesis (93,213). Patients with severe heart failure may respond poorly to diuretics. Many authors believe that this is due to a marked de- crease in the filtered load of sodium (233,282,340). It cannot be denied that in these cases the glomerular filtration rate is re- duced, but evidence that such a mechanism plays a major role in patients resistant to diuretics is very limited. In cardiac pa- tients with edema, tubular factors cannot be niled out. In ani- mals, most experiments designed to demonstrate the rote of a decreased filtration on the responsiveness to diuretics have been performed in normal dogs, in which the blood supply of the kidney was acutely restricted (91,233). For these reasons, we decided two years ago to investigate the effects of a permanent reduction of the glomerular filtration rate on tlie responsiveness to chlorothiazide and meralluride (265). It was hoped that e.K- periments performed on patients suffering from renal disease but without edema might enable us to evaluate the role of a reduced filtration per se. Our results indicated that over a wide range (20 ml/min up to normal values) a permanent reduction of the glomendar fil- tration rate had little influence on the diuretic and saluretic ef- fects of meralluride or cholorolhiazide. Below 15-20 ml/min a further reduction resulted in a sharp decrease in the diuretic and saluretic actions (Fig. 26). This can best be e.\plaincd by assuming that the diuretic agents block an increasing fraction of tlie tubular reabsorption of water, sodium and chloride re- lated to the decrease in glomerular filtration rate. This fraction, however, seems to be limited to 30-40 per cent of the filtered load. Some dispersion in the glomenilar-tribular activity prob- ably accounts for the splay of the experimental curves (265). The applicability of our findings to the problem of the re- FiffKTfjorifl/ Disturbances of Renal Hemodynamics 1S9 fraclonness to duirelics m congestue heart failure remains open to question At least our results show that a permanent reduction of (he filtration rate per sc has little influence on the diuretic response provided the fraction of the filtered sodium rejected under basal conditions is large In patients with cardiac or nc phrotic edema this fraction is verv small and even a fourfold increase will not lead to a marked salurcsis Tlie refractonness to diuretics therefore can best be correlated with a reduction of the rejected fraction This in turn largeh depends on extra renal factors rather than on the level of filtration Clinical Use of the Clearance Methods Congestive heart failure leads to albumimina even in the absence of organic renal lesions On the other hand heart fad ure maj complicate livpertensivc nephropathies like chronic nc phntis and vascular nephrosclerosis Finallv certain tvpes of renal disease may produce a picture rcsemlding congestive car diac failure (acute glomcmlonephnlis overliydrated patients witli acute or cliromc renal failure) Tlicrefore it is important o Control • after Chlorothiazide = 8 - ■I7. Eg. 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INDEX Acute renal faJure 147 clearances 149 course 151 etiology 147 lustologic picture 147 renal blood flow 148 symptoms 147 tubular functions ISO Adrenal insuffiaencj 181 Aerobacter aerogenes 137 Aging clearances in, 50 Aglomerular tubules 59 Albuminuria 73 95 111 112 122 189 Aldosterone sec Hyperaldosteroaism AlLmtoin, clearance 9 15 a ammo nitrogen clearance 40 165 Ammo acids cleanince 27 40 16o Ammoacicluna 40 163 Ammonia secretion 29 Amyloidosis 111 171 Anapb>lactic react on 147 Anemia 24 50 Ant diuresis 29 179 Anbdiuretic hormone 171 Anuna 147 178 Artenolar spasms (in chronic ne- phntis) 86 Auforegiihbon of renal blood Soyv 24 178 Azotemia 73 86 97 132 147 exfrarenal 169 177 183 "Azot^mie par manque de sel ” 180 Bacb*diiTusion (of filtrate) 148 Blood press ire see Hypertension H)Tolens on Shock Blood viscosity 24 17S 181 185 Blood volt me 93 Body surface 36 Bums 147 Calcium reabsotpUon 26 Carbon tetrachloride poisoning 147 Cathetenzation of tl e bladder 33 34 Catheterization of renal arteiy 16 134 Catheterization of renal vein 16 21 41 Cerebral blood fiou 17 19 Chloride reabsorpuon, 27 Clearance See aUa a amino nitrogen Alfantoin Ammo aads CreaCl nine Cystine Dodrast, Free tvater domeruhr £Jtf/ition Glucose CI>cme InuLn Ly $me Magnesium Mannitol PAH Phosphate Potassium Sorbitol Strong e!ectroI>*tes Thiosulfate Urea Uric acid ciunges due to aging 50 aglomerular tubules 59 glomemlar lesions 64 impotent nephrons 60 inert tissue 61 65 renal iscl emia 63 tvbular lesions 66 diiucal use 33 defiiution 7 inlcrprelatmn 49 theory 7 validity 58 66 Compulsive water dnnking 171 Concentrating ibilit) 122 149 157 169 ri Coumand catheter 16 41 Creatinine clearance (endogenous) 13 33 ccenpanson with iniilin and tlilo sulfate clearances 9 13 ^12 Clearance Tests in heart failure, 14 in renal disease, 14 clearance (exogenous), 13 concentration index in renal failure 149 liihular secretion, 14 Crush syndrome, see Acute renal failure Cj’stine, clearance, 165 C>^tinuria, 165 Diabetes insipidus, 157, 171 Diabetes melLtus, see Glomerulo- sclerosis Diabetic coma, 181 Diabetic retinopathy, 112 Diodrast clearance in glomerulonephntis, 74 in pyelonephritis, 138 maximal secretory capacity (Tmp), 30 radioactiie, 20 Dispersion of glomerular-tubular ac- tivity. 27, 59. 162, 18S Diuresis, 29 Dmreties, 168, 172, 188 Oye dilution methods, 16, 148 Eclampsia, 116 Edema in acute glomeruloneplmtis, 73, 76 in heart failure, 186 in nephrotic syndrome, 93 Endocarditis, subacute bactenal, 83 Epinepbnne, 24, 25 Ergot alcaloids, 24 Escherichia coli, 137 Faneora syndrome, 164 Ferricyarude poisoning, 162 Pick principle, 18 Filtration, see Chmenilai filtration Filtration fraction changes due to xasoactixe drugs, 25 defimtion, 24 ft* Clinical Medicine nonnal values in man, 50 values in acute renal failure, 148 adrenal insufficiency, 181 amyloidosis, 111 diabetic coma, 183 diabetic glomerulosclerosis, 113 disseminated lupus erythematosus 81 essential hypertension, 122 ^menifar diseases, 51 glomerulonephritis (acute), 25, 74, SO glomerulonephritis (chronic), 85 glwnerulonephntis (focal), 84 iieart disease. 83, 186 hydronephrosis, 25 nephrotic syndrome, 97 po-lural hypotension. 179 pyelonephnfis, 138 pyloric stenosis, 181 renal artery lesions, 132 renal gtycosuna, 158 shock, 179 subacute endocarditis, 83 toxemia of pregnancy, 116 tubular-intersbtia) diseases, 54 x-asculai diseases, 57 Forxi’ard failure, 186 Free-water clearance, 29, 171 Functional disturbances (of renal cir- culaUon), 98. 171, 177, 186 Gas diffusion methods, 18 Glomerular diseases, clearances in, 51 Glomemlar filtration. See also Inulin clearance, Thiosulfate clearance changes due to aging, 51 coccelatina wtb. strucbiral dimen- sions, 28 definibon, 8 d^nninabon, 34 normal values in man, 49 values in acute renal failure, 148 adrenal insufficiency, 181 amyloido'iis, 111 Index 213 diabetes lasipidits, 171 diabetic coma. 182 diabetic glomerulosclerosis, 113 diiseminated lupus crj-tbcunlosuv, 81 d>Mlectrolytcniia, 180 essential h>'pcrlcnsion. 122 Fanconl syndrome, Ittl plomcnihr due-iscs, 5l glomeniJofiepJiritJs (acuti), 71, 80 glomeniloncpbntis (tbronit) 85 glomcniloncpbrilis (foial) 84 gout, 172 Iieart disease, 83 ISO lij-pokalcmin, 168 nephrotic syrndromc, 07 jurathyroiJ chsfunction, 100 p«y,l\»Tal hvpoteiwloTv, 170 pyelonephritis, 138 pjlorlc stenosis, 181 refill ftrte?}’ lesions, 132 renal gl>cosiiria, 158 sliock, 170 submite endocarditis 83 toxemia of pfignincy, 110 tubular intirstitnl diseases, 5-f sasctilir diseases, 57 Cloinenibr-tiibiilar inibalance, 70 102. 187 Clomeruloneplmlis actitc cleanness. 71 course, 70 edema ineclnnism of, 70 hislologlc clianges, 73 hypeatsmsion. mcclniusm of 75 symptoms, 73 ihronic clcjnnces, 85 cs>ur*e, 87 dilTi rtaifial diagnosis 87 lustologie tlwngcs, 84 ftK-ul 8-1 lohulir. W. 101 memiinivni', 00. 101 prohfi rathr siiliaciite, 90, 101 GlomrniloHlrsosls, dlllietic clearances, 112 cenme, 112 histologic changes. 111 symptomc, 112 Clitcsssc clcannce, S muimal rcabsorptm capacity (Tro,),27,07. 15S. 165 definition, 27 determinition, -12 tn dnficlic gJomcnjlo«{Jert»Js, 112 tn Fancsini syndrome 105 in renal diabetes 158 in symptomatic renal glyxsisuria 102 realisoqition, 27 llireshnld 43 41, 163 titration 43 160 Glycine, clearance, 105 CKcoglyanuna. familial ICS Clycnsuna »ee Renal glycoMina Gout, renal fiinchons 172 Hamilton cs)nation 17 Iieart failure clearances in 83, 180 Heniatocnt 21, 1S3 Ilematuna, 73 07 Ilnnanl tc^t, 133 llynlnlarine £l llydroRm ion' 'cctction 29 Hydronepliste.1' 87 139 Hyi>eraldostemmsm, ICS, 188 Hypercilcenna, 160 Hypercliolestcmlcmia 93 IlypcTparalb'toidlsm 38 106 llvpcrttnriMWi essential 121 Ixmlgn 121 clearances. 122 coitrsc, 125 diagnosis 123 effects of IrcatnuiJt, 120 itialigniiil, 121 relation to nephn*sc!enisis 121 renal bli»id ffow, 122 symptoms, 122 symplonntic in acsite glon«'nilmrisliritis, 73 Clearance Tests in Clinical Medicine in chronic Blomeiulonephriiis, 86 in cLabctic glomerulosclerosis, 112 in nephrotic syndrome, 97 in pyelonephritis, 140 in renal artery lesion, 132 Hyixxhloremic alcalosis, 180 Hypolalemia, 38, 167, 171 Hyponatrenua, 180 Hypoparathyroidism, 38, 160 Hypophosphatemia, famJial, 39, 166 Hypoproteinemia, 93 Hypotension, postural, 179 Idiopathic m>oglobinitria, 147 Impotent nephrons, 60 Inert tissue, 61 IntcrcapiUary glomerulosclerosis, see Diabetic glomeruloscletrois loulin back diHusion, 11, 147 clearance. See eUo Glomerular filtration suitability for measuring filtration, 8, 9 determination, 35 cveretion in animals, 10 properties, 11 pyrogenicity, 11 Krypton, radioactive, 20 Lipoid nephrosis, 95, 99 Lupus erythematosus (disseminated), 81 Lysine, clearance. 165 .tfagnesium. clearance, £6 Mannitol, clearance, 9, 10, 15 Masugi nephntis, 73, 78 ^taslmal rc.absorptive capacity glucose (Tmo). 27. 44,67 phosphate (Tmr<>,), 39, 160 Maximal secretory capacity Diodrast (Tmn), 30 PAH (Tm,in),30.67, 150 Mean transit time, 17 Mercury poisoning, 147 Mismatched blixxl transfusion. 147 Ncphrocaldnosis, 171 Nephrons, normal, 58 Nephrotic syndrome, 95 clearances, 97 course, 07 diagnosis. 09 etiology, 93 liistologic picture, 03 in amyloidosis, HI diabetic glomcmlosclcrosis, 112 glomerulonephritis, 107 lipoid nephrosis, 101 symptoms, 95 Nitrons oxide methnd, 19 Oedm.an catheter, 16 Oliguria, 73. 1 17 O'lnohr clearance, 28, 171 Ostromabcia, 35, 105, 167 Os.-iliC acid poisoning, 147 Papillary necrosis, 138 Para-amino hippurate, sndiuin (PAH). See also Clearance, Ben’ll bloosl flow clearance, 8, 21 ciunecs due to aging, 51 determination, 34 normal values in man, 50 values in acute ren.xl failure, 14S adren.il insiifficicnc), 181 amyloidosis. 111 shalictes insipidus, 171 dialietic coma, 1R3 (fiafietic gfomeruIoscA’ros/j, 113 dissemin.ifcd lupus erythema- tosus, 61 dyselecirolytrmia, 180 essential hypertension. 122 Fanconl syndrome, 161 glomcrukr diseases, 51 glomerulonephritis (acute), 74. 80 Index 215 glomerulonephritis (chrome) So glomenilonephntJS (focal) S4 gout 172 heart disease 83 186 hypolaleinia 168 nephrobc syndrome 97 parathyroid dysfunction 160 postural hypotension 179 pyelonephritis 13S p>lonc stenosis 18l renal artery lesions 132 renal glycosuria 158 shoclc 179 subacute endocarditis S3 toxeima of pregnancy 116 tubular interstitial diseases 54 vascular diseases 57 extraction ratio changes due to aglomerular tubules 59 glomerular lesions 6-{ impotent nephrons 60 inert tissue 61 65 renal ischemia 63 tubular lesions 66 vasoactive drugs 24 definition 22 decerrmnation, 41 normal values in man 50 values In acute renal failure 148 anemia 24 50 diabetic coma 183 dyselectrolytemia 180 essential hypertension, 122 glomerular dueases 51 glomerulonephntis 75 80 heart failure 83 186 nephrotic syndrome 97 pyelonephritis 138 pylonc stenosis 181 shod 179 tubular interstitial diseases 54 vasnilar diseases 57 maximal secretory capacity (Tmr.n) 30 67 tubular secretion 29 Parathymid dysfunction, 38 166 Pentomtis 147 Phena2opjT7dine 33 Phenylbutazone pouoning 147 Pblonzin 10 ITiospIiate clearance 38 163 166 excretion index, 167 maximal reahsorptive capacity 39 166 reabsorpUon 26 39 «ecretion 39 Pilressm 172 Polyarteritis nodosa 171 Polycythemia 185 Polyuna 147 171 Post infectio is hypertension with etlema 76 Potassium clearance 38 168 170 depletion 38 168 losing neplinlis 168 170 reabsorpUon ^6 secretion 29 Pregnancy normal 116 Pnming infusion 34 Proteus vulgans 137 Pseudomonas aeruginosa 137 Pyeloneplmtis acute and chronic 137 acute exacerbaf ons 141 clearances 138 course 141 diagnosu 138 140 etiology 137 histologic changes 137 obgosymptomatic fonns 140 renal blood flow 139 stabilized forms 142 tubular syndromes 139 Pylonc stenosis 181 Pyrogens II 25 Renal angiography 134 Renal arteriolar resi tance 183 Renal artery lesions unilateral 132 Renal blood (plasma) flow See oho Diodrast clearance PAH clear ance PAH extraction ratio 216 Clearance Tests in Clinical Medicine Renal ischemia and Hypciemia clianges clue to vaso.ictnc dnijff, 24, 2o cortical, 22, 23, 26 effectrve, 22, 26 medullary, 23 methods of determination, 16 total, 22, 23 values in acute renal failure, 148 adrenal insufficiency, 181 anemia, 24, 50 diabetic coma, 182 dyselectroljtmia, 180 essential hypertension, 122 glomerulonephiitis, 74, 85 heart failure, 83, 186 polyc>themia, 185 postural h>'pQtension, 179 pyelonephnlis, 138 pylonc stenosis, 181 renal artery lesions, 133 shock, 179 Rena! failure, see Acute renal failure Renal glycosuria, 158 clearances, 158 diagnosis, 163 in Fancoiu syndrome, 163 in organic renal diseases, 162 in type A renal diabetes, 159. 164 in type B renal diabetes, 159, l&l Renal hyperemia, 25, 78 Renal ischemia, 25, 74, 121, 132, 148. 177, 160, 186 Renal vascular volume, 17 Renal venous pressure, 187 Renal weight, 19 Rickets, vitamin D-resistant, 165 Septic abortion, 147 Shock. 147, 178 Shock-bdney, see Acute renal failure Sodium, reabsorption, 27, 133, 187 Solute-free water, 29 Sorbitol, clearance, 10 Staphylococcus aureus, 137 Stewart principle, 16 Stop-flow, 23 Streptococcus faecalis, 137 Sfreptococais haemolyticus group A 73 Strong electiolyles, clearance, 36 Sulfonanude poisoning, 147 Sustaining infusion, 34 TTiiosulfate clearance, see also Glomerular filtra- tion comparison with Inulin clearance, 10 suitability for measuring glomer- ular filtration, 12 determination, 35 tovicity, 13 tubular secretion, 12 Thrombosis of renal \«n, 95, 104 Tilratable acidity, 30 Titration methods, 28, 42 Toxemia of pregnancy, 116 Toxic nephropathies, see Acute renal failure Traaxfer maxima, see Maximal reab- sorptive (secretory) capacity Tnmethadione, 93 Tubular-intersbtial diseases, clearances in, 54 Tububr necrosis, see Acute reail failure Tubular reabsorplion, 26 Tubular secrehon, 29 Tubular syndromes, 157 Urea clearance, 7, 33 concentration index (in acute renal failure), 148 maximal clearance, 7 reabsorption, 27 standard clearance, 7 Unc acid blood levels in gout, 172 clearance, 172 secrebon, 26 Untie flow, 33, 133, 171 Index 217 Validity of clearance methods, 58, 66 Water. See afso Free-water Variability of structural dimensions, 28 losing nephritis, 157, 171 Vascular diseases, clearances in, 57 reabsorption in renal ischemia, 133 Wilson’s disease, 165