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Note on the Interpretation of Clearance Methods in the Diseased Kidney

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Note on the Interpretation of Clearance Methods in the Diseased Kidney NOTE ON THE INTERPRETATION OF CLEARANCE METHODS IN THE DISEASED KIDNEY Homer W. Smith J Clin Invest. 1941;20(6):631-635. https://doi.org/10.1172/JCI101256. Research Article Find the latest version: https://jci.me/101256/pdf NOTE ON THE INTERPRETATION OF CLEARANCE METHODS IN THE DISEASED KIDNEY By HOMER W. SMITH (From the Department of Physiology, New York University CoUlege of Medicine, New York City) (Received for publication June 16, 1941) In interpreting the results obtained by clear- but only by investigation; but since by definition they are ance methods in the diseased kidney, the physio- unable to excrete diodrast they do not contribute to CD or TmD. logical limitations of these methods must be kept All renal parenchyma which normally lacks excretory clearly in mind. Since there has been no oppor- function, or which has lost its excretory function, will be tunity to discuss these limitations generally, it designated as inert tissue. This would include capsular has seemed desirable to emphasize certain more and connective tissue, impotent nephrons as defined above, important points in this note. injured nephrons which permit the back-diffusion of inulin and other constituents of the tubular urine, nephrons which The four methods to be considered here are are obstructed by casts or disconnected from collecting the inulin clearance (CIN), the plasma diodrast ducts so that urine formation is impossible, and fibrotic clearance (CD), the maximal rate of tubular ex- glomeruli and tubular fragments generally. cretion of diodrast (TmD) and the maximal rate of tubular reabsorption of glucose (TmG), all Total renal function and function in four methods being based on overall measure- individual nephrons ments made on the two kidneys by the collection Recognizing that there are two million-odd of bladder urine (4, 10, 12). nephrons in the two kidneys, it is self-evident that no overall method of examination can DEFINITIONS directly reveal what is occurring in individual It will aid in the following discussion if certain terms are nephrons. The total clearance method cannot given restricted definitions. reveal whether impairment in any of the above A normal active nephron designates a patent glomerulus with its tubule-both glomerulus and tubule functioning, functions is the result of the partial reduction of by virtue of an adequate supply of blood delivered at an function in all nephrons or the complete reduc- adequate pressure, in the formation of glomerular filtrate tion of function in a few. Conversely, constancy and in tubular excretion and reabsorption. of these functions does not imply constancy in At least by definition, the glomeruli and tubules of all contributing nephrons, since function may be normal nephrons may become partly or wholly inactive due to ischemia without losing their potentiality for imme- increased in some at a time when it is decreased diate return of function on the restoration of an adequate in others. blood supply. The above considerations are most obviously An aglomerular tubule is one in which excretory function applicable to CIN and CD, which in their physio- and urine formation persist after destruction of the ad- logical nature must be presumed to be highly joined glomerulus. (There is as yet no functional evidence of the existence of aglomerular tubules in the normal or labile in any one nephron. But to a lesser degree diseased human kidney; it remains to be demonstrated these considerations also apply to TmD and TmG; that the mammalian nephron, which normally reabsorbs although these measurements are based on satu- water, can acquire the capacity to excrete it, and the ration methods and presumably represent the excretion of water must be presupposed if the term maximal attainable activity in all available neph- " aglomerular nephron " is to have functional significance.) An impotent nephron is conceived as one in which the rons, nevertheless the availability of a particular tubule remains anatomically intact and connected with an nephron depends, in the case of TmD, on perfu- active glomerulus and a patent collecting duct despite the sion by blood, and in the case of TmG, on fact that it has lost its excretory activity, as tested by glomerular filtration; hence alternation of activ- diodrast. Such a tubule would act as a more or less ity and partial, as compared with complete, passive conduit to drain glomerular filtrate into the urine. Whether such impotent nephrons simultaneously lose all cessation of activity in individual nephrons are other tubular properties, such as the capacity to reabsorb theoretically possible. There is also the possi- glucose, chloride, water, etc., is not to be answered a priori bility that the functional contribution of indi- 631 632HO62HMER W. SMITH vidual nephrons may be related to " trophic " of water cannot be detected by changes in CIN, or other influences. For example, White, Hein- although, if the alternative possibility can be becker and Rolf (16) have recently shown that ruled out, it may conceivably be deduced by the TmD is decreased in hypophysectomized dogs; comparison of CIN with the clearance of some hypertrophy of the kidneys occurs in animals smaller molecule.3 receiving large doses of androgens and estrogens Lastly, it is conceivable that filtration may (5, 6, 7, 8, 9), and the hypertrophy of the kidney continue in a glomerulus after the attached induced by a high protein diet is well known. tubule has become separated from its collecting While it has not yet been shown that either TmD duct, or that the tubule may become so per- or TmG is increased in these hypertrophic kid- meable that all the constituents in the glomeru- neys, a functional change is to be anticipated. lar filtrate, including inulin, escape into the inter- stitial fluid rather than the urine. CIN represents Filtration of water and the inulin clearance only such inulin as is passed into the bladder " and will reveal nothing of these circumstances. The term " glomerular filtration may be used Whatever significance the complete local reab- primarily to designate the passage of water across sorption of glomerular filtrate may have in renal the glomerular membranes. Since a variable pathology, it remains beyond the possibility of quantity of water is reabsorbed by the tubule, total urine is it is impossible, either in a single nephron or in examination so long as only the the total kidneys, to deduce from the urine flow available for analysis. how much water is filtered from the blood. The Renal blood flow and diodrast clearance rate of filtration of water can only be deduced in either case by means of an appropriate stand- The diodrast clearance may be defined as the ard of reference, namely, a completely filtrable virtual volume of plasma completely cleared of solute which is itself neither reabsorbed nor diodrast by the renal parenchyma per unit of excreted by the tubule; and in turn the selection time. On the assumption that the diodrast is of this standard of reference can be made only completely removed from all plasma presented by a comparison of clearances (i.e., rates of ex- to active excretory tissue, it may be identified as cretion relative to plasma concentration) of vari- the actual plasma flow to this tissue. This iden- ous substances under various physiological con- tification, however, does not include plasma (or ditions. The use of inulin as the standard of blood) which perfuses inert tissue, and conse- reference for the measurement of the rate of quently CD bears no certain relation to the total filtration of plasma water rests upon good experi- renal blood flow. But inasmuch as CD ap- mental evidence, so far as the normal human proaches in magnitude the total renal blood flow, kidney is concerned (13).1 it affords in effect a method of following the In the diseased kidney, however, an increase latter, but subject only to the necessary qualifi- in permeability of the tubule may permit the cations with respect to the completeness of ex- escape of water from the tubular urine without traction from the total renal blood. permitting the escape of inulin; and, conversely, (oncotic plus capsular pressure) is not reached, or is not a decrease in permeability of the glomerular approached as closely as in the normal glomerulus (11). 3 The parallel behavior of urea and inulin in all stages of membranes may retard the filtration of inulin diffuse glomerular nephritis indicates that the reduced without proportionally retarding the filtration of excretion of both substances is primarily attributable to water; 2 in either case, the differential movement the obliteration of the filtering bed rather than increased back-diffusion of urea (1). I CQN may be calculated as cc. of plasma water instead Similarly the identity of the inulin and hexitol clearances of cc. of plasma, but this is superfluous where other analy- in women with pre-eclampsia (13) argues against a sig- ses and calculations refer to cc. of plasma, and where it is nificant decrease in glomerular permeability in a disease convenient to speak of volumes of plasma filtered. where thickening of the glomerular membranes is fre- 2A reduction in the filtration of water resulting from quently observed. There is here no reason to suspect that decreased permeability of the glomerular membranes re- a precisely compensating increase in tubular permeability quires that in the glomerular capillaries equilibrium be- has obscured a decrease in glomerular permeability, since tween the hydrostatic pressure and the opposed forces
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