Journal of Clinical InvestigationVol. 44, No. 4, 1965

Studies of Experimental Renal Failure in Dogs. I. Effect of5/6 Nephrectomy on Concentrating and Diluting

Capacity of Residual Nephrons *

JACK W. COBURN,t HARVEY C. GONICK, MILTON E. RUBINI, ANDCHARLES R. KLEEMAN t

(From the Medical Service, Wadsworth Hospital, Veterans Administration Center, LosAngeles, Calif., and the Departments of Medicine, UCLA Center for the

Health Sciences and Mount Sinai Hospital, Los Angeles, Calif.)

Two divergent theories have been offered toexplain the concentrating and diluting defects ofchronic renal disease. The conventional view at-tributes these abnormalities to damage to specificnephron sites and assumes a significant formationof urine by partially damaged nephrons. The al-ternative view postulates little or no function bydamaged nephrons and attributes virtually allfunction to the remaining "intact nephrons." Itis suggested that the increased solute excretion bythese fewer normal nephrons interferes with theability to concentrate and dilute urine (1, 2).This follows from the observations in normals,under conditions of both antidiuresis and waterdiuresis, that an increase in solute excretion causesurine osmolality to approach that of plasma (3-6).

Data supporting this latter thesis have been ob-tained in an animal model with unilateral kidneydisease. When concentrating and diluting abilitieswere expressed at equivalent rates of glomerularfiltration, these functions were approximately equalin the diseased and contralateral normal kidney(2, 7). However, extrapolation of such data to

* Submitted for publication June 4, 1964; accepted De-cember 14, 1964.

Supported in part by U. S. Public Health Servicegrants (AM 01634-06 and APD 13952) and a LosAngeles County Heart Association grant (318).

Presented in part before the Sixteenth Annual Meet-ing of the Western Society for Clinical Research, Febru-ary 1, 1963, Carmel, Calif.

t Work performed in part during tenure of U. S. Pub-lic Health Service postdoctoral research fellowship ofthe National Institute of Arthritis and Metabolic Diseases.Present address: Department of Metabolism, WalterReed Army Institute of Research, Washington, D. C.

i: Address requests for reprints to: Dr. Charles R. Klee-man, Mount Sinai Hospital, 8720 Beverly Boulevard, LosAngeles 48, Calif.

the interpretation of function in patients with bi-lateral kidney disease may not be valid. Not onlydoes the design of such a model eliminate the al-tered physiology due to uremia, but the presenceof the normal kidney may modify or abrogatestimuli causing anatomic and functional hyper-trophy in the diseased kidney (8, 9). Experi-mental and clinical data that offer support andcriticism of the intact nephron thesis are reviewedelsewhere (10-12).

It was the aim of the present experiments tostudy concentrating and diluting abilities in a kid-ney with a reduced number of intact nephrons.These functions were compared in dogs with re-nal mass surgically reduced by 5/6 nephrectomyand in normal animals receiving a urea osmoticload.' It was thus possible to compare the func-tions of the normal kidney and kidney remnant atcomparable rates of solute excretion per nephronmass.

MethodsThirty-five experiments were performed on twelve fe-

male mongrel dogs weighing from 9.5 to 18.4 kg. In sixdogs approximately five-sixths of the renal mass was re-

moved by a two-stage surgical procedure. At the firstprocedure, both poles of one kidney were resected, andthe larger of the main renal artery branches of theother kidney was ligated. Two and one-half weeks later,the hemi-infarcted kidney was removed. In order to esti-mate the proportion of renal tissue removed, a similarbipolar resection and contralateral nephrectomy were

1 Urea osmotic diuresis was chosen since urea is re-sponsible for most of the increased osmotic load per neph-ron in chronic renal disease. (Although sodium and itsattendant anions must also be excreted in increasedquantities by each remaining nephron, the possibility ofextracellular fluid expansion and cardiovascular altera-tions militates against the administration of saline as theosmotic agent.)

603

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performed in a one stage procedure in four additionalanimals that were not studied. The weight of the resectedpoles was 57 to 66% of the contralateral kidney weight,and the remaining mass was 18 to 22% of total pre-

operative kidney weight. Surgical details have beenreported elsewhere (13).

All animals were maintained on a constant canneddog food diet that gave 9 g of protein for each kg ofbody weight, and the experiments were performed in theunanesthetized state after a 22- to 24-hour fast. The ani-mals were trained to stand in a frame, loosely supportedby a canvas sling. Urine samples were obtained througha soft, multiholed, indwelling catheter; adequacy of col-lection was assured by suprapubic compression plus twoor three air washouts when urine flow was below 5 mlper minute. Blood samples were obtained at appropriateintervals from an indwelling needle inserted into a fore-leg vein, and infusions were administered with a con-

stant infusion pump into a rear leg vein.Exogenous creatinine clearance was employed as a

measure of glomerular filtration rate (GFR), and para-

aminohippurate (PAH) clearance as a measure of ef-fective renal plasma flow (RPF). Creatinine and PAHdeterminations were done by standard methods (14, 15),urea nitrogen by a modified method of Kibrick, Ross,

and Scupp (16) or the method of Skeggs (17). Plasmaand urine osmolality were measured by freezing pointdepression.

Similar experiments were done in six animals after theabove described subtotal (5/6) nephrectomy: in three ofthese animals, control studies were performed before op-eration, but in the other three there were no preoperativestudies.After 5/6 nephrectomy, all animals appeared healthy,

ate well, and maintained their weight. Initial studieswere performed between 6 and 16 weeks after the secondoperative procedure. For the entire group of animals,the mean GFR remained stable and did not vary sig-nificantly during the 6- to 16-week period after surgery(p> 0.10 by variance analysis (18) as shown in TableI, although in three individual animals (dogs 65, 83, and9) there was an increase in GFR. Mean filtration rateswere 24, 28, and 29%, and effective renal plasma flowrates (PAH clearances) were 23, 43, and 35% of con-

trol values, respectively, in the three animals studiedbefore surgery. Although only a very crude estimateof functional renal mass remaining, filtration rates inthree other animals not studied preoperatively were29, 27, and 24% of "normal" values predicted from thebody weight (19). These similarities indicate a high

TABLE II

Maximal and minimal urinary osmolalities in normal and 5/6 nephrectomized dogs

5/6 Nephrectomy

Normal 6-16 weeks* 40-80 weeks*

Uosmt Uosm UOsm UOgM UOsm UosmDog Max Min Dog Max Min Max Min

mOsm/kg mOsm/kg mOsm/kg

5t 1,296 51 5t 896 7865$ 2,028 66 65$ 765 9183$ 1,888 39 83$ 1,268 108 1,579 6612t 1,619 49 9t 966 57 1,252T1$ 1,381 42 13$ 1,510 584$ 1,889 41 15-2t 694 71 570 1463t 1,288 34

85t 1,296 97C 2 1,807 63M 1,937G 1,435H 1,314K 1,565N 1,751Q 1,776R 1,527L2 1,493A2 1,292No. 18 9 6 6Mean 1,588 48.0 1,016 77.2SD 256 10.5 314 19.7t p <.001 p <.01

* Time lapse after 5/6 nephrectomy.t Urinary osmolality.$ Subjected to subsequent urea infusions with data included in Figures 1 to 6.

605

J. W. COBURN, H. C. GONICK, M. E. RUBINI, AND C. R. KLEEMAN

o NORMAL DOGS* 56NEPHRECTOMY

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FIG. 1. EFFECT OF INCREASE IN SOLUTE EXCRETION ON MAXIMAL URINE/PLASMA (U/P) OSMOLAL RATIOS IN CONTROL AND 5/6 NEPHRECTomIZED DOGS.

Each symbol represents a collection period.

degree of reproducibility of the surgical reduction of re-

nal mass. Two animals (no. 5 and 65) died 11 and 12

weeks after the second operative procedure during anes-

thesia for another study. The four other animals were

sacrificed 40 to 84 weeks after surgery. During this

later period (40 to 84 weeks after surgery) filtration

rates were greater than the earlier values in three ani-

mals. The kidneys of all were hypertrophied with usually

one large renal pyramid remaining. Histologic sections

in five revealed glomerular and tubular hypertrophy that

was more marked in those sacrificed later. There were

rare foci of lymphocytic infiltration and focal basement

membrane thickening in a few glomeruli. In the sixth

animal (dog no. 15-2), proteinuria appeared between 18

and 40 weeks after operation, and a decrease in GFR

was noted. Functional changes in this animal are de-

scribed in detail below. Histologic examination revealed

marked tubular dilatation extending into the proximal

tubules and Bowman's space with interstitial fibrosis and

chronic inflammation, probably secondary to intrarenal

obstruction due to constrictive capsular scarring.

Antidiuresis studies. Maximal antidiuresis was

achieved by 16 to 18 hours of water deprivation and the

infusion of aqueous vasopressin (Pitressin, diluted from

a fresh ampoule before each experiment) at a rate of 50

mAi per kg per hour. After~ allowing 30 to 45 minutes

equilibration of priming and sustaining solutions, three

urine collections of 30 to 45 minutes duration were made

at basal rates of solute excretion in 18 normal dogs to

determine maximal urine/plasma (U/P) osmolal ratios.

Urea was then given to nine of these animals to produce

elevation of blood levels to approximately four and then

eight times normal by two priming infusions of 75 mmoles

each, followed by a sustaining solution delivering first 1

mmole and then 2 mmoles per minute, respectively. In

some experiments, an intermediate level was achieved

by increasing the sustaining level to 2 mmoles per min-

ute several periods before the second priming infusion.

At each level of blood urea, three specimens of urine were

obtained over periods of 12 to 20 minutes. Experiments

performed after subtotal resection were similar to those

in the normals except that urea was usually infused at

only the lower rate.

Water diuresis studies. Water intake was unrestricted

before the experiment. Water diuresis was induced by a

water load of 4% of body weight given by stomach tube

and maintained by intravenous infusion of 21% dextrose

in water administered at a rate equal to urine flow with

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CONCENTRATING AND DILUTING ABILITY OF RESIDUAL NEPHRONS IN DOGS

an additional 40 to 50 ml given per hour for loss vialungs and mucous membranes. Exogenous creatinine andPAH clearances with urea infusions were performed asin the dehydration studies. Urinary collection periodswere initiated only after urine flow had reached a con-stant rate for two or three periods (90 to 210 minutesafter the water load). The possibility of secretion ofendogenous antidiuretic hormone during urea infusioncannot be absolutely excluded; however, the degree ofdepression of urinary osmolality, the increase in freewater clearance with the rise in solute excretion, andthe absence of any sudden change in osmolality makesuch antidiuretic hormone release highly unlikely.

ResultsAntidiuresis studies. At basal rates of solute

excretion (150 to 300 juOsm per minute), therewas a significant decrease in maximal urinary os-molality in the subtotally nephrectomized animals.The maximal urinary osmolalities indicated inTable II are the highest observed during any ofseveral collection periods during the initial (6 to12 weeks postoperative) antidiuresis experiments.The mean maximal urinary osmolality of the kid-ney remnant animals differs significantly from that

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of 18 normal dogs similarly studied (p < 0.001).As solute excretion increased, the anticipated

rise in urine flow and fall in osmolality was ob-served in both groups of animals. The maximalU/P osmolal ratios achieved at all observed soluteexcretion rates were greater in the normals thanin the 5/6 nephrectomized animals (Figure 1).Rates of free water reabsorption (TCHio) increasedin both experimental groups with increased soluteexcretion approaching, but generally below, maxi-mal rates (Tm). The TcH2O rates of normals ex-ceeded those of the 5/6 nephrectomized dogs atsimilar solute excretion rates, although the differ-ences were not marked. Because the total osmoticload imposed on the kidney remnant animals wasgenerally below that in the normal, they may bestrictly compared in only a fraction of the collec-tion periods.

Since both the rate of solute excretion (UosmV)and elaboration of TCHIO occur in far fewer neph-rons in the subtotally nephrectomized animals, acorrection factor for functional mass was appliedto both parameters. Within limitations discussed

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FIG. 2. EFFECT OF "CORRECTED" SOLUTE EXCRETION (Uo.mV/GFR X 100) ON MAXIMAL U/POSMOLAL RATIOS IN NORMAL AND 5/6 NEPHRECTOMIZED ANIMALS.

607

J. W. COBURN, H. C. GONICK, M. E. RUBINI, AND C. R. KLEEMAN

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FIG. 3. EFFECT OF INCREASING SOLUTE EXCRETION ON FREE WATER REABSORPTION

(TeH20) WHEN BOTH ARE "CORRECTED"~TO RENAL MASS AND EXPRESSED PER 100 ML

OF GLOMERULAR FILTRATE AFTER 5/6 NEPHRECTOMY. The regression slope and 95%7confidence limits from the normal group are superimposed on the data from 5/6nephrectomized animals. Individual experiments in each animal are indicated bythe following symbols in Figures 3 and 6.

Dog no. Dog no.5 (7)* 83 (60)

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* The number in parentheses indicates time (in weeks) after surgery.

below, the GFR has been utilized as the estimateof functioning renal mass. In these "corrected"comparisons, both solute excretion and TCHIO areexpressed per 100 ml of glomerular filtrate (i.e.,UosmV/GFR x 100 and TCHO/GFR x 100).When maximal U/P osmolal ratios of control

and partially nephrectomized animals are com-pared at adjusted solute excretion rates (UosmV/GFR), the two groups are similar (Figure 2).Likewise, when TCHO/GFR was compared at ad-justed solute excretion rates, the 5/6 nephrecto-mized animals did not differ from controls (Fig-ure 3).With further increases in the rate of solute

excretion to above 6 mOsm per minute per GFRX 100, TCH2o/GFR approached the maximalrate of free water absorption (TemaH2O). Asthe number of collection periods with adjustedsolute loads above 6 mOsm per minute GFR X100 was small, these have been excluded fromgraphic and statistical representation. Linear re-gression slopes have been calculated from the re-maining data. A modified statistical method fortesting equality between sets of coefficients of twolinear regressions adopted from Chow (20) wasutilized to test the hypothesis that the slopes of thetwo regression lines were equal. No significantdifference was found between the two regression

608

CONCENTRATING AND DILUTING ABILITY OF RESIDUAL NEPHRONS IN DOGS

slopes: 1) normal:

TGFR X 100 = 1.548 UGFRV X 100 + 0.834

and 2) 5/6 nephrectomy:

TER20 X 100 = 1.433 (U8V X100G+ 1.134 (p = 0.10).2

Water diuresis studies. The 5/6 nephrecto-mized animals demonstrated an impaired abilityto lower minimal U/P osmolal ratios during a sus-tained water diuresis at both basal solute excre-tion rates (Table II) and at the increased ratesof solute excretion observed after urea administra-tion (Figure 4). The kidney remnant group alsohad reduced free water clearance rates (CH20) inthe range of solute excretion observed. On theother hand, when CH20 was corrected to functionalmass (CH2o/GFR X 100) and plotted against ad-justed rates of solute excretion (UosmV/GFR X100), the 5/6 nephrectomized animals demon-2This statistical comparison was kindly performed by

Edward F. Gocka, Western Research Support Center,Sepulveda Veterans Administration Hospital, Sepulveda,Calif.

strated lower U/P osmolal ratios (Figure 5) andenhanced ability to elaborate free water (Figure6).

Although the relationship between the rate ofCH2O and solute excretion is not linear, CH2O ap-proaches a maximum (CmaXH2O), and the rela-tionship has been considered linear for purposes ofdefining statistical limits. As in the antidiuresisstudies, the data for collection periods with ad-justed solute excretion above 6 mOsm per minuteper GFR X 100 have been excluded. The differ-ence between slopes of the two linear equations: 1)normal:

CHFR X 100 = 1.388 UOGFRV X 100) + 5.69

and 2) 5/6 nephrectomy:

CER2 X 100 = 1.950 UG°FR X 100 X 8.793

is significant at the 0.01 level of probability, andthe difference between Y intercepts is very highlysignificant (t = 9.30, p < 0.001).8

3 Statistical methods are similar to those described inantidiuresis studies (18, 20).

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RATIOS IN NORMAL AND 5/6 NEPHRECTOMIZED DOGS.

609

J. W. COBURN, H. C. GONICK, M. E. RUBINI, AND C. R. KLEEMAN

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NORMAL AND 5/6 NEPHRECTOMIZED ANIMALS.

In contrast to these data, rather striking dif-ferences were noted in one animal that developedintrarenal pathology after the initial studies hadbeen completed (dog no. 15-2). There was fur-ther impairment of concentrating ability and abil-ity to achieve minimal U/P osmolality. Whencompared with the initial values in this animal,both concentrating and diluting functions were

below observations made during the initial period(Table II). Values for TCHO/GFR fell belowthe normal range, and those for CHIo/GFR were

among those found in normals. With ethyl alco-hol administration, CH2O/GFR was not improved;hence, an increased level of antidiuretic hormoneactivity was probably not responsible for the pro-

gressive decrease in diluting ability observed withthe development of intrarenal obstruction andinterstitial fibrosis.

Discussion

Our data confirm findings of Bradford (21),Hayman, Shumway, Dumke, and Miller (22),

and Platt, Roscoe, and Smith (23), who demon-strated that subtotally nephrectomized animalswere unable to achieve normal maximal urinaryspecific gravity after dehydration. The presentstudy also demonstrates that the capacity to diluteurine during a sustained water load is significantlyimpaired by reduction of renal mass. As it islikely that the great majority of residual nephronswere anatomically intact, it may be presumed thatthe increased solute load per remaining nephronis largely responsible for both the abnormal di-luting and concentrating capacities. The maximalurinary concentrations are identical in normal andsubtotally nephrectomized animals when they are

compared at equivalent solute loads. On the otherhand, when the capacity to dilute urine is expressedin a similar manner, the kidney remnant animalsdemonstrate greater diluting ability than normal.

Several limitations exist in using GFR to equatethe two groups. The filtration rate per individualnephron undoubtedly increases after 5/6 nephrec-tomy with the GFR reaching 24 to 29% of con-

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610

CONCENTRATING AND DILUTING ABILITY OF RESIDUAL NEPHRONS IN DOGS

trol values during the initial study period (6 to12 weeks) after only 18 to 22%o of renal mass re-mained after surgery. Thus, one-sixth of the ini-tial renal mass filters 50 to 60%o more than thatinitially predicted, and this reaches 250 to 4007oat the later period (40 to 80 weeks). These in-creases are associated with glomerular diameters125 and 150% greater, respectively, than those inthe kidney before resection. At least 50% moresolute is filtered by each residual nephron whencompared to controls on the basis of GFR, andchanges in CH2o/GFR and TCH2O/GFR probablyrepresent changes in glomerular-tubular balance,at most. Kolberg demonstrated a shift of glo-merular-tubular balance toward tubular preponder-ance (indicated by a decrease in the ratio of inulin

clearance to maximal PAH transport) after 50and 75%o renal resection (24), and the increasein CE2o/GFR after 5/6 nephrectomy may indi-cate a similar preponderance of distal tubularover glomerular function. It is assumed, in ad-dition, that measured solute excretion per GFRis a similarly appropriate estimate of the varioussolutes reaching the concentrating and dilutingsites in both groups of animals. As there wasalways greater obligate total sodium excretion pernephron in the kidney remnant animals, ratios ofnonurea to urea solute were never equal when thetwo were compared at similar rates of solute ex-cretion per functioning mass. Within the limita-tions imposed by these assumptions, these studiesindicate a normal glomerular-tubular balance with

5y6 NEPHRECTOMY

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CLEARANCE WHEN BOTH ARE CORRECTED TO RENAL MASS AND EXPRESSED PER100 ML OF GLOMERULAR FILTRATE. The normal regression slope and 95%confidence limits are superimposed on the data from the 5/6 nephrectomizeddogs for comparison. Individual animals are indicated by symbols as

shown in Figure 3, and the water diuresis studies were performed 3 to 4weeks after times indicated for each symbol in Figure 3.

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611

J. W. COBURN, H. C. GONICK, M. E. RUBINI, AND C. R. KLEEMAN

respect to concentrating ability and a tendencytoward enhanced tubular diluting capacity afterreduction of normal nephron mass.

These data differ substantially from observationsin patients with function reduced by bilateral pa-

renchymal disease when concentrating and dilutingfunctions are related to GFR. With the excep-

tions of studies in chronic glomerulonephritis byBaldwin, Berman, Heinemann, and Smith (25),observations in patients with chronic renal diseasehave demonstrated impaired concentrating abilityas measured by TCmaxH2O/GFR or maximal U/Posmolal ratios compared at equivalent adjustedsolute excretion rates (26, 27). After removalof the intact kidney in dogs with unilateral renaldisease, Bricker and co-workers have reported de-creased maximal U/P osmolal ratios (28) and a

reduction of TcmaXH2O/GFR (29). With maneu-

vers to reduce filtered solute load, Hayman andassociates noted an increase in maximal urinespecific gravity in subtotally nephrectomized dogsto values approaching preoperative controls (22).In humans with chronic renal disease, Franklin,Niall, and Merrill found no increase in maximalurinary osmolality after reduction of the filteredsolute load by hemodialysis or hypotension (30).These data indicate that factors other than soluteload per nephron are important in the impairedconcentrating ability of patients with chronic renaldisease.

During maximal water diuresis, patients witha variety of chronic renal diseases achieve bothnormal minimal U/P osmolal ratios and CH2o/GFR at adjusted solute loads (27, 31). It hasbeen suggested from such data that the abnormaldiluting capacity in renal disease results from theincreased solute load per nephron. The behaviorof the subtotally nephrectomized animals, as a

more appropriate guide to functional capacity ofa reduced number of normal nephrons under in-creased load, indicates enhanced diluting ability;therefore, such an interpretation in chronic renaldisease may not be entirely warranted.

Although a critical analysis of the factors re-

sponsible for the increased CH2o/GFR is beyondthe scope of this study, several hypotheses may bebriefly examined. First, a change in the quantityor quality of solute reaching the distal nephronmay alter CH2o/GFR without the necessity ofinvoking increased tubular function. Increased

filtration and decreased reabsorption of filteredsodium must occur in each residual nephron, andany increase in reabsorption of such sodium pre-sented to distal diluting sites would increaseCH2o/GFR.4

Second, there may be augmented transport ofavailable sodium by hyperplastic tubular cells ina manner analogous to the increased TmPAH/CInreported by Kolberg (24). Observations byBricker and co-workers that the GFR of a uni-lateral diseased kidney increases abruptly on re-moval of the contralateral normal kidney (9)indicate that many alterations in function may beindependent of the gradual hypertrophy observedafter reduction of renal mass. The progressiveincrease in GFR with concomitant changes inCH20 and TCH20 between 12 and 40 weeks in twoanimals suggests a further gradual adaptive re-organization of function with maintenance oftubular preponderance of diluting function. Asthe quantity of sodium transported from thecortical distal tubules probably greatly exceedsthat moving into the medullary interstitium, onlythe change in CH2o/GFR might be detected byclearance techniques.

Changes in TCE2o/GFR may occur as a resultof alterations in blood flow to the kidney. Anincrease in medullary blood flow probably accom-panies the rise in blood flow occurring per neph-ron after partial nephrectomy (32). Since aninverse relationship presumably exists betweenmedullary blood flow and the hypertonicity ofthe medullary interstitium (33), a "wash-out"effect could reduce TCH2o/GFR and counteractthe factors mentioned above. The administrationof aminophylline, which increases renal bloodflow (34), is accompanied by an increase in CH2o/GFR (35) and a reduction of TCn2o/GFR (36).

Finally, increased rapidity of flow of tubularfluid through the loop of Henle might result inreduced passive diffusion of water from the de-scending limb of Henle's loop into the hypertonicmedulla and also reduce back diffusion of waterfrom the distal tubule and collecting duct (as-suming some degree of back diffusion normally

4The total sodium excreted per nephron under condi-tions of constant sodium intake must be increased, al-though with the greatly increased filtered sodium pernephron the percentage of filtered sodium reabsorbedmay be actually higher in the residual nephrons (28).

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CONCENTRATING AND DILUTING ABILITY OF RESIDUAL NEPHRONS IN DOGS

occurs in the absence of antidiuretic hormone)with increased CHSo/GFR likely in either in-stance. The present study does not allow dis-crimination between these various alternatives.

SummaryThe effect of increased osmotic load on con-

centrating and diluting abilities was studied indogs before and after resection of five-sixths ofthe renal mass. During maximal antidiuresisand sustained water diuresis graded infusions ofurea were given to normal and 5/6 nephrecto-mized dogs in order to compare these functionsat the same solute load per functioning mass (asindicated by glomerular filtration rate). Therewas impairment of both maximal and minimalurine/plasma (U/P) osmolal ratios at basal andat increased solute excretion rates in the kidneyremnant animals. When solute load was ex-pressed per functioning renal mass in the twogroups, the subtotally nephrectomized dogs hadnormal maximal U/P osmolal ratios and en-hanced minimal U/P osmolal ratios comparedwith normal. The adjusted rates of free waterclearance (CH2o/GFR) and of free water reab-sorption (TCH2o/GFR) were increased and equalto normal, respectively, after 5/6 nephrectomy.These findings differ from observations in pa-tients with functional mass reduced by diffuseparenchymal disease; thus, factors other thanincreased solute load per residual nephron maycontribute to the altered concentrating and dilut-ing ability seen in chronic renal disease.

AcknowledgmentWe are indebted to Sybil Gordon, Ophelia Kuever,

Marianne Finklestein, and John Steppe for technicalassistance, to Arnold Bragan for assistance in animalcare, and to Doris Davis and Doris Blackmon for clericalhelp in preparing the manuscript. The surgical assistanceof Dr. Emanuel Nosowsky in performing the subtotalnephrectomies and statistical compilation performed byDr. Edward F. Gocka are also gratefully acknowledged.

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