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A STUDYOF THE MECHANISMSOF EDEMAFORMATIONINPATIENTS WITH THE NEPHROTICSYNDROME1

By H. A. EDER,2 H. D. LAUSON,2 F. P. CHINARD,3 R. L. GREIF,2 G. C. COTZIAS,4ANDD. D. VANSLYKE4

(From the Hospital of the Rockefeller Institute for Medical Research, New York, N. Y.)

(Submitted for publication May 12, 1953; accepted December 31, 1953)

Accumulation of edema in the nephrotic syn-drome is the result of renal tubular reabsorption offiltered sodium, chloride, and water in excess ofthat required for maintenance of a normal extra-cellular fluid volume. This increase in tubularreabsorption ("glomerulo-tubular imbalance" (3,4) ) could be the consequence of a decrease in therate of glomerular filtration ("primary glomerularinsufficiency") or of stimuli acting directly on thetubules ("primary tubular preponderance").

Decreased glomerular filtration rate (GFR)could be due directly to glomerular lesions (2) ormight be related to a decrease in renal blood flowsecondary to decreased plasma volume with "in-adequacy" of the general circulation-a milderform of the insufficiency present in shock (5, 6).Changes in GFRdue to lesions are the result ofchanges in the area and/or characteristics of thefiltering surface. Adjustment to circulatory "in-adequacy" which results in decreased renal bloodflow would presumably be accomplished mainlyby constriction of the afferent arterioles with re-duction of pressure in the glomerular capillaries.GFRwould diminish if this decrease in net trans-capillary hydrostatic pressure were greater thanthe decrease in so-called colloid osmotic pressuredue to hypoalbuminemia. Circulatory factorswould be expected to reduce GFRby roughly thesame proportion in most glomeruli (7); however,morphologic alterations may vary greatly from oneglomerulus to another. The degree of glomerularinsufficiency resulting from the combined effects of

1 Presented in part at the Forty-First Annual Meetingof the American Society for ainical Investigation atAtlantic City, N. J., May 2, 1949. Summaries of someof the data have been published elsewhere (1, 2).

2 Present Address: Cornell University Medical College,New York, N. Y.

3 Present Address: Johns Hopkins School of Medicine,Baltimore, Md.

'Present Address: Brookhaven National Laboratory,Upton, N. Y.

these extra- and intra-renal factors might, there-fore, vary considerably from nephron to nephron.

The present studies were carried out in an at-tempt to assess the importance of glomerular in-sufficiency in the pathogenesis of edema in thenephrotic syndrome. Most measurements weremade before, during, and after periods of diuresiswhich were either spontaneous or induced by ad-ministration of concentrated human plasma albu-min.5 Because small changes in the glomerularfiltration rate can result in disproportionately largechanges in salt and water excretion (8-11), thetechnic of around-the-clock clearances, in whichmeasurements are made in successive clearance pe-riods continuing over one or more days, was fre-quently used.

METHODS

Chloride concentration was determined by the silveriodate method (12, 13). In analyzing urines with veryhigh concentrations of albumin, the proteins were pre-cipitated with a solution containing 10 Gm. of hydratedpicric acid per liter of 0.15 M phosphoric acid. Sodiumwas determined in a Model 52A Perkin-Elmer flamephotometer with lithium as internal standard. Urea ni-trogen in protein-free filtrates of blood or plasma and ofurine was measured by the gasometric hypobromitemethod (14). P-aminohippurate (PAH) was measuredby the method described by Goldring and Chasis (15).Other methods have been previously described (16, 17).

Excretion of chloride or sodium was measured con-currently with the endogenous "creatinine" clearance (C.,)(16) in around-the-clock studies in four patients (A.McE., C. M., L. B., and S. G.). In two children in whomspontaneous diuresis occurred, 24-hour chloride excretionand routine morning urea clearances were measured atirregular intervals before, during, and after the diuresis(B. M. and S. M.). In one child, excretion of chlorideand C., were measured on 24-hour urine specimens(K. S.).

5 Supplied by the National Blood Program of theAmerican Red Cross. The opinions are those of the au-thors and do not necessarily represent those of the Ameri-can Red Cross.

636

EDEMAFORMATIONIN THE NEPHROTIC SYNDROME

Contol i is 3 lotafte m

-c */ // I/ /iC n

Slodium Wexcretion,AWMir 40-

10-

urineflow 2

6 6 6 6 ~~ ~~~ ~~~66 6 6 6 6Alf. Ax AJX AR A.S AxL A. AM AJX AX

FIG. 1. SUMMARYOF AROUND-THE-CLOCKDATA ON A. McE. (FEMALE, AGE5l YEARS; ONSETOF ILL-NESS, 28 MONTHSPREVIOUSLY) BEFORE, DURNGANDAFTERA 33-DAY COURSEOF ALBUMIN THERAPY

The essential data have been simplified by combining measurements from contiguous periods into ap-proximately three-hour intervals. This gives all periods equal weight and minimizes bladder emptyingerrors (all urines were voided). The data as actually observed and including other measurements areshown in Figure 15 in the Appendix.

The arrows at the top indicate administration of 25 Gm. of albumin as 25 per cent solution, except onday 33 when 37.5 Gm. were given. On the 16th day (Nov. 16-17, 1948) 5 mg. of desoxycorticosteroneacetate were injected intramuscularly (see Figures 14 and 15 in the Appendix for other effects of thehormone). On the 18th day after the last albumin infusion (Dec. 21-22) excretion of chloride was meas-ured instead of sodium. By this time considerable edema had reaccumulated and the measurements wereagain similar to those of the control day (Oct. 27-28, 1948). During each of these days fluids as such wereingested approximately as follows: 6 a.m., 200 ml.; 8:30 a.m., 200 ml.; 10:30 a.m., 200 ml.; 12:45 p.m.,150 ml.; 2 p.m., 200 ml.; 3:15 p.m., 100 ml.; 5:30 p.m., 150 ml.; total, 1200 ml.

RESULTS

Albumin-induced diuresis

Taken as a whole, the data show a good correla-tion in a large number of the clearance periods be-tween change in Cer and change in salt excretion.This is most clearly seen in the data on A. McE.(Figures 1 and 2) whose Cer after a course ofalbumin therapy returned to the pre-treatmentlevel, thus providing satisfactory after-control as

well as fore-control data.In acute experiments on C. M., the renal clear-

ances of PAH (CPAM) and "creatinine" increasedafter albumin administration (Figure 3). During

the several months of observation, Ccr rose steadily.Nevertheless, as shown in Figure 4, there was afairly good correlation between acute increasesin Ccr and increases in salt and water excretion onmany of the days in which albumin was adminis-tered; this was especially the case during the firsttwo weeks of December, 1947 when diuresis wasmost profuse. In Figure 5, the chloride excre-tions of Figure 4 are related to concurrent Ccr.Because of the steady increase in Ccr during theperiod of study, it was thought appropriate to di-vide the data into successive groups in which theinitial Ccr'S were similar. From the data of Figure5, it is probable that factors other than change in

637

EDER, LAUSON, CHINARD, GREIF, COTZIAS, AND VAN SLYKE

Cc, also influenced chloride excretion in thispatient.

In patient L. B. (Figure 6) albumin therapyfailed on most days to induce diuresis. Correlatedwith this is the fact that Cc, showed little tendencyto increase, even though plasma volume was ex-panded considerably. On those days in which saltand water excretion did increase moderately, Cc,also increased in most of the periods concerned.

Spontaneous diuresis

In patient K. S. (Figure 7) albumin therapyinduced only slight diuresis; during the month oftreatment, 24-hour Cc, and routine urea clearancesincreased gradually. Some weeks later, spontane-ous diuresis (perhaps related in part to the para-centesis) occurred after Cc, had increased further.In B. M. (Figure 8) and S. M., (Figure 9) pro-

fuse diuresis and complete loss of edema occurredspontaneously in association with a return to nor-mal of the previously depressed urea clearance.

Diuresis associated with supernormal renal clear-ances

The above data indicate that an increased excre-tion of sodium, chloride, and water in edematouspatients is often associated with an increase inGFR (as estimated by increase in Cc,) followingalbumin administration or occurring spontaneously.Gonversely, it is possible that edema accumulationin these patients was associated with a decreasein GFR. However, edema occurs also in some pa-tients in whomGFRand other discrete renal func-tions are normal or even supernormal (19-22).It is evident, therefore, that even though GFR iswithin or above the statistical range of normal it

A..cE. S Age 6

& Control dayx 1st day of lbunino I6t&-20thI doy0 of albumin* 33rd da of albumin

and loit day afterA 18th day aftev albumin

x

00

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0

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0

ox

0

K

00

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00

000000 00

0.@0~~~00 x A

I A, * I. 'lo, h&10 20 30

3 b9ouv Iiods(approx.)

40

Endogenou0 cfeatinine clearance- ml./min.

FIG. 2. DATA OF FIGURE 1 PLOTTED TO SHOWSODIUM EXCRETION AS A

FUNCTIONOF C.,

801

.v" 60

40qoon

Il

201-

0-. I 101- . Aft. libromr-l-MRA, I I a

638


FIG. 3. DATAON C. M. (FEMALE, AGE19 YEARS; ONSETOF ILLNESS, SIX MONTHSPREVIOUSLY)BEFOREANDDURINGA COURSEOF ALBUMIN THERAPY

Renal clearances of PAH (CPAH) and "creatinine" (C,,), excretion of chloride (UcIV) andurine flow (V) were measured on a control day and on two days in which 25 and 50 Gm. of al-bumin, respectively, were administered as 10 per cent solution. The horizontal dash lines indi-cate the clearance values during the initial PAH period on each day; changes are indicated bythe hatched lines. B and L indicate the time of breakfast and lunch. The solid blocks representthe time of the albumin infusion. Urines were collected by catheterization. See Figure 16 inthe Appendix for additional data on this patient.

may nevertheless be low relative to the tubular ac-

tivities concerned with reabsorption of sodium,chloride, and water.

In S. G., a patient with supernormal renal func-tions (Table I), the around-the-clock data shownin Figure 10 were obtained. On the day shownon the left, albumin was administered. The con-

trol observations in the middle section were madeafter albumin therapy had been withheld for twodays. Edema reaccumulated until, after an inter-val of decreasing proteinuria and rising plasma al-bumin concentration, a spontaneous diuresis beganfive weeks later. On the fifth day of this diuresis,the study shown on the right was carried out.The data suggest some relationship between diu-

resis and chloruresis and increase in C,r, even

though Cer was in the range of normal to super-

normal and even though the 24-hour mean Ccrwas about the same on these three days (126, 122,and 129 ml. per min.). The lack of an exact cor-

respondence in certain periods between increasesin Cc, and in chloride and water excretion indi-cates the operation of additional factors.

Perhaps related to the problem of fluid retentionin patients with supernormal GFRare the data ofTable I. From these data and those of others (19-22), it is evident that in this type of patient themaximum tubular excretory capacity (TmPAH) andreabsorptive capacity (Tmglucose) usually are in-creased more than are GFRor CPAH. It is obvious

CC.i., 9, A9e 19

B L

CPAH

CCre loo10 E i

801- e01- 0

0.55~~~~~~~~60.25 r F F

CPAH o.2o F 020 F 0.20

0.15 - 0.15L 0.15L

UCjV 80 0 80

0

ml./min 4- 4

2 ~~~~~~~226A18 10 12'!. 2 4 6AM.8 10 I2Ht 2 4 6AM8 10 121M. 2 4

1947 Nov. 6 - Contr'ol NoV 20 - 25 gm. albumin Dec. 22 - 50 gm. Albumin

639

B L


that renal reabsorption of sodium and water doesnot necessarily parallel the tubular activity in re-gard to PAHand glucose transport. Nevertheless,these data are at least compatible with the conceptthat even in patients with supernormal kidneyfunctions, GFR is insufficient relative to tubularactivity.

DISCUSSION

The concept that primary glomerular insuffi-ciency results in excessive reabsorption of sodium,chloride, and water rests firmly on results of ani-mal experiments by Marshall and Kolls (27),Shannon (28), Selkurt, Hall, and Spencer (8, 29,30), Pitts and Duggan (9), Mueller, Surtshin,Carlin, and White (10), Post (31), Thompsonand Pitts (11) and others. These experimentsshow that as GFR is reduced, either acutely orchronically, there is a disproportionately largereduction in the excretion of sodium and water.This reduction is largely independent of the anti-diuretic and adrenocortical hormones and of the

renal nerve supply (11). In most of these animalstudies the reduction of GFRprobably reflected afairly uniform decrease in the filtration rate of allnephrons. This statement is based on the fact thatTmglucoBe and TmPAHremain relatively normal un-til GFR is reduced to less than half of the controlvalue (7, 32).

Severe circulatory insufficiency due to trauma orhemorrhage results in marked reduction of GFR(5, 6). A lesser reduction in GFR can be in-duced in man by passive tilting (33, 34); this in-duces the same disproportionately large decreasein water and salt excretion in man as is found indogs after GFRis decreased by reduction in renalarterial pressure (8-11). A similar relationshipof sodium excretion to Cer was illustrated inFigure 2.

The hypothesis that primary glomerular insuffi-ciency is an important factor in the fluid retentionof the nephrotic syndrome finds more direct sup-port in the data of other investigators (35-38):diuresis following treatment with corticotropin

I.

p. ILo0 w- -LiL : : a I --&

oS .3 ._

I-~~I-

IhaA73 Ai A~i AMk AM 4AK S 6AX AXl

S 5 5-6I& AX AM AM

SAm

FIG. 4. SUMMARYOF AROUND-THE-CLOCKDATA ON C. M.

The solid blocks under the dates indicate the time and and quantity (25 or 50 Gm.) of the albumin infusion.Edema volume was estimated by subtracting the body weight on Dec. 31, 1947 (43.7 Kg.), at which time alledema had disappeared, from the body weight of each previous day shown. Plasma volumes indicated by stip-pled columns were estimated from values found at a corresponding time of the day on a preceding or followingday. The patient fully recovered during these observations; proteinuria disappeared by Jan. 19, 1948. Fluidsas such were not given according to a rigid schedule, but the total daily intake was kept constant at 1500 ml.See Figure 16 in the Appendix for additional data.

200

flow=/AlL

o S SfiAK AX AM

I .DI 1t I -0

I' 1t 1t

640

I.

EDEMAFORMATIONIN THE NEPHROTICSYNDROME

DatesAlbumintheropyqmA./ay

Creatinine cleapanceml./tnin.

40 80 1201947 Chloride 150Nov96 1 excre- 100

9-10 0 tion14-15 - ,li/min. 50 _

15-1617-18 25 10020-21

24-25 25 100Dec. 1- 2

2003- 48- 9

100 *

200-15-16 :22-(23 100*

29-301948 5 oJan.5 - 6 010

12-13 AP,, sei19-2026-2,7 0Feb 2- 3 010

9-1010-1111-12 012-1 3 (high 10013-14 sa1t)14-15 _____

FIG. 5. CHLORIDE

0 40 80 120

ExCRrION AS A FuNcTIoN OF C.,IN C. M.

Most of the data are the same as shown in Figure 4.The bottom row shows results obtained continuously dur-

ing five days following abrupt increase of sodium chlorideintake from 21 to 123 mMper day. The patient had fullyrecovered by this time. Body weight increased 2.3 Kg.during this five-day interval. The 24-hour chloride ex-cretion was 25.5 mMon Feb. 9-10 and increased to 57, 77,89, 118, and 131 mMon the succeeding days. The data

suggest that some of the increase in chloride excretion

was related to increase in Ce1. However, comparison of

these data with those of the row next to the bottom stronglysuggests that in addition the tubules decreased their re-

absorption of chloride as an adaptation to the increasedsalt intake. See also Figure 16 in the Appendix.

(ACTH) or Cortisone has, almost without ex-ception, been associated with an increase in GFR.Our data on spontaneous diuresis (Figures 8 and9) show a similar association of diuresis with in-creased GFR (as indicated by the urea clearance).

In patients with this disease, the excessive so-dium reabsorbing activity of the tubules is strik-ingly revealed when sodium salts of unreabsorb-able anions such as thiosulfate or PAH are ad-ministered in large amounts. In normal subjectsduring such administration, the anion excretion ismatched by an equivalent excretion of sodium.However, when these substances are given toedematous patients with the nephrotic syndrome,the urinary anions are "covered" to a large extentby potassium (3941). During remission follow-ing ACTH therapy, the pattern reverts towardnormal in association with an increase in GFR(41). This excessive reabsorption of sodiumcould, of course, be due to primary tubule changes.In fact, other investigators (42) showed that asimilar though limited tendency existed duringsodium PAHloading in normal subjects receivingACTH or Cortisone. However, Lauson andThompson (43) have observed that the same phe-nomenon occurs in anesthetized normal dogs whenGFRis reduced by inflation of a balloon located inthe aorta above the renal arteries. There is noreason to believe that tubule function was primarilyaltered by any known mechanism; Thompson andPitts ( l 1 ) found that reduction in sodium excretioninduced by this technic was apparently related onlyto decreased GFRand was independent of endo-crine or neural influences.

The various possible mechanisms involved inedema formation are summarized schematically inFigure 11. Webelieve that the initial pathologicchanges in the glomeruli may have two functionaleffects: 1) Reduction in the effective filtering sur-face, which directly decreases GFR; and 2) in-crease in the glomerular permeability to albuminand other plasma proteins (16). The resultingalbuminuria lowers the plasma albumin concentra-tion. This would be expected to result in a con-

tinuing shift of fluid from plasma to interstitialspaces which would be limited by secondarychanges in mean capillary and tissue hydrostaticpressures (17). Diminution in plasma volume

641

642

Plasmaprotein

concentrationGm. /lOOcc. i

400Plasma 350Zvolume 300

Cc, 250

Urinary 0protein 6

excretion ^mg/min. 2

40(Urinary chloride 30

excreton 20,'/mrnin. l0

Indogenous 12'creatinine 10cleoronce 8

cc/mnir. 6

Urinefpow

cc/min.

Plasmaprotein

concentrationGm/100cc.

400Plasma 350volume 300

250

UrinaryI

protein &excretion 4mg/min. 21

40Urnary chloride 30

excretion 20#/d'1/lnn 10

ndeognouz 12(acreatinine 10clearance 8

cc./min.

flowccAnin.

EDER, LAUSON,

MIv.3-4,1947 Wt72.7-7241g.

4'.c6

2 .

00

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642

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CHINARD, GREIF, COTZIAS, AND VAN SLYKE

v.-11-12,1947 W.L7-71.5 rW.18-19.2947 Wt71.i-*71.8 k.B%b on 25g fiL per 15th on 25 gm. lbumin p

1

AM. ]2PM. 6 I2An. 6, AK l2xM . 6 12An. 6

Doc 9-10,19? WL69.5- -B8 k21st mon 50m. albumin p day

I~~~~~~~~~~~~~~~1f. 1 1

...J

6AMi. l2EM. 6 12AIl.6

(Fig. 6 continued on opposite page)

EDEMAFORMATIONIN THE NEPHROTICSYNDROME

would be likely, and in this circumstance circu-latory "inadequacy" could develop.

It has been difficult to determine whether the plasmavolume is actually reduced. In the past, errors in themeasurement of plasma volume by dye dilution methodshave been large because of the hyperlipemia occurring inthese patients (44). Moreover, the reductions are likelyto be only small or moderate (as compared to those insevere hemorrhage or burns). Thus, the only reallyadequate control values would be those in the patient him-self before the onset of the illness or after complete re-covery. Wehave data on only one patient in whom thisrigorous criterion was satisfied: in C. M., the plasma volumewhich repeatedly measured about 2100 ml. during thephase of severe edema increased to and stabilized at valuesaround 2800 ml. after recovery (see Figure 16 in theAppendix). The corresponding whole blood volumes wereabout 3200 ml. and 4200 ml., respectively. Another pa-tient, A. McE., was studied during two phases of severeedema (Oct. 6, 1948 and Feb. 6, 1949) and again in Nov.,

Cd'A19o M).30-3,97 Wt5&0-6 kg. JwL14-1%1947 Vt. 61

G hl/lOOcc. M.

04000'

volume I0

MmD L

Urinary Wrotn.eniexcrletion 4=/i- 20

Urifl ciryc1oide 300'excreton 200,

clearance 860

flowUr/ine 4

1949 when she was practically free of edema as the resultof a spontaneous partial remission (see Figure 14 in theAppendix). The first plasma and blood volumes wereabout 1000 ml. and 1450 ml., respectively; during the remis-sion they were 1150 ml. and 1750 ml., respectively. Duringthe interval her height increased from 106.0 cm. to 111.5cm.; it would be expected that as a result of this growthher blood volume would have increased by about 100 ml.(45, 46).

In most patients the development of circulatory"inadequacy" is probably sufficiently gradual sothat frank symptoms occur uncommonly. In some,however, severe proteinuria may appear quitesuddenly and symptoms suggestive of circulatoryinsufficiency arise. Such a sequence was observedin S. G. and is summarized in Figure 12. Proteinexcretion increased suddenly from about 5 Gm. per24 hr. to 16 Gm. per 24 hr., plasma albumin con-

@Tan2.SrD -21 18 Wt. GLO-Blx1 g. .Feh56,1948 Wt 6&3-6&O Wei ore5 day ater last albumin 20 day aft&& la t albumin

I7TTTmii 7777 I

ANt. I PFl4. IAX.t

FIG. 6 A, B, C. SUMMARYOF AROUND-THE-CLOCKDATA ON L. B. (MAim, AGE 19 YEARS; ONSETOF ILLNESS, 40MONTHSPREVIOUSLY) BEFORE, DURING, AND AFTER A COURSEOF ALBUMIN THERAPY

The solid block at top of upper row represents the time during which albumin was administered as 10 per centsolution. The solid columns in upper row indicate plasma albumin concentration (Howe's method). Plasma proteinconcentrations and plasma volumes represented by dotted lines were estimated from values at corresponding times onpreceding or succeeding days. Note the gradual decline in Ccr as renal function slowly deteriorated. During the pe-riod of these observations 24-hour fluid intake was 2400 ml. On Dec. 20, albumin therapy was stopped because of asevere upper respiratory illness with asthma. On Dec. 26, it was resumed as a second course (*).

643


FIG. 7. SUMMARYOF DATA ON K. S. (MALE, AGE FOUR AND ONE-HALFYEARS; ONSET OF ILLNESS, THREE YEARS PREVIOUSLY) BEFORE, DURING, ANDAFTER A COURSEOF ALBUMIN THERAPY

U. R. I. indicates severe upper respiratory infection which was accompaniedby dyspnea, weakness and gallop rhythm; these symptoms disappeared afteralbumin therapy was stopped and as the infection subsided. CGe was calculatedas the 24-hour excretion (in mg. per min.) divided by the plasma concentration(in mg. per ml.) of creatinine-like chromogen measured each morning. Duringthe period of albumin therapy, the urea clearance and plasma protein concentra-tions were measured in the morning prior to the albumin infusion; albumin wasestimated by Howe's method.

centration fell from 1.7 to 1.2 Gm. per 100 ml., andthe plasma volume decreased from about 2700 ml.to 2100 ml. As these changes were occurring, thepatient experienced mild vertigo, feelings of faint-ness, palpitation, and thirst. After administrationof albumin the plasma volume increased and thesymptoms disappeared.

The primary glomerular insufficiency consequentto circulatory "inadequacy" and/or decrease inarea and characteristics of the filtering surface hasalready been discussed. The observation that pe-riods of increased salt and water excretion did notalways correspond to periods of increased C,r in-dicates that other (tubular) factors were operative.Evidence suggesting that primary tubular pre-ponderance may play a part in the genesis of edema

in the nephrotic syndrome has been reviewed re-cently (2). Possible factors are antidiuretic sub-stances and adrenal cortical hormones (36, 37, 47-55), increased intrarenal pressure due to renalinterstitial edema or to ascites (29, 56-58) andautonomic nerve influences (59-62). The viewthat tubular reabsorption of sodium is influencedby the renal nerves is opposed by Surtshin, Mueller,and White (63) and by Berne (64). Nothing isas yet known of the mechanisms whereby any ofthese factors are brought into operation.

The sequential relationship of some of themechanisms shown in Figure 11 is well illustratedby the data on A. McE. presented in Figure 13.Daily administration of albumin had resulted in theloss of all edema in this five and one-half year old

644A


Vwigght 2a:(kg.) 20-

18 Ideal weight

10-

Protein _excfetion 6 _(gmzndcoy) 4 7

0

160

Chloride 120exceetion(mN/day) 80

40

0

150

Urea

clearance 110-

(7. of 90age 70normal) a

so -

10

7_

6

plo.ena 4-

protein 3 _

Previouo durationof illnems o0 20

1 month Hospital dcays

0 0

-'Ae

w v w w 7 w 9 135 259

FIG. 8. SUMMARYOF DATA ON B. M. (MALE, AGE FOURAND ONE-HALF YEARS; ONSETOF

ILLNESS, ONEMONTHPREVIOUSLY) WHOEXHIBITED SPONTANEOUSDIuRESIS WITH COMPLETEREcovERY

Protein excretion was estimated by the Shevky-Stafford method (18). The solid columnsin the lowest row indicate plasma albumin measured by Howe's method.

645


wody 16 --- -

Xg. 14MIdeail

12 weight6 -1ever (105&F)'Prtein4

texcretion

9m./dayO 0

Chloride 120excretion 80

N/day 40

3~~~~~

120

UPeaclearance 80

%ofaverage

norl 40

Previou8 duration

of i11ne« 10 20 50 60 706 weekcs Hospit days

FIG. 9. SUMMARYOF DATA ON S. M. (MALE, AGETHRE AND ONE-HALF YEARS; ONSETOF DISEASE, ONEAND ONE-HALF MONTHSPREVIOUSLY) WHOEXHIBITEDSPONTANEOUSDiuEsis WITH COMPLETERECoVERY

See legend to Figure 8 for methods.

girl. Restoration toward normal of plasma al-bumin concentration, plasma volume, and Cer hadfollowed each infusion. The changes which fol-lowed the final dose give some indication of howrapidly these measurements might decrease at theonset of the nephrotic syndrome as a result ofsudden development of massive albuminuria.

CONCLUSION

Any current hypothesis of the mechanism ofedema accumulation in the nephrotic syndrome isnecessarily tentative. There is general agreementthat the retention of water, sodium, and chlorideis the result of glomerulo-tubular imbalance. Still

undecided is the question as to which is the moreimportant cause of the excessive tubular reabsorp-tion: "primary glomerular insufficiency" or "pri-mary tubular preponderance." It is our opinionthat glomerular insufficiency is present in mostpatients with this syndrome. We regard thismechanism as the more fundamental: if GFRweresufficiently depressed, the salt and water retentionwould occur regardless of factors acting directlyon the tubules. When GFR is only slightly de-pressed or is in the normal range, these tubularfactors may be more significant.

SUMMARY

An attempt has been made to determine the im-portance of insufficiency of glomerular filtrationas a cause of the excessive renal tubular reabsorp-tion of salt and water in patients with the nephroticsyndrome.

Following the administration of concentratedhuman plasma albumin, the clearance of endoge-nous creatinine-like chromogen (Car) increased inmost patients; this increase correlated fairly wellwith increase in excretion of sodium, chloride, andwater in a large number of clearance periods.

In three patients, spontaneous diuresis was as-sociated with an increase in C,r or urea clearance.

Even in a patient with normal to supernormalCcr, there was some relationship between diuresisand chloruresis and further acute increase in C,r.In this type of patient, other tubule functions (Tmfor glucose and p-aminohippurate) were elevatedabove normal to a greater extent than was glo-merular filtration rate.

The fact that periods of change in salt and wa-ter excretion did not always correspond to pe-riods of change in Gcr suggests the operation of ad-ditional (tubular) factors. The relative importanceof the two types of glomerulo-tubular imbalance("primary glomerular insufficiency" and "primarytubular preponderance") in the causation of waterand salt retention in the nephrotic syndrome can-not be assessed at present.

APPENDIX

Case summaries of A. McE. and C. M. are presentedbelow to provide background information which will per-mit a more adequate evaluation of the data from the special

646

EDEMAFORMATIONIN THE NEPHROTICSYNDROME 647

SGO. A9 -0 you's Hoach 23-54,1948 693-- 66.4 kg. Noech 25-26,1948 Wt. 653 65.7 kg. May 5-6,1948 Vt. 71.8-10.3kg.Neplwotrc zndrose 8tn day on 25 gm. albumin p dcy 2nd day after Jast albumin 5m day of pontcneous diu.ens

6 Recumbent-H Up l*mbentl -ecumbent-l Up tRecumbentvif'lazrn 5pmen 4

concentration mGm. /100cc. 2

0

4cune 5000Not measured

20

po/rein jX 777

0~~~~~~~~~~~~~~~~1?1lasma chlopideconcentpaction

5w-15 .0

lJrinar'y chlor'ide 500

Endogenous

A n. IEn. 6 ilA 6 1Ait 12ps 12A±. 6 bA l2pn. 6 12A2 6

FIG. 10. SUMMARYOF AROUND-THE-CLOCKDATA ON S. G. (MALE, AGE 20 YEARS; ONSETOF ILLNESS, FIVE AND

ONE-HALF YEARS PREVIOUSLY) FROMA DAY IN WHICH DIURESIS FOLLOWEDALBUMIN INFUSION (AT TIME INDICATED

BY SOLID BLOCK AT TOP OF UPPER ROWON LEFTr), A DAY OF FLUID ACCUMULATIONAFTER CESSATION OF ALBUMIN

TREATMENT, AND A DAY OF SPONTANEOUSDIURESIS

The solid columns in the upper row indicate albumin concentration measured by Howe's method. Total intake of

fluids as such was 2100, 2000, and 1800 ml. on these days, respectively.

TABLE I

Supernormal tubular functions in patients with the nephrotic syndrome *

Patient Idealand surface GFR CPAH GFR GFRdate Sex Age area GFRt CPAH TmPARn Tmol CPAH TmPAH TmPAH Tm0

yrs. M' ml./min. ml./min. mg./min. mg./min.Normal II 127 655 77 375 0.19 8.4 1.6 0.34

C. C.12- 4-46 F 5 0.794 160 1120 203 0.14 5.5 0.793- 4-47 0.805 127 679 0.194-24-47 0.805 148 840 160 0.18 5.2 0.925-13-47 0.805 125 922 138 0.14 6.7 0.916-26-47 0.816 139 887 165 0.16 5.4 0.84K. S.1f2-18-47 M 4 0.671 146 548 161 0.27 3.4 0.91

J. B.12- 4-47 M 4 0.752 147 196 0.75

S. G.12-14-48 M 20 1.66 138 833 115 0.17 7.2 1.212-17-48 1.66 155 603 0.26

* All values are corrected to a surface area of 1.73 square meters on the basis of height and ideal weight (23).t Mannitol (24) clearance in C. C., K. S., and J. B.; inulin clearance in S. G.

The unbound fraction of plasma PAHwas estimated from the nomogram of Taggart (25).Glucose was determined by slight modification of the method of Miller and Van Slyke (26).Mean values for adult males were taken from Smith (1), pages 91 and 544.

1 Renal functions had decreased considerably below these values by the time that the observations shown in Figure 7were made.

648

Decreafiltering

EIDR, LAUSON, CHINARD, GREIF, COTZIAS, AND VAN SLYKE

UNKNOWNETIOLOGIC FACTOR(S)

Glomerular changes

ase in Increased glomerular permeabilitysurface to albumin (proteins)

Albuminuria (proteinuria)

Hypoalburninenmia (hypoproteinemia) Tubular changes

Continuing net transfer of fluidfrom plasma to interstitial space -

Decreased plasma (blood) volum A i rrenal

Circulatory 'inadequacy" I

--w Decrease-renal ? ? ? ? ? ? ?blood flow _ _.

fDecreased glomerularA.' Increased secretion of Increased Otherfiltration rate salt-active adrenal steroids \ intrarenal causes

and antidiuretic hormone pressure

(Primary glomerular 'insufficiency') (Primary tubdlar 'preponderance)

'Excessive tubular reabsorptionof filtered NaCl and water

Retention of NaCl and water

EDEMA

FIG. 11. PossIBL1 MECHANISMSIN THE PATHOGENESISOF EDEMAIN THE NEPHROTICSYNDROME

The line connecting "Glomerular changes" to "Decrease in filtering surface" is brokento indicate that such decrease does not always occur, as judged from the observation thatin some patients GFRmay be normal or supernormal and from the histologic evidencethat glomerular lesions are minimal in some cases. Decrease of pressure in partially orcompletely obstructed glomerular capillaries would decrease GFR. It is also possiblethat the glomerular lesions may cause afferent arteriolar constriction locally. The term"Decrease in filtering surface" is intended to apply to both of these circumstances.

-


:3G. Age 20

'Pr'oteinexcretiongm2/4hr5.

c

Plasmaalbumin 2-gm. /100 Ca

'Pla5ma 2000volume

cc. ,

01 , .SI

10 15 DDays

FIG. 12. EFFECT ON PLASMA ALBUMIN CONCENTRA-TION (HOWE'S METHOD) AND ON PLASMA VOLUMEOF

SUDDENSPQNTANEOUSINCREASE IN PROTEIN ExcRETIoNThe patient had only a moderate amount of edema and

had been admitted for another purpose a few days earlier.Routine 24-hour urine collections and hemoglobin andplasma protein measurements were made. On about day10, the patient began to complain of the symptoms de-scribed in the Text. Plasma volume was measured by theT-1824 method the next morning and on the subsequentdays shown. Plasma volumes on days 1, 4, and 8 were

then estimated in retrospect as follows: From the he-moglobin values of days 1, 4, and 8 and from the averageof the mean corpuscular hemoglobin determined on threelater days, estimates of the hematocrits for days 1, 4, and8 were made. These values (ht) were substituted in theequation, V." = V350 (1.00-0.955 ht)/0.955 ht, whereV." is the calculated plasma volume for day 1, 4, or 8and VEEC is the volume of red cells (assumed constant)calculated from the T-1824 volume and hematocrit meas-

ured on day 11.

studies described in the present report and in the preced-ing papers of the series (16, 17, 65).

A. McE. (RIH 12,352). This 5-year old female was

admitted to the Hospital of the Rockefeller Institute on

Sept. 23, 1948 because of recurrent generalized edema dur-ing a two year period. Physical examination showed se-

vere generalized edema and ascites; the blood pressurewas 115/90.

This patient's course during a period of one and one-

half years is summarized in Figure 14. During each hos-pital admission the diet was kept nearly constant with re-

spect to protein (40 to 50 Gm. per day), total fluids andchloride (15 to 20 mMper day). During each of the fourcourses of intravenous albumin the patient lost all of heredema; since Nov. 1949, edema has not been demon-strable. During the first course the decrease in thiocya-nate (SCN) space (66) and the increase in chlorideexcretion suggest that the weight loss was almost alldue to loss of extracellular fluid. Moreover, during theperiod of diuresis, the molar concentration ratio of Na/Clin urine approached that found in the extracellular fluid(plasma). In the sixth row of the figure, the scale from0 to 50 indicates ml. per min. and refers to "creatinine"and inulin clearances; the scale from 0 to 100 per cent ofnormal applies to urea clearances which were correctedfor surface area on the basis of height and ideal weight(23). During the periods of albumin therapy, the dataof the bottom two rows were obtained in the morningprior to the day's infusion of albumin. Blood volume hadincreased moderately by the time of the partial remis-sion in Nov., 1949. In the bottom row, the hatched columnindicates albumin concentration as estimated by theHowe method; the solid column represents albumin meas-ured immunochemically (16). Details of around-the-clockexperiments carried out during the first admission areshown in Figure 15.

C. M. (RIH 12,267). This 19-year old girl was ad-mitted to the Hospital of the Rockefeller Institute onSept. 20, 1947 with the complaint of swelling of the legsand abdomen of five-months duration. About two weeksbefore the onset, she had been vaccinated against smallpox and had also contracted poison ivy dermatitis.Physical examination showed generalized edema, ascitesand bilateral pleural effusion; the blood pressure was105/75.

The hospital course is summarized in Figure 16. Dailyinfusion of 25 Gm. and then 50 Gm. of albumin per dayresulted in steady weight loss; the SCN space decreasedabout the same amount as the weight. During the sus-tained diuresis, the loss of chloride could be approximatelyaccounted for on the assumption that only extracellularfluid was lost. On Feb. 10, after recovery, the intakeof NaCl was increased from 21 to 123 mMper day, andthe urinary chloride excretion increased until a newequilibrium was reached about on the fifth day (see Figure5). The 24-hour mean C., was calculated from around-the-clock data, the value of each clearance period beingweighted according to its duration. The rate of proteinexcretion was about 10 Gm. per day during the controlperiod. During administration of 25, then 50 Gm. per dayof albumin, excretion promptly increased to about 25, then50 Gm. per day. Toward the end of the treatment periodprotein excretion gradually decreased; within a weekafter the last albumin infusion, proteinuria disappearedand has not reappeared since. Plasma volume and plasmaprotein concentrations were measured in the morning be-fore the day's albumin infusion. Albumin was estimated bythe Howe method.

Albumin20- 259M.gm.10-

0

649

650 EDER, LAUSON, CHINARD, GREIF, COTZIAS, AND VAN SLYKE

40

Urinary mmetim. ~~~~~~~~~~~~~~~30of totd pfotein," ~~~~~~~~~~~~20-indalbunmin zo

Lm lo24o . 10 _ lo -

03/

0

6 . 6

'Plasma 5 _

Morning t4 40

endogalbumi 3 30

o t (SssesSsSSsSSSSSsSssesEsSsse2s

Bodywaght

O.ct.3 57 9 1315 17 19 21 Jan. 7 226.262B3013 5 221948 Dec. 1949 M1y 1949 June

FIG. 13. SEQUENCEOF CHANGESFOLLOWINGCESSATION OF ADMINISTRATION OF 25 GM. OF

ALBUMIN PER DAY IN A. McE. WHOSERENAL DISEASE REMAINEDUNIMPROVEDWITHIN EACHOF THE TWOPERIODS SHOWN

The final dose in both courses was 37.5 Gm. In the first two rows, the total height indicatestotal protein and the solid portion represents albumin determined immunochemically (16). Inthe fourth row, the values of Ccr are averages from several successive periods measured between6 a.m. and noon.

These data give an indication of the rapidity of changes which might be expected to occur

during the first few days following abrupt onset of severe proteinuria. By Dec. 3, 1948 the pa-

tient had lost all of her edema as a result of albumin therapy and was outwardly a normal child.On the morning of this day 37.5 Gm. were given; within a few hours the plasma albumin con-

centration had increased to nearly 3 Gm. per 100 ml., the plasma volume to nearly 1400 ml., andCcr to the range of 35 to 50 ml. per min. These nearly normal values may be regarded as simu-lating conditions immediately after abrupt onset of severe nephrotic syndrome. During the re-

mainder of this day albumin was excreted at the high average rate of 32 Gm. per 24 hrs. Within48 hours the plasma volume and C., had reached minimum values. The rate of weight gainof 0.12 Kg. per day was limited by the low salt intake of about 20 mMper day; excretion ofsodium was less than 6 mMper day. Had a normal amount of salt been ingested during thistime, a much more rapid weight gain would have been expected. The same measurements madeafter the course of therapy in May, 1949 show the same pattern except that because of a loweralbumin clearance (decreased glomerular permeability [16]) the plasma albumin concentrationfell more slowly and the rate of formation and the equilibrium volume of edema fluid were less.The final measurements on June 22 were obtained in the out-patient clinic. For additional databefore and after these periods, see Figure 14 in the Appendix.

30.5 2.20 -

19- {218-.

0

A 0 -a X

I~~~~~ig1 1 ~~~~~~----t Eq ~~~~~I .1. L

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April301 6 10

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a%P

I II I I 120 30 40 50 60 70 80 90 100 110 120

FIG. 16. SUMMARYOF COURSEIN C. M.

o

166 176

bodyweigfit

kg.

Fluid intakeand

urine volumecc./day

Urinaryexcretion 6nddietavyr intakeof chloride

mMn/day24 hour meanendogenousscreatinineclearance

cc./min.Dietary

nitrogen intakeand Urea+N13

nitrogenexcretion

gm./day

Urinaryprotein

excretiongm./day

Plasmavolume

Plasmaprotein

concentrationgm./IOOc

Totalcirculating

proteingm.

653


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17. Chinard, F. P., Lauson, H. D., Eder, H. A., and Greif,R. L., Plasma volume changes following the ad-ministration of albumin to patients with the ne-phrotic syndrome. J. Clin. Invest., 1954, 33, 629.

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23. Peters, J. P., and Van Slyke, D. D., QuantitativeClinical Chemistry. Vol. II. Methods. Williams &Wilkins, Baltimore, 1932.

24. Corcoran, A. C., and Page, I. H., A method for thedetermination of mannitol in plasma and urine.J. Biol. Chem., 1947, 170, 165.

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26. Miller, B. F., and Van Slyke, D. D., A direct micro-titration method for blood sugar. J. Biol. Chem.,1936, 114, 583.

27. Marshall, E. K., Jr., and Kolls, A. C., Studies on thenervous control of the kidney in relation to diuresisand urinary secretion. II. A comparison of thechanges caused by unilateral splanchnotomy withthose caused by unilateral compression of the renalartery. Am. J. Physiol., 1919, 49, 317.

28. Shannon, J. A., The control of the renal excretion ofwater. I. The effect of variations in the state ofhydration on water excretion in dogs with diabetesinsipidus. J. Exper. Med., 1942, 76, 371.

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654


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36. Luetscher, J. A., Jr., and Deming, Q. B., Treatment ofnephrosis with cortisone. J. Clin. Invest., 1950, 29,1576.

37. Luetscher, J. A., Jr., Deming, Q. B., and Johnson,B. B., Treatment of nephrosis with pituitary adreno-corticotrophin. J. Clin. Invest., 1951, 30, 1530.

38. Metcoff, J., Rance, C. P., Kelsey, W. M., Nakasone,N., and Janeway, C. A., Adrenocorticotrophic hor-mone (ACTH) therapy of the nephrotic syndromein children. Pediatrics, 1952, 10, 543.

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655

EDER, LAUSON, CHINARD, GEIF, COTZIAS, AND VAN SLYKE

62. Kaplan, S. A., Fomon, S. J., and Rapoport, S., Effectof splanchnic nerve division on urinary excretion ofelectrolytes during mannitol loading in the hydro-penic dog. Am. J. Physiol., 1951, 166, 641.

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thetized dog. Am. J. Physiol., 1952, 171, 148.65. Chinard, F. P., Lauson, H. D., and Eder, H. A., Re-

lationship of the renal clearances of T-1824 and of

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656

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