THE IN CHILDREN. AN INTERPRETATION OF ITS CLINICAL, BIOCHEMICAL, AND RENAL HEMODYNAMIC FEATURES AS VARIATIONS OF A SINGLE TYPE OF DISEASE

Jack Metcoff, … , Margaret Hasson, Bernice Goldberg

J Clin Invest. 1951;30(5):471-491. https://doi.org/10.1172/JCI102464.

Research Article

Find the latest version: https://jci.me/102464/pdf THE NEPHROTIC SYNDROME IN CHILDREN. AN INTERPRE- TATION OF ITS CLINICAL, BIOCHEMICAL, AND RENAL HEMODYNAMIC FEATURES AS VARIATIONS OF A SINGLE TYPE OF NEPHRON DISEASE1 2 By JACK METCOFF, W. M. KELSEY,3 AND C. A. JANEWAY WITH THE TECHNICAL ASSISTANCE OF AUDREY ANDREWS, MARGARET HASSON, AND BERNICE GOLDBERG (From The Department of Pediatrics, Harvard Medical School, and The Children's Medical Center, Boston) (Submitted for publication September 25, 1950; accepted, March 12, 1951) It is the purpose of this report to describe and 1) If measurements of renal function would as- interpret the varied renal hemodynamic patterns sist in the early differentiation of benign and associated clinical and biochemical features ob- from progressive , served in 29 children with the nephrotic syndrome 2) if such a differentiation were valid physio- studied between January, 1949, and June, 1950. logically, and Cases of the "nephrotic syndrome" present cer- 3) if studies of renal function would help to tain uniform and consistent clinical' features (1), elucidate the pathogenesis of the nephrotic syn- but their separation into two groups, "nephrosis" drome. A preliminary report has been published and the "nephrotic stage of nephritis," has been (16). rather arbitrary and frequently difficult. Normal Lacking the biopsy material which would peD- or supernormal renal function (2) on the one hand, mit morphologic description of the diseased organ, and , , and (3-6) the results of our physiologic studies seem to cor- on the other, have been the classical criteria for roborate an earlier suggestion, based on patho- this distinction. However, review of the clinical logic studies, that both "degenerative" lipoid ne- course of patients classified as "nephrosis" with phrosis and "inflammatory" subsequent complete remission, has shown that are characterized by anatomical lesions and dis- moderate hematuria, hypertension and azotemia turbances in function which are identical in kind, were common transiently observed phenomena (7- but different in degree (17). The data of this re- 10). Moreover, serial renal function studies have port indicate that the glomerulus is a primary site demonstrated varying degrees of functional impair- of the disease process, but the syndrome is fre- ment in patients clinically classified as instances quently characterized by reversible metabolic and of either nephrosis (11, 12) or the nephrotic stage hemodynamic rather than solely by irreversible of glomerulonephritis (13-15). anatomic damage of the nephron. This study was undertaken in order to deter- mine: CLINICAL MATERIAL AND PROCEDURES General plan of study IThese studies were supported by grants from Mead Johnson & Co. and from the National Institutes of Health, Estimations of glomerular filtration rates (GFR), renal U. S. Public Health Service. plasma flow (RPF), and maximal tubular excretory ca- 2 Presented in part before the Society of Pediatric Re- pacity (TmPAH), were made in 29 nephrotic children, search, French Lick, Ind., May 1950, and the Sixth In- with more than one series of simultaneous biochemical ternational Congress of Pediatrics, Zurich, Switzerland, and renal functional studies in 17 of these patients. In July 1950. all, 53 estimations of renal function and biochemical status 8 Post-Doctorate Research Fellow of the National In- were made and correlated with clinical courses. Of the stitutes of Health, U. S. Public Health Service; Asst. 29 patients, only two were over 6.5 years of age at the Professor of Pediatrics, Bowman Gray School of Medi- time of first admission. Three patients were over 6.5 cine, Winston-Salem, N. C. (on leave of absence). years of age at the time initial renal function studies 471 472 JACK METCOFF, W. M. KELSEY, AND C. A. JANEWAY

TABLE I ml. whole blood was collected in 10 cm. long, 3 mm. bore, Clinical status of all nephrotic patients observed during chemically clean capillary tubes-filled by direct capil- interval January, 1949-June, 1950 larity from finger puncture (18). A drop of dilute was used to wet the bore when plasma was desired; how- Clinical status* ever, a considerably better yield of serum was usually Nephrotic No. of obtained from the same aliquot of non-heparinized blood. patients patients Maleses Remission Good Poor Dead The capillary tube, when filled, was capped with flanged flexible rubber caps.4 Twenty to 40 seconds were usually This report 29 11 lot 6 3 10t required to fill a tube. After centrifugation for 30 min- utes at 2,500 rpm, the tube was scratched 1 mm. above Remainder 61 45 20 22 9 10 clinic the level of packed cells, the cap at the serum end of the group__ tube removed, and the serum-containing portion of the tube carefully broken off and recapped. The heparinized Total 90 56 30 28 12 20 blood hematocrit was read directly by alignment of the Per cent 100 62 33 31 14 22 tube against a millimeter rule. Approximately 0.2-0.3 ml. serum was thus available per tube. Two or three micro- tubes obtained per period sufficed for duplicate determina- * Remission = No edema, normal diet, full activity, minimal to absent proteinuria for at least tions. Where simultaneous thiosulfate, inulin, and PAH two months. clearances were done, four or five tubes were obtained Good = Edema, proteinuria, hypoproteinuria, per period. The relatively small yield of serum, however, hyperlipemia, no , acidosis, azo- necessitated micromodification of usual procedures. temia. Urine specific gravity 1.018 or more. Renal function studies Poor = Nephrotic syndrome with anemia, aci- dosis, azotemia, urine specific gravity Patients were hospitalized and confined to bed for 18 "fixed" 1.010. to 24 hours prior to study. Fluids were allowed ad lib. t Three patients have relapsed since this report was No food was offered during the eight hour period pre- submitted for publication. ceding the test. All clearance studies were begun at $ Two patients died shortly after this report was pre- approximately 8:30 a.m. Using a dose based on age, pared for publication. premedication with morphine sulfate and atropine sulfate was employed in about two-thirds of the studies in order were done. All other patients were less than five years to reduce apprehension in uncomfortable, edematous chil- of age. Omitting two extremes of age, the mean age of dren. In general, commonly accepted techniques with the group was 3.3 years and median age 3.0 years. Com- few minor modifications were employed. A single in- ments on the physiological disturbances of electrolytes jection of thiosulfate and constant infusion of inulin and and body fluids will be the subject of another report. PAH were used. Urine was collected through an in- Appraisal of the factors which determined the selection dwelling, multi-eyed 8-14F catheter. The bladder was of the particular patients for study from our clinic group washed at the end of each period with sterile distilled wa- was extremely difficult. Patients usually appeared in the ter and with air. Urine volumes, including wash, were clinic soon after manifestations of the disease were noted. recorded to the nearest 0.1 ml. Thirty minutes were al- The observed group of patients, therefore, was not un- lowed for equilibration after the priming injection. duly weighted by the usual preponderance of severe or Consecutive 15 minute collections of urine were then made advanced cases commonly noted in hospital samples. for six to ten periods. In the majority of instances, blood An attempt was made to select for study children with samples were obtained at approximately 30, 60, 90, 120, nephrosis and both with and without hematuria and/or 150, and 180 minutes and midpoint values of each period azotemia, and with active disease of varying duration. determined by interpolation. It was not possible to cor- The sex distribution and clinical status of the patients rect for urine delay time. A control venous blood sam- studied is related to that of the total group of 90 neph- ple was obtained under oil for blank determination and rotic children observed in this clinic during the same analysis of various serum chemical components. All sera time interval (Table I). The inclusion of fewer males in *and urine aliquots for thiosulfate and inulin analysis were the study sample may be attributed to reluctance to cath- precipitated within two to four hours. Analyses were eterize male children with marked edema of the genitalia. completed within 24 hours. Blood samples METHODS Serum or plasma concentrations of the test substances Glomerular filtration rate (GFR) was determined using employed were, in the majority of instances, measured a single injection of thiosulfate (Na,S,,O.5H,O) in "arterial" blood obtained from capillary puncture. An inlying venous needle with fitted stylette was frequently 4Obtained from the West Company, 1117 Shakamaxon used in larger children for sampling. Approximately 0.5 St., Philadelphia, Pa. THE NEPHROTIC SYNDROME IN CHILDREN 473 (19) in the initial 19 observations. In the majority of in- terms of optical density was derived. The constant, rather stances, simultaneous inulin and thiosulfate clearances than a standard transmission curve, was used for calcu- were measured. Approximately 30 mM. (8 gm.) Na2S2O, lation. Little variation in constants was observed in 5H2O per square meter of surface area were administered more than 70 multiple recovery determinations. as a freshly prepared 10-17% solution. Unpleasant re- Constant infusions of PAH following a priming dose actions to relatively rapid infusions (6-10 ml./min.) of were used to measure renal plasma flow (RPF) and max- this solution were rare. Concentrations of thiosulfate in imal tubular excretory capacity (Tm) (23). PAH was serum and urine were determined in duplicate, with diluted in 5% glucose for clearance and in distilled H2O micromodification for serum, according to the standard for Tm determinations. Priming doses were diluted in periodate titrometric method. Semilogarithmic plot of distilled H20. The observed PAH clearances may be low urinary thiosulfate excretion and of serum concentra- because of the unrecognized reaction of PAH with glu- tions against time usually followed decremental straight cose (24). In the initial renal function studies, glomeru- lines of varying slope. Initial serum concentrations ap- lar filtration rates were determined with thiosulfate im- proximating 40-60 mg./100 ml. were usually obtained. mediately prior to RPF and subsequent Tm periods. The inulin clearance determined by a constant infusion Thereafter, simultaneous inulin and PAH clearance and technique was measured simultaneously with thiosulfate saturation studies were carried out. Concentrations of and PAH clearances in the majority of instances.5 Serum PAH in serum and urine were determined by micromodi- concentrations of inulin usually approximated 20-80 mg./ fication of a standard method (22). At high serum con- 100 ml., and of PAH, 1.5-4.0 mg./100 ml. Inulin in se- centrations, 1.0 ml. aliquots of the supernatant solution ob- rum and urine was determined by method of Roe, Epstein, tained after precipitation (vide supra) were diluted 20 and Goldstein (21) with minor modification. The stand- times with distilled water and color was developed in 10 ard acid CdSO4 protein precipitating solution (22) was ml. aliquots by standard macro technique. Color was read found to give as satisfactory recoveries as the Somogyi at 540 min in the Coleman Junior spectrophotometer. reagents, and therefore this deproteinizing agent was used. Standard recoveries and determination of recovery con- For precipitation, serum in the microtubes was trans- stants were carried out with each series of analyses. ferred by capillarity into a calibrated 0.2 ml. (normax Serum blanlc was determined by difference. Urine blanks grade) ¢ pipette and delivered with three washings into were found to be negligible at the dilutions used (1: 2,500- 2.0 ml. distilled water contained in a 3-4 ml., 10 mm. bore, 10,000). precipitin tube. The standard CdSO4 precipitation was Impairment of the renal tubules may decrease the ex- completed using one-tenth quantities of reagents. After traction ratio and may invalidate the use of uncorrected standing 10 minutes, the precipitate was compacted by clearances for the measurement of renal plasma flow. centrifugation for 20 minutes at 2,000 rpm. Duplicate Renal PAH extraction data are not yet available in in- tubes were prepared for each specimen and afforded suf- fants and children. Cargill has reported values for renal ficient supernatant for duplicate determinations of PAH PAH extraction of normal adult patients and of nine and inulin. Optical density of color for inulin and PAH glomerulonephritics with varying levels of observed PAH was determined in a Coleman Junior spectrophotometer. clearance (25a). An exponential extraction curve has Maximum absorption of the resorcinol-inulin complex oc- been constructed from these data and used to "correct" ob- curred at 510 ny. Standard recoveries were determined served RPF for approximate extraction in order to af- with each series of analyses and an average constant in ford an estimate of "corrected" renal plasma flow (RPFe). An assumption of this type has obvious limi- 6A comparison of 118 simultaneous thiosulfate and inu- tations, but occasionally seemed to yield a more reason- lin clearance periods indicated fairly good agreement at able range of magnitude for renal plasma flow. all clearance levels, although the quantitative significance of values obtained at apparently low levels of filtration is Estimation of surface area questionable. Occasional widely discrepant values were The estimation of surface area in the persistently ede- noted. Thiosulfate clearances were usually greater than matous child presents an obvious problem, and ideal weight tiosulfate in relation to height and age is unreliable in children those of inulin. The average clearance ratio inulin for all periods was 1.1. Greater discrepancies were ob- whose disease is of sufficiently long duration to impair served with the highest clearance values. The correlation linear growth and induce chronic with coefficient of thiosulfate versus inulin clearance was 0.88 ± wasting. ,A reasonable approximation of "non-edematous 0.09. The mean discrepancy between all values for simul- weight" usually was derived by comparing the observed taneous thiosulfate versus inulin clearance was 5.5 + 3.9 volume of distribution (VD) of thiosulfate in the edematous patient to a presumed "normal" VD estimated from thio- C thiosulfate, ml./min. The ratio, C inulin was apparently inde- cyanate space regression equations for height (25b). pendent of serum concentration of thiosulfate, r = 0.36, SCN and S20J may occupy somewhat different apparent in contrast to observations in pregnant women (20). distributions in view of the protein binding of SCN (26); 474 JACK METCOFF, W. M. KELSEY, AND C. A. JANEWAY neither accurately measures extracellular fluid volume.6 The onset of symptoms was estimated from his- Occasionally such estimation of surface area (SA) was tory. Since many of the children who developed obviously inadequate. Post-diuresis weight then was used < , t . ~the disease were quite young, observations of to correct previous measurements of renal function to th o s of unit values. Using the derived value for "non-edematous growthdiseas and physicaliwer quitun,status, occasionallybsion including weight," SA was estimated either by calculation or from blood pressure and urine examination, had often nomograms constructed from the standard DuBois rela- been made by the family physician prior to onset of tionship: SA = W" X H72 x 71.84. the nephrotic syndrome. When available, such Other measurements information confirmed the absence of antecedent Serum proteins were determined by micro-Kjeldahl renal disease. Since renal disease of this type in analysis. Serum NPN (27), gasometric CO2 content children is usually associated with marked loss of (28), pH (29), and cholesterol (30), were determined by appetite, lassitude, , and personality change standard methods. Plasma volume determinations,7 using or irritability before edema is more than suspected, Evans blue (T-1824) and a modification of an acetone ex- werecariedoutin ll atints .parents werew apt to consult the traction technique (31), advent of definite edema. Intheirno instancephysicianwaswithgross immediately prior to clearance studies. hematuria, elevated blood pressure, or cardiac fail- RESULTS ure observed by the first physician to see the patient I. Clinical observations in the early phases of the disease. Upper respira- tory or other infections preceded the onset of the A summary of the clinical features of patients nephrotic syndrome in only seven of 29 patients. studied by clearance techniques is given in Table All patients with the nephrotic syndrome at the II. time of initial observation in this clinic presented 6 The use of VD thiosulfate for the estimation of "non- the rapid or insidious onset of edema as a chief edematous weight" is indicated by the following example: complaint. Oliguria, marked proteinuria, absence Patient CB, Male-Age 1-11/12 of gross or marked microscopic hematuria, hypo- Edematous-Before diuresis proteinemia (micro-Kjeldahl), and elevation of se- Height = 90.8 cm. rum cholesterol were constant features. Cardiac Initial volume distribution (VD) Na2S2O = 8.26 L. enlargement was not observed but variable values Predicted normal VD for height* = 3.32 L. for blood pressure and NPN were obtained in all Estimated volume edema phases of the disease (Table II). Spontaneous di- (predicted decrease VD) = 4.94 L. uresis, frequently observed in the first weeks or Estimated weight edema = 4.94 X 1.02 = 5.04 Kg. months of the disease, was usually associated with Actual weight 17.70 Kg. temporary improvement in the values for urine Edema 5.04 and blood constituents. Estimated non-edematous weight for predicted change in VD 12.66 Kg. H * Where VD (NaScN) -6.14 + 0.1042 H for SA - 0.5 ematuria, azotemia and anemia - 1.2 M' (25b). The clinical data indicated that hypertension, Non-edematous-After diuresis microscopic hematuria, and/or slight to moderate Height = 91.5 cm. azotemia during the early months of the disease Final volume distribution (VD) NagS2Oa - 3.23 L. often were unreliable indices of the functional Observed decrease (VD), 8.26 - 3.23 = 5.03 L. state of the kidney or subsequent course of the dis- Estimated weight change from observed ease. However, essentially hyperbolic correlation change in VD -5.03 X 1.02 = 5.133 Kg. ae oee,esnilyhproi orlto PredictedPredice Weightweight frOmfrom aCtUalactual VVD, was found between elevation of the NPN and di- 17.70 - 5.13 = 12.57 Kg. minutioniuinoof GFRF (FigureFgr 1))aas previouslyrvos notedoe Observed non-edematous weight = 11.88 Kg. (32-34). Similarly, the occurrence and extent of Error of prediction = 0.69 Kg. 6% acidosis, as indicated by serum CO2 content and Estimated ideal weight from height - 13.50 Kg. pH, was found to correlate roughly with reduction 11.88 of GFR (35, 36) (Figure 2). The simultaneous Error of prediction = 1.62 Kg. 14% variation of pH, CO2 content and non-CO2 serum 7 Detailed data will be the subject of another report. buffers in relation to GFR was expressed according la 0 Co 0 I. 6 A co 0 060 t.. I) 1 04 E - 0 0 -.4 I 0) a co 0 4.W E 0 ..41- .1 .guol s 0v a, ., I0 I 1-0o 4) 6. 41.0 i~ CO.0 Ir.9 1 . 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477 478 JACK METCOFF, W. M. KELSEY, AND C. A. JANEWAY

RELATION OF SERUM NON-PR,OTEIN NITROGEti TO SIMULTANEOUSLY DETERMINED GLOMERULAR FILTRATION RATE IN CHILDREN WITH THE NEPHROTIC SYNDROME

801

NPN r MEAN NORMAL GFR +2c SERUM - 60 MG/100 ML 00

40 - - ?Vp - . -i- .-0 * 5 0 0 NORMAL RANGE * O5q 0 20 _

0 20 40 60 80 100 120 . GLOMERULAR FILTRATION RATE ML/MIN/M FIG. 1.

ACIDOSIS CONCOMITTANT TO REDUCED GLOMERULAR FILTRATION IN CHILDREN WITH THE NEPHROTIC SYNDROME

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C20 40 60 80 100 120 -GLOMERULAR FILTRATION RATE* ML/ MIN/M' FIG. 2. THE NEPHROTIC SYNDROME IN CHILDREN 479 to the buffer base concept suggested by Singer and have died (Nos. 5, 11, 18, 23, 26, 28); the others Hastings (37) (Figure 3). In approximately have persistent nephrotic symptoms and ample half of the patients, whole blood buffer base was evidence of renal insufficiency. estimated. In these instances, the derived values were slightly different;.the trend and relationships Renal function data were the same. It was evident that reduction of The pertinent renal function data for each pa- serum buffer base was usually associated with re- tient are presented in Table III and may be cor- duced GFR; however, reduction of GFR was ob- related with the clinical and biochemical observa- served occasionally without concomitant lowering tions in Table II. The validity of the "clearance". of serum buffer base. Anemia, when accompany- concept in the presence of nephron damage has ing azotemia and acidosis, completed a triad which been justifiably questioned (3840). Some data indicated marked limitation of renal regulation and on the response to adrenocorticotropic hormone suggested a very poor prognosis. Anemia is rare (ACTH) therapy is included since ACTH may early in the nephrotic syndrome. These three vari- indirectly alter the metabolic activity of viable ables, rather arbitrarily related to each other, have nephron cells (41, 42).9 It can hardly be expected been expressed as a ratio and correlated with GFR to restore destroyed, fibrosed or hyalinized tissue. (Figure 4). The limitations of such an expression Therapeutic response, therefore, affords one pos- are obvious. In most instances, reduction in the sible means of contrasting reversible impairment arbitrary ratio accompanied roughly proportional of function with irreversible destruction of reduction in GFR. However, one child (No. 24),8 parenchyma. with moderate reduction in the arbitrary ratio after 17 months of active disease, appeared to be Glomerular filtration rate. in clinical remission approximately one year later The distribution of values for GFR in relation although functional data suggested residual renal to the duration of the disease is depicted in Figure damage. Several children with very low ratios 5. The course of certain patients is indicated. In 8 Here and elsewhere, patients' numbers are as in Tables 9 A detailed report concerning physiologic and clinical II and III. response to ACTH is in preparation.

AVAILABLE SERUM BUFFER BASE RELATED TO GLOMERULAR FILTRATION IN CHILDREN WITH THE NEPHROTIC SYNDROME

4' . * *ORMAL I RANGE

0 .1 * 00 SERUM BUFFER BASE MEO/L

-2 . MEAN NORMAL GFR +2 . * 0

30

0 FIXED ACID EXCESS VALUES FOR (S,. OD OR BASE DEFICtT DERIVED FROM PHs *"D [COIJ AF,TERt a SINGEReI HSTINGS 25 0 IB.I,.OCO,. NON-CO SUFFER

20 40 60 s0 120 GLOMERULAR FILTRATiON RATE ML / MIN/ M __L FIG. 3. 480 JACK METCOFF, W. M. KELSEY, AND C. A. JANEWAY

RELATION OF HEMOGLOBIN, SERUM NON-PROTEIN NITROGEN BUFFER BASE TO GLOMERULAR FILTRATION RATE IN CHILDREN WITH THE NEPHROTIC SYNDROME

25 GFR-2c

20*

NPN *

_* *______MIN IM *N L RATIO

*ESTIATED NORMAL UMIT6 MINIMUM RATIO * J40 * 12

* MAXIMUM RATIOI0 f4BA .35

O . 20 40 60 so 100 120 GLOMERUIAR FILTRATION RATE ML/MI/M

FIG. 4.

RELATION OF GLOMERULAR FILTRATION RATE TO DURATION OF THE NEPHROTIC SYNDROME IN CHILDREN

FIG. 5. THE NEPHROTIC SYNDROME IN CHILDREN 481

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filtration. An increase in filtration rate was ob- served twice in the same patient (Nos. 14, 173) fol- lowing successive courses of treatment with ACTH with diuresis. Spontaneous or ACTH induced im- provement of GFR after many months of active disease was also noted twice (Nos. 192, 242). With continuation of the disease, progressive lowering of GFR was ultimately associated with renal failure. Extreme reduction in GFR was noted (No. 18k, 2) for many months before clinical evidence of renal failure became apparent. Dem- onstration of diminished filtration after 17 months of active disease did not preclude apparent clinical remission, (No. 24). Subsidence of nephrotic symptoms and signs after a protracted course was usually characterized by persistent evidence of minimal inflammatory renal response and slightly reduced GFR (Nos. 17, 242, 29). Relatively early clinical remission was accompanied by normal GFR (No. 21). 10 20 SO 40 DURATION Of NEPHROTIC SYNDROME, MONTHS Renal plasma flow FIG. 6. Unlike GFR, greater than normal values for ap- general, glomerular function in the nephrotic syn- parent renal plasma flow were occasionally ob- drome varied with duration of the disease. Uni- served during the first months of the disease (Fig- formly reduced filtration rates were noted in nine ure 6). Marked elevation of renal plasma flow patients observed during the initial 2.5 months of was observed concomitantly with supernormal the disease. Occasionally, supernormal values GFR (Nos. 10, 16) as well as with moderately were noted in the following few months. More (No. 5,), or markedly (No. 3) reduced GFR. In commonly, progressive reduction occurred. several instances, elevation of the filtration rate was Diuresis, which occurs spontaneously in many associated with diminution of renal plasma flow nephrotic children during the first weeks or months (Nos. 11k, 17,). It was evident that change in of the disease, usually was associated with im- renal plasma flow could occur without significant provement of GFR. Increased GFR and filtration variation in GFR (Nos. 15, 3, 9, 15, 18, 22). The fraction were not essential to initiate diuresis (42). reverse also was true (Nos. 1, 12, 17). In one instance (No. 12),10 the initial diuresis was Following diuresis, either spontaneous (No. 12) spontaneous; in others (Nos. 82, 122, 171, 3), it fol- or induced (Nos. 14, 173, 122), a definite increase lowed ACTH therapy. Following the initial diure- in renal plasma flow usually was not observed. In sis and during the phase of recurring edema (Nos. one instance (No. 23), RPF was apparently 13, 83 ) reduced filtration was again noted. Four in- doubled. While normal values were occasionally stances of supernormal filtration rates were ob- noted with apparent clinical remission (Nos. 12, served after the first two months of the nephrotic 21), reduced renal plasma flow was also observed syndrome. In one patient (No. 171), the observa- (Nos. 242, 29). Persistence of the nephrotic syn- re- tion was preceded by diuresis initiated with ACTH drome was usually associated with progressive therapy. In others, (Nos. 10, 11, 16), no therapy duction in both measured and "corrected" renal had been employed. Subsequent determinations plasma flow (Nos. 5, 83, 13, 172, 18, 22). reduction of (Nos. 173, 102, 112) revealed striking Maximal tubular excretory capacity 10 Subscript refers to determination number of a given patient; in this instance, to the second renal function study Maximal tubular excretory capacity was usually of patient S. J. within normal limits or was slightly reduced during THE NEPHROTIC SYNDROME IN CHILDREN 485

RELATION OF MAXIMAL TUBULAR EXCRETORY CAPACITY TO DURATION OF THE NEPHROTIC SYNDROME IN CHILDREN

FIG. 7. the first months of the disease (Figure 7). Neither the absence of striking morphologic changes, par- spontaneous nor ACTH induced diuresis com- ticularly of the glomerulus, has been evident (9, monly was associated with significant alteration 11 ). Our data indicate a slight to moderate reduc- in this function (Nos. 12,,4, 122, 173) except tion of glomerular filtration early in the course of in (No. 23). Early reduction in maximal tubular the nephrotic syndrome. Filtration is largely the excretory capacity was apparently reversible, (Nos. resultant of hydrostatic pressure in one direction, 23, 152). With persistence of the disease, progres- oncotic and renal interstitial pressure in the other, sive reduction in TmpAH was observed. With and of the area over which the resultant pressure clinical remission, despite a protracted course, nor- is exerted. Changes in effective renal arteriolar nal values were observed (Nos. 21, 24, 29). resistance may modify filtration (45, 46). The Tubular reabsorption of PAH possibly accounts ratio of glomerular filtration to renal plasma flow for the occasional observation of negative Tm pe- (filtration fraction) defines the filtration equilib- riods (Nos. 3, 23) or apparent extreme reduc- rium. Early in the nephrotic syndrome, the filtra- tion of effective tubular mass (Nos. 5, 10, 11, 18, tion fraction (FF) occasionally was observed to 26-28) .11 be essentially normal; rarely, it was markedly ele- DISCUSSION vated; most commonly it was reduced (Figure 8). Marked distortion of the nephron and its sup- Renal plasma flow was usually reduced early in porting structures with extreme variation in archi- the disease, but filtration appeared to suffer greater tecture is not common in the early phases of the proportionate reduction, although inconstant dis- nephrotic syndrome in children (43, 44). In in- sociation of the two functions was evident (Figure stances where death has resulted from intercur- 9). The relationship between the two variables is rent infection in the early months of the disease, illustrated by means of a correlation diagram of the sort employed by Goldring and his associates 11 Despite rising serum PAH and inulin levels, consecu- (47) and Smith (48). In this diagram, the elipse tive periods commonly revealed little change in Tm al- though a slight tendency toward depression of simultaneous represents the perimeter of a normal surface within inulin clearance was noted. which 70%o of normally correlated values would 486 JACK METCOFF, W. M. KELSEY, AND C. A. JANEWAY be expected to fall. The statistical background for of time usually was associated with gradual re- the elipse was calculated from the data of Rubin, duction in all functional moities. When, in cases Bruck, and Rapoport (49). Spontaneous or in- of the protracted nephrotic syndrome progressive duced (ACTH) improvement of the nephrotic diminution of filtration fraction was observed, as- syndrome was usually associated with an increased sociated changes in RPF/TmpAH and GFR/ filtration fraction. An absolute increase of GFR TmPAH suggested extensive nephron damage. usually was responsible. Plasma protein concen- These observations are consistent with those re- tration (or content) did not appear to undergo ap- ported in glomerulonephritis (14, 15). preciable diminution with diuresis, and possibly Increased maximal tubular excretory capacity increased. Therefore, further reduction of oncotic following diuresis was occasionally observed in the pressure accounting for increased filtration first few months of the nephrotic syndrome. These seemed unlikely. An increased filtration fraction observations suggest increased activity of the tu- associated with reduced afferent and augmented bular cell. It has been demonstrated that the ex- efferent arteriolar resistance has been observed cretory capacities of the tubular cell may be altered with diuresis in nephrotic edema (42). Improved under certain conditions (50). In either case, the filtration during the nephrotic syndrome might re- concept of primary degenerative, irreversible change sult from decreased interstitial renal (subcapsular) of the tubular tissue seems untenable. With clini- pressure, alteration in membrane permeability, in- cal remission following many months of an active, crease of the effective glomerular bed by restoration persistent nephrotic syndrome, the effective tubular of normal circulatory channels, or by increase in mass appeared to be essentially normal or only glomerular pressure. It is not possible to choose slightly reduced. With relapse, or progressive, between these alternatives at present. Since re- active disease, reduction of Tm appeared to cor- duced GFRs were demonstrably reversible for relate with relatively symmetrical reduction of variable periods of time, a disease process irre- GFR (Figure 10). This phenomenon has been versibly obliterating glomeruli during the relatively interpreted as evidence for ablation of functioning early phases of the nephrotic syndrome seems un- (48). The simultaneous appearance of likely. Persistence of the nephrotic syndrome with biochemical renal insufficiency (Table II) tended evidence of active renal disease for some period to corroborate this interpretation. Reduction of

RELATION OF FILTRATION FRACTION TO DURATION OF DISEASE IN CHILDREN WITH THE NEPHROTIC SYNDROME

FIG. 8. THE NEPHROTIC SYNDROME IN CHILDREN 487

RELATION OF GLOMERULAR FILTRATION TO RENAL PLASMA FLOW IN CHILDREN WITH THE NEPHROTIC SYNDROME

FIG. 9. effective tubular mass, however, appeared dispro- FF may be contingent upon increased renal inter- portionately greater than diminution of renal stitial pressure, impaired glomerular membrane plasma flow (Figure 11), suggesting hyperemia of permeability, cortico-medullary shunts bypassing the residual tubular tissue. In view of pathologic some glomeruli, or reduction of glomerular pres- studies indicating distortion, vascular obliteration sure. Diminished oncotic pressure would tend (51), and relative renal ischemia in advanced re- to improve glomerular filtration. Physiologic ad- nal disease (15, 52), it seems likely that the ap- justment might attend reduction of subcapsular and parent hyperemia is vicarious. increased intra-glomerular pressures. Constriction Neither the clinical observations nor the renal of the efferent arterioles, if associated with some functional data clarify the etiology or pathogenesis dilatation of the afferent arterioles, reduced renal of salient features of the nephrotic syndrome such interstitial pressure and minimal alteration of the as edema, hyperlipemia, hypoproteinemia or hypo- glomerular membrane, could theoretically induce calcemia. However, the data of this report form supernormal glomerular filtration. Successful ad- the basis for an hypothesis concerning the renal justment of the metabolic activities of tubular cells hemodynamic adjustments in the nephrotic syn- might result in diuresis and at least temporary re- drome in children (Figure 12). The validity of mission. Recovery would follow successful, per- clearance measurements in the presence of nephron sistent functional reorganization of the nephron be- disease and at very reduced levels of renal function fore irreversible anatomic damage was established. is uncertain and interpretation hazardous. With Failing functional reorganization, or possibly with this reservation, further qualified by limitations of recurrent stimulation of sensitized renal tissues by sampling and the necessity for protracted observa- a primary etiologic agent, gradual distortion of the tion, it is suggested that the initial renal insult, vascular architecture and dependent nephron struc- which may be of immunogenic nature (53), in- tures characteristic of chronic renal disease might volves the entire nephron in variable degree, with then initiate a vicious cycle of glomerular oblitera- early alteration of its functional capacities. Pre- tion with diminished tubule blood flow and vascular ponderance of glomerular or tubular dysfunction shunting. Relatively increased blood flow adja- may be observed. Initial reduction of GFR and cent to residual tubular tissue would thus represent 488 JACK METCOFF, W. M. KELSEY, AND C. A. JANEWAY

RELATION OF GLOMERULAR FILTRATION RATE TO EFFECTIVE TUBULAR MASS IN CHILDREN WITH THE NEPHROTIC SYNDROME

[r IlejI

FIG. 10.

a RELATION OF RENAL PLASMA FLOW TO EFFECTIVE TUBULAR MASS IN CHILDREN WITH THE NEPHROTIC SYNDROME

FIG. 1 1. THE NEPHROTIC SYNDROME IN CHILDREN 489

HYPOTHETICAL RENAL PATTERNS CHARACTERIZING THE dynamic rather than irreversible anatomic nephron NEPHROTIC SYNDROME damage frequently occurs. With progressive dis- UNOETERMIED ? IMWGENIC fACTOWS ease of long duration, markedly impaired renal DFUPISE INVOLVEMENS function TOTAL NE suggested that irreversible parenchymal I destruction gradually supersedes the earlier physio- OUCOTNE CLEOTNOLT NEIULATION AND ICWCATE TUMA aEASONST"om OF logic changes, with culmination in renal failure. oGconT PESSUNE The primary etiologic mechanism remains un- DECREASE NIOWNONJ EN INCEASD GLOMRULAN MEMIt 1STMNE the C ASENOAP*RESIURE determined; however, idiopathic nephrotic syndrome in children, whether called "pure or REDUCED GfR S P.f, lipoid nephrosis," "mixed nephritis," or "nephrotic PwISIOLOGIC IMPAIRMENT | MOPNOLOGIC DAMAOE stage of subacute or chronic glomerulonephritis," RE1 _IIZATN OF FUNCTIONAL PATTERN INABILITY TO ADAPT appears a WITH CESSAlTON Of STIMULATON ASD CONTINUED STIMULATION to be form of nephritis in which func- mINIMAL PARENCIYMALt DESYR=ITION PARENCHYMAL ABLATION tional MAnA OLITE ATION alteration and eventual anatomical changes DECNIASED SLMCAPSLIR RNESSIR MARDESY REDUCED indicate that the glomerulus is a primary site of I If the disease process. With inhibition of the un- PROD emR * .FF. SUIERIIMA. 6Pm s IRNm REDUCED A I TLXSURDLAWe" soatTISiN known etiologic mechanism presumably before ex- tensive anatomic damage has supervened, spon- PENAL FaLR taneous or induced remissions may to ap- RECOVERYN.---REMISSION------proceed parent recovery. FIG. 12. ACKNOWLEDGMENTS a spurious hyperemia and an indication of impend- ing renal failure. We are deeply indebted to the house staff, the nursing staff and the clinical laboratories of the Children's Medi- Since young children, unlike older of- patients, cal Center for their cooperation and assistance in the recover ten following the nephrotic syndrome, the care of these children. We also wish to acknowledge the more favorable tissue reactivity of the young or- valuable assistance rendered by Lewis A. Barness and ganism may explain the different course of this dis- Malcolm Holliday in some of the initial renal function ease in these two age groups. procedures. The manuscript profited from the constructive criticism of Drs. Herbert Chasis and Homer W. Smith. We sincerely appreciate their comments. SUMMARY AND CONCLUSIONS

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