RENAL TUBULAR DYSFUNCTION COMPLICATING THE NEPHROTIC SYNDROME

(1)

RENAL TUBULAR DYSFUNCTIONCOMPLICATING

THE NEPHROTICSYNDROME

Gunnar B. Stickler, M.D., Ph.D., Alvin B. Hayles, M.D., Marschelle H. Power, Ph.D., and John A. Ulrich, Ph.D.

Sections of Pediatrics (G.B.S., A.B.H.), Biochemistry (M.H.P.) and Bacteriology (J.A.U.), Mayo Clinic and Mayo Foundation, Rochester, Minnesota

vitamin D in relatively large doses resulted in healing of the rickets. A metabolic study

of one patient (Case 2) showed that the

administration of adrenocorticosteroids was

followed by a large reduction in the loss

of protein in the urine and in improved

renal tubular function.

Case 1

P ROCRESSIVEglomerular failure as mani

fested by azotemia and hypertension

not infrequently occurs as a terminal event among patients with nephrosis. Renal tubu

lar insufficiency as manifested by amino

aciduria, glycosuria, hypophosphatemic

rickets and hypocalcemic tetany is a rare

consequence or sequela of long-standing

nephrosis. Stanbury and Macaulay1 ob

served a boy in whom nephrosis had de

veloped at the age of 2Vi2 years, and at the

age of 4 years glycosuria and amino

aciduria were present. Tegelaers and Tid

dens2 reported their observations on two

children with similar clinical courses. Tet any, rickets, growth failure, hypokalemia

and hypocalcemia had developed in their

patients and in the patient of Stanbury and Macaulay.

During recent years two girls have been

observed who have manifested evidence of

renal tubular insufficiency subsequent to

nephrosis. In each instance the classic pic

ture of the nephrotic syndrome appeared at

an early age and was followed in the en

suing 8 years by the gradual disappearance

of edema in spite of persistent protein

uria and hypoproteinemia. Retardation of

growth, polyuria, polydipsia, intermittent

attacks of tetany and evidence of rickets

soon appeared. Moderately severe metabolic

acidosis, azotemia and hypocalcemia were

observed before therapy was instituted.

Amino-aciduria and glycosuria in addition

to proteinuria and cylindruria have been

persistent findings. The administration of

CASE REPORTS

HIsToRY: An 8@M2-year-old white girl was ad

mitted to the Mayo Clinic in August, 1953, because of tetany, rickets and dwarfism. The prenatal, birth and family histories were not significant. The illness had its onset at the age

of 18 months when an acute upper respira

tory infection developed and was followed by edema and rapid gain of weight. The diagnosis of nephrotic syndrome was established at that

time. Repeated abdominal paracenteses were

necessary to relieve ascites, when she was 3 years of age. Numerous transfusions of blood were given. Massive proteinuria and intermit tent erythrocyturia persisted, glvcosuria ap peared, and edema disappeared when the child was 33@years of age.

At the age of 4 years retardation of growth was apparent and a diagnosis of rickets was established. During the patient's fifth and sixth years repeated laboratory studies were made and persistent hypoproteinemia and hyper cholesterolemia were observed. Concentration of calcium in the serum was 9.5 mg/lOO ml; phosphorus, 4 mg/100 ml; and nonprotein ni trogen, 16.5 mg/100 ml. When the patient was 8 years of age diarrhea developed and was fol

lowed by tetany which responded to intra

venously administered calcium gluconate. Sub

This investigation was supported in part by research grant A-2011 from the Public Health Service.

The Mayo Foundation, Rochester,Minnesota, is a part of the Graduate School of the Universityof

Minnesota.

ADDRESS FOR REPRINTS: Section of Publications, Mayo Clinic, Rochester, Minnesota.

PEDIATRICS, July 1960

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76 NEPHROTIC SYNDROME

scopic examination disclosed 3 to 4 diopters of chronic papilledema of each optic disk. The papilledema was considered to be associated with hypocalcemia. Slit-lamp examination of the cornea did not disclose any abnormality.

LABORATORY FINDINGS : Roentgenograms of

the thorax and of the skull were considered normal while roentgenograms of the long bones revealed evidence of changes consistent with active rickets. There were cystic changes in the proximal left humerus and pseudofractures

â€˜¿, of the proximal left fibula and the necks of the

femurs. Bone maturation was compatible with the chronologic age of approximately 33@years. A summary of the laboratory data is shown in

TableI.

THERAPY AND COURSE: A tentative diagno

sis of chronic renal insufficiency secondary to nephrotic syndrome was established and cal cium lactate solution was administered orally. A regular diet was allowed. The concentration of calcium in the serum increased to 7 to 8 mg/100 ml with this therapy and the patient had no further attacks of tetany.

The patient was re-examined in July, 1954, at the age of 9342 years. She had been asymp tomatic during the interval since her last visit except for scarlet fever in April, 1954. The

genu valgum deformity of the knees had be

come more prominent. Roentgenograms of the

extremities disclosed more evidence of rachitic activity (Fig. 2a). Vitamin D, in doses of 20,000 units daily, was added to the program of treat ment. Within 3 months there was radiographic evidence of healing of the rickets and the con centration of calcium in the serum was normal. With this treatment the patient remained free of symptoms except for polyuria. Glycosuria and proteinuria persisted.

In August, 1955, at the age of 10@42years

the child was examined again. She had re

mained normotensive and the degree of papil ledema had definitely decreased. The genu val gum deformity of the legs had not changed, but roentgenograms disclosed evidence of heal ing of the rickets (Fig. 2b). Laboratory studies

are summarized in Table I. Amino-aciduria

was present (Table II). Glycosuria and prote inuria persisted, but tetany had not recurred

and the rachitic condition was considered

healed.

A recent follow-up examination indicates that the child has continued to grow and has taken part in school activities. In 1957 the medial edges of the femoral epiphyses were immobil

I

70

goodiwso-N50

mg/mL 30

10

Fic. 1. Case 1. Height, weight and findings in the

urine in relation to age.

sequent determinations of the concentrations

of calcium disclosed hvpocalcemia, the lowest

value being 4.7 mg/100 ml. The concentration

of phosphorus in the serum varied between

4.0 and 4.9 mg/100 ml. In January â€˜¿53,the oral administration of a medication containing cal

cium was started; thereafter the number of

attacks of tetany decreased.

Three months before the child's admission to the clinic she complained of increasingly fre

quent headaches and dimness of vision. Her

admission to the clinic was prompted by the recurrence of tetany, in spite of continued ad ministration of the calcium solution. A graphic representation of some of the laboratory data and the patient's height and weight at differ ent ages is shown in Figure 1.

PHYSICAL FINDINGS: Physical examination at

the time of admission disclosed a dwarfed girl whose height was 100.5 cm and weight, 15.4 kg. The skin had a brownish tinge. There was

no evidence of edema. The epiphyseal ends

of the long bones were prominent and there

was genu valgum deformity of the legs. The

blood pressure was 95/60 mm Hg. Fundu

Ag.

1011i@

i@

WY@\WNT@

I I I II I I I

(3)

Case 1Case 28,@

yr9T7T IP'1o@% yr9i% @ir10

yrHemoglobin

(grn/100 ml)13.59.810.311.1Leukocytes

(/mm')10,2007,2005,800Serum

cholesterol (mg/100 ml)282Blood

urea (mg/100 nil)63100112124114Blood

sugar (mg/100 ml)909990Serum

albulnin (gm/100 ml)1 .651

.352.00Alphai-globulin

(gm/100 ml)I

2 .880.30.28Alpha,-globulii@

(gm/IO0 ml)

â€”¿1

.410.90Beta-globulin

(gm/100 ml)â€”

â€”¿

1 .040.72Gamma-globulin

(gm/100 ml)0.510.59Sodium

(meq/l)132127138136Potassium

(meq/l)3 .93

.43-9Chloride

(meq/l)97105.6117.9112Carbon

dioxide content (meq/l)16 . 114 .621 .320.5Serum

phosphatase (King-Armstrong units)52 .5103 .421 .771 .1Calciu;n(ing/lOOml)5.8648.95.48.0Phosphorus

(mg/100 ml)3 .44 .64 .94

.75.4Urinalysis:

SpÃ©cificgravity1.0121.0081.0091.0111.011ReactionAlkalineAlkalineAlkalineAlkalineAlkalineProtein

(grade)44444Sugar(grade)11111Erythrocytes

(grade)A few12A fewA

fewBence

Jones proteinEquivocalEquivocalEquivocal

ARTICLES

TABLE I

LABORATORY DATA ON Two PATIENTS WITH RENAL TUBULAR DYSFUNCrION

77

ized with staples to correct genu valgum. The staples were removed in November, 1958, after almost complete correction of the deformities of the knees. She continues to take 50,000 units of vitamin D every fourth day, 10 ml of cal

cium gluconate twice daily and a multiple

vitamin preparation. During recent months the

concentration of calcium in the serum has

varied between 5.8 and 8.2 mg/100 ml. The

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78 NEPHROTIC SYNDRO\IE

complaints of dwarfism and rickets. The family

history and the prenatal and perinatal histories were noncontributorv. At the age of 15 months puffiness of the eyelids and swelling of the face had developed. The diagnosis of nephrotic syndrome @s'asestablished by the presence of

anasarca and persistent massive protei1s@;ria.

The patient's blood pressure was said to have been IU)rnlal and remained norn@al during the period of her observation. The edema which persiste(l for several months was not affected by restriction of salt in the diet.

The patieiit had measles at the age of 3 @â€˜¿ears and soon thereafter meningitis developed due

to Hemophilus influenzae. The patient was

treated successfully for meningitis with peni cillin and streptomvcin. During the course of these two illnesses much of the edema sub sided and the proteinuria decreased for a short time. Since then, the patient has had no fur

ther episodes of massive edema, but has con

tinned to have I)rOteinuria . \Iininial ervthro

cyturia was noted on a few occasions.

Glvcosuria, growth retardation, and rickets were noted when the child was 5 \ears of age. The patient was treated with various medica

tions, including vitamin D in moderate amounts, thyroid extract, norethandrolone (Nilevar@), adrenocorticotropic hormone, cortisone and

sitosterols (Cvtellin @),without apparent bene

fit. At the age of 9 years she experienced re

TABLE 11

Fic. 2. Case 1. (a, left) View of knee to demonstrate rickets before vitamin I) was taken; (b, right) after

use of Vitamin 1).

tween 47 and 87 rng 100 ml, with the lower concentrations being observed during recent months. The patient continues to have poiv uria, proteinuria and glvcosuria.

Case 2

HIsTORY: A girl, 9@'@ years of age, was ad

mitted to the clinic on October 21, 1957, with

EXI;ETIorc OF â€œ¿FIIEEAMINo Acmâ€• (Mo/@24 lilt) IN Iwo PATIENTS WITh RENAL

â€˜¿1'ti@vi@ioI)ysm';No'TIoN

lrn,no Acid Excreted (rng/24 br)

(â€˜use2 (Study Periool.s)

1

@ 2

@ .1

@

@ I 5

@ (@

@

129 119 137 117 86 95 J 41

163 1(13 299 106

@ 100 1 1 1 59

84 86 146 193

@ 170

@ 147 114

I (166 1 316 1 , lU; 588

@ 280

@ 119

@ 167

202 170 244 237 I 366 200

@ 162

133 154 147 77

@ (i6 68

@ 29

505 .563 274 199 164 140

@ 81

365 452 421 392

@ 336

@ 274

@ 172

41 39 44 43

@ 35

@ 32 11

139 149 148 118

@ 103 106

@ 44

238 207 287 146

@ 110 79 69

192 177 294 216 I 157

@ 162

@ 155

36 42 36 37 33

@ 26 I 17

185 183 121 119 122

@ 118 54

413 405 362 266 233 â€˜¿214

@ 92 (a.se 1 218 264 76 896 217 124 623 480 38 226 170 224 138 431 Amino ACi(l Argiimimme @@s1)artic:;cil (â€˜ystine (lutamnimmc Ilistidine Isoleucine Leucim;e I@ySiIIe \lethionim;e I'heIlylIh hi nine Prolino â€˜¿I'l;reonine Iryptopha n 1'yrosine Valine â€œ¿,ormal

20 Â± 35

4@Â±5.1

â€˜¿.P)Â± 5.1

138 Â±21

125 Â±16.4

3.7Â± 0.4 17 Â± 2

40 Â± 4.6

1.7Â± 0.4 13 Â± 1.9

33 Â± 4.9

(5)

ARTICLES 79

l)e@1ted attacks of tetanv which sui)sicled spon taneouslv within a few months. A progressive

genii valgum deformity also developed and walking became difficult. A graphic presenta tion of her history and development is shown in Figure 3.

PHYSICAL FINDINGS: The patient was a

dwarfed, dejected girl whose height was 106.7 Clii and weight, 19.5 kg. The blood pressure was 95 60 mm Hg. The face was slightly puffy and the abdomen was prominent but ascites could not be demonstrated on examination. The edge of the liver was palpable 2 CITIbelow the right costal margin . Genu valguni deformity of the legs @s'asprominent.

LABORATORY FINDINGS: Laboratoiy studies o)btailled On this and the next visit are sum

marized in Table I. Roentgenograms of the thorax and of the extremities were interpreted as normal except for the presence of active rickets (Fig. 4a).

THERAPY AND COURSE: The administration of vitamin D in (loses of 50,000 units daily was started on October 29, 1957, and was followed by considerable improvement in the child's ability to walk. She was able to paiticipate in no)rInal activities including roller skating.

FIG. 3. Case 2. Height, weight and findings in the urine in relation to age.

â€”¿@

Fâ€”

I

@1

FIG. 4. Case 2. (a, left) View of knee to demonstrate

rickets before patient took vitamin 1); (h, right)

after use of vitalilin I).

The patient returned to the clinic for met abolic stud@ 00 March 3, 1958, at the age of 10 years, at which time her height was 1C6.7 cm and weight, 18.8 kg. The blood pressure

was normal. The results of 1)h'sical examina

tion were IlOt significantly different from those previously noted. Roentgenograms of the knees showed healing of the rickets (Fig. 4b).

SPECIAL STUDIES OF CASE 2

Methods

After 6 days of @)relin-Iinary ol)servation, the child was studied during six sequential balance periods, each of 6 days' duration. An additional study of a 6-day balance period was made 6

months later. The diet remained constant

throughout the entire studs'. The patient was allowed to determine her caloric requirements (luring the 6 days preceding the first balance period. The diet consisted of three daily menus which were used in rotation. l)istilled water was used as drinking water, and the amount needed was deterniined by the patient and re cOr(led; the teeth also were cleaned with cbs tilled water. She was weighed daily.

Administration of vitamin D was discon tinued 3 weeks before the metabolic study. Balance Periods 1 and 2 were control periods. During Periods 3 and 4, 60 mg of prednisone was given daily; during Periods 5 and 6 the

patient received 20 mg of prednisone cvei-v

HEIGHT

160

3@

* /97

-60

-50

â€˜¿50

@40 @

@30 @.

20

@10

* Percentiles

3 4 5 6 7 8 9 10 11 12

140

-.@

120-cJ

100

80 F

Age

@

@ .5 0â€” - - -- - -@

@

â€”¿-@ Trace

:@ Glucose o a o a o

@ @â€˜¿+ + ++

.

@ 1020 1008 1012

Specific_gravity 1015 1015 1010

@

@ - â€”¿â€”@I

@

(6)

Prednisone

2Omqidoy 3 times per week NEPHROTIC SYNDROME

80

third, fourth and fifth day. During the sixth metabolic period 9 gm of calcium lactate was dissolved in the drinking water because of the appearance of tetany. After the sixth metabolic period the patient was dismissed on the daily dose of 50,000 units of vitamin D in addition to 20 mg of prednisone daily for S successive days of each week. These same medications were continued during the seventh metabolic period which followed 6 months after the sixth period.

Carmine markers were given at the beginning

of each period and at the end of the sixth

period. A similar marker was used at the be ginning and at the end of the seventh period. The stools were collected and pooled for each 6-day period and analyzed as a single speci

men. Urine was collected and analyzed each

24 hours. Venous blood for the determination of electrolytes was drawn under oil into a tube containing purified heparin. The methods used for the determination of sodium, potassium, chloride, carbon dioxide content of the plasma, blood urea, blood sugar, inorganic phosphate and calcium in the serum, and sodium, potas sium, calcium, phosphorus, nitrogen, titratable acidity and ammonia in the urine have been

described previously.3 The pH of the serum

was measured by the method of Van Slyke et

al.@The methods for electrophoretic separa

tion of the serum and urinary proteins are de scribed in detail elsewhere.5 Individual â€œ¿free amino acidsâ€•were measured in the urine by a modification of Henderson and Snell's micro biologic method.6

Results

The patient excreted approximately 7 gm

of protein per 24 hours (Fig. 5) during the

control periods. The major part of the un

nary protein was albumin. Hypoalbumi

nemia, relatively low concentrations of

gamma-globulin in the serum, and elevated concentrations of alpha2-globulin as well as

serum cholesterol were present. The con

centrations of calcium and potassium in the serum were low while the concentration of

phosphorus was normal. The concentration

of the blood urea was elevated (Fig. 6), that

of the serum sodium was normal, that of

the serum chloride was elevated, and the

carbon dioxide content was reduced. The pH of the serum was 7.21 during the control

Vitamin D

50@D00untts/day

PrednisoneI

eOmg/doyJ

Months of observation

6-day periods

Fic. 5. Case 2. Serum cholesterol, serum protein fractions and protein excretion in the urine during periods of observation and metabolic study.

periods. There was decreased excretion of titratable acidity and ammonia in the urine

(Table III). The value for blood sugar re

mained normal during the control period,

but the patient excreted approximately 4

gm of glucose per 24 hours in the urine. In

creased amino-aciduria was present, with

the excretion of glutamine being greatest

(Table II). As indicated in Figure 7, the

nitrogen, phosphorus, calcium, sodium and

chloride balances, which were plotted ac

cording to the method of Albnight and

Reifenstein,7 were positive while the patient was in negative potassium balance during the control periods.

Administration of prednisone was fol

lowed by a decrease in the proteinuria and

(7)

Period123567Carbon

dioxide content in plasma (meq/1) Blood pH

Urine pH*

Titratableacidity*(meq/24hr)

Ammonia excretion* (meq/24 hr)20

â€”¿

6.5 7.6 5.718

7.21 6.6 8.7 6.314

7.24 6.5 10.4

7.914 7.31 5.9 16.9 12.117

7.32 5.7 17.7 10.518

7.28 6.3 9.5 7.821

7.38 5.8 18.5 11.6

ARTICLES 81

Prednisone 2OmÃ§./doy3 times per week

Calciumlactate

Prednisone 9gm/do Vitamin 0

4;

tI, i-i 50,000

units/day

Monthsof observation

I 3 5 â€”¿â€” 6 - â€”¿.â€˜¿â€”â€”â€”â€”7 â€”¿â€”â€˜8 10 12 13 14 16 i1iir

@

@ ii

@ Â°@ @_.

@ @ @

@ .@

@ j

@ 0%

@ 100 @0

80

140 Na .--.o

l3oE

@

â€”¿.-

.-o---.'â€”â€”â€”o.---.

.._â€”¿Â°

120

116

114

112

110

K

3.9 @7

3.5 @@â€˜¿@0.â€”â€”¿0

-3.3 I .L:@z.;@

&0 Ca

@_0@,_@ Tetany

-@ 7.0 @

5.0

@ I

7.0 I

P

@ â€˜¿P'.

____1 @0@@â€˜¿

5.0 __

1 2 3 4 5 6 7

6-day periods

FIG. 6. Case 2. Blood urea and serum electrolytes during periods of observation and metabolic study.

TABLE III

HYDROGEN-ION EQUILIBRIUM DURING METABOLIC STUDY (CASE 2)

(8)

Prednisone 20mg /doy, 3times per week

â‚¬¿42mIda Soooounts/doy

Fâ€”i

Predrisore 20mg/day, 3 times per week

Calcium lactate 9gm /day

Prednisone Vitamin 0

60m Ida 50,000 un3rJday

LI]

[Ii

123 4 5 6 7

6day periods 6doy periods

chloride was noted initially as well as an in crease in the severity of the metabolic acido sis and azotemia. The value for serum potas sium fell and the potassium balance became more negative.8 An increase in the concen

tration of blood sugar was accompanied by

increased excretion of glucose in the urine

(7.1 gm/24 hr). Diuresis was accompanied

by decreased amino-aciduria, the most strik ing decrease being in the excretion of gluta mine. Excretion of hydrogen ions increased and a correction of the metabolic acidosis

was associated with a rise in the serum pH

to 7.32.

Most of the effects of administration of

o No additional potassium was given during the metabolic study.

prednisone noted during Periods 3 and 4

were also observed during Periods 5 and 6

when prednisone was administered inter

mittently. Urinary excretion of protein and

amino acids remained low while the excre

tion of hydrogen iOnS by the kidney was not so great as it had been with the continuous

administration of prednisone. There was no

recurrence of the metabolic acidosis. During Period 5 the excretion of calcium and phos

phorus into the bowel increased and was

associated with a negative balance of cal

cium and phosphorus, a decrease in the con

centration of calcium in the serum and a

recurrence of tetany. Calcium lactate was

added to the drinking water during Period

6 in order to avoid tetany.

The seventh period of metabolic studies,

456

2 @198

@ 0

,+

₊₀₂

04 06

FIG. 7. Case 2. Data from the balance studies are plotted according to the method of Aibright and Reifenstein.7 Each column represents a 6-day period. Intake is plotted downward and excretion (fecal, hatched; urine, clear) is plotted upward. The data on the daily balances of potassium, sodium and chloride are superim

posed on the plots of the 6-day period.

0

E +2

I

(9)

ARTICLES 83

authors1Â° have encountered glycosuria and

amino-aciduria in patients with nephrotic

syndrome.

Considerable evidence has been presented to indicate that the increased loss of protein in the urine of patients with nephrotic syn

drome is due to increased glomerular per

ty11 The cause of renal tubular

failure which occasionally develops after

nephrotic syndrome is not known, but it is interesting to speculate that the continued

reabsorption of protein by the renal tubular

epithelium may have a damaging effect on

the function of the cells of the tubules.12

Such a possibility is suggested by the ex

periments reported by Rhodin.'3 This possi

bility is further supported by the descrip

tion of renal tubular insufficiency (de Toni

Debre-Fanconi syndrome) occurring among

three patients with Bence Jones protein in

the urine as the result of multiple mye

loma.14'6 In each of the patients in the pres

ent report the tests for Bence Jones protein in the urine gave equivocal results. One

patient (Case 2) showed decreased excre

tion of protein in the urine associated with improved renal tubular function after the

administration of prednisone. It is of interest

to note that glutamine, supposedly the

source of ammonia in the urine, was excreted

in large amounts in the urine of both patients

before steroid therapy was instituted (in

one patient); as this amino acid was more

completely reabsorbed, the production of

ammonia in the urine increased.

An alternative hypothesis is that the pri

mary disturbance producing the nephrotic

syndrome also may have produced renal

tubular damage. This seems unlikely in

view of the rarity of the occurrence of this complication. We cannot exclude the co

existence of two separate renal diseases. Administration of vitamin D was followed by additional improvement in renal tubular

function as indicated by a further decrease in excretion of amino acid and by improved excretion of hydrogen ion in the urine.

The mechanism whereby rickets develops

in patients with this type of renal tubular

dysfunction is not clearly understood. The

which followed 6 months after Period 6,

was carried out while the patient was re

ceiving vitamin D and intermittent doses of prednisone. During this period the value for

blood urea was 144 mg/100 ml. The amino

aciduria had decreased further; glycosuria

had decreased somewhat (to 3.2 gm/24 hr),

and the ability to excrete hydrogen ions had improved as evidenced by an increase in the

titratable acidity and production of am

monia in the urine. The ability of the kid ney to concentrate the urine was still im@ paired. The calcium and phosphorus bal

ances were now more noticeably positive,

but the potassium balance remained nega

tive.

The patient has continued on the therapy

described in Period 7 of the metabolic

studies and according to the last report she

has continued to grow and to make satis

factory progress. The concentration of blood

urea has decreased to 83 mg/100 ml, while

the serum calcium measured 10 mg/l00 ml

and the phosphorus, 5.5 mgIlOO ml.

COMMENT

Studies by Bruck et al.8 have shown that most patients suffering from the nephrotic

syndrome have normal tubular function. It

is also known that amino-acidunia is an un

common finding in the uncomplicated ne

phrotic syndrome.9 No data are available on the excretion of amino acid in the urine of the present patients during the early part of their disease; .nevertheless, it is known that they did not have glycosuria, rickets, or signs of acidosis until many months after the diagnosis of nephrotic syndrome was estab lished. It is interesting that these patients

had become free of edema in spite of mas

sive proteinuria, and it may be postulated that they had reached a state of equilibrium

in which production of protein was com

parable to the loss of protein.

The occurrence of glycosuria, growth fail ure, rickets, metabolic acidosis and the in ability to concentrate urine are considered to be indications of renal tubular dysfunc

tion. Identical sequences of events have

(10)

rickets was clearly of the hypophosphatemic

type. It should be noted that during the

two control periods the patient (Case 2)

excreted 46% of the total intake of phos

phorus in the urine, while 39 and 42% dur

ing these two periods, respectively, were

lost in the stool. It has been showni? that

normal children excrete 56 to 65% of the

daily intake of phosphorus in the urine and only 26 to 27% of the intake in the stool. In

Case 2, after the administration of vitamin

D (Period 7), 63sf of the total intake of

phosphorus was excreted in the urine and

only 10% of the phosphorus was excreted in

the stool. During this time phosphorus reten tion increased. The finding of relatively low

absorption of phosphorus in the gastroin

testinal tract has been described18 among

patients with de Toni-Debre-Fanconi syn

drome with or without cystinosis. Thus it

appears that the primary cause for the low

concentration of serum phosphorus in these patients is poor absorption rather than in

creased excretion of phosphorus in the

urine.

The effects of continuous administration

of large doses of prednisone consisted of

increased concentrations of serum glucose, increased loss of glucose in the urine, reten

tion of sodium chloride, and phosphate

diuresis. The increased excretion of calcium

and phosphorus in the feces has also been

observed to follow administration of adrenal steroids.19 Other effects of administration of adrenal steroids, namely, decreased loss of protein in the urine, elevated concentration

of serum albumin and decreased concen

tration of serum cholesterol, have been ob

served among patients with nephrotic syn

drome who were treated with steroids.

There was no improvement in azotemia or

in hyposthenuria, an indication of the severe renal damage.

The similarity of the clinical pictures pre sented by these patients and the patients described by others,1'2 and by patients with

de Toni-Debre-Fanconi syndrome without

cystinosis is so striking that one may specu

late that certain patients who are found to

have de Toni-Debre-Fanconi syndrome in

later life may have had mild or subclinical nephrotic syndrome at an earlier date.

SUMMARY AND CONCLUSIONS

Observations on two girls in whom an

unusual type of chronic renal insufficiency

developed many months after the onset of

nephrotic syndrome are reported. Each pa

tient became free of edema in spite of per sistent massive proteinuria. Growth was re tarded and rickets and attacks of tetany de veloped.

The chemical disturbances of the blood

were characterized by hypocalcemia, hy

pokalemia, azotemia and metabolic acidosis. Hyposthenuria, proteinuria, amino-aciduria, and minimal erythrocyturia, cylindruria and glycosuria were present.

Healing of the rickets and cessation of

attacks of tetany followed the administra

tion of vitamin D and calcium salts. Pred

nisone was administered to one patient and thereafter proteinuria decreased and renal tubular function improved. Both girls are relatively asymptomatic 11 and 9 years after the onset of nephrotic syndrome, although they are rather small and still have evidence of renal disease.

It is possible that cells of the renal tubules

have been damaged as a result of prolonged massive proteinuria.

Acknowledgment

We are indebted to Dr. Frederic C. Bartter, Chief, Section on Clinical Endocrinology, Na tional Heart Institute, National Institutes of Health, Bethesda, Maryland, for follow-up data on Case 1.

Addendum

Since completion of this manuscript, we have had the opportunity to study two additional pa tients with tubular dysfunction in the course of nephrotic syndrome, and we have found an additional report of a patient with a similar condition. (Hooft, C., and Vermassen, A.: Syn

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ARTICLES

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Gunnar B. Stickler, Alvin B. Hayles, Marschelle H. Power and John A. Ulrich

SYNDROME