European Journal of Endocrinology (2001) 145 463468

ISSN 0804-4643

CLINICAL STUDY

Renal loss of leptin in patients with nephrotic syndrome

Michael Schroth, Michael Groschl, Helmut G Dorr, Werner F Blum1, Wolfgang Rascher and Jorg Dotsch
Klinik mit Poliklinik fur Kinder und Jugendliche, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Loschgestrae 15, D-91054 Erlangen, Germany
and 1Lilly Deutschland GmbH, Saalburgstrae 153, D-61350 Bad Homburg, Germany
(Correspondence should be addressed to Michael Schroth; Email: michael_schroth@yahoo.de)

Abstract
Objective: In humans, short term changes of serum leptin lead to alterations in food intake and energy
expenditure. The objective of the present study was to relate urine leptin concentrations with the
extent of proteinuria in patients with nephrotic syndrome (NS). A second goal was to investigate the
impact of potential urinary leptin losses on serum leptin concentrations and body composition.
Design and Methods: Seventeen patients with proteinuria were compared with twenty patients with
remission of NS and ten healthy children. Leptin was measured by radioimmunoassay.
Results: Urinary leptin excretion in proteinuric patients was signicantly higher than in nonproteinuric patients with and without NS and in healthy controls 2:64^0:034 mg=g creatinine,
0:026^0:05 mg=g creatinine, and 0:073^0:11 mg=g creatinine respectively; P , 0:001 and
P , 0:01 respectively compared with controls). Urine leptin positively correlated with urine IgG
concentration P 0:013; r2 0:36 in the proteinuric group. No difference in serum leptin
values could be demonstrated between the three groups.
Conclusions: In summary, our data demonstrate a signicant leptin excretion in children with severe
proteinuria. Proteinuria, however, does not lead to changes in serum leptin, suggesting that the
signicant loss of leptin is compensated for by sustained up-regulation of leptin production.
European Journal of Endocrinology 145 463468

Introduction
Leptin, a 167 amino acid polypeptide with a molecular
size of 16 kDa, is synthesized in adipose tissue (1, 2).
Leptin, the product of the obese (ob) gene, plays an
important role in the regulation of appetite and food
intake in mice and humans (35). Mutations of the
leptin gene or its receptor gene lead to obesity in mice
and humans (1, 6). There is a positive correlation
between serum leptin concentrations and body mass
index (711). In adipose patients chronically raised
levels of leptin do not lead to weight reduction possibly
due to the set-point changes in the hypothalamic leptin
sensor. Long-term leptin treatment, however, causes
moderate weight reduction. Short-term changes in
leptin serum concentrations may modulate appetite
and energy expenditure in humans during fasting and
after major surgery (12). Leptin is known to play an
important role in the regulation of weight gain in early
infancy and shows a relationship between its concentration and fetal growth (1315).
The idiopathic nephrotic syndrome (INS) is an
albumin-losing nephropathy in childhood often due
to minimal change lesions of the kidneys. Severe
proteinuria (urinary protein level exceeding 1 g/m2 of
body surface area per day) leads to hypoproteinemia
(hypalbuminemia, albumin in serum ,25 g/l) and
q 2001 Society of the European Journal of Endocrinology

chronically to a catabolic nutritional state (16).

Investigations revealed that the defect in minimal
change glomerulonephritis results mainly from a loss
of charge selectivity, whereas the defect in membranous
glomerulonephritis results from a loss of size selectivity
(17, 18). As a consequence, the protein loss affects
body composition. Children are often seen in an edemic
state. Blood coagulation as well as the immunologic
system can be affected due to the loss of components of
the coagulation system or the loss of immunoglobulins.
Since proteinuria may be associated with urinary
leptin wasting in renal protein-losing diseases, the
present study was designed to examine the relationship
of serum and urine leptin concentration and proteinuria in patients with nephrotic syndrome (NS). A
second goal of the study was to examine whether or not
an increased urinary leptin excretion may inuence
serum leptin concentrations and body composition.

Experimental subjects
Thirty-seven pediatric patients with NS were studied.
Patients' characteristics are shown in Table 1. In 17
patients (group I) proteinuria (urinary protein level
exceeding 1 g/m2 of body surface area per day) was
present. Twenty patients were in remission (group II,
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M Schroth and others

EUROPEAN JOURNAL OF ENDOCRINOLOGY (2001) 145

Table 1 Patient characteristics of 37 patients suffering from nephrotic syndrome and of 10 healthy children in the control group.
Patient number, age, gender, BMI and pubertal stage (Tanner) as well as medication (prednisone, cyclosporine, tacrolimus, b-blocking
agents) and diagnoses of all patients are listed. Age and BMI are expressed as means^standard deviation and median.

Number (n)
Age (years)
Gender (m/f)
BMI (kg/m2)
Tanner 1/2
Patients receiving prednisone
Patients ever (actually) treated
with cyclosporine A or tacrolimus
Patients ever treated with
cyclophosphamid
Patients receiving b-blocking
agents
Diagnosis

Group I

Group II

Group III

17
8.8^3.8; 8
8/9
18.1^2.9; 18.1
10/7
9
6 (2)

20
9.9^3.6; 10
17/3
18.3^3.6; 17.45
11/9
1
10 (7)

10
10.5^4.2; 9.5
5/5
17.2^2.4; 17.15
4/6
0
0

10

10

12

INS (8), FGGS* (1), FSGS* (3),

MCGN (3), MPGN* (1),
congenital nephrotic
syndrome* (1)

INS (15), MCGN* (5),

Healthy

*Diagnosis conrmed by histological examination.

FGGS, focal global glomerulosclerosis; FSGS, focal segmental glomerulosclerosis; MCGN, minimal change glomerulonephritis; MPGN, membrano
proliferative glomerulonephritis.

no signicant proteinuria). In this study group

proteinuria did not exceed 100 mg/m2 of body surface
area per day. The period of remission was at least 6
months and was equal in all patients included. The
patients' groups were compared with 10 healthy
children (group III).
Leptin concentrations in serum and urine were
measured by radioimmunoassay (as shown in detail
below). After centrifugation of blood samples, which
were all drawn between 1000 and 1200 h, serum and
urine samples were kept frozen for up to 8 weeks at
220 8C and were analyzed when all specimens had
been obtained.
In all patients, body weight and body height were
measured to obtain the body mass index (BMI).
Subscapular and triceps skinfold thickness were determined with a caliper by the same trained investigator.
No patient was fasting. All clinical and auxological data
were obtained during routine visits and were recorded
using standard data sheets. Details are shown in
Table 1. The study was approved by the local ethics
committee of the University of Erlangen. Informed,
written consent was obtained from all parents and the
older patients.

Materials and methods

Leptin was measured by a specic radioimmunoassay.
Recombinant human leptin was used for raising a
polyclonal antibody in rabbits, for the production of
tracer by the Chloramine T method (Lilly, Bad
Homburg, Germany), and for the preparation of
standards. Tracer and samples were appropriately
diluted in assay buffer containing 0.05 mol/l
NaH2PO4, 0.1 mol/l NaCl, 0.05% NaN3 (Merck,
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Darmstadt, Germany), 0.1% Triton X-100 (Roth,

Heidelberg, Germany), and 0.2% (v/v) bovine serum
albumin (Serva, Heidelberg, Germany). For the dilution
of the specic antibody, rabbit immunoglobulin G (IgG)
(Sigma, Deisenhofen, Germany) was added to the
buffer. For the measurement of serum samples a
standard curve from 18.75 to 0.049 ng/ml was
prepared by geometrical dilution. The tracer activity
was ,20 000 c.p.m./100 ml, the nal dilution of the
specic antibody was 1:50 000. In the assay, 100 ml of
each of tracer, sample and antibody were added. Incubation lasted for 24 h at room temperature. Bound and nonbound fractions were separated by a goat-anti-rabbit IgG
(DSL, Sinsheim, Germany) in 4% polyethylene glycol
(PEG) at a nal dilution of ,1:100. After 2-h
incubation at room temperature the tubes were
centrifuged (15 min, 3000 r.p.m., 4 8C). Activity of
the pellet was counted for one min in a gamma counter.
Fifty percent binding occurred at 0.9 ng/ml. The
sensitivity of undiluted samples was 0.01 ng/ml.
Inter- and intra-assay coefcients of variation (%)
were 8.5 and 0.8 respectively.
Leptin in urine was measured by a highly sensitive
variation of the assay. Tracer activity was 8000 c.p.m./
25 ml. The antibody had a nal dilution of 1:8000 in
25 ml. The standard curve expanded from 1250 to
9.8 pg/ml. The buffer and 2nd antibody dilutions were
the same as described above. Urine leptin concentrations were related to the respective urine creatinine
concentration (U leptin/U creatinine (mg/g creatinine))
and are also given as absolute values (mg/l). Leptin
standard deviation scores (SDS) were calculated
according to Blum et al. by the following equation:
leptin SDS lnleptin 2 lna 2 b*BMI=day where a
and b are constants and BMI, the body mass index (19).

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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2001) 145

465

Statistical analysis
Data with Gaussian distribution were correlated by
linear regression. Parametric data were compared by
two-tailed t-test. In the case of multiple tests, data were
compared using one-way ANOVA, and, in the case of
signicance, post-hoc t-test. P values were corrected
according to Bonferroni. A P value ,0.05 was
considered statistically signicant.

Results
Figure 1 Urine leptin concentrations in group I (patients with NS
with severe proteinuria, urinary protein level exceeding 1 g/m2 of
body surface area per day), group II (patients with NS without
proteinuria) and group III (control group, healthy children). Data are
shown as scattergrams and as boxes and whiskers. Signicantly
higher levels in group I ***P 0:0005 were evaluated using oneway ANOVA, P values were corrected according to Bonferoni.
There is no difference in urinary leptin between boys and girls and
Tanner stages 1 and 2, as shown in Table 2.

To exclude the interference of massive proteinuria

with leptin measurements we have demonstrated that
in leptin-spiked urine samples even high IgG and
albumin levels do not create non-specic effects leading
to falsely high leptin levels in the urine. The amount of
leptin spiked into the urine was 3 ng/ml. Albumin
concentrations ranged from 3.13 to 100.0 mg/ml and
did not inuence leptin concentrations; IgG was added
in concentrations from 31.25 up to 1000.0 mg/ml and
did not affect leptin concentrations. There was an 8.4%
variation in the urinary leptin value over the range of
concentrations of added albumin, and an 8.8%
variation for added IgG. The measured value of leptin
in the absence of albumin was 3.13 ng/ml, and in the
absence of IgG it was 3.06 ng/ml. There was no
statistical difference in measured leptin concentrations
after adding albumin or IgG. In a further experiment,
leptin at a starting concentration of 3.18 ng/ml, was
diluted 1:2, 1:4, 1:8, 1:16 up to 1:32 (0.53 ng/ml).
Leptin dilution in urine showed linearity between
calculated leptin and measured leptin concentrations
r2 0:98; P , 0:001:

Urinary excretion of leptin in proteinuric patients

with nephrotic syndrome was signicantly higher
2:64^0:034 mg=g creatinine, absolute value 100:3^
21:23 mg=l than in patients without proteinuria
0:026^0:047 mg=g creatinine, absolute value 2:37^
1:15 mg=l; P , 0:001 or healthy controls 0:073^
0:11 mg=g creatinine, absolute value 3:83^2:06 mg=l;
P , 0:01 (P-values for all data related to creatinine as
well as for absolute values) (Fig. 1). Urine leptin values
were also related to the different pubertal stages and
sex (data shown in correlation to individual creatinine
values): there was no difference in urinary leptin
excretion between boys and girls, nor between Tanner
stages 1 and 2 (Table 2).
Urine leptin positively correlated with urine IgG
concentration P 0:01; r2 0:36; y 47:8x
44:0 mg=g creatinine) and with urine albumin concentration P 0:04; r2 0:24; y 3220x
4119 mg=g creatinine) in group I. When patients
showed signs of remission (proteinuria did not exceed
100 mg/m2 of body surface area for a period of at least
6 months, group II), a relationship of urine leptin was
only seen with the urine albumin fraction P 0:014;
r2 0:31; y 27:89x 12:9 mg=g creatinine). There
was no correlation found between urine leptin excretion and urine albumin or urine IgG in controls.
Serum leptin concentrations were similar in all three
groups (Fig. 2). There was no correlation between
serum leptin and excreted urine leptin concentrations,
which were all creatinine-corrected, in group I, group
II or in the controls. In addition, there was no
signicant difference in serum leptin concentrations

Table 2 Urinary leptin excretion in boys and girls, Tanner stages 1 and 2.

Boys, Tanner 1
Boys, Tanner 2
Girls, Tanner 1
Girls, Tanner 2

Urine leptin concentrations

in patients with
nephrotic syndrome
and with proteinuria
(.1 g/m2/day)
(mg/g creatinine)

Urine leptin concentrations

in patients with
nephrotic syndrome
without proteinuria
(mg/g creatinine)

2.41^0.02
2.62^0.03
2.68^0.02
2.64^0.04

0.024^0.02
0.029^0.01
0.032^0.03
0.026^0.02

There is no difference between boys and girls, nor between Tanner stage 1 and 2.
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M Schroth and others

EUROPEAN JOURNAL OF ENDOCRINOLOGY (2001) 145

groups I and II P 0:006; r2 0:52 and P

0:0025; r2 0:49 respectively) as well as with subscapular skinfold thickness in both groups P , 0:0001; r2
0:84 and P 0:001; r2 0:66 respectively). There was
a positive correlation between triceps and subscapular
skinfold thickness and serum leptin in nephrotic
patients with proteinuria P 0:032; r2 0:27; P
0:027; r2 0:31; in patients with remission of nephrotic
syndrome P 0:021; r2 0:33; P , 0:0001; r2
0:79 and in healthy controls P , 0:0001; r2 0:41;
P 0:028; r2 0:29: No signicant correlations
could be demonstrated between the skinfold thicknesses
and urine leptin concentrations in any group.
Figure 2 Serum leptin concentrations in group I (patients with NS
with severe proteinuria, urinary protein level exceeding 1 g/m2 of
body surface area per day), group II (patients with NS without
proteinuria) and group III (control group, healthy children). Data are
shown as scattergrams and as boxes and whiskers including
minimum and maximum data.

between male and female patients. Serum leptin SDS

were calculated in all three groups according to Blum
et al. and showed no signicant difference between
males and females (all Tanner stage 1 or 2) in any of
the groups nor between the three groups (Fig. 3) (19).
The patients' medication (cyclosporine, tacrolimus,
cyclophosphamid, b-blocking agents, prednisone) did
not signicantly inuence serum or urine leptin
concentrations when groups receiving one of the
medications were compared with non-treated patients.
A positive relationship was obtained between BMI
and serum leptin in nephrotic patients with proteinuria
P 0:016; r2 0:36; y 0:43x 2 5:92; in patients
with remission P , 0:0001; r2 0:82; y 0:74x 2
11:2 and in controls P 0:012; r2 0:41: No
signicant correlations were found between BMI and
urine leptin concentrations in any group. BMI correlated positively with triceps skinfold thickness in

Figure 3 Serum leptin SDS in male and female children in group I

(patients with NS with severe proteinuria, urinary protein level
exceeding 1 g/m2 of body surface area per day), group II (patients
with NS without proteinuria), and group III (control group, healthy
children). Data are shown as scattergrams and as boxes and
whiskers including minimum and maximum data.
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Discussion
Patients in groups I and II show similar auxological
data including BMI (Table 1). The distribution of girls
and boys and their respective pubertal stage (Tanner
stage 1 and 2) was comparable. Classication of
patients by pubertal stage revealed no signicant
difference with respect to Tanner stage or sex. These
nding are in line with data presented by Blum et al.,
who found that for Tanner stage 1 or 2 the same
normal ranges for leptin in serum can be used for boys
and girls (19).
These data demonstrate a renal urinary leptin loss in
prepubertal and early pubertal children suffering from
active nephrotic syndrome with proteinuria .1 g/m2.
Urinary leptin loss disappeared after remission and was
minimal in the control group. However, despite urinary
leptin loss, serum leptin levels were similar in all three
groups. Several studies have shown a relationship
between body mass index, methods for body fat
determination such as subscapular and triceps skinfold
thickness measurements, and serum concentrations of
leptin (811). These observations could be conrmed
in the present study. However, our data did not reveal
any relationship between urine leptin concentrations
and BMI or triceps and subscapular skinfold thicknesses. Unexpectedly, serum leptin levels did not differ
between groups despite a 100-fold increment in leptin
excretion in group I. This nding strongly suggests that
the renal loss of leptin is compensated for by a
substantial increase in leptin production. The mechanisms that cause the up-regulation of leptin synthesis
remain unclear (2025).
To answer the question as to what degree of
glomerular protein leakage allows for the loss of leptin,
excretion of leptin was related to albumin and IgG in
urine. Our data show that there is no signicant
difference in urinary leptin excretion in proteinuric
patients with an IgG/albumin ratio lower or higher
than 1. Consequently, glomerular albumin loss is
associated with the loss of leptin. According to these
data, we propose a glomerular loss of the 16 kDa
peptide leptin in patients with proteinuria that is
independent of the molecular size.

EUROPEAN JOURNAL OF ENDOCRINOLOGY (2001) 145

It would be of interest to establish data about leptin

binding proteins, or data about free leptin concentrations in urine and serum in proteinuric patients in
order to gain information about possible leptin binding
protein excretion in urine. The clearance of leptin could
help to estimate the extent of binding protein loss.
However, determination of leptin clearance is limited by
several factors: 24-h urine sampling is necessary, which
requires a urinary catheter especially in very young
children. Furthermore, from the literature we do not
have any data about tubular reabsorption of leptin and
its binding protein.
Recently published studies revealed that leptin is
cleared by the kidney, and patients with end-stage renal
disease show increased plasma leptin concentrations
(2628). Leptin promotes renal growth and brogenesis in vivo and in vitro (29). Proliferation of
endothelial cells stimulated by leptin may contribute
to a progression of renal damage and, in consequence,
may promote glomerulosclerosis. Leptin was shown to
stimulate the expression of transforming growth factorb1 (TGF-b1), a major modulator of renal brosis, in
vitro and in vivo. This may activate the transcription of
extracellular matrix proteins such as collagen type IV,
which may eventually lead to damage of renal
glomerular endothelial cells (29). It is well known
that renal injury leads to an increased generation of
angiotensin II, which induces an up-regulation of the
TGF-b1 gene. As a consequence, tubular cells show
hypertropy which, together with increased synthesis of
type IV collagen, leads ultimately to brogenesis and
renal scarring (30).
Thus, grossly elevated glomerular and urinary leptin
levels might accelerate the proliferation of endothelial
and possibly tubular cells in renal glomerula, leading to
an aggravation of (predominant) glomerulosclerosis
and tubular damage. In consequence, continuous
leptin excretion might be an additional mechanism in
the progression of renal failure.
This hypothesis may be tested by long-term observation of children with severe proteinuria and leptinuria
in relation to the progression of renal failure. Furthermore, the effect of leptin on renal endothelial and
tubular cell proliferation should be examined in vivo
and in vitro.
In summary, our data demonstrate signicant leptin
excretion in children with severe proteinuria. Elevated
urinary leptin concentrations may contribute to the
proliferation of glomerular endothelial cells and
glomerulosclerosis.

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Received 19 March 2001

Accepted 5 July 2001