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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 11 5497-5501
Copyright © 2003 by The Endocrine Society

Increased Soluble Leptin Receptor in Children with Nephrotic Syndrome

Michael Schroth, Jürgen Kratzsch, Michael Gröschl, Manfred Rauh, Wolfgang Rascher and Jörg Dötsch

Klinik mit Poliklinik für Kinder und Jugendliche (M.S., M.G., M.R., W.R., J.D.), Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany; and Institute of Laboratory Medicine (J.K.), Clinical Chemistry and Molecular Diagnostics, Hospital for Children and Adolescents, University of Leipzig, D-04103 Leipzig, Germany

Address all correspondence and requests for reprints to: Michael Schroth, M.D., Klinik mit Poliklinik für Kinder und Jugendliche Friedrich-Alexander-Universität Erlangen-Nürnberg, Loschgestrasse 15, D-91054 Erlangen, Germany. E-mail: michael_schroth{at}yahoo.de.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Materials and methods
 Results
 Discussion
 References
 
In patients with nephrotic syndrome, severe proteinuria is related to significant leptinuria; serum leptin levels remain unchanged. The goal of this study was to elucidate the role of the soluble leptin receptor (sOB-R) in maintaining serum leptin levels in nephrotic patients. Patients with proteinuria were compared with patients in remission of nephrotic syndrome. In this 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 sOB-R level (mean ± SD) in serum of patients with nephrotic syndrome was significantly higher during proteinuria (61.0 ± 17.8 ng/ml) than those in remission or in control patients (36.7 ± 7.0 ng/ml, 36.6 ± 12.0 ng/ml, respectively, P < 0.0001). The ratio between serum leptin levels and the sOB-R (free leptin index) was significantly lower in the proteinuric group (0.012 ± 0.005 vs. 0.06 ± 0.03 and 0.07 ± 0.03 in remission and control group, respectively) (P < 0.001). Urinary sOB-R excretion was similar in all groups. Our data suggest that the counteracting pathway in case of leptin loss in parallel to severe proteinuria in nephrotic syndrome is the up-regulation of its soluble binding protein in serum, which can keep total serum leptin levels constant.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Materials and methods
 Results
 Discussion
 References
 
LEPTIN, A 167-AMINO acid polypeptide with a molecular size of 16 kDa, is mainly synthesized in adipose tissue (1, 2) but also in other tissues, such as the placenta (3), the gastrointestinal tract (4, 5, 6), and neuronal tissues (7). The product of the ob gene plays an important role in the regulation of appetite and food intake in mice and humans (8, 9, 10). Mutations of the leptin gene or its receptor gene lead to obesity in mice and humans (1, 11).

Leptin circulates in murine serum in a free and bound form (11, 12, 13, 14, 15, 16). In human blood, it is bound to a high affinity binding protein, which is the soluble leptin receptor (sOB-R), modulating the effects of its ligand (17, 18). The sOB-R represents the major leptin binding protein in the circulation. The presumed biologically active form of leptin is determined by the free leptin index (FLI), the ratio between leptin and sOB-R levels (15, 17).

The idiopathic nephrotic syndrome (INS) is an albumin-loosing 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/liter) and chronically to a catabolic nutritional state (19). Our previous data revealed a renal urinary leptin loss in prepubertal and early pubertal children suffering from active nephrotic syndrome with proteinuria greater than 1 g/m2 (20). Urinary leptin loss disappeared after remission. However, despite an up to 100-fold increment in leptin excretion in proteinuria, serum leptin levels are similar in both proteinuric and nonproteinuric children (20). These findings suggest that the renal loss of leptin is counterregulated.

We, therefore, hypothesized that the sOB-R protein binding capacity counteracts the urinary losses of leptin. The FLI, representing the biologically active form of leptin, is expected to be altered in proteinuric children.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Materials and methods
 Results
 Discussion
 References
 
Pediatric patients with nephrotic syndrome (NS) were studied. The patients’ characteristics are shown in Table 1Go. 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, no significant 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).


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  		TABLE 1. Patients’ characteristics

 
Concentration of leptin in serum and urine and the levels of the soluble leptin receptor in serum and urine were measured by RIA. 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 wk at -20 C and were analyzed when all specimens had been obtained.

In four patients with NS, sequential samples were obtained over a period of 1 yr in different states of disease.

In all patients, body weight and body height were measured to obtain the body mass index (BMI). Subscapular and triceps skinfold thickness was determined with a caliper by the same trained investigator (M.S.). No patient was fasting. All clinical and auxologic data were obtained during routine visits and recorded using standard data sheets. Details are shown in Table 1Go. 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
Top
 Abstract
 Introduction
 Patients and Methods
 Materials and methods
Results
 Discussion
 References
 
Hormone measurements.

Serum levels of the sOB-R have been measured by a sensitive ligand-immunofunctional assay (17, 18). For the determination of sOB-R in urine, samples of 1 ml were 25-fold concentrated and assayed by the same method.

Serum levels of leptin were measured using a specific RIA as described in detail elsewhere (21). Leptin in urine was measured by a highly sensitive adaptation of the assay. Tracer activity was 8000 c/m·25 µl. The antiserum had a final dilution of 1:8000 in 25 µl. The standard raw expanded from 1250 to 10 pg/ml.

Statistical analysis.

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


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Materials and methods
 Results
Discussion
 References
 
The sOB-R levels in serum (mean ± SD) of patients with NS presenting with proteinuria (group I) were significantly higher (61.0 ± 17.8 ng/ml) than in patients with remission or control patients (36.7 ± 7.0 ng/ml, 36.6 ± 12.0 ng/ml, P < 0.0001), respectively (Fig. 1Go). The ratio between serum leptin levels and the sOB-R (FLI) was significantly lower in the proteinuric group (0.012 ± 0.005 vs. 0.06 ± 0.03 and 0.07 ± 0.03 in remission and control group, respectively) (P < 0.001) (Fig. 2Go). The sOB-R was also measured in urine and did not show any significant difference among the three study groups. There was no correlation between urinary sOB-R excretion and urine albumin or urine IgG in any of the groups.



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  		FIG. 1. Soluble leptin receptor 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 scattergram and box and whiskers. Significant higher levels in group I are evaluated by using one-way ANOVA; P values were corrected according to Bonferroni. ***, P = 0.0005.

 


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  		FIG. 2. FLI 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 scattergram and box and whiskers. Significantly higher levels in group I are evaluated by using one-way ANOVA; P values were corrected according to Bonferroni. ***, P = 0.0005.

 
There was no difference in urinary sOB-R between boys and girls or between Tanner stages 1 and 2. The patients’ medication (cyclosporine, tacrolimus, cyclophosphamide, ß-blocking agents, prednisone) did not significantly influence serum or urinary concentrations of sOB-R when children receiving one of the medications were compared with nontreated patients.

A positive relationship was obtained between BMI and serum sOB-R in nephrotic patients with proteinuria (P = 0.008; r2 = 0.29), patients with remission (P < 0.0023; r2 = 0.37), and controls (P = 0.012; r2 = 0.38). No significant correlations were found between BMI or subscapular skinfold thickness and urinary sOB-R concentrations in any group. Also, a positive relationship was obtained between BMI and FLI in nephrotic patients with proteinuria (P = 0.036; r2 = 0.44), patients with remission (P < 0.026; r2 = 0.49), and controls (P = 0.027; r2 = 0.32). No significant correlation was found between BMI or subscapular skinfold thickness and FLI in any group.

In four patients, long-term observations were evaluated, and the courses of urinary leptin excretion and the sOB-R in serum were parallel in all patients. When urinary leptin losses showed a decrease a parallel decrease of sOB-R concentration in serum was seen. With increasing proteinuria, concentrations of urinary leptin and serum sOB-R were elevated. In all patients, proteinuric or not, the levels of serum leptin and urinary sOB-R were parallel and did not show any changes during the period of observation (Fig. 3Go).



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  		FIG. 3. Data courses of patients 1–4. Shown are the data for sOB-R in serum, sOB-R in urine, leptin in serum, and urinary leptin to four different points of examination ({blacksquare}, sOB-R serum; {diamondsuit}, leptin urine; {blacktriangledown}, leptin serum; {blacktriangleup}, sOB-R urine).

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Materials and methods
 Results
 Discussion
References
 
We could recently demonstrate a renal urinary leptin loss in prepubertal and early pubertal children suffering from active nephrotic syndrome with proteinuria greater than 1 g/m2 (20). Urinary leptin loss disappeared after remission and was minimal in the control group. However, despite an up to 100-fold increment in leptin excretion in the protein-wasting group, serum leptin levels were similar in all three groups (20). This finding suggests that the renal loss of leptin must be compensated. One mechanism might be the up-regulation of leptin synthesis. Up to now these mechanisms still remain unclear (21, 22, 23, 24, 25, 26, 27). Elevated secretion of stored leptin, stimulated mRNA synthesis, or an increased fraction of protein-bound leptin appear possible (28). An increase in leptin binding capacity could maintain total serum leptin concentration and prevent the urinary loss of leptin. Alternatively, bioactivity might be altered by nutritional state, BMI, or gender, rather than by its soluble binding protein (29, 30).

We, therefore, studied the sOB-R, which is known to be a binding protein with high affinity to leptin in serum (17, 18). Children with massive proteinuria who reveal an enormous urinary leptin loss have significantly elevated levels of the sOB-R in serum. In all the other patients, either in state of remission of NS (i.e. without significant proteinuria) or in control patients, we could not find elevated levels of the sOB-R in serum. Both proteinuric and nonproteinuric patients had similar leptin levels in serum (20). To estimate the biologically active form of leptin, Kratzsch et al. (17) defined the ratio between serum leptin levels and its soluble receptor as FLI. These data are confirmed by others (15). We could measure a significantly decreased level of FLI in children with massive proteinuria. Reflecting these data, we postulated that the loss of leptin excreted into the urine of nephrotic patients is compensated by elevation of its sOB-R in serum. Elevated levels of the leptin binding protein are then capable to maintain the concentration of total leptin in serum. However, the biologically active form of leptin, as suggested by decreased FLI, is significantly lower in case of renal leptin loss.

The courses of four patients, all suffering from NS, emphasize the sOB-R up-regulation. In all of them, in case of proteinuria, high urinary leptin losses were found, which are paralleled by highly elevated concentrations of sOB-R in serum. In case of remission or reduction of proteinuria, urinary leptin loss decreased, and in parallel, sOB-R decreased. At all times in patients with remission of NS or massive proteinuria, serum leptin levels were kept stable. These data suggest that the counteracting mechanism in case of leptin loss might be the up-regulation of its sOB-R in serum. Alternatively, leptin loss in NS may result in an increased leptin synthesis, leading to an increase in the binding of the soluble receptor.

Huang et al. (28) demonstrated that high levels of leptin can be caused by the delayed clearance of leptin from circulation due to binding to its soluble receptor. They concluded that the soluble receptor is up-regulated and an overexpression of the sOB-R results in an increase of circulating leptin. In our study we did not find increased serum leptin levels. However, despite an enormous leptin excretion into the urine, we did not find a decrease in serum leptin levels either. Therefore, we hypothesized that the increase in serum sOB-R compensates the urinary loss of leptin from the circulating blood to keep serum leptin levels stable.

However, another reason for increased serum sOB-R levels appears possible in cases of the increased urinary loss of leptin, the shedding of the ectodomain of membrane bound, functional receptor isoforms (31). Target cells could counterregulate the density of membrane bound leptin receptor molecules based on the number of ligand-receptor interaction, which should be reduced with a decreased FLI. One important mechanism by which the increased sOB-R could be generated might be that the sOB-R is predominantly derived from the truncated leptin receptor isoform (32).

Several studies have shown a relationship among BMI, subscapular skinfold thickness measurements, and concentrations of sOB-R (15, 29, 33). These observations could be confirmed in the present study. However, our data did not reveal any relationship between concentrations of urinary sOB-R and BMI or skinfold thickness, suggesting that the sOB-R clearance is regulated by a kidney-specific mechanism.

NS is often associated with increased proteolytic activity, leading to degraded proteins with decreased bioactivity as shown for the IGF-binding proteins. Therefore, it could be argued that an altered size of the sOB-R molecule may be related with a different bioactivity in our patients. However, the use of a ligand-immunofunctional assay for sOB-R implicates the determination of the immunological and biological activity of this protein. Therefore, we measure degraded and nondegraded sOB-R molecules that are capable of binding leptin independently on their molecular size. On the other hand, the method does not recognize bioinactive degraded receptor proteins. Additionally, we compared the size of the sOB-R of patients with NS to normal controls using a Western blot analysis. We did not find any difference between healthy subjects and patients with NS, suggesting that most of the receptor protein is not degraded (data not shown). However, it cannot be totally excluded that a certain, minor fraction might be degraded. Taking both arguments together, we can conclude that our finding of increased sOB-R levels in patients with NS should be of biological relevance.

In conclusion, we can demonstrate with our data that the counteracting pathway in case of leptin loss in parallel with severe proteinuria in NS is the up-regulation of its soluble binding protein in serum, which can keep serum leptin levels equal.


   Footnotes
 
Abbreviations: BMI, Body mass index; FLI, free leptin index; NS, nephrotic syndrome; sOB-R, soluble leptin receptor.

Received March 27, 2003.

Accepted August 7, 2003.


   References
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 Introduction
 Patients and Methods
 Materials and methods
 Results
 Discussion
 References
 

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