Hyperleptinemia in uremic patients undergoing conservative management, peritoneal dialysis, and hemodialysis: A comparative analysis

Hyperleptinemia in Uremic Patients Undergoing Conservative Management, Peritoneal Dialysis, and Hemodialysis: A Comparative Analysis Miguel Pe´rez Fonta´n, MD, Ana Rodrı´guez-Carmona, MD, Fernando Cordido, MD, and Jesu´s Garcı´a-Buela, MD ● We performed a cross-sectional study in a wide sample of patients with chronic renal failure undergoing conservative therapy (CTh) (n ⴝ 79), peritoneal dialysis (PD) (n ⴝ 75), and hemodialysis (HD) (n ⴝ 51), with the aim of analyzing the impact of the different modes of therapy on serum leptin levels. We used a multivariate approach, taking into consideration the potential effects of other epidemiological, dialysis-related, nutritional, and hormonal factors on serum leptin. Leptin levels were higher in patients treated with PD (median, 36 ng/mL) than in those undergoing CTh (10.8 ng/mL) or HD (5.4 ng/mL) (P F 0.0005). This difference persisted after controlling for gender, body mass index, and fasting insulin levels, suggesting that imbalances in these factors may only partially explain the differences found between the three modes of therapy. Leptin levels showed a significant negative correlation with peritoneal protein losses in PD patients but were poorly associated with factors such as proteinuria, daily peritoneal glucose absorption (PD), renal function, or adequacy of dialysis. Leptin and insulin-like growth factor-I (IGF-I) were significantly correlated in PD patients, but the study design did not allow for establishing a meaning for this correlation. In conclusion, serum leptin levels are increased in PD patients when compared with CTh or HD patients. Differences in gender distribution, fat mass, and insulin levels may partially explain these findings, but other undefined factors also may have a role in producing these results. 娀 1999 by the National Kidney Foundation, Inc. INDEX WORDS: Chronic renal failure; peritoneal dialysis (PD); hemodialysis (HD); leptin; insulin; insulin-like growth factor (IGF-I).

Editorial, p. 947

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EPTIN, the protein product of the ob gene, seems to have a relevant, yet not fully established role in the regulation of appetite in health and disease.1 This hormone is secreted by adipocytes in response to changes in fat mass and energy balance.2,3 Factors such as gender, age, fasting, and hyperalimentation may modify leptin secretion.4-6 Several humoral factors may induce changes in leptin secretion, including insulin, ␤3 agonists, glucocorticoids, and sex steroids.7,8 The relationship between insulin and leptin secretion has been a subject of particular attention. Fasting insulin levels correlate well

From the Nephrology, Endocrinology, and Laboratory Units, Hospital Juan Canalejo, and Department of Medicine, University of A Corun˜a, A Corun˜a, Spain. Received January 19, 1999; accepted in revised form May 14, 1999. Supported in part by grant PGIDT99PXI90002A from the Galician Administration (Spain). Address reprint requests to Miguel Pe´rez Fonta´n, MD, Servicio de Nefrologı´a, Hospital Juan Canalejo, Xubias de Arriba 84, 15006 A Corun˜a, Spain. E-mail: mfontan@ canalejo.cesga.es

娀 1999 by the National Kidney Foundation, Inc. 0272-6386/99/3405-0004$3.00/0 824

with leptin levels in healthy and obese people,9-11 and sustained hyperinsulinemia is associated with increased leptin levels,10,12,13 whereas acute changes in insulin levels are not.2,9 It is well known that serum leptin levels are increased in patients with renal failure, whether they are treated with conservative therapy (CTh),13-15 with hemodialysis (HD),14-20 or with peritoneal dialysis (PD).14,15,17,21 This disorder is basically mediated by a decrease in the renal clearance of leptin, whereas the potential role of an increased secretion of this hormone awaits further confirmation.22-25 Leptin appears to be poorly removed by PD26 and also by HD, especially if low-permeability membranes are used.14,18,19,23,27 Reported leptin levels seem to be higher in patients treated with PD than in those undergoing CTh or HD.24 This has been attributed to the higher fat mass of PD patients,17 but adjusted leptin levels also have been reported to be higher in PD than in HD patients.28 This question, which has not been addressed in depth, may deserve consideration, because leptin has been postulated to be anorexigenic,6 and malnutrition has been claimed to be more prevalent in patients on PD than in those undergoing HD.29 We have performed a cross sectional study in a wide population of uremic patients treated with

American Journal of Kidney Diseases, Vol 34, No 5 (November), 1999: pp 824-831

HYPERLEPTINEMIA IN CHRONIC RENAL FAILURE

825

CTh, PD, and HD, with the aim of analyzing the impact of the mode of therapy on serum leptin levels, controlling for other determinants of leptinemia. PATIENTS AND METHODS We studied 79 patients on CTh, 75 patients treated with PD (42 treated with continuous ambulatory peritoneal dialysis [CAPD] and 33 with automated PD [APD]) and 51 patients treated with HD, 31 of them treated with lowpermeability membranes, and 20 treated with hemodiafiltration and a high-permeability membrane (AN69, Hospal, MeyZieu, France). The main characteristics of both populations are shown in Table 1. Besides epidemiological data, we scrutinized dry weight, height, body mass index (BMI) (weight/(height)2, triceps skinfold and midarm muscle circumference (both presented as percentiles, after matching with healthy people of the same age and sex30), albumin, prealbumin, serum bicarbonate, renal function (as estimated by mean clearance ⫽ [creatinine clearance ⫹ urea clearance]/ 2), Kt/V, and normalized protein nitrogen appearance (PNA),31,32 proteinuria, daily glucose absorption (PD patients, direct quantification), daily peritoneal protein losses (PD patients), and the following hormonal parameters (as determined by specific radioimmunoassay): leptin (Mediagnost, Tu¨bingen, Germany), growth hormone (GH) (Nicholls Inst. Diag., San Juan Capistrano, California), insulin-like growth factor-I (IGF-I) )(Nicholls Inst. Diag.), IGF-binding protein 3 (IGF-BP3) (Nicholls Inst. Diag.), insulin (CIS Bio International, Cedex, France) and intact parathyroid hormone (PTH) (IRMA, Incstar Corp, Stillwater, MN). Blood samples were obtained after a minimum of 8 hours of

Table 1. Study Population CTh (n ⫽ 79)

PD (n ⫽ 75)

HD (n ⫽ 51)

P

Age (yr) 64 (19-86) 66 (18-84) 63 (18-79) NS Sex (% males/ females) 61/39 56/44 62/38 NS Diabetes (%) 19 31 13 0.02 CV comorbidities (n) 0 (0-4) 1.0 (0-5) 1.0 (0-3) 0.001 Non-CV comorbidities (n) 0 (0-3) 0 (0-3) 0 (0-4) NS Time on dialysis (months) — 9.0 (3-128) 23 (3-220) 0.001 NOTE. Numerical variables expressed as median (range). Comparison by ␹2, Kruskall Wallis, and MannWhitney’s tests. Abbreviations: CTh, conservative therapy; PD, peritoneal dialysis; HD, hemodialysis; CV, cardiovascular; NS, not significant.

fasting, in the early morning in CTh and PD patients and immediately before a dialysis session in HD patients. Leptin was the main study variable. We compared serum leptin levels according to the mode of therapy of chronic renal failure, directly and after controlling for other determinants of leptinemia. Univariate analysis was based on analysis of variance, Mann-Whitney’s and Kruskall-Wallis’ tests, ␹2 test, and Spearman’s correlation coefficient. Multivariate analysis was produced by multiple regression, according to the following strategy: First, we used stepwise multiple regression analysis, searching for a basal, best-fit model. Then, we included the mode of therapy in the model, to obtain an adjusted effect of this variable on serum leptin levels. Finally, the adjusted correlation between leptin levels and the mode of therapy was corrected, step by step, for the other variables studied, to disclose potential relationships between the latter and eventual differences in leptin levels between patients undergoing CTh, PD, and HD. Multivariate comparisons relative to the mode of therapy were performed by pairs, due to the lack of linearity of this variable. Also, leptin, insulin, GH, and PTH values showed a markedly abnormal distribution, and logarithmic transformation was required to meet the assumptions of the multiple regression model. The SPSS software (SPSS Inc, Chicago, IL), was used for statistical analysis.

RESULTS

A comparative survey of the studied variables is presented in Table 2. Serum leptin levels were higher in PD patients than in CTh or HD patients, but the BMI was larger for PD patients than for HD patients, and slightly lower percentages of CTh and HD patients were of female sex (Table 1). Serum leptin levels were very similar in CAPD (median, 35.7 ng/mL) and APD (median, 36.0 ng/mL) patients, and also in patients treated with conventional HD (median, 3.5 ng/ mL), and hemodiafiltration (median, 7.1 ng/ mL)(NS). As expected (Table 3), serum leptin levels showed a good correlation with BMI. Leptin levels tended to be higher in PD patients than in CTh or HD patients, particularly in the presence of a normal or high BMI (Fig 1), whereas the difference was much less apparent in patients with lower (⬍21 kg/m2) BMI. Also, as expected, leptin levels were higher in women (median, 35.0 ng/mL) than in men (median, 7.6 ng/mL, P ⬍ 0.001). Conversely, leptin levels were similar in diabetic (median, 11.3 ng/mL) and nondiabetic (median, 13.1 ng/mL) patients (NS). Univariate analysis also disclosed a significant correlation between leptin levels and GH, IGF-I (Fig 2), and fasting insulin levels (Table 3). Finally, leptin levels correlated poorly with epi-

FONTA´N ET AL

826 Table 2. Nutritional, Adequacy, and Hormonal Variables

Body mass index (kg/m2) Triceps skinfold (%) Midarm muscle circumference (%) Albumin (g/dL) Prealbumin (mg/dL) Serum bicarbonate (mmol/L) Mean renal clearance (mL/min) Kt/V Protein nitrogen appearance (g/Kg/d) Proteinuria (g/d) Peritoneal protein losses (g/d) Peritoneal glucose absorption (g/d) Leptin (ng/mL) Growth hormone (ng/mL) IGF-I (ng/mL) IGF binding protein 3 (µg/mL) Insulin (µU/mL) Intact parathyroid hormone (pg/mL)

CTh (n ⫽ 79)

PD (n ⫽ 75)

HD (n ⫽ 51)

P

26.9 (4.3) 36 (29) 65 (27) 4.4 (0.5) 33.9 (7.4) 23.4 (4.2) 11.1 (6.1) 2.4 (1.2) 0.97 (0.33) 1.7 (0-17.6) — — 10.8 (0.4-159) 1.1 (0.1-22.0) 247 (109) 6.7 (2.2) 11.1 (3.2-49.0) 180 (14-2,009)

26.1 (4.3) 40 (31) 63 (29) 3.9 (0.5) 31.8 (9.4) 24.9 (3.6) 2.7 (2.7) 2.4 (0.6) 1.35 (0.40) 0.5 (0-4.7) 9.1 (5.0) 101 (52) 36.0 (1-477) 1.3 (0.1-14.9) 337 (144) 7.7 (2.3) 19.5 (7.4-76.0) 73 (3-691)

23.8 (3.4) 30 (26) 43 (30) 4.2 (0.4) 28.6 (9.2) 23.5 (3.1) 0.9 (1.8) 3.9 (1.0) 1.19 (0.29) 0.2 (0-2.2) — — 5.4 (0.2-143) 2.3 (0.1-16.8) 211 (108) 6.8 (1.6) 15.4 (4.5-71.0) 76 (8-1,411)

0.002 NS 0.001 0.001 0.0006 0.008 0.0005 0.0005 0.0005 0.0005 — — 0.0005 NS 0.001 NS 0.0005 0.0005

NOTE. All values presented as mean (standard deviation) (comparison by analysis of variance), except for proteinuria, leptin, GH, insulin, and PTH, presented as median (range) (comparison by Kruskali-Wallis test), attributable to abnormal distribution. Abbreviations: CTh, conservative therapy; PD, peritoneal dialysis; HD, hemodialysis; NS, not significant.

demiological factors such as age, time on dialysis, renal disease, or associated comorbidities (Table 3). Multivariate analysis confirmed BMI and sex as strong independent predictors of serum leptin levels (Table 4, adjusted R2 for these two factors, 0.53). As indicated in Patients and Methods, the impact of the mode of therapy on the model was analyzed by pairs (CTh versus PD, CTh versus HD, and PD versus HD), because of the lack of linearity of this variable. Inclusion of this factor improved the quality of the best fit model (as estimated by adjusted R2) to a variable degree (Table 4). PD patients showed higher adjusted serum leptin levels than their counterparts on CTh (R2 ⫽ 0.61) or HD therapy (R2 ⫽ 0.68). Conversely, patients treated with CTh presented slightly higher adjusted serum leptin levels than their counterparts on HD (R2 ⫽ 0.55). For the whole study group, adjusted serum leptin levels were similar in diabetic and nondiabetic patients (B ⫽ 0.02; confidence interval [CI], ⫺0.13/0.18; P ⫽ 0.72). Only in the CTh group did diabetic patients present lower adjusted leptin levels than nondiabetic patients (B ⫽ 0.26; CI, 0.05/0.47; P ⫽ 0.02). GH levels were not independently associated

with leptin levels, after controlling for sex and BMI. This was true for the whole group, and also for the three modes of therapy in separate. Conversely, and for the whole study group, IGF-I levels were significantly correlated with serum leptin levels, after controlling for gender and BMI (Table 4). However, the generation of interaction terms disclosed that this relationship was sustained by patients on PD, leptin and IGF-I levels being poorly correlated in the other two study groups. As a corollary, after controlling for the mode of therapy, IGF-I levels remained independently associated with leptin levels only when PD patients were compared with CTh or HD patients, but not when CTh and HD patients were compared. Given the poorly understood physiological relationship between leptin and IGF-I, we considered the possibility that leptin could primarily regulate IGF-I secretion, the converse relationship representing a feedback mechanism. Multiple regression showed that IGF-I levels were independently predicted by leptin (B⫽59.1; CI, 28.6/89.5, P ⫽ 0.0002), prealbumin (B ⫽ 3.6; CI, 1.1-6.1; P ⫽ 0.005), and age (B ⫽ ⫺2.37; CI, ⫺1.00/⫺3.75; P ⫽ 0.0002) (R2 ⫽ 0.25, P ⬍ 0.0005). On the contrary, the model did not

HYPERLEPTINEMIA IN CHRONIC RENAL FAILURE

827

Table 3. Main Correlations of Leptin: Univariate

Age CV comorbidities Non-CV comorbidities Time on dialysis Body mass index Triceps skinfold Midarm muscle circumference Albumin Prealbumin Mean renal clearance Kt/V Protein nitrogen appearance Proteinuria Peritoneal protein losses (PD) Peritoneal glucose absorption Growth hormone IGF-I IGF binding protein 3 Insulin Intact parathyroid hormone

CTh (n ⫽ 79)

PD (n ⫽ 75)

HD (n ⫽ 51)

0.20 ⫺0.19 0.21 — 0.57‡ 0.40‡

0.23* ⫺0.13 ⫺0.14 0.09 0.62‡ 0.51‡

0.19 0.06 ⫺0.36† ⫺0.26 0.56‡ 0.47‡

0.19 0.12 0.23* ⫺0.27* ⫺0.17

0.40‡ 0.06 0.22* ⫺0.16 ⫺0.12

0.46‡ ⫺0.01 0.11 0.11 0.06

factors independently predicted serum leptin when any two modes of therapy were compared. Neither renal function (as estimated by mean renal clearance), adequacy of dialysis (as estimated by Kt/V), proteinuria, nor any other scrutinized variable was independently associated with serum leptin using a multivariate approach. In the PD group, serum leptin levels showed a weak, but significant negative correlation with peritoneal protein losses, after controlling for sex and BMI (B ⫽ ⫺0.022; CI, ⫺0.041/⫺0.002; P ⫽ 0.03). On the contrary, daily peritoneal glucose absorption was not independently associated with leptinemia.

0.07 ⫺0.25

0.15 0.18

0.04 0.09

DISCUSSION

—

⫺0.27†

—

— ⫺0.08 0.16 0.03 0.53‡

⫺0.04 ⫺0.27* 0.30† 0.01 0.36†

— ⫺0.23 0.29* ⫺0.20 0.58‡

0.11

⫺0.14

0.01

NOTE. Results denote correlation between serum leptin and the presented variables for every study group (Spearman’s correlation coefficient). Abbreviations: CTh, conservative therapy; PD, peritoneal dialysis; HD, hemodialysis; CV, cardiovascular. *P ⬍ 0.05. †P ⬍ 0.01. ‡P ⬍ 0.001. Other coefficients not significant; CV, cardiovascular.

identify factors such as serum bicarbonate, insulin, GH, and BMI as independent predictors of IGF-I levels. This profile was true for the whole group, and also for PD and HD patients separately, whereas for CTh patients, leptin did not reach statistical significance as a predictor of IGF-I levels (B ⫽ 29.5; CI, ⫺12.6/71.5; P ⫽ 0.11). Multivariate analysis confirmed that, after controlling for gender and BMI, fasting insulin maintained a good correlation with leptin (Table 4). This correlation remained significant for PD and CTh patients separately but did not reach statistical significance in the case of HD patients. When the effects of the mode of therapy and fasting insulin were adjusted for sex and BMI, both

Decreased renal clearance is the basic mechanism for the increment of serum leptin levels in patients with chronic renal failure.16,21,24,25 Conversely, the basic mechanisms regulating leptin secretion appear to be at least partially preserved in this population. Body fat content and sex, the two main clinical correlates of serum leptin levels, are also basic predictors of leptinemia in patients with renal failure.14,15,17,21,33 Despite a well-known state of insulin resistance in uremia,34 fasting insulin and leptin levels have been reported to correlate well in uremic patients undergoing CTh35 and HD,20 but more poorly in patients on PD,21 whereas the relationship between GH and IGF-I on one side and leptin

Fig 1. Median serum leptin levels in CTh, PD, and HD patients, according to different strata of BMI. 䊐, PD; 8, HD; O, CTh

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Fig 2. Correlation between IGF-I and leptin levels in CTh, PD, and HD patients, univariate. Comparison by Spearman’s correlation coefficient. — —䊏— —, CTh; - -䉱- - -, HD; ——— 䊊 , PD.

levels on the other appears more controversial.6,36 Our study confirmed the well-known, independent correlation between fasting insulin and serum leptin (Table 49-13,35). The trend to an inverse correlation between leptin and GH levels (Table 3) was not confirmed by multivariate analysis. This lack of association between GH and leptin, after controlling for sex and BMI, is in agreement with previous reports, indicating that the effect of GH on leptin levels may be mediated by a reduction in fat mass rather than by a direct effect on leptin secretion.6 It is unclear whether Table 4. Main Correlations of Leptin: Multivariate

BMI Female gender Fasting insulin (log10) IGF-I PD (v CTh) PD (v HD) CTh (v HD)

B

95% CI

P

0.08 0.48 0.83 0.0014 0.23 0.56 0.14

0.07, 0.10 0.34, 0.62 0.51, 1.13 0.0008, 0.0019 0.17, 0.30 0.40, 0.72 ⫺0.02, 0.30

0.0005 0.0005 0.001 0.0005 0.0005 0.0005 0.07

NOTE. Best model. Dependent variable: log10 (leptin). Abbreviations: PD, peritoneal dialysis; CTh, conservative therapy; HD, hemodialysis.

leptin can modulate GH secretion as a part of its biological effects.1,37 The correlation between leptin and IGF-I levels observed in our patients is more difficult to interpret. Leptin has been shown to be directly correlated with IGF-I in healthy, lean, elderly subjects.38 However, the question may be more complicated in dialysis patients. First, factors such as malnutrition39 and chronic acidosis40 may modify IGF-I secretion in this setting. In addition, PD may result in significant peritoneal losses of IGF-I and its binding proteins.41,42 Third, evidence indicates resistance to the physiological effects of IGF-I in uremia.43 Fouque et al36 have reported that the administration of IGF-I reduces, whereas the simultaneous administration of GH and IGF-I increases, serum leptin levels in dialysis patients. An alternative possibility is that leptin may directly stimulate IGF-I secretion, thus explaining a correlation leptin– IGF-I in the absence of a correlation leptin-GH. This profile could be similar to that observed in obese patients, who display simultaneously decreased GH secretion, increased plasma leptin levels, and normal to high plasma IGF-I levels.44,45 Leptin levels have been shown to be tightly correlated with GH-binding protein (the

HYPERLEPTINEMIA IN CHRONIC RENAL FAILURE

soluble fraction of GH receptor) levels in anorectic, normal, and obese individuals.46 Our data support such a pathway in chronic renal failure patients, because leptin was a strong independent predictor of IGF-I levels. Moreover, if this were the case, increased leptin levels could contribute significantly to the increased IGF-I levels observed in our PD patients, when compared with those undergoing CTh and HD. The significance of all of these findings, and their relationship to the physiology of leptin in uremia, is largely unestablished, but the physiological links between leptin and the GH-IGF-I axis seem to be strong, in both healthy and uremic patients. Our results confirm that serum leptin levels are increased in patients with chronic renal failure,14 PD patients showing the highest levels of serum leptin in this population.28 Moreover, we have demonstrated that leptin levels are disproportionally increased in PD patients with normal and high BMI, when compared with patients undergoing CTh or HD, suggesting a particularly disordered negative feedback mechanism for leptin secretion in PD patients. The reasons for this finding are not clear. Continuous absorption of glucose from the peritoneal fluid may result in hyperinsulinism,47 which may blunt the inhibitory effect of a high fat mass on leptin secretion. Fasting insulin levels were higher in PD patients than in CTh or HD patients in our study. However, the mode of therapy remained a significant predictor of serum leptin levels after controlling for fasting insulin, suggesting that another factor(s) may mediate hyperleptinemia in this setting.20 This notwithstanding, insulin may yet be a key for the differences found. First, it can be argued that a single fasting insulin may not adequately reflect the magnitude and the profile of insulin stimulation in PD patients, when compared with those on CTh and HD. Second, it is possible that differences in the severity of insulin resistance between the three groups of patients could result in a different pattern of leptin response to physiological stimuli, a controversial point.12,13 An alternative, interesting possibility is that continuous absorption of glucose from peritoneal dialysate may directly stimulate leptin secretion. Wang et al48 have shown that leptin secretion may be stimulated by nutrients, following an insulin-independent pathway. The potential roles played by other factors, such as differ-

829

ences in ob gene expression response to changes in fat mass,25 inflammatory mediators,17 or the influence of the GH–IGF-I axis itself,36 await further analysis. Our results confirm a significant but poor correlation between serum leptin levels and renal function in patients undergoing CTh,25 as also a lack of association between leptin levels and adequacy of dialysis or proteinuria in chronic renal failure.15,18,21 Contrary to previous reports,15,28 we did not find a clear correlation between protein intake (as estimated from PNA) or markers of protein malnutrition (albumin, prealbumin, midarm muscle circumference) and leptin levels. This lack of relationship persisted after controlling for BMI and the confounding effect of other potential determinants of protein malnutrition (mode of dialysis, age, diabetes, comorbidity). The consequences of the anorexigenic effect of hyperleptinemia on chronic renal failure are difficult to study using a crosssectional design, but our results do not support a first-line role for leptin in the genesis of malnutrition of uremia. The differences in PD schedule between CAPD and APD (glucose load predominating during the night in APD versus more continuous load in PD) did not impact on leptin levels. Also, leptin levels were not affected by the permeability of the dialysis membrane in the HD group. Previous reports have indicated that high-permeability membranes may significantly clear leptin,19,27 but we did not analyze postdialysis leptin levels to test this hypothesis. The weak correlation between peritoneal protein losses and leptin levels detected in PD patients does not have a clear explanation but could be related to increased peritoneal clearance of leptin or loss of some factor(s) related to the control of serum leptin levels. In conclusion, serum leptin levels are significantly higher in patients undergoing PD, when compared with patients treated with HD or CTh. The difference is partially explained by differences in BMI, sex, and fasting insulin levels between the study groups, but other undefined factors may have a significant role in the differences found. REFERENCES 1. Friedman JM, Halaas JL: Leptin and the regulation of body weight in mammals. Nature 395:763-770, 1998

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2. Caro JF, Sinha MK, Kolaczynski JW, Zhang PL, Considine RV: Leptin: The tale of an obesity gene. Diabetes 45:1455-1462, 1996 3. Klein S, Coppack SW, Mohamed-Ali V, Landt M: Adipose tissue leptin production and plasma leptin kinetics in humans. Diabetes 45:984-987, 1996 4. Ostlund RE, Yang JW, Klein S, Gingerich R: Relation between plasma leptin concentrations and body fat, gender, diet, age and metabolic covariates. J Clin Endocrinol Metab 81:3909-3913, 1996 5. Blum WF: Leptin: The voice of the adipose tissue. Horm Res 2–8, (suppl 4) 6. Considine RV: Weight regulation, leptin and growth hormone. Horm Res 48 116-121, 1997 (suppl 5) 7. Bray GA, York DA: Clinical review 90: Leptin and clinical medicine: A new piece in the puzzle of obesity. J Clin Endocrinol Metab 82:2771-2776, 1997 8. Considine RV, Caro JF: Leptin and the regulation of body weight. Int J Biochem Cell Biol 29:1255-1272, 1997 9. Dagogo Jack S, Fanelli M, Paramore D, Brothers J, Landt M: Plasma leptin and insulin relationships in obese and nonobese humans. Diabetes 45:695-698, 1996 10. Kolaczynski JW, Nyce MR, Considine RV, Boden G, Nolan JJ, Henry R, Mudaliar SR, Olefsky J, Caro JF: Acute and chronic effects of insulin on leptin production in humans: Studies in vivo and in vitro. Diabetes 45:699-701, 1996 11. de Courten M, Zimmet P, Hodge A, Collins V, Nicolson M, Staten M, Dowse G, Alberti KG: Hyperleptinaemia: The missing link in the metabolic syndrome? Diabetes Med 14:200-208, 1997 12. Segal KR, Landt M, Klein S: Relationship between insulin sensitivity and plasma leptin concentration in lean and obese men. Diabetes 45:988-991, 1996 13. Shoji T, Nishizawa Y, Emoto M, Maekawa K, Hiura H, Tanaka S, Kawagishi T, Okuno Y, Morii H: Renal function and insulin resistance as determinants of plasma leptin levels in patients with NIDDM. Diabetologı´a 40:676679, 1997 14. Howard JK, Lord GM, Clutterback EJ, Ghatei MA, Pusey CD, Bloom SR: Plasma immunoreactive leptin concentration in end-stage renal disease. Clin Sci Colch 93:119126, 1997 15. Young GA, Woodrow G, Kendall S, Oldroyd B, Turney JH, Brownjohn AM, Smith MA: Increased plasma/ leptin fat ratio in patients with chronic renal failure: A cause of malnutrition? Nephrol Dial Transplant 12:2318-2323, 1997 16. Iida N, Murakami T, Yamada M, Sei M, Kuwajima M, Mizuno A, Noma Y, Aono T, Shima K: Hyperleptinemia in chronic renal failure. Horm Metab Res 28:724-727, 1996 17. Heimbu¨rger O, Lonnqvist F, Danielsson A, Nordenstrom J, Stenvinkel P: Serum immunoreactive leptin concentration and its relation to the body fat content in chronic renal failure. J Am Soc Nephrol 8:1423-1430, 1997 18. Merabet E, Dagogo Jack S, Coyne DW, Klein S, Santiago JV, Hmiel SP, Landt M: Increased plasma leptin concentration in end-stage renal disease. J Clin Endocrinol Metab 82:847-850, 1997 19. Nakazono H, Nagake Y, Ichikawa H, Makino H:

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