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*
Division of Renal Medicine, Karolinska Institutet, Huddinge University
Hospital, Stockholm, Sweden
Division of Baxter Novum, Department of Clinical Science, Karolinska
Institutet, Huddinge University Hospital, Stockholm, Sweden
Department of Medicine, Karolinska Institutet, Huddinge University
Hospital, Stockholm, Sweden.
Correspondence to Dr. Peter Stenvinkel, Department of Renal Medicine K56, Huddinge University Hospital, 141 86 Huddinge, Sweden. Phone : +46 8 58582532 ; Fax : +46 8 7114742 ; E-mail : peter.stenvinkel{at}klinvet.ki.se
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The relationship between leptin and body compositional changes in uremic patients is important to study, because the role of leptin in regulating nutritional intake and energy expenditure has not been clarified. There is still no direct proof of loss of appetite with an increase in leptin levels in uremic patients, as available cross-sectional data in the literature are conflicting. Although some studies have presented data that are consistent with the concept that leptin contributes to malnutrition (9, 11), others have not been able to demonstrate any relationship between serum leptin and recent weight change or various nutritional markers (7, 8). However, conclusions based on cross-sectional data are bound to be incomplete and will miss the regulatory and dynamic effects that leptin might have in the early development of changes in body composition (12). Longitudinal studies with serial measurements of leptin and body composition are therefore required to better study the dynamics and potential clinical relevance of the leptin system in CRF patients. The aim of the present prospective study was therefore to study longitudinal changes in body composition during PD and to relate the changes in body composition to changes in serum leptin levels.
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Materials and Methods |
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After an overnight fast, blood samples for the analysis of C-reactive protein (CRP), creatinine, urea, plasma insulin (n = 26), and serum leptin were taken at a time point shortly before the start of PD. Measurements of body composition by dual-energy x-ray absorptiometry (DEXA), weight, and length were also performed in all patients. DEXA was performed 20 ± 7 d (range, 48 to 156 d) after the start of PD and always after drainage of the peritoneal dialysate. Repeated measurements of body composition, weight, and length, fasting serum leptin, and CRP were performed 391 ± 9 d after the patients had started PD. Because changes in the hydration status may be a factor confounding the estimation of lean body mass by DEXA, serial multiple-frequency bioimpedance measurements were performed to estimate the extracellular volume (ECV) in 15 of the patients.
Thirty-four of the patients were initially treated with continuous ambulatory peritoneal dialysis (CAPD), whereas two of the patients were initially treated with automated peritoneal dialysis (APD) using a cycler. The prescribed dialysate volumes were individualized, and two more patients were transformed to APD during the study period. The Ethics Committee of Karolinska Institute at Huddinge University Hospital approved the study. All patients gave informed consent to participate.
Calculations of Dialysis Adequacy and Urea Kinetics
Weekly Kt/V urea and weekly CCr (L/wk 1.73 m2) were
calculated from a 24-h collection of dialysate and urine. The distribution
volume of urea, which is generally assumed to be equal to total body water,
was calculated with V, estimated from the Watson equation
(13). Weekly CCr
was calculated as peritoneal CCr plus the average of renal urea and
CCr. The residual renal function (RRF) was calculated as the
average of residual renal creatinine and urea clearances. Dietary protein
intake was estimated from the protein equivalent of nitrogen appearance (PNA)
using the recently derived equation : PNA = 15.1 + 0.195 urea appearance
(mmol/24 h) + protein losses (g/24 h). Urea appearance rate and protein losses
were determined from the measured urea and protein excretion in dialysate and
urine (14). PNA was normalized
for actual body weight to obtain nPNA (g/kg body wt/24 h). The 24-h peritoneal
glucose absorption was calculated from the used dialysate volumes and glucose
concentrations during 24 h minus the directly measured volume and glucose
concentration of the drained 24-h dialysate. The average values of total
protein loss, Kt/V urea, weekly CCr, RRF, PNA, nPNA, and 24-h
glucose absorption from all of the 24-h collections of urine and dialysate in
each patient (n = 3 to 6) during the first year of PD were used in
the statistical analysis.
Analyses
Serum leptin levels were analyzed with a commerically available RIA kit
(Linco Research, Inc., St. Charles, MO). The leptin assay is completely
homologous, since the antibody was raised against highly purified human leptin
and both the standard and tracer are prepared with human leptin. The
coefficient of variance within the sample was 6%. A specific RIA assay was
used to analyze plasma insulin (Pharmacia, Uppsala, Sweden). Determinations of
CRP, creatinine, and urea were carried out in the Department of Clinical
Chemistry, Huddinge Hospital, using routine methods. The detection limit of
CRP at the Department of Clinical Chemistry, Huddinge Hospital is 10 mg/L, and
all values <10 mg/L in the statistical evaluation were treated as 5 mg/L.
All subjects had their body composition evaluated by DEXA (Lunar Corp.,
Madison, WI) with Lunar software, version 3.4. At the same time as the DEXA
investigation, ECV was estimated in 15 of the patients by multiple-frequency
bioimpedance as described previously
(15).
Statistical Analyses
All results are given as mean ± SEM. The nonparametric Mann-Whitney
U test or unpaired t test was used to test differences
between patients who lost or gained lean body mass, as appropriate. The
nonparametric Wilcoxon rank sum test or paired t test was used to
evaluate differences over time, as appropriate. Correlations were tested by
regression analysis or the Spearman rank (rho) test, as appropriate.
Independent associations between one dependent variable and more than two
independent variables were assessed by a stepwise multiple regression
analysis. Because CRP is not a normal-distributed variable, the multiple
regression analysis was performed on log-transformed CRP values. A two-tailed
P value <0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Serum leptin levels tended to be higher in women (28.0 ± 8.6 ng/ml) than in men (15.2 ± 2.7 ng/ml), although the difference did not reach statistical significance. However, the serum leptin to body fat mass ratio was significantly elevated (1.2 ± 0.3 versus 0.6 ± 0.1 ng/ml per kg ; P < 0.05) in women. As expected, strong positive relations were found between serum leptin and both body fat mass (rho = 0.74 ; P < 0.0001) and BMI (rho = 0.52 ; P < 0.01), respectively. Initial serum leptin levels also correlated with plasma insulin levels (rho = 0.55 ; P < 0.01 ; n = 26), but not with age, lean body mass, or CRP.
Patients were also divided into two groups as follows : those who gained lean body mass (1.1 ± 0.3 kg ; n = 11) and those who lost lean body mass (-3.0 ± 0.5 kg ; n = 25) during treatment with PD (Table 2). Interestingly, none of the patients that gained lean body mass during PD had elevated initial CRP levels, whereas the mean CRP was significantly higher in those patients that lost lean body mass during PD treatment. A significant positive relation (rho = 0.46 ; P < 0.05) was observed between initial CRP and the change in serum leptin levels during PD (Figure 1). Initial CRP levels correlated significantly (rho = 0.73 ; P < 0.01) with CRP levels at follow-up. Although serum leptin levels increased significantly (P < 0.001) in those patients who lost lean body mass (mean 20.9 ± 4.2 to 42.7 ± 4.0 ng/ml ; median, 11 to 28 ng/ml), no significant changes in serum leptin levels (mean, 18.4 ± 8.4 to 19.2 ± 6.4 ng/ml ; median, 8 to 9 ng/ml) could be observed in those patients who gained lean body mass during treatment with PD (Figure 2). A highly significant positive correlation (r = 0.71 ; P < 0.0001) was observed between changes in serum leptin and body fat mass during PD treatment (Figure 3). The changes observed in lean body mass during 12 mo of PD correlated negatively with changes both in serum leptin (r = -0.41 ; P < 0.05) and the leptin : body fat ratio (r = -0.40 ; P < 0.05), as shown in Figure 4. Initial plasma insulin levels correlated positively (r = 0.40 ; P < 0.05 ; n = 26) with the changes in serum leptin during PD treatment. The prevalence of diabetes mellitus did not differ significantly between the two groups.
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All peritoneal adequacy and urea kinetic parameters in patients that gained or lost lean body mass are shown in Table 3. Significant negative correlations were observed between nPNA and changes in serum leptin (r = -0.38 ; P < 0.05) and the leptin : body fat ratio (r = -0.38 ; P < 0.05), respectively. However, when nPNA was corrected for BMI these relations did not attain statistical significance. The peritoneal glucose absorption correlated significantly (r = 0.35 ; P < 0.05) with changes in serum leptin in a univariate regression analysis.
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A stepwise multiple regression model (in which plasma insulin was not allowed to enter due to only 26 observations) demonstrated independent associations between changes in serum leptin and changes in both body fat mass (P < 0.0001) and log CRP (P < 0.0001), respectively (Table 4). In another stepwise multiple regression analysis (Table 5), an independent association (P < 0.01) between changes in lean body mass and the presence of diabetes mellitus was found, whereas a near-significant (P = 0.07) association was observed between changes in lean body mass and changes in serum leptin during PD.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The significant positive correlation between initial CRP and the increase in serum leptin levels as demonstrated in present study suggests that inflammation may be another factor that contributes to hyperleptinemia (Figure 1). Since elevated levels of proinflammatory cytokines are a common phenomenon in PD (21), it is tempting to speculate that a low-grade inflammatory process may contribute to the stimulation of leptin mRNA and thereby increase the circulating leptin levels. Indeed, Nordfors et al. (22) have observed elevated leptin mRNA levels in CRF patients with an inflammatory response. Also, in animal studies it has been demonstrated that cytokines raise leptin mRNA levels (23,24,25). However, not all studies have found an association between inflammation and elevated leptin levels in humans, and additional studies are needed to clarify whether a low-grade inflammatory response may increase serum leptin levels in PD patients.
In the present study, DEXA was used to assess body composition, and with this technique measures of bone mineral, fat, and lean body mass are directly estimated without making assumptions of the two-compartment model (26, 27). It has been demonstrated that DEXA is superior to other simple noninvasive methods for determining body composition in renal failure, particularly when emphasis is made on repeated measurements (28, 29). However, it must be noted that the estimation of lean body mass may be confounded by changes in hydration status. To evaluate this possibility, serial measurement of multiple-frequency bioimpedance was performed in a subset of patients, and our results suggest that changes in the hydration status could not explain the observed changes in lean body mass over time. Our findings are in accordance with a recent study (3), which concluded that there may be a risk of reduction of body cell mass (as estimated by total body potassium), but not total body water (estimated by tritiated water), during long-term PD treatment.
The reason(s) for the decrease in lean body mass during PD are not evident but are probably multifactorial. At first, it is likely that a continuous protein loss into the dialysate (4) may contribute to a negative protein balance. Moreover, a low eating drive has been demonstrated in PD patients despite a need for protein and calories (30). The reason(s) for the loe eating drive in PD patients are not known, but in view of the appetite-inhibiting effects of leptin, it is tempting to speculate that hyperleptinemia may be one contributing factor. It is notable that PD patients that lost lean body mass exhibited a marked and significant increase in serum leptin levels in contrast to the PD patients that gained lean body mass (Figure 2). Our results support those recently presented by Odamaki et al. (11), who demonstrated that high levels of serum leptin relative to the body fat mass were associated with weight loss in hemodialysis patients. Moreover, an association of increased leptin levels with a low protein intake and loss of lean body mass (9), as well as a significant correlation between leptin levels, serum albumin, and the protein catabolic rate (16), has been observed in dialysis patients. However, others have found no association between the leptin concentration and recent weight change or nutritional status in CRF (7, 8). Thus, at present there is some evidence from cross-sectional studies indicating that elevated leptin levels may mediate anorexia in CRF, but it is obvious that longitudinal studies are needed to substantiate this proposal. However, it should be pointed out that future studies addressing this problem might not be fruitful unless they progress beyond the observational and correlative studies that have been performed thus far.
In summary, the present study has demonstrated marked increases in both body fat mass and serum leptin levels during PD treatment. Our data suggest that not only an increased body fat mass, but also a low-grade inflammation may contribute to increased leptin levels during PD treatment. We have also demonstrated that PD is associated with a loss of lean body mass, especially in patients with diabetes mellitus. The reason(s) that patients on PD lose lean body mass are not clear but are probably multifactorial. Because the results of the present study suggest that serum leptin may be a contributing factor, additional longitudinal studies are necessary to elucidate whether hyperleptinemia may lead to a low eating drive during treatment with PD.
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Acknowledgments |
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hlén. |
References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, Jacobsson H,
Rössner S : Increase of intra-abdominal fat in
patients treated with continuous ambulatory peritoneal dialysis.
Perit Dial Int 18 :166
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and their specific inhibitors in
undialyzed chronic renal failure, CAPD and hemodialysis patients.
Kidney Int 45 :890
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) patients treated by PD.