Leptin is a hormone that is released from adipose tissue and classified as an adipokine. Leptin is sometimes thought of as a “skinny” hormone in that higher levels of this hormone are associated with satiety and decreased hunger. As adipocytes become more enriched with energy stores, leptin is released to signal the brain to reduce calorie intake.

Thus, body mass index (BMI) often has strong associations with leptin. In obese individuals, the effect of leptin on satiety is sometimes attenuated, and thus a proposed “leptin resistance” may exist. In diabetic patients, caloric restrictions have resulted in correlations between changes in leptin and changes in body fat, energy, and protein intake (J Ren Nutr 2010;20:255-262).

Some studies have suggested that chronically elevated leptin levels may induce pancreatic β-cell apoptosis. Leptin levels have been shown to significantly increase in the presence of nephropathy. Leptin has a half-life of 25 minutes and is rapidly degraded and removed from the blood through peripheral tissues and glomerular filtration.

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In chronic kidney disease (CKD) populations, leptin levels are often elevated (J Ren Nutr 2011;21:316-321), and it is unclear whether this elevated value is related to a reduced ability to clear it through the kidneys or through leptin resistance. Because malnutrition and anorexia are often seen in end-stage renal disease (ESRD) populations, questions have been raised as to whether leptin has an impact on malnutrition in this population.

A better malnutrition biomarker?

A recent group found that, in a group of 40 ESRD patients matched with healthy controls, serum leptin was significantly higher in the study group (Indian J Nephrol 2012;22:419-423). C-reactive protein was also significantly higher in the study group, but when comparing each of these parameters with BMI, only leptin was found to have a significant positive association.

The authors of this study indicate that this information may indicate that leptin is a better biomarker for malnutrition. Leptin concentrations, however, are often simply reflective of adipose stores in general, and thus only a secondary indication of an individual’s BMI (J Ren Nutr 2010;20;151-157).

Similar results were found in a cohort of 107 CKD patients, 77 of whom were on dialysis, and 31 healthy controls (J Ren Nutr 2011;21:316-321). Leptin was significantly associated with BMI, whereas ghrelin and obestatin—two other hormonal regulators of appetite—were not significantly associated with BMI.

An additional result was that leptin was significantly higher in the peritoneal dialysis group than the hemodialysis group by over six-fold, most likely due to glucose infusions.

In the previously mentioned study, BMI was inversely correlated with duration of dialysis. These associations between leptin, BMI, and changes over time have been observed in a prospective trial in dialysis patients over 24 months (Nutr J 2011;10:68).

At baseline, leptin was associated with anthropometric parameters such as BMI, tricep skinfold, mid-arm circumference, and mid-arm circumference calculated, as well as bioelectrical impedance analysis (BIA) measurements such as fat mass index and fat free mass index. Although these correlations indicate that leptin is positively associated with indicators of adequate nutritional stores, leptin was not associated with intake of energy or protein after adjustments for bodyweight.

After 24 months, reductions were seen in all of the anthropometric and BIA data, but these changes were not related to changes in leptin levels. Decreases in leptin levels during the study were associated with time and with FMI. After 24 months, 33 of the 101 patients died. Dividing leptin levels into tertiles, no significant difference in mortality rate was found between the three groups, indicating that leptin’s indication of nutritional status was not indicative of survival.

Results from other studies have suggested correlations between leptin levels and protein intake as estimated by nPNA. These data led investigators to conclude that higher leptin concentrations have a positive effect on appetite in dialysis populations.

As noted previously, the prospective cohort study found no association between leptin and dietary intake after controlling for BMI; these results could possibly be reinterpreted to suggest that the increased BMI was a result of increased dietary intake in the first place. Many studies are now analyzing leptin changes in the context of ghrelin changes.

The effect of ghrelin on appetite in CKD patients will be explored further next month, but one particular study found that, in dialysis patients with protein-energy wasting (PEW), leptin levels were significantly higher as ghrelin levels decreased as opposed to patients without PEW (Kidney Int 2011;79:749-756).

Reverse epidemiology

The results from these studies should be analyzed in the context of the “reverse epidemiology” model, whereby dialysis patients exhibit improved outcomes with higher BMI. Leptin levels appear to directly correlate with BMI such that as fat mass increases and decreases, leptin changes accordingly. Reduced leptin levels thus would indicate reduced BMI and lower nutritional stores.

High levels of leptin, however, trigger hormonal releases of pro-inflammatory cytokines, which also promote poor nutritional factors. At this time, leptin changes appear to be most strongly influenced by BMI and the effect of leptin levels on appetite in dialysis populations appears to minimal, if at all, present when compared with the more pronounced and classical uremic factors.

Thus, using leptin as a nutritional outcome measure may be unnecessary, as BMI is measured much more easily and cost effectively. Related hormones of interest include ghrelin, adiponectin, resistin, and obestatin. Future articles will review whether these outcome measures can be of more pertinent use.