Int Urol Nephrol DOI 10.1007/s11255-013-0623-8

NEPHROLOGY - REVIEW

Leptin in chronic kidney disease: a link between hematopoiesis, bone metabolism, and nutrition Jingjing Zhang • Ningning Wang

Received: 23 August 2013 / Accepted: 3 December 2013 Ó Springer Science+Business Media Dordrecht 2013

Abstract Anemia, dyslipidemia, malnutrition, together with mineral and bone disorders are common complications in patients with chronic kidney disease (CKD). All are associated with increased risk of mortality. Leptin is a small peptide hormone that is mainly but not exclusively produced in adipose tissue. It is also secreted by normal human osteoblasts, subchondral osteoblasts, placental syncytiotrophoblasts, and the gastric epithelium. Leptin binds to its receptors in the hypothalamus to regulate bone metabolism and food intake. Leptin also has several other important metabolic effects on peripheral tissues, including the liver, skeletal muscle, and bone marrow. Leptin is cleared principally by the kidney. Not surprisingly, serum leptin appears to increase concurrently with declines in the glomerular filtration rate in patients with CKD. A growing body of evidence suggests that leptin might be closely related to hematopoiesis, nutrition, and bone metabolism in CKD patients. Results are conflicting regarding leptin in patients with CKD, in whom both beneficial and detrimental effects on uremia outcome are found. This review elucidates the discovery of leptin and its receptors, changes in serum or plasma leptin levels, the functions of leptin, relationships between leptin and the complications mentioned above, and pharmaceutical interventions in serum leptin levels in patients with CKD.

Introduction Chronic kidney disease (CKD) is defined as kidney damage or glomerular filtration rate (GFR) \ 60 ml/min/1.73 m2 lasting 3 months or more, irrespective of cause [1]. Complications of CKD include anemia, dyslipidemia, malnutrition, mineral and bone disorders, and so on [2–4]. The exact causes of these decompensation among CKD patients are not yet fully characterized, and it is likely that myriad of factors contribute to it. The most important of these factors is increased concentrations of uremic toxins, such as parathyroid hormone (PTH), blood urea nitrogen (BUN), and possibly leptin [5]. Leptin, an adipocytokine, is secreted mainly by adipocytes. Serum levels of leptin are higher in CKD patients than in the general population. The impact of leptin on CKD processes is poorly understood because leptin has a wide spectrum of biological activities, and it has been found to be related to various dysfunctions and alterations of normal cell metabolism, such as appetite control, regulation of food intake, and energy expenditure in CKD [6]. For this reason, the purpose of this review is to focus on recent advances in the pathophysiology of leptin in complications of CKD [7].

Keywords Leptin  Chronic kidney disease  Nutrition  Hematopoiesis  Bone metabolism

Discovery of leptin and its receptors

J. Zhang  N. Wang (&) Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, People’s Republic of China e-mail: [email protected]

Leptin was first discovered in 1994 by Zhang et al. [8]. It is a 16.7-kDa plasma protein encoded by the obesity gene (ob). It is secreted mainly by adipocytes. In humans, leptin is also produced by normal human osteoblasts [9], subchondral osteoblasts [10], placental syncytiotrophoblasts [11], and the gastric epithelium [12].

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Leptin exerts its effects by interacting with six different receptors (ObRa, ObRb, ObRc, ObRd, ObRe, and ObRf) [13]. Its receptors are found both centrally in the hypothalamus and peripherally in pancreatic islets, liver, kidney, skeletal muscle, and bone marrow [14]. In addition to its role in appetite, leptin affects various metabolic pathways, including those regulating hematopoiesis, glycometabolism, and bone and lipid metabolism [15].

Changes of serum leptin levels in CKD There is some dispute regarding whether the concentration of serum or plasma leptin of uremic patients differs significantly from that of non-uremic individuals. Most studies suggest that the level of serum or plasma leptin is increased in patients with CKD [5]. Leptin is cleared from circulation by the kidney through glomerular filtration and metabolic degradation in the renal tubules, which accounts for the increased level of serum leptin in CKD [16]. Aminzadeh et al. [17] and Kalbacher et al. [18] demonstrated that the incubation of mouse 3T3-L1 adipocytes in culture medium containing plasma from hemodialysis (HD) or end-stage renal disease (ESRD) patients could elicit a much greater leptin release by adipocytes than medium containing normal plasma. This suggested that plasma hyperleptinemia in patients with CKD could also be attributed to the increased production of leptin by the adipose tissue. However, Ho et al. [19] found that uremic patients had one-tenth of the levels of leptin of non-uremic patients (P \ 0.001), as indicated by examination of the supernatant of subcutaneous adipose tissue. Silva et al. [20] found serum leptin levels in CKD patients with normal body mass indexes (BMI) to be similar to those observed in healthy subjects but lower than those in overweight and obese patients (BMI C 25 kg/m2). This is consistent with the results of other studies [21]. Leal et al. [22] showed there was no statistically significant difference in plasma leptin levels of hemodialysis patients and healthy subjects with the same BMI (BMI of 25.0 ± 4.2 kg/m2).

Leptin and bone metabolism Leptin inhibits bone formation through a serotonin central relay (brainstem to hypothalamus) and through hypothalamus-generated sympathetic tone [23]. However, in vitro studies suggest that leptin has osteogenic effects that are mediated by its receptors in osteoblasts, osteoclasts, and chondrocytes, through which it can increase bone mineralization [9, 24, 25]. The effects of leptin in bone metabolism are multifaceted. The relationships between serum

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leptin levels and factors known to influence bone metabolism in uremic patients, such as serum calcium (Ca), phosphate (P), alkaline phosphate (ALP), and PTH levels are also a matter of debate. Coen et al. [26] showed serum lnleptin (leptin values have been expressed as natural logarithms) to be positively correlated with serum Ca in HD patients. Ahmadi et al. [27] showed that serum leptin has a positive correlation with serum Ca levels in female HD patients and no relationship with serum P for the HD patients in general or either gender separately. Zoccali et al. [28] reported an inverse correlation between plasma leptin and skeletal alkaline phosphatase in male, but not in female dialysis patients. Ahmadi et al. [27] found no correlation between bone alkaline phosphates (BAP) and serum leptin for either patients in general or either gender separately, but women with BAP \ 300 IU/L showed significantly higher serum leptin levels than those with BAP 300–600 IU/L. Other studies have shown serum BAP have no relationship with serum leptin levels [29, 30]. Relationships between serum leptin levels and intact parathyroid hormone (iPTH) or PTH 1–84 in uremic patients are controversial. Most studies revealed a negative correlation, but other studies showed no correlation. The details of these relationships are shown in Table 1.

Actions of leptin on hematopoiesis A study by Axelsson et al. [33] performed on 166 ESRD patients who were just beginning renal replacement therapy (RRT) provided clinical evidence that serum leptin levels are stronger predictors of epoetin (EPO) sensitivity than fat mass, independently of age, malnutrition, or inflammation and after correction for body weight. Nasri et al. [34] showed serum leptin to be strongly positively associated with hemoglobin levels and BMI in a study on 36 patients (men: 21, diabetics: 11) under regular HD conditions. In a study of 479 African-American HD patients, EPO requirements were reduced, and EPO resistance was improved in patients with high total adipose tissue and subcutaneous adipose tissue. This was found to be because the production of leptin had increased [35]. Results from cell culture experiments are consistent with previous studies in humans. High levels of leptin expression have been observed in bone marrow, and leptin receptors have been found on CD34-positive hematopoietic stem cells and in hematopoietic cells [12, 36, 37]. Incubation of bone marrow cells (BMC) from normal or db/db mutant mice with recombinant mouse leptin can induce the formation of granulocyte macrophage (GM) colonies in a dose-dependent manner. Remarkable synergism has been

Int Urol Nephrol Table 1 Correlations between serum leptin levels and PTH Authors (year)

Population

Findings

Serum iPTH (pg/mL)

Serum PTH 1–84 (pg/mL)

Kokot et al. [31]

73 HD patients

iPTH had a negative effect in leptin

339 ± 65 in men

NA

Coen et al. [26]

46 HD patients

455.2 ± 601.6

227.44 ± 300.7

Zoccali et al. [28]

161 HD patients

SDS leptin correlated inversely with iPTH and PTH1-84 Leptin (BMI adjusted) related inversely to iPTH and PTH1-84 in 93 men HD

193 (71.5–395.5) in men

108 (38.5–286.0) in men

313 ± 40 in women

203 (72.5–476.7) in women

122(43.7–316.5) in women Ahmadi F et al. [27]

72 HD patients

Leptin level is lower in women with iPTH [ 300 pg/mL when compared with iPTH = 100–300 pg/mL

174.4 ± 189 (16–953)

NA

198 ± 207 in men 139 ± 157 in women

Merabet et al. [32]

141 HD patients

No association

NA

NA

Polymeris et al. [29]

37 HD patients

No association

4–320.6

NA

observed between recombinant mouse leptin and stem cell factor (SCF) [38]. Bacterial recombinant leptin has also been shown to act synergistically with EPO to stimulate end-stage colony-forming-unit erythroid development in humans [39].

Relationships between leptin and nutrition Multiple reports have stressed nutritional status as a predictor of morbidity and mortality in patients with CKD [40, 41]. Hyperleptinemia is related to improved markers of nutritional status in CKD patients [42, 43]. For this reason, it has drawn considerable interest. BMI is one marker used to assess nutritional status. Many studies have evaluated correlations in the relationships between leptin levels and BMI in patients with CKD undergoing hemodialysis [20, 32]. Most studies on the issue have shown a strong direct relationship between serum leptin levels and BMI [20]. Merabet et al. [32] found plasma leptin concentrations in ESRD patients to be directly correlated with BMI but observed no correlation between plasma leptin levels and recent changes in the patients’ weight. In a study of 72 HD patients, Ahmadi et al. [27] demonstrated there was no correlation between serum leptin levels and BMI either across the entire patient group or for each gender separately. An increasing number of studies have suggested that serum leptin is also related to other markers of nutritional status in CKD patients [44, 45]. Aguilera et al. [44] showed direct correlations between plasma leptin levels and serum markers of nutritional status, including albumin and cholesterol, in 14 non-obese peritoneal dialysis (PD) patients

(BMI \ 25 kg/m2). Taskapan et al. [45] studied 30 HD patients and 30 continuous ambulatory peritoneal dialysis (CAPD) patients and 30 controls, none of whom were diabetic. They found serum leptin levels to be positively correlated with serum triglycerides, total cholesterol, and low density lipoprotein (LDL) levels in these two dialysis groups. Rodriguez-Carmona et al. [46] found serum leptin level was correlated positively with both cholesterol and triglycerides in pre-dialysis patients. However, some studies are contradictory to the former point of views. Ahmadi et al. [27] showed serum leptin levels to be negatively correlated with albumin levels in 72 non-diabetic HD patients. This shows that the relationship of leptin and nutrition must be studied in greater depth.

Effect of medications on leptin levels Few studies have assessed the effects of serum leptin by cinacalcet and active vitamin D compounds. Hryszko et al. [47] assessed 18 secondary hyperparathyroidism (SHPT) patients undergoing 6-month treatment with cinacalcet. This resulted in a decrease in serum levels of calcium, phosphate, and PTH levels but no significant changes were observed in serum leptin levels. This study may have been compromised by the complex and multivariate relation between adipokines and bone metabolism. Ulutas et al. [48] studied 18 (94.7 %) PD patients with vitamin D deficiency who were receiving alpha-calciferol for PTH control and cholecalciferol for vitamin D replacement. After this treatment, an increase was observed in serum leptin levels, and a decrease was observed in serum PTH levels. However, no changes in serum Ca or P levels were

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reported. The results of this study need to be confirmed in larger clinical trials. A study by Rossi et al. [49] reported dietary fish oil could positively regulate plasma leptin levels in insulinresistant rats that otherwise ate only sucrose. Guebre-Egziabher et al. [50] evaluated 12 non-dialyzed patients with stage 4–5 CKD. They were randomly treated with 1.8 g or 3.6 g/d of x-3 polyunsaturated fatty acid (PUFA) for 10 weeks. A dose of 3.6 g resulted in decreased serum triacylglycerol and increased high-density lipoprotein (HDL) levels, but the 1.8 g dose was associated with increased LDL levels. Neither regimen was found to affect serum leptin, but leptin gene expression of subcutaneous abdominal white adipose tissue was found to have been upregulated in the 3.6 g/d group. Some other medications have also been reported to promote serum and plasma leptin secretion. Dialysis patients who received growth hormone or appetite stimulators such as megestrol acetate showed higher plasma leptin levels [51–53].

Serum leptin levels in renal transplant patients The serum leptin levels have been found to vary over-time after successful renal transplantation. Most studies showed a decrement in serum leptin levels during the period immediately following renal transplantation [54–56]. Nicoletto et al. [54] found that serum leptin levels continued to decrease for 3 months after transplantation, but later increased to values similar to those seen at the time of transplantation. This took place at 1 year after transplantation in men and 5 years in women.

Conclusion Anemia, nutritional deficits, dyslipidemia, together with bone disease are common complications of CKD patients, and they have received considerable attention. The mechanisms involved in these decompensations are complex. This review shows the relationships between leptin and biochemical indicators related to hematopoiesis, nutritional status, and bone metabolism. This article also discusses medications and renal transplantation that influence serum leptin levels. More clinical studies must be performed to foster better understanding of the multifarious functions of leptin in ESRD patients. Acknowledgments This review was funded by the National Natural Science Foundation of China (81270408), RC201162, 2010(IB10), LJ201125, Chinese Society of Nephrology (13030300415). There were no financial supports or other benefits from commercial sources for this work.

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Conflict of interest There were no interests that could create a potential conflict of interest or the appearance of a conflict of interest with regard to this work.

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Leptin in chronic kidney disease: a link between hematopoiesis, bone metabolism, and nutrition.

Anemia, dyslipidemia, malnutrition, together with mineral and bone disorders are common complications in patients with chronic kidney disease (CKD). A...
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