Piotr Kuczera, Marcin Adamczak, *Andrzej Więcek
Three months treatment with cinacalcet does not change plasma leptin concentration in hemodialysis patients with secondary hyperparathyroidism**
Trzymiesięczne leczenie cynakalcetem nie zmienia stężenia leptyny w osoczu u hemodializowanych chorych z wtórną nadczynnością przytarczyc
Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia in Katowice
Head of Department: Professor Andrzej Więcek, MD, PhD
Streszczenie
Wstęp. Cynakalcet jest kalcimimetykiem, czyli lekiem zwiększającym wrażliwość receptora wapniowego (CaSR) na wapń w surowicy. Ekspresja CaSR zachodzi między innymi w adipocytach. Leptyna jest hormonem wytwarzanym przez adipocyty, który jest związany z bilansem energetycznym ustroju. Jest ona również uważana za wskaźnik odżywienia.
Cel pracy. Celem niniejszego badania była ocena wpływu 3-miesięcznego leczenia cynakalcetem na stężenie leptyny w osoczu u hemodializowanych chorych (HDP) z wtórną nadczynnością przytarczyc (sHPT).
Materiał i metody. U 65 HDP z sHPT leczonych cynakalcetem (30-90 mg/dzień) oznaczano stężenia parathormonu (PTH) w surowicy oraz leptyny w osoczu. Próbki krwi były pobierane przed rozpoczęciem leczenia cynakalcetem i po 3 miesiącach powyższego leczenia.
Wyniki. Po 3 miesiącach leczenia zaobserwowano znamienne zmniejszenie stężenia PTH w surowicy z: 1089 (891-1286) pg/ml do 775 (574-976) pg/ml (p < 0,0001). Nie zaobserwowano natomiast znamiennych różnic w stężeniu leptyny w osoczu (wynosiło ono odpowiednio: 30,4 (21,1-39,8) ng/ml i 33,7 (23,6-43,9) ng/ml (p = 0,063)).
Wnioski. Trzymiesięczne leczenie cynakalcetem nie wpływa znamiennie na stężenie leptyny w surowicy u chorych hemodializowanych z wtórną nadczynnością przytarczyc.
Summary
Introduction. Cinacalcet is a calcimimetic which increases the sensitivity of calcium sensing receptor (CaSR) to the serum calcium. CaSR is expressed among others also in adipocytes. Leptin is a hormone synthetized by the adipocytes which is involved in the regulation of energy balance and seems to be a marker of nutrition.
Aim. The aim of this study was to assess the influence of 3 months treatment with cinacalcet on plasma leptin concentration in hemodialysis patients (HDP) with secondary hyperparathyroidism (sHPT).
Material and methods. In 65 HDP with sHPT treated with cinacalcet (30-90 mg/day) serum parathyroid hormone (PTH) and plasma leptin concentrations were assessed before the first dose of cinacalcet and then after 3 months of treatment.
Results. During 3 month treatment with cinacalcet a significant decrease in serum PTH concentration was found: from 1089 (891-1286) pg/ml to 775 (574-976) pg/ml, respectively (p < 0.0001). There was no significant change of plasma leptin concentration after 3 months of treatment with cinacalcet: 30.4 (21.1-39.8) ng/ml and 33.7 (23.6-43.9) ng/ml, respectively.
Conclusions. Three months treatment with cinacalcet does not significantly influence the plasma leptin concentration in hemodialysis patients with sHPT.
Introduction
In the last decade new pharmacological agents – the calcimimetics have been added to the armamentarium of treatment of hemodialysis patients with secondary hyperparathyroidism (sHPT). The calcimimetics bind to calcium sensing receptor (CaSR) leading to its positive allosteric modulation, what results in the increased sensitivity of CaSR to serum calcium thus leading to the decrease of parathormone (PTH) secretion by the parathyroid glands (1, 2). Cinacalcet is mostly used in the treatment of sHPT in patients with chronic kidney disease (CKD) stage 5, who require renal replacement therapy.
Results of many clinical studies in hemodialysis patients with sHPT suggest that treatment with cinacalcet with addition of small doses of active vitamin D analogues is efficient in reducing the serum PTH concentration and causes more pronounced reduction in the progression of cardiovascular and heart valve calcification, than treatment with vitamin D analogues alone (3-5). However, it should be mentioned, that the result of the EVOLVE study did not confirm the improvement of the cardiovascular prognosis of hemodialysed CKD patients with sHPT treated with cinacalcet (6).
Calcium sensing receptor (CaSR) is a seven-transmembrane G-protein-coupled receptor. It’s main function is to modulate the parathormone (PTH) secretion by the parathyroid glands in response to changes of serum calcium concentrations (1, 7). Recently the existence of CaSR has been described in a number of tissues besides the parathyroid glands.
CaSR expression has been documented among others in adipocytes (8, 9), in which CaSR stimulation leads to the decrease of lipolysis (10, 11) and an increase of adipogenesis (through the intensification of preadipocyte to adipocyte differentiation) (12). Additionally, CaSR stimulation increases the synthesis and secretion of proinflammatory cytokines such as: interleukin-6 (IL-6), interleukin-1 β or tumor necrosis factor α by the adipocytes (13). What is more we have described an increase of plasma concentration of another adipokine – adiponectin in chronic hemodialysis patients with sHPT as a result of cinacalcet treatment (19).
Leptin is a 16 kDa protein synthesized predominantly by adipocytes. Firstly leptin was regarded as a “satiety hormone” which down-regulates the neuropeptide Y (one of the most potent appetite regulating hormones) mRNA transcription in the hypothalamus. Nowadays leptin is considered mostly as a marker of nutrition, as its plasma concentration strictly reflects the total adipose tissue content and is markedly elevated in obese patients (14, 15). Kidney is the organ where majority of leptin is biodegraded and eliminated and thus plasma leptin concentration is significantly increased in patients with CKD and normalizes after successful kidney transplantation (16, 17).
Leptin directly stimulates the activity of sympathetic nervous system. Moreover, leptin receptors have been identified in the endothelium, platelets, and monocytes/macrophages. These properties of leptin seem to be involved in the negative impact of adipose tissue on the cardiovascular system in obese subjects. Additionally, increased plasma leptin concentration has been shown to be the independent (from the body mass) predictor of cardiovascular complications in the WOSCOPS Study (18).
As CaSR is expressed in adipocytes, stimulation of this receptor may influence the secretion of different adipokines and cytokines. It has been recently shown, that treatment with cinacalcet increases plasma adiponectin concentration (19). Therefore it seems reasonable to assess the influence of CaSR stimulation by calcimimetic on plasma leptin concentration (secreted mainly by adipocytes). Such a speculated additional effect of calcimimetics seems to be clinically important taking into consideration the potential harmful consequences of increased plasma leptin concentration (20) and could explain the potential beneficial impact of cinacalcet treatment on the cardiovascular morbidity and mortality suggested in some studies (4-6).
Aim
The aim of this study was to assess the influence of 3 months treatment with cinacalcet on plasma leptin concentration in hemodialysis patients with secondary hyperparathyroidism.
Material and methods
Seventy one adult, hemodialysis patients with end stage kidney disease – ESKD (40 males and 31 females) and sHPT (serum PTH concentration > 300 pg/ml) recruited from 9 hemodialysis centers were enrolled in this prospective, open-label, single arm study. Mean age of patients was 53.3 (49.8-56.9) years, median vintage of dialysis was 32 months (interquartile range (IQR) – 28 months). Exclusion criteria were as follows: age below 18 years, severe liver insufficiency, oversensitivity to any of the study drug compounds, high probability of non-compliance and suspected short life expectancy.
All enrolled patients were treated with cinacalcet. Initial dose was 30 mg once daily and was modified, if necessarily, every 4 weeks accordingly with the serum PTH concentration. The target of treatment was to decrease serum PTH concentration to 150-300 pg/ml. Maximal allowed dose of cinacalcet was 120 mg daily.
The dosing of alfacalcidol and/or calcium carbonate was flexible in order to avoid hypocalcaemia and hypophosphatemia related to the cinacalcet treatment. The doses of abovementioned medications were titrated monthly, accordingly with the results of routine biochemical analyses.
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