Parathyroidectomy And Leptin In Chronic Kidney Disease-Mineral And Bone Disorder

Objective:Chronic kidney disease(CKD)is a global public health problem,CKD-related complications have an adverse influence on patients'quality of life and survival.The common complications in chronic kidney disease-mineral and bone disorder(CKD-MBD)patients contain anemia,malnutrition,and cardiovascular disease(CVD).Secondary hyperparathyroidism(SHPT)is a familiar clinical manifestation of CKD-MBD.Parathyroidectomy(PTX)is recommended to severe SHPT patients refractory to medical treatment.Successful PTX can correct mineral and bone metabolism abnormalities,improve anemia and malnutrition,and reduce the risk of CVD in severe SHPT patients.It is reported that leptin,a protein hormone which is mainly secreted by adipocytes,interacts with hematopoiesis,bone,and cardiovascular metabolism.Low serum leptin can serve as a biomarker of malnutrition.Circulating leptin levels in CKD patients are still controversial.The correlations between leptin and anemia,malnutrition,and CVD in patients with CKD-MBD are also unknown.Effect of PTX on circulating leptin levels and their associations with above complications in severe SHPT patients need more exploration.Methods:In the first part,clinical data of four hundred and ninety-six severe SHPT patients undergoing PTX in our hospital were recorded.The characteristics of age distribution and clinical nutritional parameters in severe SHPT patients were analyzed.In the second part,this is a cross-section study including 141 stage 5 CKD patients and 100 controls,and a longitudinal observation on 36 SHPT patients with PTX(median follow-up time of 6.1 months).HRV were measured by 24 hour Holter and serum leptin were measured by ELISA.Serum leptin levels were adjusted by BMI and transformed using natural logarithm(lnleptin/BMI).Mean HRV were compared across the quartiles of lnleptin/BMI.In the third part,we conducted a cross-sectional study including 100 controls and 209 stage 5 CKD patients,and a longitudinal observation on 40 PTX patients with median follow-up interval of 5.7 months.Serum leptin levels were determined by ELISA and adjusted by body mass index(BMI).3T3-L1 adipocytes were stimulated with 10%human serum or different concentrations of phosphorus,calcium,and parathyroid hormone(PTH).The serum stimulated groups included healthy controls,No-PTX stage 5 CKD patients,preoperative and followed-up postoperative PTX patients,and postoperative PTX patients+LY294002[phosphoinositide 3 kinese/protein kinase B(PI3K/Akt)signaling inhibitor].The stimulating concentrations of calcium were 2.5mM and 3.5mM,the same as concentrarions of phosphorus.The stimulating concentration of PTH were 0.1 nM and 1.0nM.Leptin in the medium were measured by ELISA.The leptin,phosphate-Akt and Akt protein in cytoplasm were detected by Western Blot.Results:Part 1:There were 274 males and 222 females aged of(46.0±11.4)years.Chronic glomerular nephritis was the primary cause of end stage renal disease for 92.1%and diabetic nephropathy for 1.2%of patients.Their dialysis vintage were(7.7±3.6)years and the majority of them(92.9%)were receiving hemodialysis.In SHPT patients,serum levels of calcium,phosphorus,intact PTH(iPTH)and alkaline phosphatase(ALP)were(2.6±0.2)mmol/L,(2.2±0.5)mmol/L,(2290.0±1294.2)pg/ml,(564.7±537.8)u/L,respectively.Serum albumin(Alb)were lower than the reference range.Serum calcium,ALP,and iPTH levels in PTX patients were different among the groups with the stratifications of age,while serum phosphorus showed none significant difference.Compared to patients aged<18 years old and 18?30 years old,the levels of InALP were lower in patients aged 60?70 years old.Part 2:CKD patients(77 males,64 females)were aged(49.6±12.3)years with(5.2±4.3)years of mean dialysis vintage.Serum lnleptin/BMI and IniPTH in CKD patients were(5.5±1.4)and(6.3±1.3),respectively.CKD patients were divided into 4 groups according to the interquartile range of serum lnleptin/BMI.With a gradient of lnleptin/BMI across quartiles from Q1 to Q4,blood pressure(BP)and HRV indices showed nonlinear diversity without statistically significant difference.In multivariate stepwise regression,leptin/BMI was an independent predictor for low frequency/high frequency(LF/HF).HRV indices and lnleptin/BMI levels were increased in severe SHPT patients after PTX.Compared to other quartiles,SHPT patients in Q1 group had larger improvement of InVLF after PTX.Part 3:Approximate lnleptin/BMI between controls and patients were observed because of a larger proportion of CKD patients with BMI<23 kg/m2(a marker of malnutrition).Serum lnleptin/BMI was positively correlated with serum levels of hemoglobin and albumin in CKD group.Higher IniPTH was associated with lower lnleptin/BMI in PTX patients.Retrieved preoperative anemia and low serum albumin were related with postoperative increased lnleptin/BMI.Severe SHPT inhibited uremia-enhanced leptin production in adipocytes.Inhibition effect of SHPT on leptin production was attenuated in 3T3-L1 adipocytes after PTX.High PTH,not calcium or phosphorus,reduced leptin production and inhibited both Akt phosphorylation in vitro.Up-regulated Akt signaling mediated postoperative increased leptin production in vitro.Conclusions:1.The majority of severe SHPT patients were receiving hemodialysis and aged between 30 and 60 years old.In our research,the majority of CKD etiology was chronic glomerular nephritis.The proportion of CKD etiology with diabetic nephropathy was low.Malnutrition was common in severe SHPT patients.2.Circulating leptin levels are suggested to be a novel target to reduce the risk of CVD for patients with CKD-MBD.3.Controls and CKD patients had approximate serum leptin levels in that a larger proportion of CKD patients with low BMI;serum lnleptin/BMI related with anemia,protein,lipid and bone metabolism disorder in CKD patients.Successful PTX was found to improve anemia and malnutrition in severe SHPT patients,and correlated with increased circulating leptin levels via up-regulated Akt signaling in adipocytes.These findings indicated the therapeutic potential of leptin and related target pathway for improving survival and quality of life in CKD patients.