Intact Parathyroid Hormone in Egyptian Type 2 Diabetics with Chronic Hemodialysis: Impact of Glycaemic Control

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1 DOI /s z Intact Parathyroid Hormone in Egyptian Type 2 Diabetics with Chronic Hemodialysis: Impact of Glycaemic Control Ahmed Ramadan Ali & Ahmed Alsayed Emam & Heba S. Assal & Alaa B. Abbas Received: 22 June 2009 / Accepted: 19 August 2009 # Springer Science + Business Media, LLC 2009 Abstract Osteodystrophy is one of the long-term haemodialysis complications. In diabetic end stage renal failure patients, it mainly occurs as an aplastic or low-turnover bone disease due to their low serum intact parathyroid hormone (ipth) levels. The aim of the present study is to evaluate intact PTH level in in Egyptian type 2 diabetics with chronic hemodialysis and its relation to glycaemic control.patients. 140 Egyptian patients, their mean age was 60.4±10.6 years were evaluated. They were maintained on regular hemodialysis (HD); 3 times/week, and the patients were divided into two groups according to primary kidney disease, diabetic (98 patients) and non-diabetic (42 patients) groups. Diabetic group was furtherly subdivided according to glycated hemoglobin to controlled (32 patients) and noncontrolled diabetics (66 patients). Intact parathyroid hormone (ipth), glycated hemoglobin (HbA1c), serum bone specific alkaline phosphatase, Albumin, Glucose, calcium, phosphorus and magnesium were estimated. Urea reduction ratio (URR) was estimated to evaluate the hemodialysis adequacy. The diabetic group had significantly lower values of ipth and serum magnesium than non-diabetic group (p<0.03 and p<0.001 respectively). The uncontrolled diabetics had significantly lower values of ipth, serum magnesium and serum albumin (p<0.002, p<0.002& p< A. R. Ali Internal medicine department, Ain-Shams University, Cairo, Egypt A. A. Emam (*) : H. S. Assal Internal medicine department, National Research Center, Cairo, Egypt ahmedemam6@hotmail.com A. B. Abbas Health lab. Ministry Of Health, Cairo, Egypt 0.03 respectively) than the controlled group. The serum HbA1c levels were strongly correlated with the serum ipth levels (P<0.003). intact PTH was lower in diabetic hemodialysis patients; also, glycaemic control was associated with higher PTH levels. Keywords Parathyroid hormone. haemodialysis. type 2 diabetes. glycaemic control Abbreviations ipth Intact parathyroid hormone HbA1c glycated hemoglobin HD hemodialysis ESRD end stage renal disease URR Urea reduction ratio Introduction For the last several years, the dialysis population in Egypt has been increased from 225 per million population (pmp) in 1996 [1] to 483 pmp in 2008[Dr. Adel Afifi, 2008, Head of Egyptian renal registry].the predominant primary disease of ESRD is diabetic nephropathy, its prevalence was gradually increased from 8.9% in 1996 [2] to13.5% in 2008[Dr. Adel Afifi, 2008]. In patients on haemodialysis, both elevated and low circulating ipth levels have been linked respectively to high and low bone turnover osteodystrophy(or adynamic bone disease ) [3, 4]. Diabetes per se has been associated with lower ipth levels when compared to nondiabetic haemodialysis patients [5] In diabetic haemodialyzed patients, impaired ipth secretion appears to be the main determinant responsible for decreased bone turnover and adynamic bone

2 Table 1 Exclusion criteria Exclusion criteria: 1- liver diseases 2- cardiac diseases 3- acute illness 4- parathyroidectomy 5-premenopausal female patients 6-Drugs: hormonal replacement therapy aluminum hydroxide steroids bisphosphonates Cinacalcet disease. Also diabetes mellitus confers a protective effect from the skeletal manifestations of secondary hyperparathyroidism [6] An interesting association between intact parathyroid hormone (ipth) circulating levels and glycaemic control in diabetic patients on haemodialysis was described by Murakami et al. [7]. The findings describe an inverse correlation between ipth serum levels and glycaemic control. Specifically, diabetic patients with poor glycaemic control are characterized by low circulating ipth,which is conversely found at higher levels in diabetic patients with good glycaemic control. Avram et al. suggested that raised ipth levels in diabetic patients with better glycaemic control could be paralleled by a lower mortality risk, as low ipth levels have been prospectively related to increased mortality in uraemic patients, independent of the diabetic status or duration of diabetes [8].Guh et al. reported that low ipth levels have been associated with vascular calcification and increased cardiovascular mortality [9] it could be speculated that low bone turnover osteodystrophy represents a risk factor for accelerated peripheral vascular disease in patients on haemodialysis [10]. The aim of the present study is to evaluate intact PTH level in in Egyptian type 2 diabetics with chronic hemodialysis and its relation to glycemic control Patients and Methods 140 End Stage Renal Diseases (ESED) patients were participated in the study from July 2007 to May They were maintained on more than 6 months regular bicarbonate haemodialysis using polysulfone membrane dialyzer; 3 times/ week,with a dialysis fluid of 3.0 meq/l of calcium concentration, and there was no difference in dialysis frequency and efficacy between diabetic and non-diabetic patients(urea Reduction Ratio URR>65%).We used one alpha (OH)D3 and calcium carbonate routinely for all patients in a low dose of 0.25 ug 0.75 ug daily to maintain a corrected serum calcium around mmol/l before dialysis session The patients were divided into two groups according to the cause of ESRD, diabetic and non-diabetic groups and also the diabetic group was subdivided into controlled and noncontrolled diabetics according to HbA1c. None of the patients had clinical evidence of liver diseases,cardiac diseases or any other acute illness or parathyroidectomy during our study. We also excluded premenopausal female patients to avoid the effect of menopause on bone metabolism and none of the female patients underwent hormonal replacement therapy. None of the patients took aluminum hydroxide as a phosphate binder, or steroids or bisphosphonates or Cinacalcet. The patients with previously mentioned exclusion criteria were excluded from our study to avoid any interference with PTH levels especially those given mentioned medications and those underwent parathyroidectomy. Exclusion criteria was expressed in Table (1) The patients gave informed voluntary consent to participate in the study according to the protocol approved by the local ethics committee and in accordance with the ethical standards of the Helsinki declaration.. The Table 2 Comparison between diabetics and non-diabetic group diabetic Non-diabetic P value BMI(body mass index),hd(hemodialysis duration),alb(albumin), FBS(fasting blood sugar), Ca (calcium),po4(phosphorus), ALK (alkaline phosphatase), Mg (magnesium). *Significant difference Patient(number) Male/ Female 98 45/ /22 Age (years) 61.8± ± BMI 19.8± ±2 0.6 ALB( gm/l) 29.4±4 28.3± HD ( month) 28.7± ± PTH(pmol/l) 25.8± ± * FBG (mmol/l) 11.4± ± * HbA1C % 8.0± ± * Ca( mmol/l) 2.3± ± PO4( mmol/l) 1.5± ± ALK (IU/l) 105.9± ± Mg( mmol/l) 0.76± ± *

3 Fig. 1 ipth levels in the studied groups Pmol/l diabetics non-diabetic controlled diabetics uncontrolled diabetics data of the patient characteristics were collected from clinical records included: sex, age, Hemodialysis (HD) duration, Body mass index (BMI). Blood samples were obtained after an overnight fasting before dialysis sessions, and the interval from the last HD session was 48 h for all patients.fasting Glucose (BG), calcium(ca), Albumin(ALB), phosphorus(p), alkaline phosphatase and magnesium(mg), were measured using a standard autoanalyser (Hitachi, Ltd, Japan).. HbA1c was measured using high-performance liquid chromatography instruments (HLC-723 GHB IIIs; Tosoh Corporation, Tokyo, Japan). Intact PTH was assayed by a solid phase two site chemiluminescent enzyme labelled immunometric assay( DPC,5700 West 96 street, los Angeles,CA ,USA). We used a HbA1c 7% as index of glycaemic control according to the American Diabetes Association Guidelines 2006 [11]. Out of the 98 patients with diabetic nephropathy, 32 had a serum haemoglobin A1c (HbA1c) level <7% (good glycaemic control), while the other 66 had an HbA1c >7% (poor glycaemic control). Statistical Analysis The Statistical Package for Social Sciences version 12.0 (SPSS Inc, Chicago, IL, USA) was used for data processing. Quantitative data were presented as mean and standard deviation and the Student t-test was used for a comparison of the means. As serum ipth was not normally distributed, Mann Whitney s U-test was used for comparing PTH values. A correlation between variables was done and the Pearson correlation coefficient was calculated. All tests were twotailed and considered statistically significant at p<0.05. Results Our results showed that PTH and Mg levels were significantly lower in diabetic patients when compared with non-diabetic group (P value 0.03 and respectively).on the other hand fasting blood sugar and HbA1c levels were significantly higher in diabetic patients when compared with non-diabetic group (P value 0.001) as shown in Table 2 & Fig. 1. In diabetic group, serum albumin, PTH and Mg levels were significantly higher in controlled diabetic patients when compared with noncontrolled diabetics (P value 0.03, and respectively) as shown in Table 3. Table 4, shows comparison between controlled diabetics and non-diabetic group, we found that PTH levels were not statistically different between the two groups. In diabetic group, there was significant inverse correlation between serum ipth and HbA1C(r 0.256, P 0.01) as shown in Fig. 2. ipth levels were correlated with dialysis duration, Alkaline phosphatase and serum Mg in diabetic group. as shown in Table 5, Fig. 3. Discussion The present study showed that serum ipth levels in diabetic haemodialysis patients were lower when compared with those in nondiabetic patients,also poor glycaemic control further reduced the serum ipth level and good glycaemic control was associated with higher serum ipth Table 3 Controlled versus uncontrolled diabetic ESRD patients Controlled diabetics uncontrolled diabetics P value Patient(number) Male/ Female 15/17 27/39 Age (years) 64.7± ± * BMI 20± ± ALB( gm/l) 30.6± ± * HD ( month) 27.2± ± PTH(pmol/l) 38.5± ± * FBG(mmol/l) 8.2±2 12.9± * HbA1C % 6.2± ± * Ca( mmol/l) 2.3± ± PO4(mmol/l) 1.4± ± * ALK (IU/l) 104.1± ± Mg( mmol/l) 0.9± ± * BMI(body mass index),hd(hemodialysis duration),alb(albumin), FBS(fasting blood sugar),ca (calcium),po4(phosphorus), ALK (alkaline phosphatase),,mg(magnesium). *Significant difference

4 A1C MG Kidney Table 4 Controlled Diabetics versus non-diabetic patients controlled Diabetics Non-diabetic P value Patient(number) Age (years) 64.7± ± BMI 20± ± ALB( gm/l) 30.6± ± HD ( month) 27.2± ± PTH(pmol/l) 38.5± ± FBG (mmol/l) 8.2±2 5.3± * HbA1C % 6.2± ± * Ca( mmol/l) 2.3± ± PO4( mmol/l) 1.4± ± * ALK (IU/l) 104.1± ± Mg( mmol/l) 0.9± ± BMI(body mass index),hd(hemodialysis duration),alb(albumin), FBS(fasting blood sugar),ca (calcium),po4(phosphorus), ALK (alkaline phosphatase), Mg(magnesium). *Significant difference Linear Regression Table 5 Correlation between ipth and HbA1c, Dialysis Duration, Alkaline phosphatase,mg. in diabetic group HbA1c Dialysis Duration Alkaline phosphatase Mg ipth r r r r P 0.01 P P 0.05 P 0.01 level, lastly The serum HbA1c levels were strongly correlated the serum ipth levels. The serum Ca does not show a significant difference between the diabetic and non-diabetic groups; it does not appear that the plasma calcium is responsible for the differences noted in PTH levels Synthesis and secretion of PTH is suppressed by hyperglycemia as shown in studies on bovine parathyroid cell culture [12].this may explain in a part our results, which showed low PTH in diabetic patients. also advanced glycation endproducts (AGEs) which produced in diabetic state play an important role in the pathogenesis of both impaired secretion of ipth and decreased bone formation [13].,furthermore (AGEs) inhibit hypersecretion of PTH in response to low serum calcium[14].also diabetic nephropathy is associated with adynamic bone disease due to deficiency of insulin-like growth factor [15]. In our study, the diabetic nephropathy group had significantly lower values of serum magnesium than nondiabetic group (p<0.001), not only this, the poorly controlled diabetics had lower values of serum magnesium than diabetics with good glycaemic control. It was reported that the reduced PTH secretion occurring in patients with poorly controlled diabetes is related to low serum magnesium [16].Although many studies have shown that poor diabetes mellitus control is associated with calcium, phosphorus and magnesium wastage [17], most of our patients have very low residual renal function and inadequate urinary output to explain this hypomagnesaemia, dietary factors and poor gastrointestinal Mg absorption in diabetics are possible explanations. Since only severe hypomagnesaemia (less than 0.7 mmol/l inhibits the secretion of PTH [18], hypomagnesaemia in our diabetic patients was mild and less likely to be the cause of the low PTH level The serum HbA1c levels were strongly correlated with the serum ipth levels in diabetic group moreover; diabetic 1.25 Linear Regression MG = * PTH R-Square = A1C = * PTH R-Square = PTH Fig. 2 The inverse correlation betweenn serum ipth and HbA1C in diabetic group PTH Fig. 3 Correlation between ipth and serum Mg in diabetic group

5 patients with good glycaemic control have higher PTH levels when compared with poorly controlled diabetics, similar results were obtained by Paula et al. [19]. An inverse correlation between ipth serum levels and glycaemic control, was described by Murakami et al. [7].They reported that, diabetic patients with poor glycaemic control are characterized by low circulating ipth,and higher levels was observed in diabetic patients with good glycaemic control Our results slowed that no statistical difference of ipth levels between controlled diabetics and non-diabetic patients, we suggested that proper glycaemic control could eliminate the effects of diabetic state on PTH level. The interpretation of the HbA1c levels in diabetic haemodialysis patients as a measure of glycaemic represents one limitation of our study because of reduced erythropoietin levels and red blood cell survival; this was also mentioned by Murakami et al. [7]. Established methodology to evaluate the real glycaemic control should be considered to make a verification of our results. The inhibitory effects of ipth on both insulin action and secretion in both primary and secondary Hyperparathyroidism has been described [19].which results in derangement of the glycaemic control ;however, it is still unclear as studies suggest that poor metabolic control per se, could inhibit low calcium-mediated ipth secretion [20]. The protective effect of diabetic process on the development of hyperparathyroidism. and development of an adynamic bone lesion is parallel with increased risk of vascular calcification and increased cardiovascular mortality [9]. Also Gnudi [21].reported that low bone turnover osteodystrophy represents a risk factor for accelerated peripheral vascular disease in patients on haemodialysis. While low blood levels of intact PTH strongly suggest the presence of adynamic bone, a high PTH level does not exclude this possibility. Histological studies have found adynamic bone despite PTH values well above 44.0 pmol/l. This may be related to limitations of the PTH assay due to accumulation of inhibitory PTH fragments [22]. Conclusion and Recommendations Tight metabolic control of the diabetic process is very important to avoid hypoparathyroidism and low bone turnover in these patients. Bone biopsy may be required to establish or rule out the diagnosis of adynamic bone disease even when the level of PTH is at or above target levels. Further studies should be done to investigate whether targeting ipth and other determinants involved in renal bone disease in dialysis patients may prevent or delay the development of vessel calcifications and frail bones. Acknowledgments We are grateful to all the staff in the diabetes and dialysis units and for their support. Also we would like to thank all the patients who participated in this study. No funds were received in support of this study. References 1. 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