Mineral Metabolism Management in Hemodialysis Patients with Secondary Hyperparathyroidism in Japan: Baseline Data from the MBD-5D

Background/Aims: The Mineral and Bone Disorder Outcomes Study for Japanese CKD Stage 5D Patients (MBD-5D) is a multicenter, prospective observational study of hemodialysis patients with secondary hyperparathyroidism (SHPT) in Japan, where the national guideline recommends targets for serum calcium (8.4–10.0 mg/dl), phosphorus (3.5–6.0 mg/ dl), and intact parathyroid hormone (PTH) (60–180 pg/ml). Methods: The MBD-5D involved patients who were receiving hemodialysis for more than 3 months and met at least one of the following conditions: having intact PTH levels 1 180 pg/ml, or receiving intravenous vitamin D receptor activators (VDRAs) or oral VDRA analog. This report describes the baseline characteristics of the study participants and examines factors associated with mineral metabolism controlReceived: January 19, 2011 Accepted: March 14, 2011 Published online: April 21, 2011 Nephrology American Journal of Prof. Masafumi Fukagawa, MD, PhD, FJSIM, FASN Division of Nephrology, Endocrinology and Metabolism Tokai University School of Medicine 143 Shimo-Kasuya, Isehara 259-1193 (Japan) Tel. +81 463 93 1121, ext. 2351, E-Mail fukagawa @ tokai-u.jp © 2011 S. Karger AG, Basel 0250–8095/11/0335–0427$38.00/0 Accessible online at: www.karger.com/ajn Parts of this paper were presented at the XLVII ERA-EDTA Congress in Munich, Germany, June 26, 2010. D ow nl oa de d by : 54 .1 91 .4 0. 80 9 /1 6/ 20 17 9 :0 6: 15 P M Fukagawa et al. Am J Nephrol 2011;33:427–437 428 Introduction Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a common complication of dialysis patients, which not only contributes to the development of bone disease [1–3] , but also increases the risk for all-cause and cardiovascular mortality [3–8] , potentially mediated through vascular calcification [9, 10] . It is, therefore, crucial to control biochemical parameters of CKD-MBD [e.g., serum calcium, phosphorus, and parathyroid hormone (PTH) levels]. Many national [11, 12] and international [13] guidelines recommend control of these parameters within specific target ranges. Secondary hyperparathyroidism (SHPT), characterized by increased secretion of PTH [14, 15] , is one of the major abnormalities underlying CKD-MBD. In patients receiving dialysis, SHPT is frequently associated with alterations in calcium and phosphorus metabolism, as a result of either excess PTH alone or the therapeutic use of vitamin D receptor activators (VDRAs) [16] . Generally, SHPT progresses with increasing dialysis vintage, leading to the development of parathyroid hyperplasia. As parathyroid hyperplasia progresses to advanced stages, the expression of calcium-sensing receptors (CaSR) and vitamin D receptors (VDR) is progressively reduced [17– 19] , resulting in resistance to treatment with VDRAs [20– 22] and, finally, requiring parathyroidectomy (PTx) [23] . Despite considerable advances in the understanding and management of SHPT, however, mortality rates for patients on maintenance dialysis remain extremely high, with substantial variations between countries. The Dialysis Outcomes and Practice Patterns Study (DOPPS) reported that the crude 1-year mortality rates were 6.6% in Japan, 15.6% in Europe, and 21.7% in the United States [24] . Due to such lower mortality and limited chance for kidney transplantation, a growing number of Japanese patients receive dialysis therapy for a longer time. This could increase the prevalence and degree of SHPT in this population and may differentiate practice patterns for the management of SHPT from that of the rest of the world. The Japanese Society for Dialysis Therapy (JSDT) guideline, released in 2006, recommends target ranges for serum levels of calcium (8.4–10.0 mg/dl), phosphorus (3.5–6.0 mg/dl), and intact PTH (60–180 pg/ml) [12] . This guideline is characterized by a lower target range for intact PTH compared with that of the KDOQI guidelines (150–300 pg/ml) [11] and the KDIGO guideline (two to nine times the upper limits of normal, corresponding to 130–600 pg/ml) [13] . The threshold beyond which surgical PTx is indicated in the JSDT guideline is intact PTH 1 500 pg/ml, which is also lower than that of the KDOQI guidelines (intact PTH 1 800 pg/ml). The JSDT guideline is, however, mainly based on retrospective analysis of the nationwide survey [7] and expert opinion, due to a paucity of high-level evidence. In addition, cinacalcet hydrochloride [25, 26] and lanthanum carbonate [27, 28] were launched on the Japanese market after publication of the guideline. These introductions brought about significant changes in the management of CKD-MBD in Japanese dialysis patients. The Mineral and Bone Disorder Outcomes Study for Japanese CKD Stage 5D Patients (MBD-5D) is a multicenter, prospective observational study of hemodialysis patients with SHPT to examine the impact of patient characteristics and practice patterns on mortality, hospitalization and other clinical outcome measures [29] . This report describes the baseline characteristics of the study participants and examines factors associated with controllability of biochemical variables of CKD-MBD. Materials and Methods Study Design The MBD-5D is a 3-year prospective observational study with a case-cohort and a cohort design. Details of the study design have been published [29] . In brief, patients were eligible for inclusion if they had received dialysis regularly for more than 3 months at the participating facilities as of January 1, 2008, and if they met at least one of the following conditions: (1) having intact PTH levels 1 180 pg/ml, or (2) receiving intravenous VDRAs (calcitriol or maxacalcitol) or oral VDRA analog (falecalcitriol), the only oral drug approved in Japan for the treatment of SHPT. The whole cohort was planned to assess rare clinical events such as all-cause and cardiovascular death, and the subcohort, a random sample (40%) of the whole cohort, was planned to assess more frequent clinical events and longitudinal laboratory and medication data. The study protocol was approved by central and local ethical review boards. The study was conducted in accordance with the principles of the Declaration of Helsinki, and it was registered at ClinicalTrials.gov, No. NCT00995163. Data Collection Background and demographic information included age, sex, cause of end-stage renal disease (ESRD), dialysis vintage, height, body weight, comorbid conditions, and medical histories. Dialysis prescription, laboratory data, and medication were collected prospectively. Baseline laboratory data, analyzed in local laboratories, were obtained from July 1 to December 31, 2007. Serum levels of calcium, phosphorus, creatinine, hemoglobin, albumin, alkaline phosphatase (ALP), total cholesterol, and C-reactive protein were measured using standard methods. Serum calcium levels were corrected for albumin concentration using Payne’s formula [30] . Measurements of intact PTH were performed by various second-generation assays depending on the different participating facilities. Serum whole PTH levels measured with a D ow nl oa de d by : 54 .1 91 .4 0. 80 9 /1 6/ 20 17 9 :0 6: 15 P M MBD-5D Baseline Data Am J Nephrol 2011;33:427–437 429 third-generation PTH assay (Whole PTH; Scantibodies Laboratories, Santee, Calif., USA) were converted to intact PTH levels by the following equation: intact PTH = whole PTH ! 1.7 [12] . Serum bone-specific ALP (BAP) levels were mostly measured with an enzyme immunoassay kit (Osteolinks BAP; Quidel Corpora Serum, San Diego, Calif., USA), and values measured with other than this assay were not included in the analyses. Statistical Methods Continuous variables were expressed as mean 8 SD and compared with Student t tests or one-way ANOVA (analysis of variance), as appropriate. Categorical variables were expressed as proportions and compared with  2 test. We used Pearson’s correlation analysis to test the association between total ALP and BAP. We used logistic regression to test the association between the achievement of the JSDT targets for calcium and phosphorus and the following factors: severity of SHPT according to the JSDT guideline (60–180, 181–300, 301–500, and 1 500 pg/ml), history of successful PTx (defined by having a history of PTx and intact PTH levels ! 300 pg/ml), and dialysate calcium use (2.5 or 3.0 mEq/l). For each analysis, three types of models were examined: (1) unadjusted models included only the independent variable of interest; (2) case-mix adjusted models included age, sex, dialysis vintage, and cause of ESRD, and (3) multivariable adjusted models included the case-mix covariates plus body mass index (BMI), dialysis adequacy (Kt/V), history of cardiovascular disease (ischemic heart disease, coronary artery disease, congestive heart failure, cerebrovascular diseases), creatinine, hemoglobin, albumin, total cholesterol, and VDRA use. We also examined the association between the achievement of targets for calcium and phosphorus and the severity of SHPT according to the KDOQI guidelines ( ! 150, 150–300, 301–600, and 1 800 pg/ml) and the KDIGO guideline ( ! 130, 130–600, and 1 800 pg/ml). A 10 g dose of maxacalcitol was considered to be equal to 1.5 g of calcitriol, and all results for injectable vitamin D sterol dosages are presented as calcitriol equivalents. p values ̂ 0.05 were considered as statistically significant. All statistical analyses were performed with SAS software, version 9.1 (SAS Institute, Cary, N.C., USA).