Randomized Crossover Study of the Efficacy and Safety of Sevelamer Hydrochloride and Lanthanum Carbonate in Japanese Patients Undergoing Hemodialysis

Insufficient control of serum calcium and phosphate levels in patients undergoing hemodialysis is associated with increased mortality. As commonly used calcium‐containing phosphate binders can cause arterial calcification, newly developed calcium‐free phosphate binders, such as sevelamer hydrochloride (SH) and lanthanum carbonate (LC), have received much attention. We assessed the efficacy and safety of SH and LC treatment in Japanese patients undergoing hemodialysis in a prospective randomized open blinded endpoint (PROBE) crossover study. Forty‐two patients were randomized to receive SH or LC for 13 weeks, with the dosages adjusted every 2 weeks, followed by treatment with the other drug for another 13 weeks. The average daily doses of SH and LC were 2971 ± 1464 mg and 945 ± 449 mg, respectively. The mean dosage ratio of SH to LC was 3.05, which was maintained throughout the treatment period. SH and LC were similarly effective at controlling serum calcium and phosphate levels in the majority of patients (78–93%). A few serious adverse events (AEs) involving the biliary system occurred during the LC treatment period, but they were not considered to be treatment‐induced. Although the incidence of constipation, the most common treatment‐related AE, was higher during the SH period (27% vs. 5%; P < 0.05), no difference was observed in total treatment‐related AEs. This study demonstrates that SH and LC are comparable treatments for controlling serum phosphate and calcium levels, and that both compounds are safe and well‐tolerated in Japanese patients undergoing hemodialysis.     

烟酰胺联合碳酸钙对血透患者高磷血症的治疗观察

观察在常规口服碳酸钙降磷无效的患者加用烟酰胺对血液透析患者高磷血症的疗效。方法：给予30例单纯碳酸钙降磷治疗无效或出现血钙水平偏高的维持性血液透析患者加服烟酰胺片,观察治疗前、治疗一个月及三个月时血磷、血钙、钙磷乘积及血清全段甲状腺旁素（iPTH）水平的影响。结果：与治疗前相比,治疗一个月及三个月时血磷水平[（2.135±0.56）mmol/L比（1.826±0.45）mmol/L比（1.721±0.31）mmol/L]、钙磷乘积[（59.517±10.7）mg2/dl 2比（51.513±9.8）mg2/dl 2比（47.123±8.6）mg2/dl 2]明显下降（P〈0.05,P〈0.01）;治疗3个月时62.5%的患者血磷水平达标,烟酰胺对血钙、iPTH水平无明显影响。结论：口服烟酰胺片可有效降低维持性血液透析患者血磷和钙磷乘积,不影响血清钙水平,无增加血管钙化的风险。     

Influence of sevelamer on mineral metabolism and hyperparathyroidism in Japanese hemodialysis patients

In June 2003, sevelamer hydrochloride became widely available in Japan and was expected to control hyperphosphatemia in hemodialysis patients without inducing hypercalcemia. To evaluate the impact of sevelamer therapy on mineral metabolism, we recruited 954 hemodialysis patients from 21 renal units just before the general release of sevelamer in Japan. The serum calcium, phosphate, and parathyroid hormone levels determined on enrollment were compared with those later measured in June 2004. Sevelamer was prescribed for 169 of the 859 patients for whom data were available in 2004. The mean calcium level, phosphate level, and calcium x phosphate product were all significantly reduced during the 12-month study period, but the intact parathyroid hormone (iPTH) level did not change. As a result, the percentage of patients who achieved a calcium x phosphate product of <55 mg(2)/dL(2) was significantly increased, but there were no changes in that of patients who achieved the target ranges for phosphate (3.5-5.5 mg/dL) or iPTH (150-300 pg/mL). Among sevelamer-treated patients, iPTH significantly increased, and this change was more marked in the patients with an initial iPTH level <150 pg/mL. Sevelamer was useful for reducing the serum calcium level and calcium x phosphate product, but hyperphosphatemia and hyperparathyroidism were not improved in our study population at 12 months after the release of sevelamer. A decrease in the calcium load might result in the exacerbation of hyperparathyroidism. However, among patients with relative hypoparathyroidism, sevelamer therapy may be beneficial for the prevention of adynamic bone disease.     

Sevelamer hydrochloride improves hyperphosphatemia in hemodialysis patients with low bone turnover rate and low intact parathyroid hormone levels

Sevelamer improves hyperphosphatemia without increasing the calcium load. However, it remains unknown whether sevelamer restores bone metabolism in hemodialysis patients with low bone turnover osteodystrophy and hypoparathyroidism. We investigated the changes in serum intact parathyroid hormone (iPTH) and bone metabolic marker levels after replacing calcium carbonate with sevelamer in these patients. We also conducted stratified analysis based on patient background and multivariate analysis to determine the factors affecting these parameters. During sevelamer replacement therapy, serum calcium and phosphate concentrations, and the calcium phosphate product were measured at 0, 1, 3, and 6 months. Serum iPTH, bone alkaline phosphatase and osteocalcin concentrations were measured at 0 and 6 months. In hemodialysis patients (71 men and 46 women, 63 +/- 12 years old) serum calcium levels and the calcium phosphate product decreased significantly at 1 month. Serum iPTH, bone alkaline phosphatase and osteocalcin levels increased significantly at 6 months. Increases in serum iPTH concentrations were observed in all stratified groups. Significant increases in serum bone alkaline phosphatase and osteocalcin concentrations were found only in the relative hypoparathyroidism group (iPTH levels > or =51.5 pg/mL, the median pretreatment level). Multivariate analysis showed that the factors affecting change in serum iPTH level are baseline serum iPTH, baseline calcium level (> or =9.5 mg/dL), and dialysis duration of 10 years or longer. Sevelamer appears useful for the treatment of hyperphosphatemia in these patients. Particularly, in the relative hypoparathyroidism group, the iPTH secretory response is probably enhanced and bone turnover may have been improved as a result of reducing the calcium load.     

Hypercalcemia in rheumatoid arthritis: relationship with disease activity and bone metabolism

To investigate the relationship between ionized calcium and disease activity, parameters of bone metabolism and bone mineral density (BMD) at the lumbar spine (BMD-LS) and the femoral neck (BMD-FN) measured by dual X-ray absorptiometry in rheumatoid arthritis (RA). In 146 patients with RA, the following parameters were investigated: serum levels of ionized calcium, total calcium, vitamin D metabolites 25-hydroxyvitamin D3 (25D3) and 1,25-dihydroxyvitamin D3 (1,25D3), intact parathyroid hormone (iPTH), interleukin-6, osteocalcin, erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP); renal excretion of pyridinolin (PYD)- and desoxypyridinolin (DPD)-crosslinks. A total of 30.1% of the patients were hypercalcemic (ionized calcium >1.30 mmol/l). In comparison with normocalcemic patients, those with hypercalcemia had significantly higher ESR (P<0.01) and CRP values (P<0.05) and significantly lower serum levels of both iPTH (P<0.01) and 1,25D3 (P<0.05) and a significantly lower BMD-LS (P<0.05). The results indicate that a substantial part of RA patients is hypercalcemic. Hypercalcemia is associated with high disease activity and may contribute to suppression of PTH secretion and vitamin D hormone synthesis. High levels of ionized calcium may be a reflection of disease-activity-related systemic bone loss, and could be a predictor of BMD at the lumbar spine in RA.     

Does Concomitant Administration of Sevelamer and Calcium Carbonate Modify the Control of Phosphatemia?

There is no guideline regarding the concomitant or distant administration of sevelamer and calcium carbonate. Our aim was to determine whether serum phosphate varied when sevelamer and calcium carbonate were administered concomitantly in comparison to administration at separate meals. Fourteen chronic hemodialysis patients were enrolled in this cross-over, randomized trial. Each subject underwent two four-week study periods. During the “concomitant” period, subjects were instructed to take both sevelamer and calcium carbonate together at each meal, whereas in the “separate” period, they were required to take them at separate meals. The order of the “concomitant” and “separate” periods was randomized. Phosphate-binding agents were stopped for a one-week washout period before each study period. The total dose of sevelamer and calcium carbonate for each subject remained the same for the whole duration of the study and had been determined according to their usual dose of phosphate binders. Patients were instructed to keep their usual eating habits constant and a nutritionist evaluated the daily phosphate intake three times per week. Dialysis parameters were kept constant. Pre-dialysis serum phosphate, calcium, bicarbonate, and albumin were measured at the end of each week. The average daily dietary phosphate intake remained unchanged throughout the study. At the end of the two study periods there was no significant difference in serum phosphate (1.50 ± 0.46 mmol/L in the “concomitant” period vs. 1.51 ± 0.31 mmol/L in the “separate” period, P = 0.97), calcium (2.26 ± 0.19 mmol/L in the “concomitant” period vs. 2.27 ± 0.15 mmol/L in the “separate” period, P = 0.64), calcium × phosphate product (3.36 ± 0.94 mmol²/L² in the “concomitant” period vs. 3.41 ± 0.71 mmol²/L² in the “separate” period, P = 0.84) and bicarbonate levels (21.5 ± 3.3 mmol/L for the “concomitant” period vs. 21.6 ± 3.1 mmol/L for the “separate” period, P = 0.81). Our results show that simultaneous administration of calcium carbonate and sevelamer does not decrease phosphate-binding capacity. Hence, patients can choose to take their phosphate binders concomitantly or at separate meals, according to their preference.     

Role of sevelamer hydrochloride in the coronary artery calcification score

The coronary artery calcification score (CACS) is higher in hemodialysis (HD) patients than in non-HD patients for each age group from the fifth to the eighth decade of life. In order to clarify the relationship between the rate of change in the CACS and several factors related to calcium (Ca) and phosphate (P) metabolism in HD patients, we determined the CACS twice in 144 HD outpatients at an interval of approximately 12 months (2003 and 2004). The dosage of vitamin D formulations (alfacalcidol or maxacalcitol) was reduced or ceased if the serum Ca concentration exceeded 5.0 mEq/L, or the serum P concentration exceeded 6.0 mg/dL, and the dosage of combined sevelamer hydrochloride (SH) and calcium carbonate (CaCO3), as the phosphate binder, was adjusted to maintain the concentrations below these levels. The study parameters were: (1) the total dosage of alfacalcidol (microg), maxacalcitol (microg), SH (mg), and CaCO3 at the time of each CACS measurement; and (2) serum concentrations of Ca, P, alkaline phosphatase, high-sensitivity parathyroid hormone (HS-PTH), total protein, albumin, total cholesterol, triglycerides (TG). Regression analysis showed a significant correlation among the total SH dosage, TG, and alphaCACS. Future investigations will include the differences in alphaCACS between patients treated with SH who experience a rise in Ca and/or P and those with a decrease in Ca and/or P.     

Effects of raloxifene on bone mineral metabolism in postmenopausal Japanese women on hemodialysis

In addition to renal osteodystrophy, postmenopausal women on hemodialysis are at high risk for osteoporosis. Recent studies reported the effects of raloxifene, a selective estrogen receptor modulator for osteoporosis, in postmenopausal women. The present study evaluated the efficacy of raloxifene and its effects on bone mineral metabolism in postmenopausal Japanese patients on dialysis. In a prospective, multicentre study, 17 postmenopausal women on chronic hemodialysis with severe osteoporosis (bone mineral density [BMD]≤2 SD by bone densitometry) were treated with 60 mg/day raloxifene hydrochloride for 12 months. The study also included 10 age-matched control women. Vitamin D and calcium salts were not changed during the study. Intact parathyroid hormone (iPTH), serum calcium and phosphorus, and bone resorption marker (NTx) were measured, and BMD were determined by DEXA, at 0, 6, and 12 months after administration of raloxifene. The mean lumbar spine BMD at baseline was similar in the two groups. Raloxifene therapy (for 12 months) improved lumbar spine BMD (by 2.6%) in 53% of the patients, while 70% of the control group showed a reduction in BMD (by 4.0%). Raloxifene significantly decreased serum calcium and increased iPTH. Our results suggested that raloxifene improved trabecular BMD in postmenopausal Japanese women on hemodialysis. The effects of raloxifene on serum calcium and serum iPTH level suggest it improves bone resorption. Vitamin D and/or calcium salts should be added to raloxifene treatment to avoid secondary hyperparathyroidism.     

Effect of salmon calcitonin on bone mineral density and calcium-phosphate metabolism in chronic hemodialysis patients with secondary hyperparathyroidism

The aim of the study was to evaluate the effect of salmon calcitonin on bone mineral density, parathyroid and thyroid C cells, and calcium-phosphate metabolism in chronic hemodialysis patients with uremic hyperparathyroidism. Forty five patients with serum 1-84 PTH >220 pg/ml were divided into 2 groups: group I (n = 25), treated with intranasal salmon calcitonin (200 IU, thrice a week) and control group II (n = 20). Patients received calcium carbonate (up to 6 g/d) alone or with aluminum hydroxide (up to 3 g/d) as phosphate binders; dialysate calcium was 1.75-2 mmol/l. The observation period was 12 months. The following parameters were measured: bone mineral density (BMD) with dual-energy X-ray absorptiometry in: lumbar spine (L2-L4), femoral neck and total body, before and after the study; serum endogenous calcitonin, before and after the study; serum PTH, alkaline phosphatase and total hydroxyproline, before and after 1, 3, 6, and 12 months; and serum calcium and phosphate monthly. During 12 months of the study, a substantial reduction in BMD was observed in all examined regions in group II (-2.8 +/- 2.1%; p<0.01 in L2-L4, -2.4 +/- 2.0%; p<0.01 in femoral neck, and -1.9 +/- 1.4%; p<0.01 in total body), whereas in group I a slight increase of bone mineral was noted, however insignificant. The inhibition of bone resorption was accompanied by a marked decrease in serum hydroxyproline. No changes in parathyroid activity were noted nor any decrease in serum phosphate. The treatment had no influence on serum endogenous calcitonin; initial concentrations were elevated in 47% of patients. CONCLUSION: Intranasal salmon calcitonin: 1) has no influence on bone mineralization in dialysis patients with uremic hyperparathyroidism; 2) has no significant effect on serum phosphate concentration; 3) provided adequate calcium supplementation doesn't stimulate parathyroid glands; 4) has no influence on endogenous calcitonin secretion.     

Divalent cation metabolism: Familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism

Twenty-three members of three families with a syndrome of hypercalcemia without hypercalciuria (familial hypocalciuric hypercalcemia) were compared to a group of 64 subjects with hypercalcemia due to typical primary hyperparathyroidism. Patients with familial hypocalciuric hypercalcemia had higher creatinine clearance values than those with primary hyperparathyrodism (115 ± 27 versus 87 ± 27 ml/min/1.73 m² (mean ± 1 standard deviation [SD] p < 0.0001). Although renal function was well preserved, the group with familial hypocalciuric hypercalcemia showed a mean serum magnesium concentration of 2.05 ± 0.17 meq/liter, significantly higher than that in normal subjects (1.74 ± 0.12 meq/liter, p < 0.0001) or than in the group with primary hyperparathyroidism (1.71 ± 0.21 meq/liter, p < 0.0001). In familial hypocalciuric hypercalcemia the degree of hypermagnesemia was directly proportional to the degree of hypercalcemia (R = +0.54, p < 0.01), contrasting with an inverse relation of serum calcium and magnesium concentrations in primary hyperparathyroidism (R = ?0.32, p < 0.02). Urinary excretion of both calcium (calcium:creatinine clearance ratio 0.006 ± 0.004 versus 0.024 ± 0.01, p < 0.0001) and magnesium (magnesium:creatinine clearance ratio 0.031 ± 0.0008 versus 0.047 ± 0.03, p < 0.003) was significantly lower in familial hypocalciuric hypercalcemia than in primary hyperparathyroidism. There was no evidence that abnormal protein binding of cations in serum from those with familial hypocalciuric hypercalcemia accounted for the hypercalcemia and hypermagnesemia or for the disproportionately low urinary excretion of divalent cations by rendering them resistant to glomerular filtration. After fractionation by electrophoresis on cellulose acetate, the major plasma protein components were quantitatively similar in both groups. Furthermore, ionized and ultrafiltrable calcium and ultrafiltrable magnesium showed consistent relations to total calcium and total magnesium concentrations in plasma from both groups. Therefore, in familial hypocalciuric hypercalcemia there are increased serum concentrations of the physiologically active forms of both calcium and magnesium, and the renal handling of the filtered load of these divalent cations differs in familial hypocalciuric hypercalcemia and primary hyperparathyroidism.     

Combination therapy with sevelamer hydrochloride and calcium carbonate in Japanese patients with long-term hemodialysis: alternative approach for optimal mineral management

Calcium (Ca) overload by Ca-containing phosphorus (P) binder has been suggested to be implicated in the pathogenesis of soft tissue and vascular calcification, which contribute to increased morbidity and mortality of cardiovascular disease in patients undergoing dialysis. Recently, a noncalcium P binder, sevelamer hydrochloride (sevelamer), has become available in Japan. However, Japanese patients undergoing dialysis might be less tolerant of sevelamer treatment, and it is likely to cause hypocalcemia because their dietary Ca intake is less than that in European and American patients. We evaluated the effects of combination therapy with sevelamer and calcium carbonate (CC) on mineral metabolism in Japanese hemodialysis patients, as an alternative form of P management. A total of 210 hemodialysis patients were enrolled, and were given a small dose of sevelamer (0.75-1.5 g/day) on CC treatment. Sevelamer dose was gradually increased, while CC decreased during 24 weeks. Five patients discontinued sevelamer treatment because of severe constipation, anorexia, and parathyroidectomy for severe secondary hyperparathyroidism. After 24 weeks, the dose of sevelamer was significantly increased to 3.29 g/day (initial dose: 1.47 g/day), while CC was decreased by 54%. Adjusted serum Ca significantly decreased (9.63 +/- 0.57-9.45 +/- 0.67 mg/dL; P = 0.0012), although serum P increased (5.89 +/- 1.32-6.25 +/- 1.32 mg/dL; P = 0.017). Serum intact PTH (iPTH) significantly increased in patients with a low or normal iPTH level (< or =300 pg/mL), while it did not change in patients with secondary hyperparathyroidism (>300 pg/mL). The results suggest that the therapeutic regimen is more tolerant and reduces Ca load in Japanese hemodialysis patients while avoiding hypocalcemia. In addition, the mitigated Ca overload could improve PTH hyposecretion in patients with adynamic bone disease, which is associated with soft tissue calcification and higher mortality in uremia.     

Humoral hypercalcemia of benignancy secondary to parathyroid hormone-related protein secreting uterine leiomyoma

A 48-year-old women admitted with polyuria and polydipsia. She was found to be hypercalcemic despite suppressed parathormone (iPTH) levels. Subsequently checked parathormone related-protein (PTHrP) level was 2.5 pmol/L (expected normal level <1.3 pmol/L). An extensive workup for a malignancy revealed no abnormality, except for an uterine leiomyoma, 7.1 cm in size. Total abdominal hysterectomy and salpingo-oophorectomy were performed. After the surgical removal of uterine leiomyoma, serum calcium (9.3 mg/dL), iPTH (29.4 pg/mL), and PTHrP (<1.3 pmol/L) levels were normalized. The diagnosis of humoral hypercalcemia of benignancy secondary to PTHrP was confirmed. One month later, her calcium and iPTH levels were normal and 1 year later still remain within the normal ranges. Our case indicates that PTHrP associated hypercalcemia does not solely result from a malignant tumor. Benign tumors like uterine leiomyoma might also cause humoral hypercalcemia.     

THE EFFECT OF OESTROGENS ON HUMAN CALCITONIN SECRETION AFTER CALCIUM INFUSION IN ELDERLY FEMALE SUBJECTS

The effect of oestrogen administration (4–6 weeks) on the response of human calcitonin (hCT) secretion to 5 min calcium infusions was studied in ten elderly women. There was no significant difference in mean basal plasma hCT levels before and after oestrogen administration. However, the mean increment in plasma hCT in response to calcium infusion (ΔhCT) increased significantly (P < 0·001) from 21·9±6·6 (mean ±SE) before treatment, to 79·6±15·5 ng/l after oestrogen administration. Mean serum calcium levels decreased significantly (P < 0·001) from 2·42 ±0·06 before to 2·19·0±07 mmol/l after oestrogen treatment. Mean plasma immunoreactive PTH (iPTH) levels increased significantly (P < 0·05) from 521·41 before to 696·96 ng/l after oestrogen treatment. To exclude out the possibility that the decreased serum calcium level itself might have influenced ΔhCT, 1α-hydroxycholecalciferol (1α-OH-D₃) was administered with oestrogens. While this resulted in a slight increase in serum calcium level, there was no significant difference in ΔhCT in response to calcium infusion following oestrogen treatment alone, and after combination therapy of oestrogen and 1 α-OH-D₃. The primary action of administered oestrogen may be in stimulating hCT secretion which results in a decrease in plasma calcium concentration and an increase in plasma iPTH level.     

Effects of serum calcium, phosphorous, and intact parathyroid hormone levels on survival in chronic hemodialysis patients in Japan

Disturbances in bone mineral metabolism are common in chronic hemodialysis (HD) patients and often underlie morbid conditions and mortality; however, no large epidemiological study for Asian dialysis patients has been performed. We analyzed the database of the Japanese Society for Dialysis Therapy registry. In this study, data from patients who were on HD at the end of 2000 was compiled. The Cox's proportional hazard analysis was carried out to evaluate the significance of the impact of variables related to bone mineral metabolism on survival after adjusting for possible confounding variables. The study period was three years, and a cohort of 27 404 HD patients was studied. The hazard ratios were 1.098 (P = 0.0129) for serum calcium levels ranging 10.0-10.9 mg/dL, and 1.243 (P = 0.0001) for serum calcium levels >11.0 mg/dL when the reference serum calcium level range was 9.0-9.9 mg/dL. Similarly, the hazard ratios were significantly higher in a serum phosphorous level of 5.0 mg/dL than for the reference serum phosphorous level range of 4.0-4.9 mg/dL. For intact parathyroid hormone (iPTH), the hazard ratios were significantly small (<119 pg/mL) when the reference iPTH level range was 180-359 pg/mL. However, the hazard ratio did not increase when the iPTH level increased to >360 pg/mL. Results showed that disturbances in bone mineral metabolism, such as those involving serum calcium, phosphorous, and iPTH, have a significant impact on survival in Japanese dialysis patients.     

Dose-response study of 22-oxacalcitriol in patients with secondary hyperparathyroidism

The dose-response relationships and the safety of administering 22-oxacalcitriol (OCT) to patients with secondary hyperparathyroidism (2HPT) under regular three-times-weekly hemodialysis (HD) were evaluated by double-blind parallel group design. A total of 203 patients with 2HPT were randomly allocated into four groups, and 5 microg (Group L), 10 microg (Group M), or 15 microg (Group H) OCT, or placebo (Group P) was administrated at the end of every HD for 12 weeks. Reductions of intact-parathyroid hormone (iPTH) concentration greater than 30% from baseline were observed in 7.7% of Group P as compared to 77.3% of the pooled OCT groups after 12 weeks of treatment (Mantel test: P < 0.001). Time-trends (slopes) of log-iPTH concentration calculated by least-squares line fitting to each patient's data during treatment differed between Group P and the pooled OCT groups (t-test: P < 0.001) and these iPTH slopes decreased dose-dependently (linear trend by t-test: P < 0.001). Slopes of serum calcium corrected for albumin (corrected-sCa) concentrations also differed between Group P and the pooled OCT groups (t-test: P < 0.001), and increased dose-dependently (linear trend by t-test: P < 0.0001). Serum phosphorus and Ca x P product increased significantly only in high dose groups. Slopes of log(iPTH) and corrected-sCa concentrations were reciprocally related. Most adverse events were hypercalcemia and dose-related, but occasionally comprised pruritus or increased serum creatinine phosphokinase. These results indicate that OCT produced a strong and dose-dependent suppression of PTH and an increase of corrected-sCa concentration in patients with 2HPT. The recommended initial dosages of OCT would appear to be 5 microg when pretreatment iPTH concentrations are less than 500 pg/mL, and 10 microg when greater than 500 pg/mL for safe and effective treatment. As in the case of PTH, calcium and phosphorus showed dose-dependent increases. It is therefore essential to take precautions as to possible increases in calcium and phosphorus.     

Distribution of coronary atherosclerosis in patients with coronary artery disease

The distribution of coronary atherosclerosis has not been fully clarified. We measured coronary artery calcium score (CACS) in 624 consecutive patients for the right coronary artery (RCA), left main trunk (LMT), left anterior descending coronary artery (LAD), and left circumflex coronary artery (LCx), then calculated total CACS. Coronary artery calcium score was measured using the Agatston method. We divided these patients into four groups: CACS 1–100 (Group A, n = 267), CACS 101–400 (Group B, n = 160), CACS 401–1000 (Group C, n = 110), and CACS >1000 (Group D, n = 87). In Group A, B, and C, the CACS in LAD was significantly higher than in the other three arteries (P < 0.0001). In Group D, the CACS was not significantly different between LAD and RCA (P = 0.6930). In Groups A, B, and C, coronary artery calcium (CAC) was more frequently found in LAD compared with other arteries (P < 0.0001). However, in Group D the prevalence of CAC was not significantly different among the three arteries (P = 0.4435). Coronary artery calcium was found more frequently in LAD than in the other coronary arteries in patients with mild to high CAC, but not in those with very high CAC.     

Effects of In‐Center Nocturnal Versus Conventional Hemodialysis on Endothelial Dysfunction

Cardiovascular disease is the leading cause of morbidity and mortality in patients with end‐stage renal disease who undergo hemodialysis and endothelial dysfunction is an early key step in the development of atherosclerosis. The aim of this study was to investigate the effect of thrice‐weekly in‐center nocturnal hemodialysis (INHD, 8 h per session and three sessions per week) and conventional hemodialysis (CHD, 4 h per session and three sessions per week) on endothelial dysfunction in patients with end‐stage renal disease. 32 INHD and 58 matched CHD patients were enrolled, baseline and 12‐month measures of blood pressure (BP), serum calcium and phosphorus, serum intact PTH (iPTH) and brachial artery flow‐mediated dilation (FMD) were collected and analyzed. Baseline characteristics were similar between groups except that serum phosphorus and calcium × phosphorus were higher in the INHD group. At the 12‐month follow‐up, there was a significant increase in FMD (6.0 ± 1.5% to 7.1 ± 1.8%, P < 0.01) in INHD patients. Multivariate analysis showed that FMD was inversely correlated with systolic BP (SBP) (β = ?0.485, P < 0.01), diastolic BP (DBP) (β = ?0.428, P < 0.01), iPTH (β = ?0.405, P < 0.01) and serum phosphorus level (β = ?0.375, P < 0.01). There was no significant change in FMD in the CHD group. Compared with CHD, INHD improves endothelial function, and control of serum phosphorus is associated with the improvement of endothelial function.     

Chronic Hemodialysis Patients Without Marked Elevation of Intact Parathyroid Hormone Are Also Good Candidates for Early Intervention With Cinacalcet

Management of calcium (Ca) and phosphorus (P) metabolism is crucial in chronic hemodialysis (HD) patients. Cinacalcet is usually used for chronic kidney disease‐mineral and bone disorders (CKD‐MBD) patients with elevated intact parathyroid hormone (iPTH) levels. However, a certain number of CKD‐MBD patients have normal iPTH levels and are not subjected to cinacalcet therapy. Here, we evaluated the efficacy of a new treatment algorithm of early initiation of cinacalcet therapy in this subgroup of patients, mainly for correcting Ca and P metabolism. Seventy‐one HD patients, including 44 patients without marked elevation of iPTH (102 < iPTH ≤ 300 pg/mL), who received cinacalcet therapy, were enrolled in this study. Serum parameters relating to CKD‐MBD patient metabolism, doses of phosphate binders, and type of vitamin D sterols were compared between pre‐ and post‐cinacalcet administration retrospectively. Sixty‐four of 71 patients did not require discontinuation of cinacalcet. In these 64 patients, serum Ca (P = 0.0003), P (P = 0.0153), and iPTH (P < 0.0001) levels were significantly reduced after cinacalcet administration, even in those without marked elevation of iPTH (Ca; P < 0.0001, P; P = 0.0422, and iPTH; P = 0.0018). The proportion of patients who received vitamin D sterols was unchanged (P = 0.5930) but the proportion of patients who received maxacalcitol was significantly reduced after cinacalcet administration (P = 0.0108). The new treatment algorithm of early initiation of cinacalcet is considered to be well tolerated and effective for controlling hypercalcemia, and/or hyperphosphatemia and/or increased iPTH of CKD‐MBD patients.     

Correlation of Coronary Artery Calcification With Pre‐Hemodialysis Bicarbonate Levels in Patients on Hemodialysis

Coronary artery calcification (CAC) leads to a significant increase in cardiovascular morbidity and mortality in hemodialysis (HD) patients. Metabolic acidosis, which is common in HD patients, promotes bone resorption in human and animals as a result of buffer function of bone, and calcium and phosphate elute from bone into blood stream. However, the effect of acidosis on CAC in HD patients has never been precisely investigated. This is a cross‐sectional observational study performed in a single center. One hundred and seven prevalent HD patients (35 women and 72 men) underwent electron‐beam computed tomography (EBCT) to evaluate CAC score (CACS), and then we evaluated associated factors of CACS with clinical and laboratory parameters including pre‐HD pH and bicarbonate levels. Pre‐HD pH and bicarbonate levels were 7.35 ± 0.04, and 17.6 ± 1.8mmol/L, respectively. The pre‐HD pH had no significant correlation to CACS (r = ?0.025, P = 0.81). CACS was significantly negatively correlated with pre‐HD bicarbonate levels (r = ?0.329, P = 0.0009) and serum albumin levels (r = ?0.298, P = 0.0467), while it was positively correlated with age (r = 0.319, P = 0.0008) and HD duration (r = 0.385, P = 0.0004). Serum levels of calcium, phosphorus, intact parathyroid hormone, and use of phosphorus binders were not related to CACS. Multivariate analysis indicated that plasma pre‐HD bicarbonate level was independently associated with CACS. The present study showed that blood levels of pre‐HD bicarbonate were significantly associated with CAC in HD patients. Further studies are needed to confirm these results and to determine whether correction of metabolic acidosis prevents the development of CAC, one of the features of accelerated atherosclerosis in HD patients.     

One Year Efficacy and Safety of Lanthanum Carbonate for Hyperphosphatemia in Japanese Chronic Kidney Disease Patients Undergoing Hemodialysis

Lanthanum carbonate is a non-calcium-based phosphate binder for hyperphosphatemia in patients with chronic kidney disease (CKD). The efficacy and safety of lanthanum carbonate (LaC) on hyperphosphatemia in patients has been well documented in clinical trials in Western countries and recent relatively short-term clinical trials in Japan. Evidence supporting its safety and efficacy in Japanese patients for longer-term treatment is now desired for clinical practice. A non-controlled, open-label, multicenter, one year study of LaC to assess safety and its effect on the levels of serum phosphate, serum calcium and parathyroid hormone was performed with Japanese dialysis patients. Lanthanum carbonate was administered to patients at variable doses for a period of 46–52 weeks. Evaluation of the safety and efficacy of LaC in reducing serum phosphate was performed, in addition to extensive and systematic monitoring of the laboratory parameters related to bone turnover and cardiac health. A significant reduction in the serum phosphate level was demonstrated throughout the treatment period (P < 0.05), without any increase in the frequency or severity of drug-related adverse events such as vomiting, nausea, and stomach discomfort. There was no clinically relevant change in vital signs, or electrocardiograms for a period. The profiles for parathyroid hormone, bone alkaline phosphates, and osteocalcin were stable in the patients concomitantly treated with vitamin D. This study provides further evidence that the administration of LaC over a period of one year is safe and effective for the reduction of serum phosphate levels in CKD patients undergoing hemodialysis.