Association between warfarin use and incidence of ischemic stroke in Japanese hemodialysis patients with chronic sustained atrial fibrillation: a prospective cohort study.

BACKGROUND: Although generally recommended for atrial fibrillation (AF) in the general population, the efficacy and safety of warfarin in hemodialysis patients remains controversial. Warfarin use in hemodialysis patients may confer an additional risk of bleeding that is not appreciated in patients without renal failure because hemodialysis patients have platelet defects and receive anticoagulation agents during dialysis. The incidence of major bleeding was reported to be higher in Japanese AF patients on warfarin therapy compared to patients in other countries, suggesting that racial differences may influence bleeding tendency. Thus, examining risks and benefits of warfarin therapy in Japanese hemodialysis patients with AF is important. METHODS: In order to determine associations between warfarin use and new ischemic stroke events, major bleeding, and all-cause mortality, a prospective cohort study of 60 Japanese hemodialysis patients with chronic sustained AF was conducted using Cox proportional modeling and propensity score matching. RESULTS: The mean patient age was 68.1 years. During 110 person-years of follow-up, 13 ischemic strokes occurred. After adjusting for CHADS2 score, warfarin use was not associated with a significant reduction in ischemic stroke events [hazard ratio (HR) 3.36; 95 % confidence interval (CI) 0.94-11.23]. Similar results were obtained after propensity score matching (HR 3.36; 95 % CI 0.67-16.66). Warfarin use was not associated with significant increases in major bleeding or all-cause mortality. CONCLUSIONS: These results suggest that warfarin may not prevent ischemic stroke in Japanese hemodialysis patients with chronic sustained AF. Adequately powered studies are needed to determine the risks and benefits of anticoagulation therapy in these patients.

Effect of lanthanum carbonate treatment on bone in Japanese dialysis patients with hyperphosphatemia.

Lanthanum carbonate (LC), a newly developed non-calcium-containing phosphate binder, has been shown to possess high phosphate-binding capacity and safety when used for hyperphosphatemia in patients with chronic kidney disease undergoing dialysis. The effects of LC on bone metabolism in Japanese dialysis patients have not been investigated; therefore, we performed histomorphometric analysis on bone from dialysis patients with hyperphosphatemia. This was a prospective, open-label study in Japanese chronic kidney disease patients on dialysis, with a flexible daily dosage of 750-4500 mg to achieve target phosphorus levels of 3.5-5.5 mg/dL (1.10-1.78 mmol/L). Bone biopsy samples for histomorphometric analysis were obtained at baseline and after treatment with LC. The median bone lanthanum level increased during the LC treatment from 54.1 µg/kg at baseline to 4270.9 µg/kg at three years. After one year of treatment with LC, two cases with an initial classification of osteitis fibrosa improved toward normal bone turnover. The diagnosis of normal remained the same for up to three years. We also noted that two cases with a baseline classification of adynamic bone disease improved after one year, and was maintained for three years. Our data suggest that LC is effective not only for treating hyperphosphatemia, but also for improving renal osteodystrophy in Japanese dialysis patients.

Cancellous bone volume is an indicator for trabecular bone connectivity in dialysis patients.

BACKGROUND AND OBJECTIVES: A new assessment system for bone histology, termed the turnover-mineralization-volume system, is advocated for patients with chronic kidney disease-related mineral and bone disorder. The system measures cancellous bone volume (BV/TV) as a third major evaluation axis; however, the physiologic significance of BV/TV remains unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Conventional bone histomorphometry was performed in 75 iliac bone samples obtained from dialysis patients. In 47 of the 75 samples, the remaining samples were subjected to direct microfocus x-ray computed tomographic observation. Quantitative morphologic examinations, including micro-bone mineral densitometry, and marrow space star volume, Euler number, and node-strut analyses, were performed in the virtual three-dimensional space reconstructed from the microfocus x-ray computed tomographic images. RESULTS: The levels of BV/TV were comparable in each of the conventional bone histomorphometric criteria. No significant correlations were found between BV/TV and other parameters. Two- and three-dimensional BV/TVs were significantly correlated with cancellous bone mass but not with cortical bone thickness or cortical bone mass. Two- and three-dimensional BV/TVs were significantly correlated with trabecular bone connectivity as determined by marrow space star volume, Euler number, and node-strut analyses. CONCLUSIONS: In dialysis patients, BV/TV is not dependent on bone turnover or bone mineralization. BV/TV is unlikely to indicate the balance between bone formation and bone resorption. Instead, it reflects trabecular bone connectivity, and improved trabecular bone connectivity is physiologically beneficial in terms of bone quality. The turnover-mineralization-volume system offers an advantage over the conventional system for the assessment of bone quality.

Bone metabolism after cinacalcet administration in patients with secondary hyperparathyroidism.

Cinacalcet, an allosteric modulator of a calcium (Ca)-sensing receptor, significantly suppresses parathyroid hormone (PTH) secretion and bone turnover rate in chronic hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). In this study, bone metabolism after cinacalcet treatment was examined, because hungry bone syndrome is sometimes experienced after parathyroidectomy in severe SHPT. We conducted a prospective observational study in 17 HD patients with SHPT. Cinacalcet was started at 25 mg/day, and the dose was increased step by step based on serum calcium level. A significant decrease in serum Ca and intact PTH concentration was found within 2 weeks. Tartrate-resistant acid phosphatase 5b, a good bone resorption marker, was significantly decreased at week 2 of the study. Serum bone alkaline phosphatase, a marker of bone formation, was increased at week 2 compared with the basal level. It became, however, gradually decreased until week 14. Only one patient whose bone turnover was considerably high had a mild numbness feeling. These results suggest that cinacalcet treatment might transiently accelerate bone formation with rapid suppression of bone resorption. This uncoupling could be involved in a mechanism by which cinacalcet decreases serum Ca level.

Comparison of quantitative cancellous bone connectivity analyses at two- and three-dimensional levels in dialysis patients.

Assessment of cancellous bone connectivity has the potential to aid in predicting fracture risk. Today, cancellous bone connectivity is generally assessed using bone sections obtained from biopsy. However, how reliably such two-dimensional (2-D) analyses visualize the 3-D properties has not been evaluated. Biopsied iliac bone samples were obtained from 47 chronic hemodialysis patients. Bone samples were observed using a microfocus X-ray computed tomography (microCT) system en bloc, and the cancellous bone microstructure was quantitatively assessed at both the 2- and 3-D levels. Cancellous bone microarchitecture was successfully reconstructed from the data obtained by the microCT system. Most of the results from node-strut analysis (NSA) revealed no statistically significant correlations between the 2- and 3-D analyses, with the exception that the number of nodes (N.Nd/TV) showed a mild but significant correlation. In contrast, the marrow space star volumes (V*m) of the 2- and 3-D analyses were highly correlated. NSA parameters including N.Nd/TV showed significant correlations with V*m at the 3-D level. In conclusion, V*m values were similar in the 2- and 3-D analyses, while most of the 2-D NSA parameters did not reflect the 3-D ones. Since V*m and most of the NSA parameters were correlated in the 3-D analyses, 2-D NSA would seem to have serious limitations for the assessment of cancellous bone microstructural properties. Further studies will thus be needed to establish appropriate methods for assessing cancellous bone connectivity in clinical practice.

Sevelamer hydrochloride and calcium bicarbonate reduce serum fibroblast growth factor 23 levels in dialysis patients.

Fibroblast growth factor 23 (FGF23) is a member of the fibroblast growth factor superfamily which displays a strong phosphaturic action and an inhibition of vitamin D 1-alpha hydroxylase activity. Fourty-six patients undergoing maintenance hemodialysis therapy participated in the study. They were randomly divided into 2 groups, and treated with either 3 g sevelamer hydrochloride+3 g of calcium bicarbonate (CaCO3), or 3 g of CaCO3 alone. Serum FGF23 levels were determined by a sandwich enzyme-linked immunosorbent assay (ELISA) system that detects the intact form of FGF23 molecules. Although the serum inorganic phosphate (Pi) levels were comparable before treatment, the levels were significantly lower in the patients treated with sevelamer hydrochloride+CaCO3 than those with CaCO3 alone after 4 weeks of treatment (P<0.05). Serum FGF23 levels significantly decreased after 4 weeks of the treatment with sevelamer hydrochloride+CaCO3 from the pretreatment levels (P<0.05), while no changes were found in the patients treated with CaCO3 alone. Thus, the use of sevelamer hydrochloride and CaCO3 reduced serum FGF23 levels in dialysis patients presumably through inhibiting phosphate load into the intestine.

Prospective randomized multicenter trial of sevelamer hydrochloride and calcium carbonate for the treatment of hyperphosphatemia in hemodialysis patients in Japan.

A prospective, randomized open-label trial of sevelamer hydrochloride with or without calcium carbonate (CC) involved 86 hemodialysis patients in Japan. The dosage of CC was fixed at 3.0 g/day for the 12-week study. After the first 4 weeks all subjects were changed from CC to sevelamer 3.0 g/day for another 4 weeks, then allocated randomly to three groups for the final 4 weeks: group A, sevelamer 6.0 g/day; group B, sevelamer 3.0 g/day and CC 3.0 g/day; group C, CC 3.0 g/day. The target serum phosphorous concentration (P)=5.5 mg/dL and the corrected calcium concentration (Ca) was 9.0-10.0 mg/dL. Of the 86 patients, 62 finished the study without a change of dosage and their data were analyzed (group A, N=16; group B, N=26; group C, N=20). At week 8 compared with week 4, the concentration of P increased from 5.7+/-1.4 to 6.4+/-1.7 mg/dL in group A, and decreased significantly in groups B and C, and in group B compared with groups A and C; groups A and C had similar concentrations at week 8. The Ca concentration decreased significantly from 9.7+/-1.0 to 9.1+/-0.7 mg/dL after the change to sevelamer. At week 8 Ca was not significantly changed in group A, whereas a significant increase occurred in groups B and C. Side-effects with sevelamer administration occurred in 34 of the 86 patients and 24 dropped out of the study, with a high frequency in group A (13/29; 44.8%). In conclusion, there was an additive effect of sevelamer for the treatment of hyperphosphatemia with CC. The combination therapy was better tolerated and showed higher patient compliance than CC or sevelamer monotherapy.

[Expectation for Whole PTH assay in the dialysis field].

In uremic plasma, it was proven that not only 1-84 PTH but a large C fragment PTH (probably 7-84 PTH) existed considerably and Intact PTH assay measured both PTH molecules. Whole PTH was developed to measure 1-84 PTH exclusively. From our study of the iliac bone biopsy, Whole PTH and Whole PTH/7-84PTH ratio were superior indicator to Intact PTH in diagnosis of adynamic bone disease. Although there is possibility of induction of adynamic bone disease in vitamin D treatment, Whole PTH will serve as a useful monitoring method in order to prevent such risk.