[A fundamental proposal to establish an investigative system for medical accidents].

For more than a decade, numerous disputes over medical errors and other safety issues in the healthcare system have occurred and attracted growing interest from society. As a result, through the Model Project for the Investigation of Death Associated with Medical Practice, the Outline Proposal of the Measure to Establish an Investigative Commission on Medical Accidents was proposed by the Japanese Ministry of Health, Labour and Welfare. However, this measure was not finalized. The course of the controversies involved has various implications. The Project Committee of the Japan Medical Association proposed the fundamental viewpoints to establish an exploratory system for medical accidents and to change the stressful medical environment for both physicians and patients based on the principle of the occupational autonomy of physicians.

Vitamin K2 alters bone metabolism markers in hemodialysis patients with a low serum parathyroid hormone level.

BACKGROUND: A low level of intact parathyroid hormone (PTH) is an indicator of adynamic bone disease in hemodialysis patients, and is associated with a significant increase of all-cause mortality. Thus, effective treatment for adynamic bone disease is required. We previously investigated the effect of vitamin K2 on adynamic bone disease. In this study, we assessed the efficacy of oral vitamin K2 in a controlled trial. METHODS: Forty hemodialysis patients with low intact PTH levels (<100 pg/ml) were randomly divided into two groups, which were a vitamin K2 group receiving oral menatetrenone (45 mg/day) for 1 year and a control group without vitamin K2. Venous blood samples were collected at baseline and during the study for measurement of bone metabolism parameters. RESULTS: Thirty-three patients completed follow-up. There was a significant increase of the serum intact osteocalcin level after 1 month of vitamin K2 administration. Serum levels of intact PTH, bone alkaline phosphatase, and cross-linked N-terminal telopeptide of type I collagen increased significantly after 12 months in the vitamin K2 group. The serum osteoprotegerin level was decreased after 12 months in the vitamin K2 group, but the change was not significant. CONCLUSION: Vitamin K2 therapy improves bone remodeling in hemodialysis patients with a low intact PTH level.

Response of secondary hyperparathyroidism to cinacalcet depends on parathyroid size.

BACKGROUND/AIMS: Several reports have indicated that the measurement of parathyroid gland size assists the management of patients with secondary hyperparathyroidism. This study examined whether parathyroid gland enlargement influenced the response of secondary hyperparathyroidism to cinacalcet. METHODS: Clinically stable hemodialysis patients with secondary hyperparathyroidism that was resistant to conventional treatment received cinacalcet for 6 months. Based on the parathyroid gland size measured by ultrasonography, the patients were divided into group S (gland <500 mm(3)) and group L (gland >or=500 mm(3)). Serum levels of intact parathyroid hormone (intact PTH), bone-specific alkaline phosphatase, osteocalcin, and cross-linked N-terminal telopeptide of type 1 collagen were measured over time. RESULTS: Twenty-four patients completed the study. In group S, all markers of bone metabolism and intact PTH were significantly decreased after 3 months of cinacalcet treatment. In contrast, there were no significant changes of these parameters, except for intact PTH, after 3 months in group L. After 6 months of cinacalcet treatment, however, all of the markers of bone metabolism were significantly decreased in both groups. CONCLUSIONS: The response to cinacalcet differed between groups S and L. Thus, the presence of parathyroid enlargement (nodular hyperplasia) may delay the response of secondary hyperparathyroidism to cinacalcet.

Dose conversion ratio one year after switching from epoetin alpha to darbepoetin alpha in Japanese hemodialysis patients.

BACKGROUND/AIMS: Darbepoetin alpha is effective for renal anemia when epoetin is insufficient. We previously reported that the dose conversion ratio from epoetin alpha to darbepoetin alpha was 1:350.5 after 24 weeks of follow-up. This study assessed the conversion ratio in stable Japanese hemodialysis patients after 52 weeks. METHODS: A total of 104 hemodialysis patients who were stable on intravenous epoetin alpha were switched to intravenous darbepoetin alpha according to the 1:200 rule. Then they were followed for 52 weeks to assess changes of hemoglobin and the darbepoetin alpha dose. RESULTS: Eighty-five patients completed the study. Their hemoglobin increased very rapidly during the first 8 weeks. The final conversion ratio was 1:286.6 at 52 weeks. Darbepoetin alpha showed similar efficacy in diabetics and non-diabetics. Patients switching from a high epoetin alpha dose (> or =4500 IU/week) had a higher conversion ratio compared with those switching from a low dose (<4500 IU/week). CONCLUSIONS: The dose conversion ratio of 1:200 was unsuitable and led to a rapid increase of hemoglobin. A conversion ratio of 1:250 to 1:300 should be employed when switching from epoetin alpha to darbepoetin alpha in Japanese patients.

Switching from epoetin alpha to darbepoetin alpha in Japanese hemodialysis patients: dose conversion ratio.

BACKGROUND/AIMS: Darbepoetin alpha is an erythropoietic agent with a 3-fold longer elimination half-life than epoetin. The recommended conversion ratio from epoetin to darbepoetin alpha is 1:200 (1 microg of darbepoetin alpha = 200 IU of epoetin), but several observations have suggested that this ratio overestimates the required dose of darbepoetin alpha. This study assessed the actual conversion ratio for stable Japanese hemodialysis patients and investigated whether darbepoetin alpha promotes uniform erythropoiesis. METHODS: A total of 104 hemodialysis patients who were stable on epoetin alpha therapy at Hakuai Clinic in Japan were switched to intravenous darbepoetin alpha according to the 1:200 rule. They were followed for 24 weeks to assess changes of hemoglobin and the dose of darbepoetin alpha, as well as changes of the reticulocyte count. RESULTS: One hundred patients completed the 24-week study and the final conversion ratio was 1:350.5. Darbepoetin alpha showed a similar effect in diabetics and nondiabetics. Data on the reticulocyte count demonstrated that darbepoetin alpha had a sustained effect on erythropoiesis. CONCLUSION: Darbepoetin alpha is effective for Japanese dialysis patients at a lower dose than expected.

Serum cross-linked N-terminal telopeptide of type I collagen for evaluation of renal osteodystrophy in hemodialysis patients.

BACKGROUND: Useful markers of bone resorption are needed for hemodialysis patients with renal osteodystrophy. This study investigated the use of a new immunoassay for cross-linked N-terminal telopeptide of type 1 collagen to assess bone changes in hemodialysis patients. METHODS: Radial bone mineral density was examined in 178 hemodialysis patients at baseline and after 12 months. Serum levels of N-terminal telopeptide and other markers were measured. RESULTS: The annual percent change of radial bone mineral density was negatively correlated with the levels of N-terminal telopeptide, intact osteocalcin, tartrate-resistant acid phosphatase, bone-specific alkaline phosphatase, and intact parathyroid hormone. The annual percent change of radial bone mineral density showed a stronger correlation with N-terminal telopeptide levels than with the other markers, except for intact parathyroid hormone. Also, intact parathyroid hormone and N-terminal telopeptide levels showed a stronger correlation than that of either tartrate-resistant acid phosphatase or cross-linked carboxyterminal telopeptide of type 1 collagen with intact parathyroid hormone. CONCLUSION: Serum N-terminal telopeptide may be the most useful bone resorption marker in renal osteodystrophy and its use combined with bone formation markers may improve the management of this condition.

Association between ENOS gene polymorphism and cardiovascular events in nondiabetic hemodialysis patients: a prospective study.

BACKGROUND: Synthesis of nitric oxide by endothelial nitric oxide synthase (ENOS) plays a key role in the atherosclerotic process. Several polymorphisms of the gene encoding ENOS are now known and have been investigated with respect to their influence on cardiovascular disease risk in the general population. The authors prospectively investigated whether ENOS gene polymorphisms determined the risk of cardiovascular complications in a cohort of hemodialysis patients. METHODS: A total of 335 nondiabetic hemodialysis patients were genotyped for 3 ENOS polymorphisms (T-786-->C, intron 4, and Glu298Asp polymorphism) and were followed up prospectively for a mean of 44.2 +/- 9.0 months. The end-points of the study were major cardiac, cerebrovascular, or peripheral vascular events. RESULTS: Two ENOS polymorphisms were associated with cardiovascular events: a T to C substitution at position -786 of the promoter and a deletion-insertion in intron 4 (the a allele having 4 repeats of a consensus sequence and the b allele having 5 repeats). A total of 84 subjects were -786C carriers (CC+TC), and 15 (18%) suffered from cardiovascular events compared with only 13 of 251 TT patients (5%). The relative risk of cardiovascular events was higher for -786C carriers compared with noncarriers (relative risk: 2.05, P = 0.0003). It was also higher for a allele carriers (intron 4 polymorphism) compared with noncarriers (relative risk: 1.97, P = 0.0005). CONCLUSION: T-786-->C polymorphism and intron 4 polymorphism, but not Glu298Asp polymorphism, of the ENOS gene can influence the risk of cardiovascular events in Japanese nondiabetic hemodialysis patients.

Association of nodular hyperplasia with resistance to cinacalcet therapy for secondary hyperparathyroidism in hemodialysis patients.

There have been few long-term prospective studies investigating the effect of cinacalcet on secondary hyperparathyroidism with or without nodular hyperplasia. We examined whether the effect of cinacalcet on secondary hyperparathyroidism differed between patients with or without nodular hyperplasia. Stable hemodialysis patients with secondary hyperparathyroidism resistant to conventional treatment received cinacalcet for 12 months. Based on ultrasonography findings, patients were divided into group S (gland < 500 mm(3) without nodular hyperplasia) and group L (gland ≥ 500 mm(3) with nodular hyperplasia). Serum levels of intact parathyroid hormone, bone-specific alkaline phosphatase, osteocalcin, and cross-linked N-terminal telopeptide of type 1 collagen were measured. Thirty-one patients completed the study. The changes of parameters from the baseline did not differ significantly between the two groups after 6 months. However, the percentage reduction of each parameter was significantly smaller in group L compared with group S after 12 months. Nodular hyperplasia is associated with resistance to cinacalcet therapy in patients on chronic dialysis with secondary hyperparathyroidism.

C-C chemokine receptor 2 expression by circulating monocytes influences atherosclerosis in patients on chronic hemodialysis.

Mortality from cardiovascular or cerebrovascular disease due to atherosclerosis is increased in patients on chronic hemodialysis. Monocyte chemoattractant protein-1 and its receptor, C-C chemokine receptor 2, play an important role in recruiting monocytes to atherosclerotic lesions. The relationship between atherosclerosis in hemodialysis patients and C-C chemokine receptor 2 expression is unknown. Fifty-six patients on chronic hemodialysis and 27 age- and sex-matched controls were enrolled. Serum levels of monocyte chemoattractant protein-1 and expression of C-C chemokine receptor 2 by circulating monocytes were determined. Atherosclerosis was evaluated from the carotid intima-media thickness and cardio-ankle vascular index. Serum levels of monocyte chemoattractant protein-1 and expression of C-C chemokine receptor 2 by monocytes were significantly higher in the hemodialysis patients than the controls. Multiple regression analysis showed a positive correlation between receptor expression and both indexes of atherosclerosis. C-C chemokine receptor 2 expression by circulating monocytes influences atherosclerosis in patients on chronic hemodialysis.

Performance of polysulfone membrane dialyzers and dialysate flow pattern.

BACKGROUND: It is important to observe the flow pattern of dialysate when evaluating dialyzer function and developing the most appropriate design. We investigated dialysate flow through two polysulfone membrane dialyzers (TS-UL [Toray Medical] and APS-S [Asahi Medical]) by computed tomography (CT), with barium sulfate as the contrast medium. We also performed a clinical comparison of these two dialyzers. METHODS: For the in vitro experiment, after confirming the steady-state flow of mock blood (xanthan gum solution; 200 ml/min) and dialysate (500 ml/min), fresh dialysate, containing 5% (w/v) barium sulfate was perfused, and longitudinal CT scans of the dialyzer were obtained. Then the concentration of barium sulfate was measured (in Hounsfield units) in three fixed regions of interest. For the in vivo experiment, 12 patients on stable hemodialysis who had been using the APS-S for more than 1 month were switched to the TS-UL for 1 month and changes in various parameters were assessed. RESULTS: The distribution of dialysate was homogeneous on CT scans of the TS-UL, but not on scans of the APS-S. The dialysate concentration curves for the three regions of interest were similar with the TS-UL, but not with the APS-S. Clearance of urea nitrogen and albumin loss were both significantly higher with the TS-UL than with the APS-S. The decrease in alpha 1-microglobulin was larger with the TS-UL than with the APS-S, but not significantly. CONCLUSIONS: Clearance of substances over a wide range of molecular weights was higher with the TS-UL than with the APS-S, and differences in the design of the dialysate compartment may have been involved in this feature.