Low health-related quality of life is associated with all-cause mortality in patients with diabetes on haemodialysis: the Japan Dialysis Outcomes and Practice Pattern Study.

AIMS: Whether health-related quality of life (HRQoL) can be accurately predicted in patients with extremely low HRQoL as a result of diabetic complications is unclear. We investigated the impact of HRQoL on mortality risk in patients with diabetes on haemodialysis. METHODS: Data from the Dialysis Outcomes Practice Pattern Study (DOPPS) were analysed for randomly selected patients receiving haemodialysis in Japan. Information regarding the diagnosis of diabetes and clinical events during follow-up was abstracted from the medical records at baseline and HRQoL was assessed by a self-reported short form (SF)-36 questionnaire. The association between physical component score and mental component score in the SF-36 and mortality risk was analysed using a Cox proportional hazard model. RESULTS: Data from 527 patients with diabetes on haemodialysis were analysed. The mortality age-adjusted hazard ratio of having a physical component score greater than or equal to the median was 0.27 [95% confidence interval (CI) 0.08-0.96] and the multivariable-adjusted mortality hazard ratio of having an mental component score greater than or equal to the median was 1.21 (95% CI 0.44-3.35). CONCLUSIONS: The physical component score derived from the SF-36 is an independent risk factor for mortality in patients with diabetes on haemodialysis who generally had very low HRQoL scores. Baseline mental component score was not predictive of mortality. Patient self-reporting regarding the physical component of health status may aid in risk stratification and clinical decision making for patients with diabetes on haemodialysis.

Depressive symptoms predict the future risk of severe pruritus in haemodialysis patients: Japan Dialysis Outcomes and Practice Patterns Study.

BACKGROUND: Recent reports suggest a cross-sectional association between psychiatric distress and pruritus in patients on haemodialysis (HD). However, no study has examined the likelihood of developing severe pruritus in patients on HD with depressive symptoms. OBJECTIVES: To evaluate the relationship between baseline depressive symptoms and subsequent risk of developing severe pruritus. METHODS: A longitudinal study with a 0.5-2.5-year follow-up period was performed using 1799 patients on HD who had no/mild pruritus at baseline, based on the Japan Dialysis Outcomes and Practice Patterns Study (1996-2004), a cohort study composed of a representative sample of patients on HD. We assessed pruritus after the follow-up period using a self-reported questionnaire and depressive symptoms using scores from the five-item version of the Mental Health Inventory (MHI-5). RESULTS: The 1799 patients had a mean age of 56.9 years, 59.5% were men, and 23.6% presented depressive symptoms. Multivariable analysis revealed that patients with depressive symptoms had significantly higher odds of developing severe pruritus during the 0.5-2.5-year follow-up period [adjusted odds ratio (AOR) 1.57, 95% confidence interval 1.22-2.01, P < 0.001]. In addition, a significant linear trend was observed between baseline MHI-5 scores and risk of developing severe pruritus, with AORs for third, second and first MHI-5 score quartiles of 1.08, 1.51 and 1.95, respectively (P for trend < 0.0001). CONCLUSIONS: Our results suggest that depressive symptoms measured by MHI-5 may predict the future risk of developing severe pruritus in patients on HD.

Diabetes, glycaemic control and mortality risk in patients on haemodialysis: the Japan Dialysis Outcomes and Practice Pattern Study.

AIMS/HYPOTHESIS: There are few data on the target level of glycaemic control among patients with diabetes on haemodialysis. We investigated the impact of glycaemic control on mortality risk among diabetic patients on haemodialysis. SUBJECTS AND METHODS: Data were analysed from the Dialysis Outcomes Practice Pattern Study (DOPPS) for randomly selected patients on haemodialysis in Japan. The diagnosis of diabetes at baseline and information on clinical events during follow-up were abstracted from the medical records. A Cox proportional hazards model was used to evaluate the association between presence or absence of diabetes, glycaemic control (HbA(1c) quintiles) and mortality risk. RESULTS: Data from 1,569 patients with and 3,342 patients without diabetes on haemodialysis were analysed. Among patients on haemodialysis, those with diabetes had a higher mortality risk than those without (multivariable hazard ratio 1.37, 95% CI 1.08-1.74). Compared with those in the bottom quintile of HbA(1c) level, the multivariable-adjusted hazard ratio for mortality was not increased in the bottom second to fourth quintiles of HbA(1c) (HbA(1c) 5.0-5.5% to 6.2-7.2%), but was significantly increased to 2.36 (95% CI 1.02-5.47) in the fifth quintile (HbA(1c) > or = 7.3%). The effect of poor glycaemic control did not statistically correlate with baseline mortality risk (p = 0.27). CONCLUSIONS/INTERPRETATION: Among dialysis patients, poorer glycaemic control in those with diabetes was associated with higher mortality risk. This suggests a strong effect of poor glycaemic control above an HbA(1c) level of about 7.3% on mortality risk, and that this effect does not appear to be influenced by baseline comorbidity status.

Symptoms of depression, prescription of benzodiazepines, and the risk of death in hemodialysis patients in Japan.

Many hemodialysis patients in Japan have symptoms of depression, but whether those patients are treated appropriately is unknown. As part of the Dialysis Outcomes and Practice Patterns Study, data on symptoms of depression, physician-diagnosed depression, prescribed medications, and death were collected prospectively in cohorts in Japan (n=1603) and 11 other countries (n=5872). Symptoms of depression were as prevalent in Japan as elsewhere, but in Japan a much smaller percentage of patients had physician-diagnosed depression: only 2% in Japan vs 17% elsewhere. Antidepressants were much less commonly prescribed in Japan: only 1% in Japan vs 17% elsewhere for patients with many and frequent symptoms of depression, and 16% in Japan vs 34% elsewhere for patients with physician-diagnosed depression. In Japan, symptoms of depression were associated with prescription of benzodiazepines (without antidepressants), and patients with physician-diagnosed depression were twice as likely to be given benzodiazepines: 32% in Japan vs 16% elsewhere. Benzodiazepine monotherapy was associated with death (relative risk 1.56, 95% confidence interval (CI), 1.25-1.94), even after adjustments for 13 likely confounders (relative risk 1.27, 95% CI, 1.01-1.59). Hemodialysis patients in Japan with symptoms of depression are given not antidepressants but benzodiazepines, a practice associated with higher mortality.

Incidence and risk factors for hip or other bone fractures among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study.

The available data on bone fractures in hemodialysis (HD) patients are limited to results of a few studies of subgroups of patients in the United States. This study describes the prevalence of hip fractures and the incidence and risk factors associated with hip and other fractures in representative groups of HD facilities (n=320) and patients (n=12 782) from the 12 countries in the second phase of the Dialysis Outcomes and Practice Patterns Study (2002-2004). Among prevalent patients, 2.6% had a prior hip fracture. The incidence of fractures was 8.9 per 1000 patient years for new hip fractures and 25.6 per 1000 for any new fracture. Older age (relative risk (RR)(HIP)=1.91, RR(ANY)=1.33, P<0.0001), female sex (RR(HIP)=1.41, P=0.02; RR(ANY)=1.59, P<0.0001), prior kidney transplant (RR(HIP)=2.35, P=0.04; RR(ANY)=1.76, P=0.007), and low serum albumin (RR(HIP)=1.85, RR(ANY)=1.45, per 1 g/dl lower, P<0.0001) were predictive of new fractures. Elevated risk of new hip fracture was observed for selective serotonin reuptake inhibitors and combination narcotic medications (RR=1.63, RR=1.74, respectively, P<0.05). Several medications were associated with risk of any new fracture: narcotic pain medications (RR=1.67, P=0.02), benzodiazepines (RR=1.31, P=0.03), adrenal cortical steroids (RR=1.40, P<0.05), and combination narcotic medications (RR=1.72, P=0.001). Parathyroid hormone (PTH) levels >900 pg/ml were associated with an elevated risk of any new fracture (RR=1.72, P<0.05) versus PTH 150-300. The results suggest that greater selectivity in prescribing several classes of psychoactive drugs and more efficient treatment of secondary hyperparathyroidism may help reduce the burden of fractures in HD patients.

Direct injection of calcitriol or its analog into hyperplastic parathyroid glands induces apoptosis of parathyroid cells.

Hyperplasia of the parathyroid gland (PTG) is associated not only with excessive secretion of parathyroid hormone (PTH) but also with changes in the parathyroid cell (PTC) characteristics (i.e. hyperproliferative activity, and low contents of vitamin D and calcium-sensing receptors). Control of PTG hyperplasia is most important in the management of secondary hyperparathyroidism, but the advanced stage of hyperplasia is considered irreversible. In the present study, dialysis patients with PTG hyperplasia underwent direct injection of calcitriol or maxacalcitol (OCT) into the PTG. Ultrasonography showed that this treatment had significantly reduced PTG volume and tissue analysis using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) method and DNA electrophoresis indicated that cellular apoptosis had been induced. The mechanism of apoptosis was evaluated in detail in uremic rats fed a high-phosphate diet. OCT or its vehicle was directly injected into the rats' PTGs. In the PTGs treated by OCT, there was a significantly increased number of TUNEL-positive PTCs and DNA electrophoresis revealed the characteristic ladder pattern of DNA fragmentation, both findings indicative of apoptosis. There was also a significant upregulation of both vitamin D and Ca-sensing receptors in the PTCs and a clear shift of the Ca-PTH response curve to the left and downward. None of these findings was observed in the PTGs treated by vehicle. This novel treatment is successful in causing regression of PTG hyperplasia. Thus, it is expected to significantly reduce the PTH level and ameliorate the abnormal bone turnover and mineral metabolism.

Direct maxacalcitol injection into hyperplastic parathyroids improves skeletal changes in secondary hyperparathyroidism.

Direct maxacalcitol (OCT) injection into a parathyroid gland (PTG) ameliorates several important etiologic factors of resistance to medical treatments for secondary hyperparathyroidism (s-HPT): the upregulations of vitamin D receptor (VDR) and Ca-sensing receptor (CaSR) in PTGs and the regression of PTG hyperplasia by the induction of apoptosis. In this study, we evaluated the bone histomorphology on the basis of maintaining these effects in advanced s-HPT. Five/six nephrectomized Sprague-Dawley rats were fed a high-phosphorus and low-calcium diet for 8 weeks. These rats were divided into four treatment groups: (1) basic uremic (at the baseline), (2) direct OCT single injection into PTGs (DI-OCT) followed by OCT intravenous administration for 4 weeks (IV-OCT), (3) direct vehicle injection and IV-OCT, and (4) no treatment for an additional 4 weeks. The effects of these treatments on serum intact-parathyroid hormone (PTH) level, PTG weight, VDR and CaSR expression levels in PTGs, and bone histomorphometric parameters were investigated. In the DI-OCT+IV-OCT group, the significant decrease in serum intact-PTH level was maintained by the following IV-OCT. A significant decrease in PTG weight and the upregulations of VDR and CaSR expression levels in PTGs were also observed. Bone histomorphometric analysis showed significant improvements in osteitis fibrosa in both cancellous and cortical bones. However, these findings were not observed in the other groups. These results suggest that osteitis fibrosa caused by advanced s-HPT can be successfully reversed by a control of PTH at an appropriate level through the improvement of PTG hyperplasia as induced by DI-OCT+IV-OCT.

Clinical effect of intravenous calcitriol administration on secondary hyperparathyroidism. A double-blind study among 4 doses.

BACKGROUND/AIMS: Although the PTH-suppressive effect of intravenous calcitriol has already been demonstrated by various studies, the precise dose-response to calcitriol has not been fully determined for uremic secondary hyperparathyroidism (2HPT). In order to investigate in detail the dose-response of intravenous calcitriol and the adequate initial dose against 2HPT, a randomized prospective double-blind study was conducted. METHOD: One-hundred and sixty-two patients with 2HPT undergoing hemodialysis three times per week were randomly assigned to four calcitriol (Ro21-5535) treatment groups, 0 (placebo), 1, 1.5 or 2 microg. Calcitriol or placebo was given intravenously after each dialysis for 12 weeks under double-blind conditions. RESULTS: Calcitriol dose-dependently reduced both intact-PTH and high-sensitivity assay mid-terminal (HS)-PTH levels. The rate of per-week change in intact-PTH was 0.0% in the placebo group, -7.8% in the 1-microg group, -18.9% in the 1.5-microg group and -24.1% in the 2-microg group. Calcitriol dose-dependently increased the rate of increase in serum Ca adjusted by albumin level. The per-week increases in adjusted serum Ca were -0.01, 0.08, 0.23 and 0.35 mg/dl in the placebo, 1-, 1.5- and 2-microg groups, respectively. Although the degree of PTH suppression was correlated with the adjusted serum Ca increase, by-patients investigation revealed that the number of patients with suppression of PTH despite of no or slight elevation of adjusted serum Ca level was largest in the 1-microg group among the three calcitriol groups. CONCLUSION: Intravenous calcitriol was found to have a clear dose-dependent effect on PTH reduction in patients with 2HPT, and the appropriate initial dose of this agent was determined to be 1 microg per dialysis session.

Clinical effects of maxacalcitol on secondary hyperparathyroidism of uremic patients.

Maxacalcitol (22-oxacalcitriol [OCT]) is a newly developed vitamin D analogue in Japan. OCT has shown less calcemic action and a strong suppressive effect on parathyroid hormone (PTH) in uremic rats and dogs. In uremic patients with secondary hyperparathyroidism, OCT dose-dependently suppressed PTH secretion and increased serum calcium levels. However, more than 60% of patients achieved a greater than 30% decrease in intact PTH level from baseline with long-term OCT treatment up to 1 year without an unphysiological increase in mean serum calcium levels. Long-term treatment also brought about a reduction in bone metabolic markers, including bone alkaline phosphatase, tartrate-resistant acid phosphatase, and bone gra-protein. These results suggest that although careful attention should be paid to the onset of hypercalcemia and oversuppression of PTH, OCT is one of the effective tools for the treatment of secondary hyperparathyroidism.

A case of thrombotic thrombocytopenic purpura refractory to plasma exchange.

We experienced a case of thrombotic thrombocytopenic purpura (TTP) finally relieved after 74 sessions of plasma exchange (PE). The patient was a 56-year-old male. In August 1999, he was examined in emergency because of brown urine and a lowered level of consciousness. As TTP was suspected according to the laboratory findings of abnormally high lactate dehydrogenase and total bilirubin, decreased platelet counts, and numerous fragmented erythrocytes, he was admitted to the ICU of our hospital. Immediately after admission, PE was started consecutively. Upon concomitant use of antiplatelet drugs and prostacyclin, the level of platelet counts recovered to 100,000/microl once, but decreased again. Thus, in addition to the PE, prednisolone and vincristine were administrated, which elevated the level of platelet counts to 200,000 to 300,000/microl. Since the erythrocyte fragmentation was noted frequently, PE was continued twice a week. From the 60th day of admission onward, however, his body temperature rose above 40 degrees C with a rapid increase of C-reactive protein. A blood culture detected methicillin-resistant Staphylococcus aureus (MRSA) which derived from a left lung abscess. During the course of anti-MRSA treatment, he presented acute renal failure and acute hepatic dysfunction, but survived because of the combined therapy. He was discharged on the 180th day of admission. These results suggest that a combined therapy of steroid and vincristine is effective to treat TTP refractory to PE, but careful attention should be paid to the complications caused by immunosuppression.

A new method for removal of albumin-binding uremic toxins: efficacy of an albumin-dialysate.

It is difficult for conventional hemodialysis to remove albumin-binding uremic toxins (ABUTs) even though they are low molecular weight substances. We investigated the efficiency of albumin-dialysate (AD) for removal of ABUT. Phenols and indoxyl sulfate were selected as ABUT. In vitro dialysis was performed for 2 h in the closed circuit with ABUT containing plasma as a test solution using conventional dialysate (CD) or AD. By the use of CD, the ABUT concentration in the test solution only was reduced by 20 to 30%. On the other hand, AD caused a marked reduction and an increase in test solution and dialysate concentration of ABUT, respectively. ABUT in AD could be adsorbed effectively by activated-charcoal column; accordingly, the ABUT concentration in the test solution continued to decrease throughout the study period. These results suggest that AD could remove ABUT more efficiently than CD, and AD may be useful for reducing accumulated ABUT levels.

Determination of bufalin-like immunoreactivity in serum of humans and rats by time-resolved fluoroimmunoassay for using a monoclonal antibody.

The existence of a mammalian natriuretic substance or endogenous digitalis-like factor, which inhibits Na+,K+-ATPase and thereby regulates body fluid volume, has been speculated for a long time but has yet to be defined. We established in the present study a simple and highly sensitive procedure to measure bufalin, a constituent of toad venom preparation and a specific inhibitor of Na+,K+-ATPase by time-resolved fluoroimmunoassay (TR-FIA) and using a monoclonal antibody. The antibody was specific to bufalin and resembled bufadienolides but showed no cross-reactivity with digitoxin and ouabain. A bufalin-like immunoreactivity was detectable in serum of humans and rats by the proposed TR-FIA. The levels of bufalin-like immunoreactivity in serum of healthy volunteers were significantly correlated with their systolic blood pressure. Moreover, bufalin-like immunoreactivity in serum of Dahl-S rats increased in parallel with a period of high-salt diet. These results suggest that increased bufalin-like immunoreactivity may be associated with certain types of hypertension.

Double filtration plasmapheresis for the treatment of bullous pemphigoid: a three case report.

Bullous pemphigoid (BP) is an autoimmune disease caused by an antidermal basal lamina antibody. In recent years double filtration plasmapheresis (DFPP) has been reported to be an effective therapy for BP. We experienced 3 cases of BP treated by DFPP. DFPP resulted in an improvement in clinical symptoms and remission allowing a decrease in the required dose of corticosteroid. DFPP was found to be an effective treatment for all 3 patients without noticeable adverse events resulting from DFPP. From these results it is concluded that DFPP is worth considering as an option as treatment for BP patients who were unresponsive to conventional steroid therapy, those in whom corticosteroids should be reduced or discontinued because of complications such as diabetes mellitus and/or osteoporosis.

Plasma exchange for the treatment of human T-cell lymphotropic virus type 1 associated myelopathy.

A 55-year-old man was admitted to our hospital because of myelopathy. He had a history of chronic renal failure due to polycystic kidney disease at the age of 39, being treated by hemodialysis for 9 years with several blood transfusions for the treatment of renal anemia. After cadaver renal transplantation at the age of 48, he discontinued hemodialysis. At 50 years of age, he had pulmonary tuberculosis and tuberculous arthritis of the left elbow joint. He has experienced difficulty in walking since he was 48 years old, with mild dysuria. Gait disturbance gradually aggravated after that, and urinary retention was observed. When he was 55 years old, being human T-cell lymphotropic virus type-1 (HTLV-1)-positive in the serum and cerebrospinal fluid, he was diagnosed as having HTLV-1-associated myelopathy (HAM). As active steroid therapy was unapplicable because of the history of pulmonary tuberculosis and immunosuppression for transplanted kidney, a series of plasma exchanges (PE) was performed with fresh frozen plasma as a replacement fluid. After PE, dyskinesia of the left leg and dysuria subjectively and objectively improved. These results suggest that PE seems to be one of the therapeutic tools for the treatment of HAM.

[Effect of concomitant therapy on adynamic bone disease].

PTH deficiency and/or skeletal resistance to PTH in uremia has been regarded the major cause of adynamic bone. Considering the pathogenesis, correction of hypercalcemia is the first management to increase PTH secretion. For that purpose administrating regimen of calcium-containing phosphate binder and active vitamin D sterols should be changed to prevent hypercalcemia. And it is also important to determine an adequate calcium concentration of dialysate for the stimulation of PTH secretion.

[Hyperphosphatemia and hypoparathyroidism].

There are great differences in causes and treatments of hypoparathyroidism between patients with normal renal function and those with impaired renal function (dialysis patient). In patients with normal renal function, hypocalcemia and hyperphosphatemia develop because of the decrease in PTH synthesis or PTH function, and major target for treatment is hypocalcemia. In dialysis patients, hyperphosphatemia inevitably develops by the decrease in urinary excretion of phosphate and about three to six times greater concentration of PTH is required to maintain the normal bone metabolism. Hyperphosphatemia should be strictly treated, but it remains still unsure what is the real pathogenesis of hypoparathyroidism, and whether hypoparathyroidism should be treated or not in dialysis patient.