Transfusion-dependent anaemia treatment using continuous erythropoietin receptor activator (epoetin ß pegol) and roxadustat after darbepoetin treatment failure in low-risk myelodysplastic syndrome: a case report.

Treatment of anaemia and reduction of transfusion are major therapeutic goals in patients with low-risk myelodysplastic syndrome (MDS). Although erythropoiesis-stimulating agents (ESAs) are widely used to reduce transfusion requirement, ESAs lose effectiveness within 12 months. We report a 65-year-old Japanese woman diagnosed with low-risk MDS who underwent long-term use of continuous epoetin ß pegol, an erythropoietin receptor activator (CERA), and her treatment after CERA failure. She received darbepoetin alpha (DPO) for transfusion-dependent anaemia and was free from transfusion. However, after 8 months, DPO lost effectiveness. She then received CERA and recovered from anaemia. Her haemoglobin level remained >10 g/dl for 3 years and 4 months. However, even CERA lost effectiveness, and she received roxadustat treatment with CERA, leading to recovery from anaemia again. Although further evidence is required, the extension of the no-transfusion period provided by ESAs and roxadustat is important and is awaited among low-risk MDS patients.

Investigation of small intestinal lesions in dialysis patients using capsule endoscopy.

INTRODUCTION: Although gastrointestinal hemorrhage is an important complication for dialysis patients, the details of many points remain unclear with regard to small intestinal lesions. METHODS: Capsule endoscopy was performed in fecal occult blood-positive dialysis (n =16) and non-dialysis (n = 20) patients after upper and lower gastrointestinal endoscopies failed to reveal hemorrhagic lesions. FINDINGS: Erosive lesions were observed in 50.0% (8/16) and 25.0% (5/20) of the dialysis and non-dialysis groups, respectively. Vascular lesions were observed in 62.5% (10/16) and 25.0% (5/20), respectively. Vascular lesions were observed at a significantly higher rate in the dialysis patients (P = 0.041), but no significant difference was noted in erosive lesions (P = 0.188). Of patients taking proton pump inhibitor (PPI), Non-Steroidal Anti-Inflammatory Drugs, and antiplatelet drugs, only oral PPI administration was associated with vascular lesions (P = 0.02). DISCUSSION: In dialysis patients, vascular lesions are the most common among small intestinal lesions, suggesting that they may have caused previously unexplained gastrointestinal hemorrhage in dialysis patients. It was also suggested that the frequent use of PPI may be a cause of small intestinal lesions.

Cost-Effectiveness Analysis of Percutaneous Vertebroplasty for Osteoporotic Compression Fractures.

STUDY DESIGN: Single-center, single-arm, prospective time-series study. OBJECTIVE: To assess the cost-effectiveness and improvement in quality of life (QOL) of percutaneous vertebroplasty (PVP). SUMMARY OF BACKGROUND DATA: PVP is known to relieve back pain and increase QOL for osteoporotic compression fractures. However, the economic value of PVP has never been evaluated in Japan where universal health care system is adopted. METHODS: We prospectively followed up 163 patients with acute vertebral osteoporotic compression fractures, 44 males aged 76.4±6.0 years and 119 females aged 76.8±7.1 years, who underwent PVP. To measure health-related QOL and pain during 52 weeks observation, we used the European Quality of Life-5 Dimensions (EQ-5D), the Rolland-Morris Disability Questionnaire (RMD), the 8-item Short-Form health survey (SF-8), and visual analogue scale (VAS). Quality-adjusted life years (QALY) were calculated using the change of health utility of EQ-5D. The direct medical cost was calculated by accounting system of the hospital and Japanese health insurance system. Cost-effectiveness was analyzed using incremental cost-effectiveness ratio (ICER): Δ medical cost/Δ QALY. RESULTS: After PVP, improvement in EQ-5D, RMD, SF-8, and VAS scores were observed. The gain of QALY until 52 weeks was 0.162. The estimated lifetime gain of QALY reached 1.421. The direct medical cost for PVP was ¥286,740 (about 3061 US dollars). Cost-effectiveness analysis using ICER showed that lifetime medical cost for a gain of 1 QALY was ¥201,748 (about 2154 US dollars). Correlations between changes in EQ-5D scores and other parameters such as RMD, SF-8, and VAS were observed during most of the study period, which might support the reliability and applicability to measure health utilities by EQ-5D for osteoporotic compression fractures in Japan as well. CONCLUSIONS: PVP may improve QOL and ameliorate pain for acute osteoporotic compression fractures and be cost-effective in Japan.

Effects of nocturnal oxygen therapy on heart function in SDB patients undergoing dialysis.

There is a close relationship between sleep disordered breathing (SDB) and heart failure. We performed home oxygen therapy (HOT) in patients with SAS undergoing dialysis, and investigated its effects on the heart function. The subjects were 10 SDB patients on dialysis. On retiring at night, oxygen was transnasally administered at 1.0 L/min. The human atrial natriuretic peptide (hANP), brain natriuretic peptide (BNP), total protein, Alb, cholesterol and phosphorus levels were measured before the start of oxygen therapy and after 6 weeks. The mean SpO2 increased from 93.5% [91.5, 97.0] to 96.3% [94.8, 97.4] (median [interquartile range]) (p = 0.015). The hANP (p = 0.0039), BNP (p = 0.0098) and serum Alb (p = 0.015) levels significantly improved. There were no significant changes in the cholesterol, phosphorus or total protein levels. These results suggest that nocturnal oxygen therapy improves indices of heart failure, contributing to the prevention and treatment of heart failure in dialysis patients with SDB.

Visceral fat level is an independent risk factor for cardiovascular mortality in hemodialysis patients.

BACKGROUND: Obesity is an independent risk factor for morbidity and mortality in cardiovascular diseases not only in the general population, but also in hemodialysis (HD) patients. We previously reported that an increased visceral fat area (VFA) determined using computed tomography (CT) scans was associated with atherosclerosis in HD patients. However, whether a high VFA is associated with increased cardiovascular mortality in HD patients remains unknown. Therefore, we investigated the relationship between VFA and prognosis in HD patients. METHODS: VFA was estimated in 126 patients on maintenance HD using CT scans. These patients were followed for 60 months. RESULTS: Kaplan-Meier analysis revealed that the cardiovascular survival rate was significantly lower in the high-VFA group, with a VFA of 71.5 cm(2) or greater, than in the low-VFA group, with a VFA of less than 71.5cm(2). In univariate Cox proportional hazards analyses, age, albumin, low-density lipoprotein cholesterol, cardio-thoracic ratio and VFA above 71.5 cm(2) were significantly correlated with cardiovascular deaths. In multivariate analyses testing these factors as dependent variables, VFA above 71.5 cm(2) was estimated to be an independent predictor of cardiovascular deaths. CONCLUSION: These results suggest that an increased VFA is a stronger risk factor for cardiovascular deaths in HD patients. Measuring VFA may be recommended for predicting the risk of cardiovascular diseases in HD patients.

Increment of cerebral blood flow by LDL-apheresis in dialysis patients with arteriosclerosis obliterans: a pilot study.

OBJECTIVE: The prevalence of thrombotic cerebral infarction is higher in dialysis than in general patients. Changes in cerebral blood flow (CBF) during low-density lipoprotein cholesterol-apheresis (LDL-A) in dialysis patients with arteriosclerosis obliterans (ASO) were evaluated employing xenon-CT (Xe-CT) to investigate the possibility of CBF improvement. SUBJECTS AND METHODS: Xe-CT was performed before LDL-A in 4 dialysis patients with ASO (3 males and 1 female). LDL-A was then performed once a week 10 times. After the completion of LDL-A treatment, Xe-CT was performed again to observe changes in CBF. RESULTS: Before treatment, CBF in the 4 patients was lower than that in the general population in the same age group. After LDL-A treatment, CBF was improved. The improvement was observed in the cerebral cortex rather than the basal ganglia. The grade of improvement and improved cerebral region varied among the patients. CONCLUSION: It was suggested that LDL-A may improve not only lower limb blood flow but also CBF. However, further investigation is necessary with regard to the influence of CBF improvement on the brain function and clinical application. The reported results need to be confirmed in larger studies.

Towards developing new strategies to reduce the adverse side-effects of nonsteroidal anti-inflammatory drugs.

The antipyretic and analgesic actions of nonsteroidal anti-inflammatory drugs (NSAIDs) are caused by the inhibition of prostaglandin E(2) (PGE(2)), thromboxane A(2) and prostacyclin (PGI(2)) production. Accumulating evidence suggests that the inhibition of PGE(2) production can cause adverse side-effects of NSAIDs on fluid and blood pressure regulation, such as hypertension and edema formation. Since both cyclooxygenase (COX)-1 and COX-2 isoforms contribute to the production of PGE(2), selective COX-2 inhibitors are not free of these adverse side-effects although they may be less severe. Four subtypes of PGE(2) receptors have been identified. The antipyretic action of blunted PGE(2) production is mediated predominantly by a reduced input to the prostaglandin E receptor 3 (EP(3)) pathway, whereas the analgesic action is mediated predominantly by a reduced input to the EP(1) pathway and perhaps by contributions from the other EP receptors. Accordingly, some of the adverse side-effects might be moderated by combined use of NSAIDs with selective EP(2) or EP(4) agonists that do not block the antipyretic or analgesic actions of NSAIDs that are mediated by reduced activation of EP(1) or EP(3) receptors. Moreover, EP(2) receptor-deficient mice had salt-sensitive hypertension and EP(4) receptor blockade moderated salt and water excretion and both EP(2) and EP(4) agonists had renoprotective effects. This suggests that strategies to maintain activation of EP(2) and EP(4) receptors during NSAID administration may not only reduce adverse effects but might confer additional benefits. In conclusion, enhancing EP(2) and EP(4) receptor activity by administration of selective agonists during the administration of NSAIDs has the potential to permit treating fever, inflammation and pain but with marginal adverse effects on fluid or blood pressure regulation.

Urinary type IV collagen in nondiabetic kidney disease.

BACKGROUND: Type IV collagen is one of the major components of basement membrane. In diabetic nephropathy, it is already known that urinary excretion of type IV collagen increases with the disease progression. However, in nondiabetic kidney disease, urinary type IV collagen (u-IVc) levels have not been extensively investigated. The aim of this study was to evaluate u-IVc levels in various nephropathies except diabetic nephropathy. METHODS: u-IVc levels were measured cross-sectionally from 527 biopsy-proven nondiabetic renal disease patients at tertiary care hospitals by one-step sandwich enzyme immunoassay. RESULTS: On simple regression analyses, u-IVc levels had positive correlation with age, blood pressure, urinary protein (u-Prot), urinary ß(2) microglobulin, urinary N-acetyl-ß-D-glucosaminidase, HbA(1)c, and selectivity index (SI), while u-IVc had negative correlation with eGFR and serum albumin. Multiple regression analyses revealed that u-IVc was positively correlated with u-Prot, HbA(1)c and SI. Among biopsy-proven nondiabetic nephropathies, elevation of u-IVc was distinctively observed in membranous nephropathy and anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. CONCLUSION: u-IVc levels were elevated with the increase in u-Prot, HbA(1)c and SI. In addition, among nondiabetic kidney disease, elevation of u-IVc was observed in patients with membranous nephropathy and ANCA, which might reflect the thickening of basement membrane or severe kidney damage.

Microarray analysis of tonsils in immunoglobulin A nephropathy patients.

BACKGROUND: Recently, combination of tonsillectomy and steroid pulse therapy was reported to be effective as the treatment of the immunoglobulin A nephropathy (IgAN). However, the gene expression difference between the tonsils in patients with IgAN and those in control patients is not established. METHODS: We performed tonsillectomy combined with steroid pulse as a treatment to IgAN, analyzed the gene expression in the tonsils (N=23) using microarray, compared with those with patients suffering from chronic tonsillitis (N=22). From some candidate genes related with IgAN, we confirmed the apolipoprotein B messenger RNA-editing enzyme catalytic polypeptides 2 (APOBEC2) gene expression in the tonsil and we also analyzed its expression levels and clinical features. RESULTS: Up-regulated genes seem to be categorized into two groups. One group belongs to the muscle related genes which might be caused by structural differences. The other group includes the immune system-related genes, such as APOBEC2, CALB2, DUSP27, and CXCL11. APOBEC2 was positively stained in the epithelium and the peripheral region of the germinal center in both tonsils. APOBEC2 expression level was negatively related with serum igg level, but did not correlate with clinical course after tonsillectomy. CONCLUSION: We confirmed gene expression differences related with immune system and muscle structure. The APOBEC2 was confirmed to be elevated in the tonsils with IgAN patients, and the gene expression level was negatively related with serum igg level in overall patients. These results might be helpful to reveal the mechanism of IgAN.

Specialist care and improved long-term survival of dialysis patients.

BACKGROUND: The quality of dialysis care provided by specialists is expected to be superior to that by nonspecialists. However, little is known about the actual effect of specialist care on long-term prognosis in dialysis patients. We sought to determine whether specialist care can actually be associated with better survival rates in a nationwide Japanese dialysis cohort. METHODS: The Japanese Society for Dialysis Therapy (JSDT) has annually reported clinical and demographic variables of dialysis patients for each prefecture in Japan since 1983. We analysed the data for the 47 prefectures from 1983 to 2006 to evaluate the relationship between the proportion of specialists and the cumulative survival rates for 5-year periods. RESULTS: Trend analyses revealed that a higher quintile of specialists was associated with a better cumulative survival rate at 5-, 10-, 15- and 20-year periods. Univariate analyses for the 47 prefectures showed a higher proportion of specialists to be correlated with a better cumulative survival at 10-, 15- and 20-year periods. Multivariate analyses revealed that the proportion of specialists persisted as an independent contributor for better survival at 10-, 15- and 20-year periods even after adjustment for age, sex, diabetes mellitus and socioeconomical status, while the survival rate at 5 years was at a nonsignificant level. CONCLUSIONS: While our study should be confirmed using data for individuals, this was not possible due to privacy issues. Therefore, based on our current findings, we conclude that for patients on maintenance dialysis, specialist care can be associated with better survival rates, particularly with longer follow-up.

Early plasma exchange for progressive liver failure in recipients of adult-to-adult living-related liver transplants.

BACKGROUND/AIMS: Little information is available concerning the effectiveness of plasma exchange for progressive liver failure in liver transplant recipients. The aims of the present study were to evaluate the effectiveness of plasma exchange and discuss its indication. METHODS: Forty-six ABO-compatible recipients of living-related liver transplants operated on in Osaka University hospital were retrospectively studied. RESULTS: Total bilirubin was identified as the most accurate predictor of the short-term prognosis of 46 recipients (optimal cut-off point: 13.3 mg/dl). Eleven patients received 14 plasma exchange sessions. Elevation of total bilirubin was significantly suppressed after plasma exchange in the patients with total bilirubin below the median (24 mg/dl), whereas total bilirubin significantly increased even after plasma exchange in those with total bilirubin above the median. CONCLUSION: Plasma exchange improved liver function in recipients with progressive liver failure and appears to be indicated in patients with total bilirubin levels ranging between 13 and 24 mg/dl.

Severe adverse effects of 5-fluorouracil in S-1 were lessened by haemodialysis due to elimination of the drug.

S-1 and cisplatin are used as one of the first-line chemotherapies for gastric cancer in Japan. The plasma concentration of 5-fluorouracil (5-FU) is increased in patients with renal dysfunction because gimeracil in S-1 inhibits the degradation of 5-FU and about 50% of gimeracil is excreted in the urine. We describe a 35-year-old man with acute kidney injury while taking S-1 and cisplatin for advanced gastric cancer and who presented severe adverse effects of 5-FU. This case report describes the evolution of the plasma concentrations of 5-FU with haemodialysis along with a decrease in the adverse drug effects.

Effect of renin-angiotensin-aldosterone system triple blockade on non-diabetic renal disease: addition of an aldosterone blocker, spironolactone, to combination treatment with an angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker.

Although dual blockade of the renin-angiotensin-aldosterone system (RAAS) with the combination of an angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) is generally well-established as a treatment for nephropathy, this treatment is not fully effective in some patients. Based on the recent evidence implicating aldosterone in renal disease progression, this study was conducted to examine the efficacy of blockade with three different mechanisms by adding an aldosterone blocker in patients who do not respond adequately to the dual blockade. A 1-year randomized, open-label, multicenter, prospective controlled study was conducted, in which 32 non-diabetic nephropathy patients with proteinuria exceeding 0.5 g/day were enrolled after more than 12 weeks of ACE-I (5 mg enalapril) and ARB (50 mg losartan) combination treatment. These patients were allocated into two groups of 16 patients each: a triple blockade group in which 25 mg of spironolactone daily was added to the ACE-I and ARB combination treatment, and a control group in which 1 mg of trichlormethiazide or 20 mg of furosemide was added to the combination treatment instead of spironolactone depending upon the creatinine level. After 1 year of treatment, the urinary protein level decreased by 58% (p<0.05) with the triple blockade but was unchanged in the controls. Furthermore, urinary type IV collagen level decreased by 40% (p<0.05) with the triple blockade but was unchanged in the controls. The decreases in urinary protein and urinary type IV collagen were not accompanied by a decrease in blood pressure. Mean serum creatinine, potassium and blood pressure did not change significantly by either treatment. In conclusion, triple blockade of the RAAS was effective for the treatment of proteinuria in patients with non-diabetic nephropathy whose increased urinary protein had not responded sufficiently to a dual blockade.

Integrated therapies including erythropoietin decrease the incidence of dialysis: lessons from mapping the incidence of end-stage renal disease in Japan.

BACKGROUND: Erythropoietin (EPO) has been reported to slow the decline of renal function in predialysis chronic kidney disease (CKD) patients. On the contrary, in the recent large-scale randomized controlled trial (RCT), CREATE and CHOIR, which aimed to keep a higher haemoglobin (Hb) level than former trials, the renoprotective effect of EPO was not observed. Today, the renoprotective effect of EPO has become controversial. In order to test the hypothesis that the usage of EPO in predialysis CKD patients may ameliorate the progression of renal disease, we conducted a macro-level observational study dealing with all Japanese predialysis CKD patients. METHODS: Annually since 1982, the Japanese Society for Dialysis Therapy reports the number of patients that have entered maintenance dialysis in each prefecture of Japan. Based on the 2002-2004 data, we calculated the annual incidence of end-stage renal disease (ESRD) in each of the 47 prefectures. The annual amounts paid for EPO by each prefecture, presumably corresponding to the amounts used, corrected for the estimated predialysis CKD patients, were calculated. We examined the relationship between the incidence of new dialysis and the usage of EPO in each prefecture. Furthermore, the usage of EPO was compared with that of antihypertensive agents including angiotensin converting enzyme inhibitor (ACE-I), and that of statin. RESULTS: There were prefectural differences in the annual incidence of ESRD from 2002 to 2004. We also found prefectural differences in the usage of EPO for the three consecutive years. The usage of EPO in predialysis patients was negatively correlated with the incidence of ESRD on linear and multiple regression analyses. At the same time, the usage of EPO had strong positive correlations with the usage of antihypertensive agents including ACE-I and with that of statin. CONCLUSION: Our nationwide epidemiologic study revealed that a higher use of EPO was associated with a decreased incidence of new dialysis in daily clinical practice. In addition, there were strong correlations among the usage of EPO, antihypertensive agents and statin. These data are supportive of, but do not prove, the hypothesis that EPO may be renoprotective, when used in combination with other strategies.

Prospective randomized study evaluating the efficacy of the spherical adsorptive carbon AST-120 in chronic kidney disease patients with moderate decrease in renal function.

AIMS: We studied whether adding the spherical adsorptive carbon AST-120 to conventional treatments is effective in inhibiting progression of chronic kidney disease (CKD) at the stage of moderate decrease in renal function. METHODS: 43 CKD patients with moderately impaired renal function indicated by glomerular filtration rate (GFR) of 20-70 ml/min as measured by non-radiolabeled iothalamate clearance method were enrolled in the study. 26 patients showing a decrease of GFR by 5 ml/min during a 1-year observation period were randomized to receive ongoing treatments only (control group, 12 cases) or with AST-120 co-administered with ongoing treatment (AST-120 group, 14 cases). The intervention period was 1 year and the change in GFR was the primary evaluation variable. RESULTS: The mean changes of GFR per month (DeltaGFR) in the intervention period were not significantly different between both groups. However, when comparing the DeltaGFR in the observation and intervention periods for each group, the rate of decline in GFR was significantly retarded (p < 0.001) in the AST-120 group while no significant difference was observed in the control group. CONCLUSION: These results suggest that co-administration of AST-120 with conventional treatments retards decline in renal function in CKD patients with moderate decrease in renal function.