Favorable therapeutic efficacy of low-density lipoprotein apheresis for nephrotic syndrome with impaired renal function.

Many reports have shown the therapeutic efficacy of LDL apheresis (LDL-A) in drug-resistant nephrotic syndrome (NS) for improvement of heavy proteinuria and severely impaired renal function. To obtain comprehensive results in a large number of cases, a post hoc analysis of the Prospective Observational survey on the Long-Term Effects of the LDL-Apheresis on the Drug Resistant Nephrotic Syndrome (POLARIS) study was performed by stratifying enrolled cases according to the pretreatment estimated glomerular filtration rate (eGFR) levels indicating normal (N) (≥60 ml/min/1.73 m2 ), moderately impaired (M) (≥30 to <60 ml/min/1.73 m2 ), and severely impaired (S) (<30 ml/min/1.73 m2 ) renal function. Significant improvements of proteinuria and renal function were found in Group N and, most interestingly, in Group M. A tendency for improvement in proteinuria was found in Group S. Most cases in all groups had not entered end-stage renal disease at 2 years after LDL-A treatment. These results suggest that LDL-A has therapeutic efficacy even in cases in which renal function has declined to 30 ml/min/1.73 m2 .

Mizoribine therapy combined with steroids and mizoribine blood concentration monitoring for idiopathic membranous nephropathy with steroid-resistant nephrotic syndrome.

BACKGROUND: We designed a prospective and randomized trial of mizoribine (MZR) therapy combined with prednisolone (PSL) for idiopathic membranous nephropathy (IMN) with steroid-resistant nephrotic syndrome (SRNS). METHODS: Patients with IMN were divided into 2 groups, and MZR combined with PSL was administered for 2 years. PSL was initially prescribed at 40 mg/day and tapered. MZR was given once-a-day at 150 mg and 3-times-a-day at 50 mg each to groups 1 and 2. Serum MZR concentrations from 0 to 4 h after administration were examined within one month of treatment. The concentration curve and peak serum level (C max) of MZR were estimated by the population pharmacokinetic (PPK) parameters of MZR. RESULTS: At 2 years, 10 of 19 patients (52.6 %) in group 1 and 7 of 18 patients (38.9 %) in group 2 achieved complete remission (CR). The time-to-remission curve using the Kaplan-Meier technique revealed an increase in the cumulative CR rate in group 1, but no significant difference between the groups. Meanwhile, there was a significant difference in C max between groups 1 and 2 (mean ± SD: 1.20 ± 0.52 vs. 0.76 ± 0.39 µg/mL, p = 0.04), and C max levels in CR cases were significantly higher than those in non-CR cases. Receiver operating characteristic analysis showed that C max more than 1.1 µg/mL was necessary for CR in once-a-day administration. CONCLUSION: Administration of MZR once a day is useful when combined with PSL for treatment of IMN with SRNS. In addition, it is important to assay the serum concentration of MZR and to determine C max, and more than 1.1 µg/mL of C max is necessary for CR.

A new peritoneal dialysis fluid for Japanese patients: a randomized non-inferiority clinical trial of safety and efficacy.

BACKGROUND: We report here two new peritoneal dialysis fluids (PDFs) for Japan [BLR 250, BLR 350 (Baxter Limited, Japan)]. The PDFs use two-chamber systems, and have bicarbonate and lactate buffer to a total of 35 mmol/L. In separate trials, the new PDFs were compared to two "standard" systems [PD-4, PD-2 (Baxter Limited, Japan)]. The trials aimed to demonstrate non-inferiority of peritoneal creatinine clearance (pCcr), peritoneal urea clearance (pCurea) and ultrafiltration volume (UF), and compare acid-base and electrolyte balance. METHODS: We performed randomized, multicenter, parallel group, controlled, open-label clinical trials in stable continuous ambulatory peritoneal dialysis (CAPD) patients. The primary endpoints were pCcr and UF. The secondary endpoints were serum bicarbonate and peritoneal urea clearance. The active phase was 8 weeks. These trials were performed as non-inferiority studies, with the lower limit of non-inferiority for pCcr and UF set at 3.2 L/week/1.73 m2 and 0.12 L/day, respectively. RESULTS: 108 patients (28 centers) and 103 patients (29 centers) took part in the two trials. Groups were well balanced at baseline. The investigative PDFs were non-inferior to the "standard" ones in terms of primary endpoints, comparable in terms of pCurea, and superior in terms acid-base balance, especially correcting those with over-alkalinization at baseline. CONCLUSIONS: We demonstrated fundamental functionality of two new PDFs and showed superior acid-base balance. Given the propensity of Japanese CAPD patients for alkalosis, it is important to avoid metabolic alkalosis which is associated with increased cardiovascular mortality risk and accelerated vascular calcification. The new PDFs are important progress of CAPD treatment for Japanese patients.

A Prospective Observational Survey on the Long-Term Effect of LDL Apheresis on Drug-Resistant Nephrotic Syndrome.

BACKGROUND/AIMS: LDL apheresis (LDL-A) is used for drug-resistant nephrotic syndrome (NS) as an alternative therapy to induce remission by improvement of hyperlipidemia. Several clinical studies have suggested the efficacy of LDL-A for refractory NS, but the level of evidence remains insufficient. A multicenter prospective study, POLARIS (Prospective Observational Survey on the Long-Term Effects of LDL Apheresis on Drug-Resistant Nephrotic Syndrome), was conducted to evaluate its clinical efficacy with high-level evidence. METHODS: Patients with NS who showed resistance to primary medication for at least 4 weeks were prospectively recruited to the study and treated with LDL-A. The long-term outcome was evaluated based on the rate of remission of NS 2 years after treatment. Factors affecting the outcome were also examined. RESULTS: A total of 58 refractory NS patients from 40 facilities were recruited and enrolled as subjects of the POLARIS study. Of the 44 subjects followed for 2 years, 21 (47.7%) showed remission of NS based on a urinary protein (UP) level <1.0 g/day. The UP level immediately after LDL-A and the rates of improvement of UP, serum albumin, serum creatinine, eGFR, and total and LDL cholesterol after the treatment session significantly affected the outcome. CONCLUSIONS: Almost half of the cases of drug-resistant NS showed remission 2 years after LDL-A. Improvement of nephrotic parameters at termination of the LDL-A treatment was a predictor of a favorable outcome.

Determinants of coronary artery calcification in maintenance hemodialysis patients.

In addition to the well-known traditional risk factors, uremia-related so-called novel risk factors and medications appear to affect coronary artery calcification in hemodialysis patients. This study was performed to evaluate coronary artery calcification score (CACS) in maintenance hemodialysis (MHD) patients, and to identify significantly related factors. We assessed CACS using Agatston Score by MDCT, sex, age, dialysis vintage, presence of diabetes mellitus, smoking history, presence of ≥100 ml urine volume/day, normalized protein catabolic rate, geriatric nutritional risk index, administration of active vitamin D3, cinacalcet, phosphate binders or antihypertensive agents, and circulation parameters including creatinine, albumin, corrected calcium and phosphate in 207 MHD patients. Coronary artery calcifications were observed in 192 patients (92.8%). In multivariate analysis, CACS showed direct associations with age (p < 0.001), dialysis vintage (p < 0.001) and presence of diabetes mellitus (p < 0.01), and an inverse association only with active vitamin D3 administration (p < 0.001) in MHD patients. Patients with active vitamin D3 showed significantly lower CACS than in those without it (1349.6 ± 1635.0 vs. 2475.6 ± 2646.6 H, p < 0.05). Older age, longer duration of dialysis and diabetes mellitus are risk factors and administration of active vitamin D3 is protective factor for coronary artery calcification in MHD patients.

Hepatitis B virus infection in hemodialysis patients in Japan: Prevalence, incidence and occult hepatitis B virus infection.

AIM: A survey of hepatitis B virus (HBV) infection in hemodialysis (HD) patients was conducted to determine the burden and risk of infection and to suggest preventive measures against HBV infection among HD patients at nine hospitals in Hiroshima, Japan, from 1999 to 2003. METHODS: HBV markers were investigated for 1860 HD patients. The prevalence, incidence of HBV and prevalence of occult HBV were calculated. RESULTS: The prevalence of hepatitis B surface antigen (HBsAg) was 2.6%, the positive rate of anti-hepatitis B core (HBc) was 20.6% and that of anti-hepatitis B surface (HBs) was 11.7%. Among 1372 patients who started HD after the approval of erythropoietin in Japan in 1991, the prevalence of HBsAg was 2.1%. The incidence rate of HBsAg positivity was 0/1000 person-years and the incidence of anti-HBc was 0.3/1000 person-years. Among 1812 HBsAg negative patients HBV DNA was detected in two: one case was negative for anti-HBc and anti-HBs, and the other was only positive for anti-HBc. Prevalence of occult HBV was 0.11%. CONCLUSION: The incidence rate of HBV was much lower than that of hepatitis C virus (HCV) in the same cohort. We supposed that the discrepancy between incidence rate of HBV and that of HCV was caused by the difference of their carrier rates and of their characteristics for persistent infection. So, we concluded that it is prerequisite to grasp the burden of HBV carriers in the group to prevent new HBV infections in HD patients.

Efficacy of a disease management program focused on acquisition of self-management skills in pre-dialysis patients with diabetic nephropathy: 24 months follow-up.

PURPOSE: We previously performed a preliminary 6-month controlled trial to examine the effect of a disease management education program on prolongation of the time to renal replacement therapy (RRT) and/or avoidance of RRT for patients with diabetic nephropathy. However, its duration was too short to follow the changes of renal function, so we performed the present study for 24 months. METHODS: This was a two-group comparative study. The intervention group received self-management education from disease management nurses and was supported by the nurses in cooperation with their primary physicians for 12 months. Then this group was followed for a further 12 months. The control group received standard care and was followed for 24 months. RESULTS: Of the 31 subjects enrolled in each group, 26 subjects in the intervention group and 27 subjects in the control group were analyzed after excluding drop-outs. During the study period, 0 and 2 subjects in the intervention and the control group started RRT, respectively. In the intervention group, renal function was maintained, while significant worsening was observed in the control group. Hemoglobin A1c (HbA1c) improved in the intervention group, but became significantly worse in the control group. In the intervention group, all process indicators of behavior modification increased significantly after intervention. CONCLUSION: A well-designed disease management program might be useful for maintaining renal function and improving HbA1c in patients with diabetic nephropathy. It is considered that modification of patient behavior contributed to these results.

Immediate therapeutic efficacy of low-density lipoprotein apheresis for drug-resistant nephrotic syndrome: evidence from the short-term results from the POLARIS Study.

BACKGROUND: Hyperlipidemia is not merely a complication but a major exacerbating factor in longstanding nephrotic syndrome (NS). Low-density lipoprotein apheresis (LDL-A) has been reported to ameliorate dyslipidemia and induce rapid remission of NS. Several clinical studies have suggested the therapeutic efficacy of LDL-A, but the level of clinical evidence is insufficient. Therefore, a multicenter prospective study, POLARIS (Prospective Observational Survey on the Long-Term Effects of LDL Apheresis on Drug-Resistant Nephrotic Syndrome), was initiated in Japan. METHOD: Patients with drug-resistant NS were prospectively recruited into the study and treated with LDL-A in facilities that were registered in advance. In the POLARIS study design, the clinical data are to be followed up for 2 years. In the current study, we aimed at evaluating the short-term efficacy based on the treatment outcome of LDL-A immediately after completion of treatment. RESULTS: Along with rapid improvement of hyperlipidemia, LDL-A significantly improved proteinuria and hypoproteinemia after treatment. More than half of the patients showed remission of NS based on the urinary protein level at the completion of LDL-A. The duration of NS before the start of treatment was significantly shorter in patients who responded to LDL-A. CONCLUSIONS: An analysis of patients registered in the POLARIS study indicated that LDL-A has short-term efficacy for drug-resistant NS. Rapid relief of dyslipidemia by LDL-A may provide early remission in about half of the NS patients who are resistant to conventional medication. Completion of the POLARIS study may reveal additional long-term effects of LDL-A in these patients.

Telomeric g-tail length and hospitalization for cardiovascular events in hemodialysis patients.

BACKGROUND AND OBJECTIVES: Telomeric G-tails play a pivotal role in maintaining the intramolecular loop structure of telomeres. Previous in vitro studies have suggested that the erosion of telomeric G-tails triggers cellular senescence, leading to organ dysfunction and atherosclerosis. The authors recently established a method to measure telomeric G-tail length using a hybridization protection assay. Using this method, this study investigated whether telomeric G-tail length could be used as a novel predictor for future cardiovascular events in hemodialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A prospective observational study was performed involving a cohort of 203 Japanese hemodialysis patients to examine the lengths of telomeric G-tails and total telomeres and subsequent cardiovascular events during a median follow-up period of 48 months. The lengths of telomeric G-tails and total telomeres were also measured in 203 participants who did not have CKD and who were age- and sex-matched to hemodialysis patients. RESULTS: The lengths of telomeric G-tails and total telomeres were significantly shorter in hemodialysis patients than in control subjects. Telomeric G-tails, but not total telomeres, were independently and negatively associated with clinical history of cardiovascular disease. During follow-up, 80 cardiovascular events occurred. Total telomere length did not predict cardiovascular events. However, the length of telomeric G-tails was associated with new-onset cardiovascular events (hazard ratio per log luminescence signals, 0.12; 95% confidence interval, 0.12 to 0.50) that persisted after adjustment for age, sex, diabetes mellitus, clinical history of cardiovascular disease, inflammation, use of vitamin D, and serum levels of phosphate and intact parathyroid hormone. CONCLUSIONS: Longer telomeric G-tail length is associated with a lower risk of future cardiovascular events in hemodialysis patients.

Significance of combined cyclosporine-prednisolone therapy and cyclosporine blood concentration monitoring for idiopathic membranous nephropathy with steroid-resistant nephrotic syndrome: a randomized controlled multicenter trial.

BACKGROUND: Combined treatment with cyclosporine microemulsion preconcentrate (CyA MEPC) and steroids has been widely used for idiopathic membranous nephropathy (IMN) associated with steroid-resistant nephrotic syndrome (SRNS). Recent studies have shown that once-a-day and preprandial administration of CyA MEPC is more advantageous than the conventional twice-a-day administration in achieving the target blood CyA concentration at 2 h post dose (C2). We designed a randomized trial to compare these administrations. METHODS: IMN patients with SRNS (age 16-75 years) were divided prospectively and randomly into 2 groups. In group 1 (n = 23), 2-3 mg/kg body weight (BW) CyA MEPC was given orally once a day before breakfast. In group 2 (n = 25), 1.5 mg/kg BW CyA MEPC was given twice a day before meals. CyA + prednisolone was continued for 48 weeks. RESULTS: Group 1 showed a significantly higher cumulative complete remission (CR) rate (p = 0.0282), but not when incomplete remission 1 (ICR1; urine protein 0.3-1.0 g/day) was added (p = 0.314). Because a C2 of 600 ng/mL was determined as the best cut-off point, groups 1 and 2 were further divided into subgroups A (C2 ≥600 ng/mL) and B (C2 <600 ng/mL). Groups 1A and 2A revealed significantly higher cumulative remission (CR + ICR1) (p = 0.0069) and CR-alone (p = 0.0028) rates. On the other hand, 3 patients with high CyA levels (C2 >900 ng/mL) in Group 1A were withdrawn from the study because of complications. CONCLUSION: CyA + prednisolone treatment is effective for IMN with associated SRNS at a C2 of ≥600 ng/mL. To achieve remission, preprandial once-a-day administration of CyA at 2-3 mg/kg BW may be the most appropriate option. However, we should adjust the dosage of CyA by therapeutic drug monitoring to avoid complications.

Mesenchymal stem cells ameliorate experimental peritoneal fibrosis by suppressing inflammation and inhibiting TGF-ß1 signaling.

Mesenchymal stem cells (MSCs) are multipotent adult stem cells that have regenerative capability and exert paracrine actions on damaged tissues. Since peritoneal fibrosis is a serious complication of peritoneal dialysis, we tested whether MSCs suppress this using a chlorhexidine gluconate model in rats. Although MSCs isolated from green fluorescent protein-positive rats were detected for only 3 days following their injection, immunohistochemical staining showed that MSCs suppressed the expression of mesenchymal cells, their effects on the deposition of extracellular matrix proteins, and the infiltration of macrophages for 14 days. Moreover, MSCs reduced the functional impairment of the peritoneal membrane. Cocultures of MSCs and human peritoneal mesothelial cells using a Transwell system indicated that the beneficial effects of MSCs on the glucose-induced upregulation of transforming growth factor-ß1(TGF-ß1) and fibronectin mRNA expression in the human cells were likely due to paracrine actions. Preincubation in MSC-conditioned medium suppressed TGF-ß1-induced epithelial-to-mesenchymal transition, α-smooth muscle actin, and the decrease in zonula occludens-1 in cultured human peritoneal mesothelial cells. Although bone morphogenic protein 7 was not detected, MSCs secreted hepatocyte growth factor and a neutralizing antibody to this inhibited TGF-ß1 signaling. Thus, our findings imply that MSCs ameliorate experimental peritoneal fibrosis by suppressing inflammation and TGF-ß1 signaling in a paracrine manner.

Morning blood pressure is useful for detection of left ventricular hypertrophy in hemodialysis patients.

BACKGROUND: When diagnosing hypertension (HT) it is essential to determine not only the level of raised blood pressure (BP), but also how the condition relates to organ damage. The best time to measure BP for diagnosing HT in patients on hemodialysis (HD) remains unclear. METHODS: A total of 100 HD patients (mean age 63.8 years, 60 males) were studied. Left ventricular hypertrophy (LVH) was detected by echocardiography and BP monitored for 1 week at 20 different times in the morning and night, before and after dialysis. We also checked for masked HT, i.e., patients with weekly morning HT, but not pre-dialysis HT. RESULTS: Average BP for the week was 141.9 ±19.0/79.6 ± 10.6 mmHg, with 68 patients classified as hypertensive. Average morning BP was 144.6 ± 19.8/81.7 ± 11.3 mmHg, and 71 patients had weekly morning HT. In addition, 62 patients had LVH and 51 patients had relative morning HT. Multiple logistic analyses showed that LVH was associated with weekly morning HT, morning HT on HD and non-HD days, average HT, and relative morning HT. However, evening, pre-dialysis, and post-dialysis HT showed no association with LVH. Masked HT was found in 20 % of patients. If HT had been diagnosed using only pre-dialysis BP, 20 of the 71 patients with weekly morning HT would not have been detected. CONCLUSION: Morning BP is useful for detecting LVH in HD patients. Monitoring of morning BP may be superior to measurements taken at other times for diagnosing HT.

[N-terminal pro brain natriuretic peptide predicts hospitalization of hemodialysis patients for cardiovascular disease].

We investigated whether or not N-terminal pro brain natriuretic peptide (NT-proBNP) could predict hospitalization for cardiovascular disease (CVD) among Japanese hemodialysis patients. A total of 104 patients on maintenance dialysis 3 times per week were enrolled. We followed the patients for 23.9 +/- 4.2 months and 19 hospitalizations for CVD occurring during this period. The area under the curve (AUC) for the risk of CVD hospitalization was calculated after drawing a receiver operating characteristic curve. Predialysis NT-proBNP showed a larger AUC value than both postdialysis NT-proBNP and brain natriuretic peptide. The optimal cut-off value of predialysis NT-proBNP for predicting CVD hospitalization was 5,894 pg/mL, (sensitivity of 60 % and specificity of 76 %). Diabetes mellitus, a history of CVD, and the predialysis NT-proBNP level were significant determinants of CVD hospitalization according to Cox proportional hazards analysis. In conclusion, predialysis NT-proBNP is useful for predicting CVD hospitalization in hemodialysis patients.

Environmental factors influencing the survival of chronic dialysis patients.

BACKGROUND: There have been few investigations into the effects of environmental factors on the outcome of end-stage renal disease. METHODS: We investigated factors influencing the survival of dialysis patients in each prefecture of Japan by analyzing data from the Japan Statistics Bureau and Japanese Society for Dialysis Therapy using univariate and multivariate regression analysis. RESULTS: Univariate analysis showed that the number of dialysis specialists (p = 0.028, r = 0.319), the density of dialysis centers (the number in relation to the area of each prefecture, p = 0.018, r = 0.344), the average annual temperature (p < 0.0001, r = 0.686), and the mortality rate of the general population with cerebrovascular disease (p = 0.014, r = -0.355) were correlated with the 1-year survival of new dialysis patients from 2005 to 2007. Multivariate regression analysis showed that the average annual temperatures were extracted as determinants of the 1-year survival rate of new dialysis patients (p < 0.0001, F = 40.11, R(2) = 0.471, R(2)' = 0.460). CONCLUSION: The average annual temperatures could have an influence on the survival of dialysis patients. Survival of new dialysis patients by prefecture in Japan may be influenced by environmental factors that cannot be controlled medically after the initiation of dialysis.

Klotho inhibits transforming growth factor-beta1 (TGF-beta1) signaling and suppresses renal fibrosis and cancer metastasis in mice.

Fibrosis is a pathological process characterized by infiltration and proliferation of mesenchymal cells in interstitial space. A substantial portion of these cells is derived from residing non-epithelial and/or epithelial cells that have acquired the ability to migrate and proliferate. The mesenchymal transition is also observed in cancer cells to confer the ability to metastasize. Here, we show that renal fibrosis induced by unilateral ureteral obstruction and metastasis of human cancer xenografts are suppressed by administration of secreted Klotho protein to mice. Klotho is a single-pass transmembrane protein expressed in renal tubular epithelial cells. The extracellular domain of Klotho is secreted by ectodomain shedding. Secreted Klotho protein directly binds to the type-II TGF-ß receptor and inhibits TGF-ß1 binding to cell surface receptors, thereby inhibiting TGF-ß1 signaling. Klotho suppresses TGF-ß1-induced epithelial-to-mesenchymal transition (EMT) responses in cultured cells, including decreased epithelial marker expression, increased mesenchymal marker expression, and/or increased cell migration. In addition to TGF-ß1 signaling, secreted Klotho has been shown to inhibit Wnt and IGF-1 signaling that can promote EMT. These results have raised the possibility that secreted Klotho may function as an endogenous anti-EMT factor by inhibiting multiple growth factor signaling pathways simultaneously.

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.

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.

Point mutation (C to T) of the LCAT gene resulting in A140C substitution.

Familial lecithin: cholesterol acyltransferase (LCAT) deficiency is an autosomal recessive disorder characterized by corneal opacity, hemolytic anemia, proteinuria, and a low serum level of high-density lipoprotein cholesterol (HDL-C). Also, LCAT activity is remarkably decreased or absent. A 57-year-old Japanese man presented with corneal opacity, proteinuria, and a very low serum level of HDL-C. His LCAT activity was too low to measure. From clinical observations and results of examinations, we suspected LCAT deficiency. We performed a kidney biopsy and gene analysis. Light microscopy revealed the vacuolation of glomerular capillary tufts. Electron microscopy revealed small deposits in the glomerular basement membrane (GBM), extracellular matrix, and vascular endothelial cells. We identified a homozygous C to T point mutation at nucleotide 501 (g.501 C>T) of exon 4 at codon 140, resulting in an arginine (Arg) to cysteine (Cys) amino acid substitution (A140C) in the patient. These findings were characteristic of LCAT deficiency, which was confirmed to be due to a mutation that has only been reported in Japan.

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.

15-Deoxy-Delta12,14-prostaglandin J2 inhibits angiotensin II-induced fibronectin expression via hepatocyte growth factor induction in human peritoneal mesothelial cells.

15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) is an endogenous peroxisome proliferator-activated receptor gamma (PPARgamma) agonist that suppresses progressive matrix deposition; however, little is known about the effects of 15d-PGJ(2) on human peritoneal mesothelial cells (HPMCs). We investigated the following: (i) the expression of PPARgamma; (ii) the effect of 15d-PGJ(2) on angiotensin II (Ang II)-induced fibronectin (FN) expression and secretion; (iii) the effect of 15d-PGJ(2) (with or without Ang II and with or without the specific PPARgamma antagonist GW9662) and pioglitazone, a synthetic PPARgamma agonist, on hepatocyte growth factor (HGF) expression and secretion; (iv) the effect of HGF on Ang II-induced FN expression and secretion; (v) the expression of c-Met (a specific HGF receptor) and its phospho-signal; and (vi) the involvement of HGF in the effect produced by 15d-PGJ(2) using selective c-Met inhibitor PHA-665752. The presence of PPARgamma was detected by western blot analysis. 15d-PGJ(2) inhibited Ang II-induced FN expression and increased HGF expression, even in the presence of Ang II. This effect of HGF expression was completely prevented by co-treatment with GW9662. Additionally, upregulation of HGF secretion induced by 15d-PGJ(2) and HGF production induced by pioglitazone was revealed. We demonstrated the presence of c-Met, and presented evidence that HGF inhibits Ang II-induced FN expression and activates phosphorylation of c-Met, which is blocked by PHA-665752; 15d-PGJ(2) also activated c-Met phosphorylation. Furthermore, PHA-665752 attenuates the inhibitory effects of 15d-PGJ(2) on FN secretion. These findings suggest that 15d-PGJ(2) has a novel and potent antifibrotic effect in HPMC and this action is likely mediated by HGF.