Keiichi Fukudome

Incidence of ANCA-Associated Primary Renal Vasculitis in the Miyazaki Prefecture: The First Population-Based, Retrospective, Epidemiologic Survey in Japan

Clinicoepidemiological manifestations of the vasculitides differ geographically. According to a nationwide, hospital-based survey in Japan, the prevalence of microscopic polyangiitis (MPA) and/or renal-limited vasculitis (RLV) is much higher than that of Wegeners granulomatosis (WG). However, little is known about the incidence of antineutrophil cytoplasmic autoantibodies (ANCA)-associated primary renal vasculitis (PRV) in Japan. The incidence of PRV was retrospectively determined by a population-based method in Miyazaki Prefecture in Japan between 2000 and 2004. PRV was defined according to the following criteria from the European Systemic Vasculitis Study Group: (1) new patients with WG, MPA, Churg-Strauss syndrome (CSS), or RLV, (2) renal involvement attributable to active vasculitis, and (3) ANCA considered positive if the disease was not histologically confirmed. The numbers of patients with PRV in the years 2000, 2001, 2002, 2003, and 2004 were 9, 9, 9, 16, and 13, respectively. The male to female ratio was 24:32 and the average age was 70.4 +/- 10.9 (mean +/- SD) yr. The estimated annual incidence of PRV was 14.8 (95% confidence interval [CI] 10.8 to 18.9) and 44.8 (95% CI 33.2 to 56.3) per million adults (>15 yr old) and seniors (>65 yr old), respectively. Ninety-one percent of the patients were myeloperoxidase (MPO)-ANCA positive, but none were positive for proteinase 3 (PR3)-ANCA. There were no WG or CSS patients. The incidence of PRV did not differ between Japan and Europe, but WG was not widespread in Japan. Furthermore, the ratio of serum MPO to PR3-ANCA among Japanese with PRV was much higher than that found among European and US patients.

Effect of Sevelamer on Dyslipidemia and Chronic Inflammation in Maintenance Hemodialysis Patients

Background: Hemodialysis (HD) patients often experience cardiovascular events, that might be related to altered calcium–phosphate metabolism, dyslipidemia, and chronic inflammation in addition to hypertension. Sevelamer, a non-calcium-containing phosphate binder, may improve the lipid profile of HD patients. However, the influence of sevelamer on chronic inflammation has not been clarified. Methods: We enrolled 36 maintenance HD patients with a serum calcium (Ca) or phosphate (P) level constantly greater than 9.5 mg/dL and 5.5 mg/dL, respectively. The dose of sevelamer was titrated to achieve a serum Ca and P in the target ranges. The study period was 24 weeks. Patients underwent the following measurements: bone mineral markers, lipids, and a high-sensitivity C-reactive protein (hs-CRP). Results: In the 28 patients who completed the study, sevelamer significantly reduced the mean non-high-density lipoprotein cholesterol (non-HDL-C) level by 15% and 20% (p < 0.0001) after 12 and 24 weeks, respectively, in addition to reducing the serum P level and Ca × P product. Similarly, there was a significant reduction of the serum hs-CRP level after 12 and 24 weeks [median at baseline: 1.03 mg/dL (interquartile range 0.26–3.98 mg/dL) versus 0.57 (0.17–1.47) and 0.38 (0.16–1.03), respectively, p = 0.0259]. The reduction rate of hs-CRP was significantly correlated with those of non-HDL-C (r = 0.451, p < 0.0401) and P (r = 0.453, p < 0.0008) Conclusion: Hs-CRP levels were reduced by sevelamer administration, as well as non-HDL-C, P, and the Ca × P product. Sevelamer may have an anti-inflammatory effect, in addition to lowering phosphate and lipid levels in HD patients.

Peritonitis Increases MMP-9 Activity in Peritoneal Effluent from CAPD Patients

Patients undergoing long-term continuous ambulatory peritoneal dialysis (CAPD) sometimes experience ultrafiltration failure. Mesothelial basement membrane thickening and the accumulation of submesothelial fibrotic tissue are common features of the diseased peritoneum. Peritonitis can lead to ultrafiltration failure, but the precise mechanism is not clear. The key enzymes in extracellular matrix (ECM) remodeling, namely matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), are produced by human peritoneal mesothelial cells. Using peritoneal effluent from 13 CAPD patients with peritonitis and 7 noninfected CAPD control individuals, we examined MMP and TIMP activities by gelatin and reverse zymography. Latent and activated types of MMP-2 and -9, and TIMP-1 and -2 were identified in peritoneal effluent (from all CAPD patients). Levels of latent and activated type MMP-9, as well as of TIMP-1 activities were higher at the onset of peritonitis than either during the recovery phase of peritonitis and/ or in control individuals. Activated MMP-9 activity positively correlated with leukocyte numbers and IL-6 levels in peritoneal effluent. Activities of MMP-2 and TIMP-2 in peritoneal effluent did not change between the onset of peritonitis and recovery. We concluded that increased MMP-9 and TIMP-1 levels might be associated with peritoneal ECM remodeling during peritonitis.

Effect of lanthanum carbonate vs. calcium carbonate on serum calcium in hemodialysis patients: a crossover study.

BACKGROUND Lanthanum carbonate (LC) is a non-calcium-containing phosphate binder and shows a comparable effect with other phosphate binders on hyperphosphatemia in dialysis patients. LC also contributes to a reduced oral calcium load compared with calcium carbonate (CaC) treatment. However, no crossover studies which compare the influence on serum calcium level between treatments with LC and CaC in hemodialysis (HD) patients have been carried out. METHODS After washout for 2 weeks, 50 patients on HD were randomized (1 : 1) to receive LC or CaC for 3 months. Thereafter, patients underwent a second 2-week washout period and were switched to the alternative binder for the next 3 months. Mineral and bone metabolism markers were measured with the changes of vitamin D doses. RESULTS The serum phosphate level showed a similar decrease from baseline to 3 months in both groups. During the study periods, hypercalcemia was observed only in patients taking CaC. The dose of vitamin D analogue was increased more frequently in the patients of the LC group compared with LC group. The iPTH level showed a significant decrease in the CaC group, but not in the LC group. Serum levels of BAP, TRAP5b, and ALP were significantly elevated in the LC group, whereas the FGF-23 level showed a significant decrease. CONCLUSION LC effectively reduced the serum phosphate level (like CaC) and allowed the vitamin D analogue dosage to be increased without hypercalcemia in HD patients. LC is one of the useful phosphate binders without hypercalcemia. (UMIN-CTR registration number: UMIN000002331).

Comparison of the effects of intravenous methylprednisolone pulse versus oral prednisolone therapies on the first attack of minimal-change nephrotic syndrome in adults

Aim:  Minimal‐change nephrotic syndrome (MCNS) is characterized by a good response to corticosteroid, but a high incidence of relapse. We compared the effect of intravenous methylprednisolone pulse plus oral prednisolone therapy (pulse group) with that of conventional oral prednisolone alone therapy (oral group) on the responsiveness and relapse in the first attack of adult‐onset MCNS patients.

Recent Therapeutic Strategies Improve Renal Outcome in Patients with IgA Nephropathy

Background/Aims: Various treatment options for IgA nephropathy (IgAN) have been developed, particularly over the past decade. Nevertheless, whether such therapeutic interventions improve actual renal outcome as compared with previous therapies remains obscure. Methods: We examined data from 304 patients with IgAN whose serum creatinine value at renal biopsy was <2.0 mg/dl and who had been followed up for >12 months. We assigned the patients to groups according to the period of diagnosis (group E, between 1981 and 1995, n = 130; group L, between 1996 and 2006, n = 174). Results: Significantly more patients had received steroid therapy and renin-angiotensin system inhibitors (RAS-I) in group L than in group E (steroid 51.7 vs. 15.4%, p < 0.001; RAS-I 42.0 vs. 1.5%, p < 0.001). Forty patients overall reached end-stage renal disease (ESRD) within 81.9 ± 55.1 months of observation. Kaplan-Meier analysis showed that the 10-year renal survival rate of group L persisted and significantly differed from that of group E (95.7 vs. 75.2%, p = 0.005). The Cox proportional hazards model adjusted for known prognostic markers demonstrated that initial therapeutic interventions in group L prevented ESRD, with a hazard ratio of 0.29 (95% CI 0.11–0.76, p = 0.011). Conclusion: Although this study is not a prospective trial, our results indicate that aggressive therapeutic intervention for IgAN over the past decade has improved actual renal outcome.

Long‐term change of glomerular gelatinolytic activity in rats with streptozotocin‐induced diabetes

SUMMARY: In diabetic nephropathy, a decrease in the activity of matrix metalloproteinase (MMP) might contribute to the build‐up of extracellular matrix protein in the mesangium and the glomerular basement membrane (GBM). Levels of MMP activity were measured as gelatinolytic activity in glomerular homogenates isolated from rats 1, 4, 12, 24 and 48 weeks after inducing diabetes mellitus (DM) with streptozotocin. The level of glomerular gelatinolytic activity after 1 week in DM rats was significantly increased compared with that in controls (224.8% of control; DM vs. control, 13.58 vs. 6.04 mU/glomerulus; P < 0.05), then decreased by 48 weeks (week 4, 92.8% of control; week 12, 81.9% of control; week 24, 31.8% of control; week 48, 47.3% of control). Glomerular metalloproteinase migrated on gelatin zymography at positions representing molecular weights of approximately 97, 80, 70 and 65 kDa. The intensity of these lytic bands was increased at 1 week but decreased at 24 and 48 weeks. Light microscopy revealed hypercellularity in the mesangial area at 1 week, followed by mild and marked mesangial expansion with GBM thickening at 12 and 48 weeks respectively. These data suggest that the persistent decrease in glomerular gelatinolytic activity during the chronic phase contributes to mesangial expansion and GBM thickening in DM rats. Moreover, the activity may play different roles at the time of onset and during the progression of diabetic nephropathy.