Shigemi Chiba

Cohort Study of Advanced IgA Nephropathy: Efficacy and Limitations of Corticosteroids with Tonsillectomy

Background: Elevated serum creatinine is associated with poor outcome in IgA nephropathy (IgAN). The efficacy and limitations of corticosteroids in advanced IgAN (Cr ≧1.5 mg/dl), however, remains controversial. Methods: We retrospectively investigated 70 patients with advanced IgAN (Cr ≧1.5 mg/dl) classified into three groups according to their treatment regimens, that is, steroid pulse with tonsillectomy, conventional steroid, and supportive therapy. We evaluated the three groups to elucidate predictors for the endpoints ESRF and doubled serum creatinine from baseline. Results: Steroid pulse with tonsillectomy, conventional steroid and supportive therapy were performed in 30, 25 and 15 patients, respectively. During the mean follow-up period of 70.3 (12–137) months, 41.4% of patients reached ESRF (13.3 vs. 56.0 vs. 73.3%, p < 0.001) and 45.7% doubled serum creatinine from baseline (16.7 vs. 64.0 vs. 73.3%, p < 0.001). The incidence of ESRF in the patients treated by steroid pulse with tonsillectomy was significantly lower than the incidences in the patients treated by conventional steroid and supportive therapy at a baseline creatinine level of 1.5–2 mg/dl, but no statistical difference was observed at a level of >2 mg/dl. The Kaplan-Meier estimated probability of renal survival without ESRF was 89.2, 74.1 and 72.2% at 5 years and 82.8, 51.0 and 45.1% at 8 years, respectively (p = 0.017). The predictors for ESRF, identified in a Cox proportional hazards model, were baseline serum creatinine (p < 0.001) and interstitial infiltrate (p = 0.003). Steroid pulse with tonsillectomy also had a protective effect on the risk of reaching ESRF (p = 0.013). By target cross-stratification, the patients with baseline creatinine of 1.5–2 mg/dl who underwent steroid pulse with tonsillectomy showed a better renal survival rate than the others (p < 0.001). Conclusion: Steroid pulse therapy combined with tonsillectomy may be more effective than conventional steroid therapy in patients with a baseline creatinine level of ≤2 mg/dl.

Lymphocytapheresis to treat rapidly progressive glomerulonephritis: a randomised comparison with steroid-pulse treatment

Rapidly progressive glomerulonephritis (RPGN) may progress to end-stage renal failure within weeks and to death from organ damage induced by systemic vasculitis or from immune system failure due to immunosuppressive therapy. Death or the need for dialysis has variously been reported to occur in 17% to 73% of patients treated for RPGN. The need exists for a means promptly to stop disease activity without compromising the patient’s immune system. Macrophages and cytotoxic T cells play a central role in the glomerular injury of RPGN, and the removal of these cells by lymphocytapheresis is effective in the treatment of rheumatoid arthritis. We investigated the efficacy of lymphocytapheresis for treatment of RPGN, in comparison with steroid-pulse treatment. 24 patients with RPGN proven by biopsy were enrolled in RESEARCH LETTERS

Involvement of neutrophil elastase in crescentic glomerulonephritis

To elucidate the role of neutrophils in the tissue damage of crescentic glomerulonephritis (GN), we examined neutrophils infiltrated in renal tissues and the localization of neutrophil elastase (NE), as a neutrophil-derived tissue destructive mediator, using an immunohistochemical technique with antibodies specific for neutrophils and neutrophil elastase; the enzyme histochemical technique (chloroesterase staining) also was used to detect neutrophils. In normal controls, neutrophil infiltration was scarce, and NE was localized in neutrophil cytoplasm. Neutrophils were abundant in crescentic GN and infiltrated in the glomerulus and interstitium; the infiltrating neutrophils were often aggregated. NE was localized in the cytoplasm of neutrophils and also appeared extracellularly (in granular or diffuse patterns) in glomerular necrotizing lesions, crescents, ruptured portions of Bowmans capsules, and in periglomerular and perivascular sites of the interstitium. Moreover, urinary concentration of NE measured by enzyme-linked immunosorbent assay (ELISA) in crescentic GN patients was significantly higher than in normals (93.6 +/- 13.3 v 1.4 +/- 0.5 microg/g x Cr, respectively; P < .001). These data suggest that NE plays a significant role in renal tissue damage, especially in the formation of glomerular necrotizing and crescentic lesions and in periglomerular interstitial lesions of crescentic GN.

Immunosuppressive effect of deoxyspergualin in proliferative glomerulonephritis

A clinical trial of the immunosuppressive drug deoxyspergualin (DSG) was conducted in five patients with various forms of proliferative glomerulonephritis (immunoglobulin A nephropathy in two patients, purpura nephritis in one patient, membranoproliferative glomerulonephritis in one patient, and rapidly progressive glomerulonephritis in one patient). DSG was intravenously administered at 0.25 or 0.5 mg/kg/d for 4 weeks. A marked decrease in proteinuria (to <50% of baseline) was observed in four patients, and the other patient showed a 38% reduction in proteinuria, but the proteinuria was exacerbated again after discontinuation of DSG in three patients during a 4-week follow-up period. Proinflammatory CD16(+) (FcgammaRIII) monocytes disappeared from the peripheral blood during the administration of DSG but reappeared after DSG treatment was discontinued. A significant decrease in urinary macrophage counts that was far more marked than the decrease in peripheral blood monocyte counts was observed after administration of DSG. Interestingly, we also observed that the CD16 marker on the CD14(+) macrophage population in the urine disappeared in response to DSG treatment. These findings suggest that DSG may have a unique effect of suppression of FcgammaRIII expression on monocytes and/or macrophages that may result in amelioration of activated macrophage-mediated glomerulonephritis.

Possible Relationship Between Hyperinsulinemia and Glomerular Hypertrophy in Nephrosclerosis

Hyperinsulinemia is potentially associated with the development of vascular sclerosis. On the other hand, the relationship between hyperinsulinemia and nephrosclerosis has not been elucidated. In this investigation clinicopathological studies were performed in 40 patients with nephrosclerosis, with special attention to the relationship between hyperinsulinemia and glomerular hypertrophy. Forty patients with biopsy-proven nephrosclerosis were divided into two groups by the 75-g oral glucose tolerance test (OGTT): group A, 2-hr plasma glucose concentration > 140 mg/dL (n = 25); group B, 140 < or = 2-hr plasma glucose < 200 mg/dL (n = 15). Patients with diabetes mellitus or diabetic nephropathy were not included. Morphometric analysis of the glomeruli revealed a significantly larger mean glomerular volume in subjects with nephrosclerosis in both subgroups. In addition, the mean glomerular volume was significantly correlated with the fasting insulin level, while no significant correlation was observed between the mean glomerular volume and creatinine clearance or degree of global sclerosis. These results indicate that hyperinsulinemia may be intimately related to glomerular hypertrophy in patients with nephrosclerosis.

Decreased CD4 Lymphocyte Count as a Marker Predicting High Mortality Rate in Managing ANCA Related Rapidly Progressive Glomerulonephritis

As antineutrophil cytoplasmic antibody positive rapidly progressive glomerulonephritis (ANCA-RPGN) has a high risk of end stage renal failure and is a potentially life threatening disease, early aggressive therapy is recommended. However, aggressive immunosuppressive therapy may lead to immunodeficiency and subsequent mortality in the patients with this disease. Therefore, we need the index of immunodeficiency to cure the disease. To evaluate any risk factors, including therapies, on mortality in ANCA-RPGN, we conducted a retrospective investigation on patient survival in 32 patients with ANCA-RPGN by Kaplan-Meier analysis and the Cox regression model. Fourteen patients were treated with leucocytapheresis (LAP group) and the 18 patients were treated by steroid pulse therapy (steroid pulse group) as initial treatment. The patients were chosen for the different therapies at random. Two patients in the LAP group, and eight patients in the steroid pulse group had died within 6 months. The lymphocyte counts and CD4 cell counts after complete course of therapy were lower in the patients who died than in those who survived in the steroid pulse group. Patient survival was higher in the LAP group than in the steroid pulse group, but did not reach statistical significance. Multivariate Cox regression analysis showed that the factors influencing patient survival were initial serum creatinine, LAP therapy, CD4 cell counts, and lymphocytes at the end of treatment. Age, titer of MPO-ANCA, and percent of glomerular crescents were not found to have an effect on the patient survival. We recommend: that early diagnosis should be established, and immunosuppressive therapy may be done with monitoring of the lymphocyte and CD4 cell count.

Steroid Pulse Therapy Combined with Tonsillectomy in IgA Nephropathy Associated with Diabetes mellitus

Ten patients with biopsy-confirmed IgA nephropathy associated with diabetes mellitus underwent dietary weight control and three courses of intravenous pulses of methylprenisolone followed by prednisolone for 6–12 months and tonsillectomy. The average length of the follow-up period was 47.8 (range 30–96) months. As compared with pretreatment values, hematuria, proteinuria, body mass index, and hemoglobin A1c were significantly improved after treatment. There were no significant differences with regard to blood pressure and glycemic blood glucose control. There was no worsening of diabetic retinopathy and nephropathy. During steroid pulse therapy, the patients who were treated with insulin needed a higher dosage of insulin; after steroid pulse therapy, the dosage returned to baseline. Even patients with IgA nephropathy and diabetes mellitus could be treated with combined therapy and showed beneficial responses, it they succeeded in reducing body mass index.

Administration of Triton WR 1339 aggravates chronic aminonucleoside nephrosis.

Katsuya Obara, MD, Second Department of Internal Medicine, Tohoku University, School of Medicine, 1-1 Seiryo-cho, Aobaku, Sendai 980 (Japan) TR or Saline mini obtained before the initial AN administration and on days 10, 24, 42, 54, 66, 78 and 90. TC and TG levels were also assayed before and 1, 2 and 4 days after the initial TR injection. Renal tissues were removed for histology on day 90. Coronal sections were stained with periodic acid-Schiff, and more than 150 glom-eruli from each specimen were examined. Dear Sir, It has recently been suggested that abnormalities in lipid metabolism may play an important role in the pathogenesis of focal glom-erulosclerosis (FGS) [1]. Previous studies [2^‡] have shown that diet-induced hyperlipidemia aggravates various experimental FGS. On the other hand, it is known that Triton WR 1339 (TR), a nonionic detergent, produces hyperlipidemia when injected intravenously into experimental animals [5]. Therefore, we have examined by using the chronic aminonucleoside model whether TR-induced hyperlipidemia also aggravates FGS. Ten-week-old male Sprague-Dawley rats were first uninephrectomized and then injected with puromycin aminonucleoside (AN; 10 mg/day/kg body weight s.c.) for 4 days, and after a 10day interval, again with AN (now 5 mg) for 4 days. Twelve days after the last AN injection, TR at a dose of 250 mg/kg body weight dissolved in 0.9% saline or saline alone was intravenously injected, and the injection was subsequently repeated every 4 days for 2 months (fig. 1). Urine was collected over a 24-hour period. During the urine collection, rats were deprived of food, but had free access to water. Blood was obtained from the tail veins of rats subjected to light ether anesthesia at the end of the 24-hour period. Urinary protein and fasting serum total cholesterol (TC) and triglyceride (TG) levels were