Hiroo Noshiro

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.

Effect of Disopyramide on Initiation of Atrial Fibrillation and Relation to Effective Refractory Period

Electrophysiologic studies were performed before and after intravenous administration of disopyramide (2 mg/kg) to 40 patients with either documented or suspected atrial fibrillation (AF). In control studies, sustained AF (greater than 1 minute), nonsustained AF (1 to 60 seconds) and no AF were found in 14, 18 and 8 patients, respectively. After disopyramide, the ability to initiate AF was totally lost in 18 patients (group A), while 22 patients (group B) showed sustained AF (11 patients) or nonsustained AF (11 patients). The effective refractory period of the atrium was 232 +/- 41 ms in the control study and 266 +/- 49 ms after disopyramide. Atrial functional refractory periods before and after disopyramide were 282 +/- 43 and 317 +/- 48 ms, respectively. The differences and ratios of the refractory periods after and before disopyramide were higher in group A than in group B (p less than 0.001). The prolongation of atrial refractoriness after disopyramide was important to suppress the initiation of AF in group A. In some group B patients, on the other hand, the initiation of AF was promoted after disopyramide. Disopyramide may alter the atrial electrophysiologic substrate required for AF initiation.

Effect of class Ia antiarrhythmic agents on fasciculoventricular fibers

In four patients with fasciculoventricular (FV) fibers, the electrocardiographic and electrophysiologic characteristics were studied based on their response to class Ia antiarrhythmic agents. Three patients had paroxysmal atrial fibrillation, and one showed atrioventricular nodal Wenckebach-type block with dual pathways. Three of the four patients showed complete block of FV fibers after administration of disopyramide 0.28-0.60 mg/kg, procainamide 1.7-2.6 mg/kg, and ajmaline 0.18-0.26 mg/kg, respectively. Normalization in the remaining patient was not seen after disopyramide 2 mg/kg or procainamide 10 mg/kg, but was achieved by ajmaline 0.86 mg/kg. Ventricular preexcitation beats showed initial q waves (3 patients) or a decrease in the height of the r wave (1 patient) in V1, no initial q wave in V6 (4 patients), and ST-T changes (1 patient). Since these findings resemble ischemic change or intraventricular conduction disturbance, drug testing is necessary for precise diagnosis and proper clinical management.

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.

Quantitation of C4 nephritic factor by an enzyme-linked immunosorbent assay

We have developed an enzyme-linked immunosorbent assay (ELISA) for the quantitation of C4 nephritic factor (C4NeF). Incubation of the C4NeF-positive serum from patient M.I. with normal human serum (NHS) in the presence of human aggregated IgG (AHG) resulted in the formation of stable C4-C2 complex. No complex was formed in EDTA or under the condition free of AHG. The reaction mixture was filtered through an ACA 22 column, from which the C4-C2 complex was eluted at the first protein peak. When IgG purified from M.I. serum was incubated with NHS and AHG, C4-C2 complex also increased in proportion to dose of the purified M.I. IgG. These results show that C4NeF in M.I. serum stabilizes C4b2a convertase of the classical complement pathway, and is quantified by the ELISA. C4NeF activity was measured, using the ELISA method, in patients with various glomerular diseases, and found elevated in three of 24 patients with membranoproliferative glomerulonephritis (MPGN) type I and slightly but distinctly positive in seven of 24. No C4NeF was detected in two C3 nephritic factor-positive patients with MPGN type II and six with active systemic lupus erythematosus. The new method was more simple and quantitative than C4b2a stabilization assay for C4NeF.

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.

Alteration of C3 Nephritic Factor in a Patient with Membrano- proliferative Glomerulonephritis Type II

J. Seino, 2nd Department of Internal Medicine, Tohoku University School of Medicine, 1-1 Seiryo-Cho, Aoba-Ku, Sendai 980 (Japan) Dear Sir, C3-nephritic factor (C3NeF) is often found in patients with membranoprolifera-tive glomerulonephritis (MPGN) type II [1]. In plasma, low levels of C3, caused by activation of the alternative pathway of complement, are accompanied by relatively normal levels of Cl, C4, and C2 [2]. Performing immu-nohistological studies, C3 deposition is also frequently observed in the glomeruli. However, the relationship between C3NeF, hypo-complementemia, and immunological renal lesions is still controversial. We observed a case with MPGN type II who developed chronic renal failure and whose C3NeF level decreased and disappeared with progression of chronic renal failure and reappeared after starting hemodialy-sis. The relation between CH50/C3 and C3NeF levels was completely reciprocal during the clinical course of this patient. A 7-year-old girl presented with facial edema and oliguria 2 weeks after catching a common cold in 1975. Heavy proteinuria and slight microhematuria were pointed out by her doctor. There was no family history of any medical diseases. In 1977, a renal biopsy specimen was obtained because of a persistent proteinuria. She was diagnosed as having MPGN by light microscopy, showing lobular formation with mesangial and endocapillary proliferation in all glomeruli. However, the study by electron microscopy demonstrated no dense deposits in the glomerular basement membrane, but only lamellation of the lamina densa. In 1982, a second renal biopsy specimen was obtained because heavy proteinuria and nephrotic syndrome had continued. Electron microscopy revealed typical dense deposits of MPGN type II on the lamina densa in all glomerular basement membranes [3]. A detailed complement profile of this patient was first studied in 1983. Then renal function tests revealed values within normal ranges: serum creatinine 0.6 mg/dl, blood urea nitrogen 11 mg/dl, and creatinine clearance (C„) 96 ml/min. Complement assays showed extremely reduced CH5Π (15 U/ml) and C3 (10 mg/dl) levels (fig. 1), a high titer of C3d, and a normal C4 titer (34 mg/dl).