Increase of Peripheral Blood B Cells with Fc Receptor for IgA in Patients with IgA Nephropathy

A B-cell subset with Fc receptors for IgA (B alpha cells) has been observed in human peripheral blood. To investigate aberrations of B cells in a diseased state, the percentages of B alpha cells were enumerated in peripheral blood from patients with IgA nephropathy, which is characterized by preponderant deposition of IgA-dominant immune complexes in the glomerular mesangial area. The present study showed a significant increase in B alpha cells in peripheral blood from patients with IgA nephropathy but not in those with chronic proliferative glomerulonephritis without mesangial IgA deposition. Most Fc alpha R-bearing cells were observed in surface IgA bearing lymphocytes. No linear correlation was observed between the levels of serum IgA and the percentages of B alpha cells. The addition of aggregated IgA to cultures did not induce Fc alpha R-bearing B cells in vitro. It is postulated that B alpha cells might have some pathogenetic role in the development of IgA nephropathy and that some antigenic stimuli might play a role in the increase of peripheral blood B alpha cells in patients with IgA nephropathy.     

Clinical Significance of Consecutive Shocks in Patients with Left Ventricular Dysfunction Treated with Implantable Cardioverter Defibrillators

The purpose of the present study was to determine the clinical significance of consecutive automatic shocks delivered by implantable cardioverter defibrillators (ICDs). Sixty-four patients who received ICDs at our institution between January 1990 and July 1997 were included in this study. There were 53 men and 11 women with a mean age of 50 ± 14 years. During a follow-up period ranging between 0.2 and 73 months (mean 23 ± 21 months), 17 patients received consecutive shocks (group A), 29 patients received single shocks (group B), and 18 patients received no ICD therapy (group C). Clinical characteristics, episodes of ICD therapy, and prognosis were compared among the three groups. There were no significant differences among the three groups with regard to clinical characteristics, time to first ICD therapy, number of antitachycardia pacing episodes, or frequency of inappropriate discharges. The mortality rate was higher in group A than in groups B and C (P = 0.0021). The sensitivity of consecutive shocks in predicting death was 70%, the specificity was 88%, and the predictive accuracy was 81% in patients with left ventricular ejection fractions < 35%. In summary, consecutive shocks are a clinically important event in patients with ICDs. Specifically, patients who receive consecutive shocks and have a depressed left ventricular function should be considered particularly high risk.     

Value of pathological grading in prediction of renal survival in IgA nephropathy

Summary: In order to clarify the most reliable risk factor to predict renal outcome, 206 patients with IgA nephropathy were studied for mean period of 9.2 years. the histopathological changes of this disease using light microscopy were divided into four grades (grade 1–4). These grades included glomerular, interstitial and vascular lesions. the cumulative rate of kidney survival progressing to end stage renal failure (ESRF) in all patients was 94% at 5 years, 87% at 10 years and 80% at 15 years after renal biopsy. None of the patients in grade 1 reached ESRF. the cumulative rate of kidney survival in grade 2 was 99% at 5 years, 98% at 10 years and 89% at 15 years after renal biopsy. In grade 3, it was 94% at 5 years, 79% at 10 years and 75% at 15 years. In grade 4 it was 53% at 5 years, 33% at 10 years and 22% at 15 years after renal biopsy. Forward stepwise multivariate regression analysis revealed that, in addition to the histopathological findings, three more risk factors were found to influence actuarial renal survival rate. These factors were: (i) the levels of serum creatinine; (ii) the level of serum albumin; and (iii) the amount of proteinuria at the time of renal biopsy. In parallel studies, forward stepwise multivariate regression analysis isolated three risk factors that influenced the progression of the reciprocal of serum creatinine. These factors were: (i) the levels of total protein; (ii) the degree of our pathological grading; and (iii) the amount of proteinuria. It was concluded that our pathological grading was useful as a prognostic parameter because of its simplicity and availability in routine clinical activities.     

Intrarenal synthesis of IL-6 in IgA nephropathy

Summary: Recent in vitro studies have shown the synthesis of interleukin-6 (IL-6) in glomerular mesangial and epithelial cells, and suggested the involvement of IL-6 in mesangial proliferative glomerulonephritis. However, the expression site of IL-6 mRNA in renal tissue of IgA nephropathy (IgAN), the most common chronic mesangial proliferative glomerulonephritis, remains obscure. to localize IL-6 mRNA in renal biopsy specimens of IgAN, we used nonradioactive in situ hybridization (ISH) developed in our laboratory, sensitive in detecting individual cells positive for a specific mRNA. In some sections, periodic acid-Schiff staining was performed after ISH in order to identify the topographical relation between IL-6 mRNA positive cells and glomerular basement membrane and mesangial area. In situ hybridization for IL-6 mRNA and immunohistochemistry for CD3 and CD68, markers for lymphocytes and monocytes, respectively, were also performed on serial sections to examine the contribution of infiltrated mononuclear cells to cells positive for IL-6 mRNA in glomeruli. Glomerular resident cells, including glomerular mesangial and epithelial cells and cells of Bowman's capsule, as well as tubular epithelial cells and infiltrated mononuclear cells expressed IL-6 mRNA. We also compared the localization of IL-6 mRNA and protein and showed different distribution between the gene product and protein. the expression of IL-6 mRNA correlated with the degree of mesangial cell proliferation and tubulointerstitial changes. Our results indicate that IL-6 is synthesized in renal tissues of IgAN and suggest that the increased IL-6 expression may be important in the pathogenesis of IgAN.     

Cellular immunity in IgA nephropathy

Summary: A comprehensive study on the role of various cytokines in the regulation of IgA synthesis and progression of glomerular damage in IgA nephropathy was attempted. Semi-quantitative PCR for IL-I, IL-2, IL-4, IL-6, IL-10, IL-12, interferon (IFN)-γ, transforming growth factor (TGF)-β, tumour necrosis factor (TNF)-α, platelet derived growth factor (PDGF) and monocyte chemoattractant protein-1 (MCP-1) was performed. In parallel studies, protein production of some cytokines was also determined. It was demonstrated that IL-4, IFN-γ and presumably IL-12 expressed predominantly in peripheral blood mononuclear cells in patients with IgA nephropathy. Some positive correlations between the mRNA expression of these cytokines and the degree of tissue damage were observed. It was concluded that these cytokines may play some role in the alteration of cellular immunity in this disease.     

In situ hybridization studies of stromelysin and tissue inhibitor of metalloproteinase 1 in IgA nephropathy

Summary: Accumulation of the extracellular matrix (ECM) in IgA nephropathy (IgAN) is thought to cause deterioration of glomerular function. Stromelysin and tissue inhibitor of matrix proteinase 1 (TIMP1) may play an important role in the turnover of the glomerular ECM. However, the expression of these enzymes in human renal tissues remains undefined. In the present study, non-radioactive in situ mRNA hybridization, which permitted the analysis at a cellular level, was performed to localize stromelysin and TIMP1 in renal tissue of IgAN. We also determined the percentage of cells positive for stromelysin or TIMP1 mRNA among intraglomerular cells. A total of 16 patients with IgAN were examined, including eight patients with severe histopathological changes and eight with mild changes. Three patients without glomerular disease were also studied. Stromelysin and TIMP1 mRNA were weakly expressed in the mesangium of normal kidneys and IgAN renal tissues with mild damage. However, the expression of both mRNA was significantly increased in the area of mesangial proliferation, in glomerular epithelial cells and in Bowman's capsule of advanced lesions. Several cells in the area of mesangial proliferation were double positive for stromelysin and TIMP1 mRNA, while certain cells positive for stromelysin mRNA did not express TIMP1 mRNA. In the interstitium, epithelial cells of certain tubules and some mononuclear cells were positively stained for these mRNA, especially in advanced lesions. Our results indicated that stromelysin and TIMP1 genes were expressed in glomerular resident cells, tubular epithelial cells and infiltrated mononuclear cells in IgAN, and their expression was enhanced in advanced tissue damage. the demonstration of a co-expression and discordant expression of the genes indicates that each gene expression may be regulated in a cell type-specific manner and that it could also be altered by cellular environmental factors.