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Renal disease is a common complication of rheumatoid arthritis (RA) and can occur secondary to RA or be induced by therapeutic agents. Recently, glomerular deposition of galactose-deficient IgA1 (Gd-IgA1) was identified as a feature of primary IgA vasculitis with nephritis (IgA-VN). We herein report a case of IgA-VN in an RA patient whose disease activity was controlled by treatment with etanercept. To distinguish between primary IgA-VN and secondary IgA-VN caused by RA or etanercept, we performed immunostaining of renal biopsy sections with the Gd-IgA1-specific antibody KM55. Positive KM55 staining confirmed the diagnosis of primary IgA-VN in a patient with RA.

Background: Previous studies have recognized risk factors for recurrent IgA nephropathy (r-IgAN) in renal transplantation. However the clinical significance of latent IgA deposition from the donor kidney remains to be determined., Patients and Methods: Between 1992 and 1999, 0-hour allograft biopsies were performed in 510 renal transplantation recipients at the Kidney Center of Tokyo Women's Medical University. Among these 510 patients, there were 49 whose primary disease was identified as IgAN. Among these 49 patients, 13 patients (26.5%) were diagnosed as having r-IgAN based on renal biopsy. We compared risk factors of r-IgAN, including IgA deposition, between the r-IgAN and non-r-IgAN groups., Results: We assessed factors previously reported to be risk factors for r-IgAN, such as follow-up period after transplantation, sex, ages of donors and recipients, donor type, ABO compatible or incompatible transplantation, number of HLA-A, B, and DR mismatches, number of donors with HLA-A2, B35, B46, and/or DR4, duration to end stage renal disease, duration of dialysis, and latent IgA deposition from donor kidneys. Latent IgA deposition was the only risk factor that differed significantly in frequency between patients with and without recurrence (38.5% in r-IgAN group vs. 9.1% in non-r-IgAN group, p = 0.037). Other factors did not differ significantly between the two groups. Clinical factors, such as urinary protein excretion, urinary red blood cell sediment and serum creatinine, were significantly worse and the number of patients who required hemodialysis 5 yr after transplantation was significantly higher in the r-IgAN group than in the non-r-IgAN group (38.5 vs. 5.6%, p = 0.001). Four of the five patients who required hemodialysis in the r-IgAN group had latent IgA deposition from the donor kidney., Conclusion: Our data suggest that 26.5% out of patients with primary IgAN will develop recurrence within 5 yr after transplantation. Latent IgA deposition from the donor kidney was one of the risk factors of r-IgAN and it would lead to the development of r-IgAN. Moreover, r-IgAN will compromise graft survival, especially in cases with latent IgA deposition from the donor kidney.

Immunotactoid glomerulopathy (ITG) demonstrates glomerular deposits that are characterized by highly organized ultrastructure. The deposits appear to be composed of immunoglobulin and complement that were negative for amyloid by Congo red stain. However, it has been difficult to distinguish the difference between ITG and fibrillary glomerulonephritis. In the present study, we performed an immunoelectron microscopic study to identify the factors that seemed to be associated with the glomerular deposits in a case of IgA-dominant ITG. IgA, light chain kappa and fibrinogen were colocalized in association with fibrillar deposits in the extracellular matrix of mesangial cells. Therefore, it is likely that the complex of IgA, light chain kappa and fibrinogen are associated with the formation of highly organized ultrastructural deposits in a case of IgA-dominant ITG.

Background: The adaptation of steroid therapy and the effect of renin-angiotensin-aldosterone system inhibitors (RASIs) for advanced immunoglobulin A nephropathy (IgAN) patients with impaired renal function are still controversial. Methods: We divided 63 IgAN patients with an estimated glomerular filtration rate (eGFR) of <60 ml/min/1.73 m and proteinuria ≥ 0.5 g/day into two groups: the RASI group (RASI, n = 33), treated with RASIs alone; and the combination group (COMBI, n = 30), treated with corticosteroids and RASIs. We analyzed the clinical and histological background, renal survival rate, and the risk factors for progression. Results: Renal function (mean eGFR: COMBI 46.4 vs. RASI 47.0 ml/min/1.73 m), the amount of proteinuria (median: COMBI 1.39 vs. RASI 1.17 g/g creatinine) and histological backgrounds were not significantly different between the groups, but urinary red blood cells (U-RBCs) were significantly higher in the COMBI group than in the RASI group (median: COMBI 30.0 vs. RASI 10.0 counts/high-power field, P = 0.0171). The serial change in proteinuria did not differ until 5 years after treatment, but U-RBCs were significantly decreased in both groups ( P < 0.0001), and eGFR was significantly decreased in the RASI group ( P < 0.001) but not in the COMBI group. The results for each year after treatment did not differ significantly between both groups. The renal survival rate was not significantly different between the groups. There was no independent risk factor for progression by Cox regression analysis. Conclusion: Combination therapy with steroids and RASIs was not superior to monotherapy with RASIs for advanced IgAN with impaired renal function. [ABSTRACT FROM AUTHOR]

Background: A paradigm shift from such toxic 'nonspecific' therapies to selective immunomodulating regimens is necessary for glomerular diseases. Rituximab, which acts by inhibiting CD20-mediated B cell proliferation and differentiation, could be effective in the treatment of nephrotic syndrome as shown in recent reports. Design: To assess the effects of rituximab in patients with primary glomerular diseases, including minimal-change disease, immunoglobulin A (IgA) nephropathy, focal segmental glomerulonephritis, membranous nephropathy and membranoproliferative glomerulonephritis, we performed a prospective trial of the effects of single-dose rituximab therapy in 24 patients. We prospectively evaluated the serum and urinary biochemical parameters before and after 6 months of therapy. Results: In all of the patients studied, depletion of CD19 and CD20 cells was noted, with significant reduction in the degree of proteinuria from 3.7 ± 3.4 g/day at baseline to 1.3 ± 2.0 g/day at 6 months after the drug administration (p = 0.002). However, no significant changes of the serum creatinine, urinary RBC sediment, serum CD4/8 or serum IL-4 levels were observed at 6 months after the drug administration. In subjects with IgA nephropathy, while depletion of CD19 and CD20 cells was noted, no significant change in the severity of proteinuria was observed at 6 months after the drug administration as compared with the level at the baseline. Conclusion: For the treatment of primary glomerular diseases, the use of a single dose of rituximab is demonstrated with no serious adverse events. Further study of the mechanism of action of rituximab in successfully treated patients could encourage new perspectives in the treatment of primary glomerular diseases. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

There are immunoglobulin (Ig)A nephropathy (IgAN) cases showing mesangial IgG and/or IgM deposition, however, their characteristics have remained unknown. Three hundred and eighty-four IgAN patients were divided according to the existence of mesangial IgG and/or IgM deposition: IgA deposition only (A group, n = 77); IgA and IgM deposition (AM group, n = 114); IgA and IgG deposition (AG group, n = 36); and IgA, IgG and IgM deposition (AGM group, n = 157). Clinical and histological findings, and outcomes were examined and compared among these four groups. At the time of renal biopsy, serum creatinine was significantly higher in the A and AM group, however, creatinine clearance did not differ among the four groups. The ratio of glomerular obsolescence was significantly higher in the AM group than in the A and AGM group, and the ratio of glomerular tuft adhesion was significantly higher in the AM, AG and AGM group than in the A group. However, the other clinical and histological findings, electron microscopic findings and renal survivals did not differ among the four groups. Proteinuria was independently associated with an increase in risk of doubling of creatinine ( P = 0.005), however, IgG and IgM depositions were not by multivariate Cox regression. The presence of other Ig classes, besides IgA deposits, was found to be associated with glomerular obsolescence and tuft adhesions, however, without any effect on renal survival in IgAN. Relationships between glomerular immunoglobulin deposition patterns and clinical or pathological findings in immunoglobulin A nephropathy were examined in this study of 384 immunoglobulin A nephropathy patients [ABSTRACT FROM AUTHOR]

Background: Evaluating the frequency of renal disease according to sex, age, time period and ethnicity is of considerable importance. Methods: Disease frequency was evaluated in a total of 2,404 cases that had undergone a renal biopsy at Tokyo Women’s Medical University between 1979 and 2008. Results: The overall frequencies of primary glomerulonephritis (GN) and secondary GN were 77.8 and 14.4%, respectively. Primary GN and nephrosclerosis occurred more frequently among men, while secondary GN was more frequent among women. Primary GN decreased and secondary GN increased with advancing age. Immunoglobulin A nephropathy was the most common form of primary GN during each time period and also gradually increased over time (44.4–57.4%). The most common form of secondary GN was lupus nephritis (59.0%); this disease was commonly observed in women (79.3%) but not as frequently among men (27.9%). Our data regarding the frequencies of each form of primary GN were almost the same as data from other regions of Japan and East Asia but were quite different from data originating in West Asia and South America. Conclusions: Our epidemiological results may be useful for analyzing the morbidity of renal disease. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Steroid therapy appears to be beneficial in patients of immunoglobulin A nephropathy (IgAN), as it causes a reduction in the proteinuria and improves the renal survival. Methods: A retrospective review of the 5 year follow-up data of 60 patients with IgAN who were treated with steroids was conducted. Steroid non-responders were defined as patients in whom the primary end-point of a 30% decrease of the estimated glomerular filtration rate from baseline was reached. The patients were divided into two groups, namely, the steroid responder group ( n = 47) and the steroid non-responder group ( n = 13), and the clinicopathophysiological characteristics were compared between the two groups. Results: Significant decrease of the proteinuria was observed in the responder group over the 5 year follow-up period, whereas no significant change of the urinary protein excretion was observed in the non-responder group during the same period. In regard to the pathological findings, significantly higher ratios of glomerular obsolescence and glomerular tuft adhesion to the Bowman's capsule, and significantly higher severity of interstitial fibrosis at the time of diagnosis in the non-responder group than in the responder group were found. The rates of glomerular obsolescence and glomerular tuft adhesion to the Bowman's capsule, the severity of interstitial fibrosis, serum albumin and urinary protein excretion were identified as independent risk factors influencing the rate of renal function deterioration. Conclusion: To develop effective therapeutic modalities, it is important to have a thorough understanding of the clinicopathophysiological characteristics of IgAN patients showing poor treatment response to steroids (non-responder group in this study). [ABSTRACT FROM AUTHOR]

Previously, we discovered single-nucleotide polymorphisms (SNPs) associated with Immunoglobulin A (IgA) nephropathy in selectin genes, which were 712C>T(P238S) in L selectin, –642A>G in the promoter region of L selectin, and 1402C>T(H468Y) in E selectin. Interestingly, these SNPs were in nearly complete linkage disequilibrium, thus two haplotypes, disease-associated TGT and wild-type (Wt) CAC, were constructed. To investigate the functional significance of TGT haplotype, a stable CHO transfectant expressing a P238S-L-selectin variant (CHO-varL) and a recombinant adenovirus vector containing an H468Y-E-selectin variant (Ad-varE) were established and compared to their Wt counterparts. Under flow, CHO-varL exhibited significantly less adhesion over IL-1β-activated HUVEC monolayers compared to CHO-wtL. Furthermore, a luciferase reporter construct, containing a promoter region of the L-selectin variant (luc-varL), exhibited significantly less transcription activity compared to Wt (luc-wtL). These results suggest that the adhesive interactions and expression level of L selectin in disease-associated haplotypes are significantly compromised, indicating a potential role of these SNPs in the pathogenesis of inflammatory diseases, including IgA nephropathy. [ABSTRACT FROM AUTHOR]

Immunoglobulin A nephropathy (IgAN) is a primary glomerulonephritis of common incidence world-wide whose etiology and pathogenesis remain unresolved, although genetic factors are assumed to be involved in the development and progression of this disease. To identify genetic variations that might confer susceptibility to IgAN, we performed a case-control association study involving 389 Japanese IgAN patients and 465 controls. Genome-wide analysis of approximately 80,000 single-nucleotide polymorphisms (SNPs) identified a significant association between IgAN and six SNPs located in the PIGR (polymeric immuoglob-ulin receptor) gene at chromosome 1q31-q41. One of them, PIGR-17, caused an amino-acid substitution from alanine to valine at codon 580 (χ[SUB2]=13.05, P=0.0003, odds ratio [OR] =1.59, 95% confidence interval [95% CI] =1.24-2.05); the OR of minor homozygotes to other was 2.71 (95% CI=1.31-5.61). Another SNP, PIGR-2, could affect promoter activity (χ[SUB2]=11.95, P=0.00055, OR=1.60, 95% CI=1.22- 2.08); the OR of minor homozygotes to others was 2.08 (95% CI=0.94-4.60). Pairwise analyses demonstrated that all six SNPs were in almost complete linkage disequilibrium. Biopsy specimens from IgAN patients were positively stained by antibody against the secretory component of PIGR, but corresponding tissues from non-IgAN patients were not. Our results suggest that a gene associated with susceptibility to IgAN lies within or close to the PIGR gene locus on chromosome 1q in the Japanese population. [ABSTRACT FROM AUTHOR]

Although intensive efforts have been undertaken to elucidate the genetic background of immunoglobulin A ne-phropathy (IgAN), genetic factors associated with the pathogenesis of this disease are still not well understood. We designed a case-control association study that was based on linkage disequilibrium among single-nucleotide polymorphisms (SNPs) in the selectin gene cluster on chromosome 1q24-25, and we found two SNPs in the E-selectin gene (SELE8 and SELE13) and six SNPs in the L-selectin gene (SELL1, SELL4, SELL5, SELL6, SELL10, and SELL11) that were significantly associated with IgAN in Japanese patients. All eight SNPs were in almost complete linkage disequilibrium. SELE8 and SELL10 caused amino acid substitutions from His to Tyr and from Pro to Ser (x² = 9.02, P = .0026, odds ratio = 2.73 [95% confidence interval [CI] 1.38 - 5.38] for His-to-Tyr substitutions; x² = 17.4, P = .000031, odds ratio = 3.61 [95% CI 1.91 - 6.83] for Pro-to-Ser substitutions), and SELL1 could affect promoter activity of the L-selectin gene (x² = 19.5, P = .000010, odds ratio = 3.77 [95% CI 2.02 - 7.05].) The TGT haplotype at these three loci was associated significantly with IgAN (x² = 18.67, P = .000016, odds ratio = 1.88 [95% CI 1.41-2.51]). Our results suggest that these eight SNPs in selectin genes may be useful for screening populations susceptible to the IgAN phenotype that involves interstitial infiltration. [ABSTRACT FROM AUTHOR]