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Histological classification is essential in the clinical management of immunoglobulin A nephropathy (IgAN). However, there are limitations in predicting the prognosis of IgAN based on histological information alone, which suggests the need for better prognostic models. Therefore, we defined a prognostic model by combining the grade of clinical severity with the histological grading system by the following processes. We included 270 patients and explored the clinical variables associated with progression to end-stage renal disease (ESRD). Then, we created a predictive clinical grading system and defined the risk grades for dialysis induction by a combination of the clinical grade (CG) and the histological grade (HG). A logistic regression analysis revealed that the 24-h urinary protein excretion (UPE) and the estimated glomerular filtration rate (eGFR) were significant independent variables. We selected UPE of 0.5 g/day and eGFR of 60 ml/min/1.73 m 2 as the threshold values for the classification of CG. The risk of progression to ESRD of patients with CG II and III was significantly higher than that of patients with CG I. The patients were then re-classified into nine compartments based on the combination of CG and HG. Furthermore, the nine compartments were grouped into four risk groups. The risk of ESRD in the moderate, high, and super-high-risk groups was significantly higher than that in the low-risk group. Herein, we are giving a detailed description of our grading system for IgA nephropathy that predicted the risk of dialysis based on the combination of CG and HG.

Background: High circulating levels of soluble tumor necrosis factor receptors (TNFRs: TNFR1, TNFR2) predict renal function decline in a variety of kidney diseases. Tonsillectomy with steroid pulse (TSP) therapy has been reported as a remission induction therapy in IgA nephropathy (IgAN), mainly in Japan. However, little is known about whether TNFR levels change after TSP therapy in patients with IgAN., Methods: Two hundred twenty-three patients with IgAN were stratified according to the estimated glomerular filtration rate (eGFR): Group I (eGFR ≥ 60 mL/min/1.73 m 2 , n = 172) and Group II (eGFR < 60 mL/min/1.73 m 2 , n = 51). We measured serum TNFR levels with immunoassay in all patients at the time of renal biopsy, and also in patients whose samples just before the first (after tonsillectomy) (n = 34) and/or the third steroid pulse therapy (n = 77) were available., Results: The TNFR levels were significantly higher in Group II than in Group I. A significant negative correlation was observed between TNFR levels and eGFR at baseline (TNFRs: r > -0.50). In multivariate logistic regression analysis, both TNFRs were associated with renal function decline, independent of age and uric acid levels. Proteinuria and hematuria remarkably improved after TSP therapy, as expected. In comparison with baseline TNFR levels, the levels of TNFR2, but not TNFR1, decreased significantly just before the third steroid pulse therapy, although both levels did not change after tonsillectomy., Conclusions: The TNFR2 level did not change after tonsillectomy alone but decreased significantly after steroid pulse therapy in patients with IgAN.

We examined the pathogenesis of glomerular damage in Th2 type-dependent GATA-3 transgenic (GATA-3 Tg) mice with IgA nephropathy (IgAN). GATA-3 Tg mice were immunized orally using OVA plus cholera toxin B (CTB), and measurement of the serum IgA antibody level and histopathological examination were performed. Marked increases in the serum levels of OVA-specific IgA antibody, IgA and IgG, C3 deposits analogous to those seen in IgAN, and expansion of the matrix in association with mesangial cell proliferation were observed. Furthermore, glomerular IgA deposits were co-localized with mannan-binding lectin (MBL) deposits, which might actually have been abnormal IgA deposits. In GATA-3/TCR-Tg mice that had been orally sensitized with CTB plus OVA and were re-stimulated with OVA in vitro, cultured Peyer's patch cells showed the enhanced production of IL-5 and supernatants from cultures of spleen cells showed a reduction of TGF-β production with a simultaneous increase in IL-2 production and the recovery of IFN-γ formation. The amount of TGF-β produced by the spleen cells was found to be correlated with the amount of IFN-γ and IL-IL-2 produced by the cells. Also, the percentage of regulatory T cells (Treg) in the spleens of mice sensitized with OVA plus CTB was lower than that in mice orally sensitized with OVA alone. These results suggest that the increased production of IL-5 from Peyer's patch cells (PPc) and the restored Th1-type immune response might cause the production of abnormal IgA and might induce the deposition of IgA in glomeruli., (Copyright © 2015 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: The impact of being overweight remains unclear in Asian populations that tend to be lean. The objective of this study is to clarify the impact of body mass index (BMI) and metabolic factors on the prognosis of Japanese patients with IgA nephropathy (IgAN)., Methods: A total of 193 patients with IgAN were divided into three groups equally according to BMI: Group L (lean group, BMI: 15.6-20.1 kg/m(2) ), Group M (middle group, BMI: 20.2-23.0 kg/m(2) ), and Group O (obesity group, BMI: 23.1-31.9 kg/m(2) ). Clinical data at the time of renal biopsy and the progression of the patients after renal biopsy were analyzed., Results: At the time of renal biopsy, hypertension, dyslipidemia, hyperuricemia, and hypercomplementemia in Group O were more significant compared with those in Group L and/or Group M. Uric acid, triglyceride, C3, C4, high-density lipoprotein cholesterol, serum creatinine, systolic blood pressure (BP), and diastolic BP were significantly correlated with BMI. In Group O, the remission of urinary protein over 5 years was significantly delayed using a log-rank test. At the final observation, the BMI of each group was as similar as that at renal biopsy. The patients with aggressive therapy, such as steroid therapy and/or tonsillectomy in Group O did not have major side effects, except for a slight elevation of total cholesterol and low-density lipoprotein cholesterol., Conclusion: Even slightly high BMI seems to be a risk factor for progress in Japanese patients with IgAN., (© 2014 Wiley Periodicals, Inc.)

Background: The TNF-like weak inducer of apoptosis (TWEAK) contributes to kidney inflammation producing secretion by renal cells. The present study examined whether the level of TWEAK is associated with histologic findings in patients with IgA nephropathy (IgAN)., Methods: The levels of urinary TWEAK (uTWEAK) from 116 IgAN patients, 50 non-IgA kidney disease patients, and 50 healthy individuals were measured by ELISA. Histological findings of renal biopsy specimens of patients with IgAN were evaluated according to the Oxford classification and histological classification for IgAN in Japan. We investigated the expression of TWEAK/Fn14 in renal tissues of those patients and assessed the effect of TWEAK in glomerular mesangial cells and podocytes., Results: The levels of uTWEAK in the patients with IgAN and other renal diseases were significantly higher than in the healthy controls (P < 0.001). In the IgAN patients, the levels of uTWEAK correlated significantly with urinary protein excretion and extracapillary proliferation (r = 0.54, P < 0.001 and r = 0.32, P < 0.001, respectively). In a comparison of the levels of uTWEAK at diagnosis with that of follow-up, the levels of uTWEAK in patients with clinical and partial remission decreased significantly. We showed not only increased expression of both TWEAK and Fn14 in IgAN patients with glomerular crescents but also TWEAK-induced cell motility in podocytes., Conclusions: The relationship between the levels of uTWEAK and clinicopathological findings observed in this study suggests that TWEAK/Fn14 system affects crescent formation and proteinuria in patients with IgAN.

Background and Objectives: Megalin is highly expressed at the apical membranes of proximal tubular epithelial cells. A urinary full-length megalin (C-megalin) assay is linked to the severity of diabetic nephropathy in type 2 diabetes. This study examined the relationship between levels of urinary C-megalin and histological findings in adult patients with IgA nephropathy (IgAN)., Design, Setting, Participants, & Measurements: Urine samples voided in the morning on the day of renal biopsy were obtained from 73 patients with IgAN (29 men and 44 women; mean age, 33 years) and 5 patients with membranous nephropathy (MN). Renal pathologic variables were analyzed using the Oxford classification of IgAN, the Shigematsu classification and the Clinical Guidelines of IgAN in Japan. The levels of urinary C-megalin were measured by sandwich ELISA., Results: Histological analysis based on the Oxford classification revealed that the levels of urinary C-megalin were correlated with mesangial hypercellularity in IgAN patients (OR = 1.76, 95% CI: 1.04-3.27, P<0.05). There was a significant correlation between the levels of urinary C-megalin and the severity of chronic extracapillary abnormalities according to the Shigematsu classification in IgAN patients (β = 0.33, P = 0.008). The levels of urinary C-megalin were significantly higher in all risk levels of IgAN patients requiring dialysis using the Clinical Guidelines of IgAN in Japan than in the control group. The levels of urinary C-megalin were significantly higher in the high risk and very high risk grades than in the low risk grade (P<0.05). The levels of urinary C-megalin were significantly higher in MN patients compared to the control group., Conclusions: The levels of urinary C-megalin are associated with histological abnormalities in adult IgAN patients. There is a possibility that urinary C-megalin is an independent predictor of disease progression of IgAN. In addition, our results suggest that urinary C-megalin is a marker of glomerular abnormalities in various glomerular diseases as well as IgAN.

Whether IgA nephropathy is attributable to mesangial IgA is unclear as there is no correlation between intensity of deposits and extent of glomerular injury and no clear mechanism explaining how these mesangial deposits induce hematuria and subsequent proteinuria. This hinders the development of a specific therapy. Thus, precise events during deposition still remain clinical challenge to clarify. Since no study assessed induction of IgA nephropathy by nephritogenic IgA, we analyzed sequential events involving nephritogenic IgA from IgA nephropathy-prone mice by real-time imaging systems. Immunofluorescence and electron microscopy showed that serum IgA from susceptible mice had strong affinity to mesangial, subepithelial, and subendothelial lesions, with effacement/actin aggregation in podocytes and arcade formation in endothelial cells. The deposits disappeared 24-h after single IgA injection. The data were supported by a fluorescence molecular tomography system and real-time and 3D in vivo imaging. In vivo imaging showed that IgA from the susceptible mice began depositing along the glomerular capillary from 1 min and accumulated until 2-h on the first stick in a focal and segmental manner. The findings indicate that glomerular IgA depositions in IgAN may be expressed under the balance between deposition and clearance. Since nephritogenic IgA showed mesangial as well as focal and segmental deposition along the capillary with acute cellular activation, all glomerular cellular elements are a plausible target for injury such as hematuria.

Background: The primary abnormal manifestation in immunoglobulin A nephropathy (IgAN) is recurring bouts of hematuria with or without proteinuria. Although immunohistochemical analysis of renal biopsy tissue remains the gold standard not only for diagnosis but also for evaluating the activity of IgAN, new sensitive and reasonably specific noninvasive tests are emerging to guide therapeutic strategy applicable to all stages of IgAN. The present study examined serum levels of galactose-deficient IgA1 (Gd-IgA1) and its immune complex (IgA/IgG-IC) as noninvasive markers for the disease activity., Methods: We enrolled 50 IgAN patients (male 40 %, median age 37 years) showing complete or partial clinical remission after steroid pulse therapy with tonsillectomy (TSP) whose clinical data and serum could be followed up for 3-5 years., Results: Cross-sectional analysis revealed that the degree of hematuria and proteinuria were significantly associated with levels of Gd-IgA1 and levels of IgA/IgG-IC. Longitudinal analysis further showed that from the group of 44 patients with heavy hematuria before TSP, 31 patients showed complete disappearance of hematuria (group A), but the remaining patients did not (group B). Although the levels of Gd-IgA1 and IgA/IgG-IC in the two groups before TSP were similar, percentage decrease of Gd-IgA1 and IgA/IgG-IC levels in group A was significantly higher than in group B., Conclusion: Disease activity of IgAN assessed by hematuria and proteinuria correlated with serum levels and changes of Gd-IgA1 and IgA/IgG-IC. These new noninvasive disease activity markers can be useful for future activity scoring system and guiding therapeutic approaches.

Background: The study aim was, for the first time, to conduct a multicenter randomized controlled trial to evaluate the effect of tonsillectomy in patients with IgA nephropathy (IgAN)., Methods: Patients with biopsy-proven IgAN, proteinuria and low serum creatinine were randomly allocated to receive tonsillectomy combined with steroid pulses (Group A; n = 33) or steroid pulses alone (Group B; n = 39). The primary end points were urinary protein excretion and the disappearance of proteinuria and/or hematuria., Results: During 12 months from baseline, the percentage decrease in urinary protein excretion was significantly larger in Group A than that in Group B (P < 0.05). However, the frequency of the disappearance of proteinuria, hematuria, or both (clinical remission) at 12 months was not statistically different between the groups. Logistic regression analyses revealed the assigned treatment was a significant, independent factor contributing to the disappearance of proteinuria (odds ratio 2.98, 95% CI 1.01-8.83, P = 0.049), but did not identify an independent factor in achieving the disappearance of hematuria or clinical remission., Conclusions: The results indicate tonsillectomy combined with steroid pulse therapy has no beneficial effect over steroid pulses alone to attenuate hematuria and to increase the incidence of clinical remission. Although the antiproteinuric effect was significantly greater in combined therapy, the difference was marginal, and its impact on the renal functional outcome remains to be clarified., (© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Although serum under-O-glycosylated IgA1 in IgA nephropathy (IgAN) patients may deposit more preferentially in glomeruli than heavily-O-glycosylated IgA1, the relationship between the glomerular IgA deposition level and the O-glycan profiles of serum IgA1 remains obscure., Methods: Serum total under-O-glycosylated IgA1 levels were quantified in 32 IgAN patients by an enzyme-linked immunosorbent assay (ELISA) with Helix aspersa (HAA) lectin. Serum under-O-glycosylated polymeric IgA1 (pIgA1) was selectively measured by an original method using mouse Fcα/μ receptor (mFcα/μR) transfectant and flow cytometry (pIgA1 trap). The percentage area of IgA deposition in the whole glomeruli (Area-IgA) was quantified by image analysis on the immunofluorescence of biopsy specimens. Correlations were assessed between the Area-IgA and data from HAA-ELISA or pIgA1 trap. The relationships between clinical parameters and data from HAA-ELISA or pIgA1 trap were analyzed by data mining approach., Results: While the under-O-glycosylated IgA1 levels in IgAN patients were significantly higher than those in healthy controls when measured (p<0.05), there was no significant difference in under-O-glycosylated pIgA1. There was neither a correlation observed between the data from HAA-ELISA and pIgA1 trap (r2=0.09) in the IgAN patients (r2=0.005) nor was there a linear correlation between Area-IgA and data from HAA-ELISA or the pIgA1 trap (r2=0.005, 0.03, respectively). Contour plots of clinical parameters versus data from HAA-ELISA and the pIgA1 trap revealed that patients with a high score in each clinical parameter concentrated in specific areas, showing that patients with specific O-glycan profiles of IgA1 have similar clinical parameters. A decision tree analysis suggested that dominant immune complexes in glomeruli were consisted of: 1) IgA1-IgG and complements, 2) pIgA1 and complements, and 3) monomeric IgA1-IgA or aggregated monomeric IgA1., Conclusions: Serum under-O-glycosylated IgA1 levels are not correlated with glomerular IgA deposition based upon heterogeneity in the composition of glomerular immune complexes in IgAN patients.

Background: The current (2012) histological classification of immunoglobulin A nephropathy was established using a case-control study of 287 patients. However, the risk of progression to end-stage renal disease (ESRD) has not been validated for the previous (2002) classification. This study aimed to determine whether the previous classification could identify the risk of long-term renal outcome through re-analysis of the 2012 cohort., Methods: On the basis of the 2002 classification, namely 'good prognosis', 'relatively good prognosis', 'relatively poor prognosis', and 'poor prognosis', we examined the clinical data at the time of biopsy, the correlation between the 2002 classification and long-term renal outcomes, and a patient-by-patient correlation between the 2002 and 2012 classification systems. This was performed by analyzing samples from the 287 patients used to establish the 2012 classification., Results: The rate of decline of estimated glomerular filtration rate was greater and the odds ratio of progression to ESRD was higher in the 'poor prognosis' group. In contrast, the odds ratio for renal death was comparable between the groups described as 'relatively poor prognosis' and 'relatively good prognosis' in the 2002 classification. Many patients in the 2002 classification were classified with a lower histological grade in the current classification, but none were classified with a higher grade., Conclusions: The 2002 classification could also identify the risk of progression to ESRD. However, it was overestimated for patients in the 'poor prognosis' group in the 2002 classification, as that group included patients with milder histological damage.

Background: Recent studies have shown that galactose-deficient IgA1 (GdIgA1) has an important role in the pathogenesis of IgA nephropathy (IgAN). Although emerging data suggest that serum GdIgA1 can be a useful non-invasive IgAN biomarker, the localization of nephritogenic GdIgA1-producing B cells remains unclear. Recent clinical and experimental studies indicate that immune activation tonsillar toll-like receptor (TLR) 9 may be involved in the pathogenesis of IgAN. Here we assessed the possibility of GdIgA1 production in the palatine tonsils in IgAN patients., Methods: We assessed changes in serum GdIgA1 levels in IgAN patients with clinical remission of hematuria and proteinuria following combined tonsillectomy and steroid pulse therapy. Further, the association between clinical outcome and tonsillar TLR9 expression was evaluated., Results: Patients (n = 37) were divided into two groups according to therapy response. In one group, serum GdIgA1 levels decreased after tonsillectomy (59%) alone, whereas in the other group most levels only decreased after the addition of steroid pulse therapy to tonsillectomy (41%). The former group showed significantly higher tonsillar TLR9 expression and better improvement in hematuria immediately after tonsillectomy than the latter group., Conclusions: The present study indicates that the palatine tonsils are probably a major sites of GdIgA1-producing cells. However, in some patients these cells may propagate to other lymphoid organs, which may partially explain the different responses observed to tonsillectomy alone. These findings help to clarify some of the clinical observations in the management of IgAN, and may highlight future directions for research.

Background: A wide variety of treatments, including tonsillectomy and steroid pulse therapy (TSP), are performed for the various stages of IgA nephropathy (IgAN) in Japan. However, the current status of treatments for IgAN patients in Japan is still unclear. The objective of the present study was to investigate the current status of treatments for IgAN patients., Methods: A nationwide survey was conducted in 2008 by sending questionnaires to the 1,194 teaching hospitals of the Japanese Society of Nephrology (JSN) via Progressive Renal Diseases Research, Research on intractable disease, from the Ministry of Health, Labour and Welfare of Japan., Results: Among the total 376 hospitals (31.4 %) that responded, 188 hospitals (66.2 % in the internal medicine departments) performed TSP, out of which 137 hospitals (61.4 %) had begun to perform TSP in the period from 2004 to 2008. The following two major steroid pulse protocols in TSP were used: (1) three cycles over 3 consecutive weeks and (2) three cycles every 2 months. Approximately 68 % of pediatric hospitals (68 hospitals) performed combination therapy with prednisolone, azathioprine, heparin-warfarin and dipyridamole. The clinical remission rates for hematuria and proteinuria after TSP tended to be higher than those following other corticosteroid therapies. Almost all hospitals prescribed antiplatelet agents and renin angiotensin system inhibitor (RAS-I)., Conclusion: In addition to popular treatments such as antiplatelet agents and RAS-I, TSP is becoming a standard treatment for adult IgAN patients in Japan.

Background: It has been reported that podocytopenia has been occurring with increasing disease severity in patients with IgA nephropathy (IgAN). Dendrin is localized at the slit diaphragm (SD) in podocytes. We showed that dendrin translocates to the nucleus of injured podocytes in experimental nephritis and the nuclear dendrin promotes podocyte apoptosis. It is still unknown whether dendrin translocates from the SD to podocyte nucleus in IgAN. We investigated the presence of nuclear dendrin in patients with IgAN and the association between the translocated dendrin to the podocyte nucleus and disease activity., Methods: Fourteen adult patients with IgAN were enrolled. The pathological parameters were analyzed. Immunostaining of renal biopsy specimens and urinary sediments from IgAN or minimal change nephrotic syndrome (MCNS) as the control was performed., Results: A positive correlation was observed between an acute extracapillary change and the number of dendrin-positive nuclei. The location of dendrin in the nuclei was found in urinary podocytes of IgAN. The number of dendrin-positive nuclei in urinary podocytes of IgAN was significantly higher than that of MCNS. Urinary podocytes, which expressed the apoptosis marker annexin V, were also detected in IgAN. The translocation of dendrin to the podocyte nucleus as well as strong cathepsin L staining were detected in the glomeruli of IgAN., Conclusion: An increasing number of dendrin-positive nuclei in the glomeruli suggest acute glomerular injury in IgAN. Apoptotic podocytes were detectable in the urine of IgAN. It appears that the translocation of dendrin to the podocyte nuclei enhances podocyte apoptosis in acute glomerular injury and leads to podocytopenia in patients with IgAN.

Background: The aim of the present study was to explore the significance of extraglomerular (Bowman's capsule and/or arteriole) C3 (ex-C3) deposits in IgA nephropathy (IgAN)., Methods: One hundred and seventy patients with IgAN were divided into two groups: Group A (n=79), patients who did not have ex-C3 deposits, and Group B (n=91), patients who had ex-C3 deposits., Results: At the time of renal biopsy, Group B was characterized by a marked increase in diastolic blood pressure, total cholesterol, triglyceride and low-density lipoprotein-cholesterol compared with those of Group A. After 4 years, the estimated glomerular filtration rate (eGFR) in Group B was significantly worse than that of Group A. Upon examination by electron microscopy, the arteriolar dense deposits in Group B were found to occur in significantly higher amounts than in Group A. One hundred and thirty-four patients underwent a 3-year follow-up study after intervention and were re-divided by therapeutic factors as follows: 'conventional therapy', treatment with anti-hypertensive drugs and/or anti-platelet drugs, and 'aggressive therapy', additional treatment with either tonsillectomy or corticosteroid. Patients treated with conventional therapy in Group B had significantly higher body mass index and levels of C3 and CH50 compared with other Groups. Aggressive therapy was significantly effective in urinary protein reduction in both Group A and Group B. Except for the patients who received aggressive therapy in Group A, the levels of the eGFR gradually declined., Conclusions: It appears that IgAN patients who have ex-C3 deposits have worse clinical outcomes.

Background: We focused on the fluctuations of serum C3 levels throughout the clinical course of patients and investigated the relationship between these fluctuations and clinical findings., Methods: IgA nephropathy patients (n = 122) were enrolled in the present study. Serum C3 and other clinical markers were compared at the time of renal biopsy and at last follow-up (6.67 ± 2.07 years). Patients were divided into 3 groups based on serum C3 levels: Group I with first C3 levels below the mean -1 SD, which turned into an increase at last observation; group II with first C3 levels more than the mean +1 SD, which turned into a decrease at last observation; and group III, with first C3 levels more than the mean +1 SD, which turned into an increase at last observation. First and last levels of clinical markers were compared among the 3 groups., Results: Serum C3 levels of the patients whose renal symptoms, including hematuria, proteinuria and estimated glomerular filtration rate (eGFR), were improved, were significantly increased at last observation (p<0.05, p<0.01, p<0.01, respectively). Age, total cholesterol and triglyceride levels in group III were significantly higher than those in group I. Group II showed a significant reduction of urinary protein. Groups I and II maintained renal function, but group III showed a significant deterioration of renal function., Conclusions: The levels and fluctuations of serum C3 might reflect the disease activity and metabolic alteration in patients with IgA nephropathy.

Background: A multicenter case-control study on IgA nephropathy (IgAN) was conducted to develop an evidence-based clinicopathologic classification of IgAN for predicting long-term renal outcome., Methods: Two hundred and eighty-seven patients including those with isolated hematuria or very mild proteinuria were enrolled. During a median follow-up of 9.3 years after biopsy, 49 patients (17%) progressed to end stage renal disease (ESRD). The associations between pathological variables and the need for chronic dialysis was examined by multivariate logistic regression analysis separately in patients who required dialysis earlier than 5 years (Early Progressors) and those who required dialysis within 5 to 10 years (Late Progressors) after biopsy., Results: Independent pathological variables predicting progression to ESRD were global sclerosis, segmental sclerosis and fibrous crescents for Early Progressors, and global sclerosis and cellular/fibrocellular crescents for Late Progressors. Four histological grades, HG 1, HG 2, HG 3 and HG 4, were established corresponding to <25%, 25-49%, 50-74% and =75% of glomeruli exhibiting cellular or fibrocellular crescents, global sclerosis, segmental sclerosis or fibrous crescents. Eleven (7%) patients in HG 1, 12 (16%) in HG 2, 13 (31%) in HG 3 and 13 (68%) in HG 4 progressed to ESRD. Multivariate logistic analysis revealed that the risk of progression to ESRD was significantly higher in HG 2, 3 and 4 than in HG 1 (odds ratio, 2.4, 5.7 and 27.6 vs. 1.0)., Conclusions: Our evidence-based histologic classification can identify the magnitude of the risk of progression to ESRD and is useful for predicting long-term renal outcome in IgAN.

Background: Since the pathogenesis of immunoglobulin A (IgA) nephropathy (IgAN) remains unclear, the rationale for current IgAN therapies is still obscure. Recent studies have shown that galactose-deficient IgA1 (GdIgA1) plays a critical role in the pathogenesis of IgAN and can be a non-invasive IgAN biomarker, although the origin of the pathogenic cells producing GdIgA1 is unknown. We examined the cell types and localization of pathogenic cells in IgAN-prone mice., Methods: We transplanted bone marrow (BM) or spleen cells with or without specific cell types from IgAN-prone mice, which have many features similar to human IgAN, to identify cell types responsible for the IgAN phenotype and to determine their localization., Results: BM transplantation and whole spleen cell transfer from IgAN-prone mice reconstituted IgAN in normal and severe combined immunodeficiency mice. Depletion of CD90(+) spleen cells had no affect on reconstitution, whereas CD19(+) B cells from the spleen were sufficient to reconstitute IgAN in both recipients., Conclusions: These results indicate that CD19(+) B cells, which can regulate nephritogenic IgA production in a T-cell-independent manner, are responsible for the disease and are disseminated in peripheral lymphoid organs.

Immunoglobulin A nephropathy (IgAN) is characterized by mesangial cell proliferation and mesangial expansion with mesangial depositions of IgA. We have found that electron-dense deposits (EDD) are often observed in areas other than paramesangial areas in glomeruli. To compare electron microscopic findings with light microscopic findings and clinical data, we examined the biopsies from 178 patients with IgAN. Patients were divided into two groups: group A had only paramesangial deposits and group B had deposits not only in paramesangial areas but also in other areas. All patients examined in this study had EDD in glomerular paramesangial areas. Thirty-six patients were included in group B. Cellular crescent formation in glomeruli and urinary protein in group B were significantly higher than those in group A (P < 0.01). Serum albumin and estimated glomerular filtration rate (eGFR) in group B were significantly lower than those in group A (P < 0.05). Group B showed a significant positive correlation with histological severity, which is defined in the Japanese Clinical Guidelines on IgAN. In patients with broad distribution of EDD, urinary protein was significantly increased (P < 0.05). Detailed observation of EDD distribution has an impact on evaluation of the disease activity of IgAN.

Background and Objectives: Podocalyxin (PCX) is present on the apical cell membrane of podocytes and is shed in urine from injured podocytes. Urinary podocalyxin (u-PCX) is associated with severity of active glomerular injury in patients with glomerular diseases. This study examined the relationship between number of urinary podocytes, levels of u-PCX, and glomerular injury in adults with IgA nephropathy (IgAN)., Design, Setting, Participants, & Measurements: Urine samples voided in the morning on the day of biopsy were obtained from 51 patients with IgAN (18 men and 33 women; mean age, 31 years). All renal biopsy specimens were analyzed histologically. Pathologic variables of IgAN were analyzed per Shigematsu classification, the Oxford classification of IgAN, and the Clinical Guidelines of IgAN in Japan. Levels of u-PCX were measured by sandwich ELISA., Results: Histologic analysis based on Shigematsu classification revealed a significant correlation between levels of u-PCX and severity of acute extracapillary abnormalities (r=0.72; P<0.001), but levels of urinary protein excretion did not correlate with acute glomerular abnormalities. Levels of urinary protein excretion in patients with segmental sclerosis (n=19) were higher than in patients without (n=22) (0.49 [interquartile range (IQR), 0.20-0.88] g/g creatinine versus 0.20 [IQR, 0.10-0.33] g/g creatinine; P<0.01). The number of urinary podocytes in patients with segmental sclerosis was higher than in patients without (1.05 [IQR, 0.41-1.67] per mg creatinine versus 0.28 [IQR, 0.10-0.66] per mg creatinine; P<0.01)., Conclusions: Levels of u-PCX and the number of urinary podocytes are associated with histologic abnormalities in adults with IgAN.

Background: Patients with IgA nephropathy (IgAN) often show aggravation of renal injury with macroscopic hematuria after mucosal infections, especially tonsillitis. We previously demonstrated the important role of mucosal Toll-like receptor 9 (TLR9) activation in the pathogenesis of murine IgAN. Moreover, a single nucleotide polymorphism (SNP) in TLR9 was significantly associated with pathological severity in human IgAN. In this study, we investigated correlations between tonsillar TLR9 messenger RNA expression, TLR9 SNP genotypes and clinical outcomes following tonsillectomy with steroid pulse therapy (SPT) in IgAN patients., Methods: Tonsillar TLR9 expression was examined in IgAN (n = 49) and control (n = 15) patients who had undergone tonsillectomy. The correlations between tonsillar TLR9 expression level, TLR9 SNP genotypes and clinical outcomes after tonsillectomy with SPT were examined., Results: High expression of tonsillar TLR9 was observed in ∼23% of IgAN patients. These patients showed stronger and earlier remission of hematuria and proteinuria than those with low TLR9 expression. Patients with the TT genotype of TLR9 SNP (rs352140) had more severe renal damage than those with other genotypes. Patients whose serum IgA level decreased more than average after tonsillectomy (large ΔIgA) showed higher cumulative remission rates of proteinuria than patients with a smaller decrease in these levels (small ΔIgA). CT/CC genotypes were more dominant and tonsillar TLR9 expressions significantly higher in large ΔIgA patients than in small ΔIgA patients., Conclusion: In IgAN patients, expression levels of tonsillar TLR9 and TLR9 SNP were well correlated with the efficacy of tonsillectomy with SPT.

Background: Glomerular damage in IgA nephropathy (IgAN) is mediated by complement activation via the alternative and lectin pathways. Therefore, we focused on molecules stabilizing and regulating the alternative pathway C3 convertase in urine which might be associated with IgAN pathogenesis., Methods: Membrane attack complex (MAC), properdin (P), factor H (fH) and Complement receptor type 1 (CR1) were quantified in urine samples from 71 patients with IgAN and 72 healthy controls. Glomerular deposition of C5, fH and P was assessed using an immunofluorescence technique and correlated with histological severity of IgAN and clinical parameters. Fibrotic changes and glomerular sclerosis were evaluated in renal biopsy specimens., Results: Immunofluorescence studies revealed glomerular depositions of C5, fH and P in patients with IgAN. Urinary MAC, fH and P levels in IgAN patients were significantly higher than those in healthy controls (p < 0.001), but CR1 was significantly lower than that in healthy controls (p < 0.001). Urinary MAC and fH levels were positively correlated with serum creatinine (sCr), urinary N-acetyl-β-D-glucosaminidase (u-NAG), urinary β2 microglobulin (u-Bm), urinary protein (p < 0.001), interstitial fibrosis (MAC: p < 0.01, fH: p < 0.05) and the percentage of global glomerular sclerosis (p < 0.01). Urinary P was positively correlated with u-NAG, u-Bm, and urinary protein (p < 0.01)., Conclusions: Complement activation occurs in the urinary space in IgAN and the measurement of levels of MAC and fH in the urine could be a useful indicator of renal injury in patients with IgAN.

Although pathogenesis of IgA nephropathy (IgAN) is still obscure, pathological contribution of mucosal immunity including production of nephritogenic IgA and IgA immune complex (IC) has been discussed. We have reported that mucosal toll-like receptor (TLR)-9 is involved in the pathogenesis of human and murine IgAN. However, cell-type expressing TLR9 in mucosa remains unclear. To address this, we nasally challenged cell-specific CpG DNA ((i): dendritic cell: (DC), (ii): B cell, (iii): both), known as ligand for TLR9, to IgAN prone mice and analyzed disease phenotype of each group. After 8 times of the weekly administration, every group showed deterioration of glomerular damage. However, CpG-A-group showed clear extension of mesangial proliferative lesions with increase of serum IgA-IgG2a IC and its glomerular depositions, while CpG-B-group showed extent of glomerular sclerotic lesions with increase of serum and glomerular IgA and M2 macrophage infiltration. Present results indicate that mucosal TLR9 on B cells and DC may differently contribute to the progression of this disease via induction of nephritogenic IgA or IgA-IgG IC, respectively. This picture is suggestive for the pathological difference between child and adult IgAN.

Background: IgA nephropathy is one of the most common primary glomerulonephritides, and the clinical course of almost 40% of the patients progresses to end-stage renal disease (ESRD) within 20 years. Angiotensin-converting enzyme (ACE) inhibitors and/ or angiotensin II receptor blockers (ARBs) induce a marked renoprotective effect in nondiabetic chronic proteinuric nephropathies including IgA nephropathy. However, in Japan, ACE inhibitors and ARBs are not used for normotensive patients. The purpose of the present study was to evaluate the antiproteinuric effect of olmesartan, one of the ARBs, in normotensive patients with IgA nephropathy in Japan., Methods: Olmesartan was given to 25 patients for 16 weeks. The initial dose was 5 mg and was increased stepwise to 10 mg, 20 mg and 40 mg., Results: Final doses were 40 mg (n=11), 20 mg (n=5), 10 mg (n=7) and 5 mg (n=2). The change in urinary protein to creatinine ratio was -56.2%+/-22.8% at week 16. Creatinine clearance showed no changes throughout the study period. Blood pressure (systolic/diastolic) was 118.9+/-7.0 / 76.8+/-7.4 mm Hg in the lead-in period and decreased to 107.0+/-10.1/66.3+/-7.8 mm Hg at week 16. At the end of treatment with olmesartan, no correlation was observed between changes in the urinary protein to creatinine ratio and mean blood pressure based on investigation of dispersion diagrams., Conclusions: Olmesartan monotherapy showed robust reduction of urinary protein in normotensive IgA nephropathy patients, suggesting that this effect is independent of its blood pressure-lowering properties.

Environmental pathogens are suspected to aggravate renal injury in IgA nephropathy (IgAN), but neither underlying mechanisms nor specific exogenous antigens have been identified. In this study, a genome-wide scan of ddY mice, which spontaneously develop IgAN, was performed, and myeloid differentiation factor 88 (MyD88) was identified as a candidate gene for progression of renal injury (chi(2) = 21.103, P = 0.00017). For evaluation of the potential influence of environmental pathogens on progression of renal injury, ddY mice were housed in either conventional or specific pathogen-free conditions. Expression of genes encoding toll-like receptors (TLR) and the signaling molecule MyD88 were quantified by real-time reverse transcription-PCR in splenocytes. Although the housing conditions did not affect the prevalence of IgAN, the severity of renal injuries was higher in the conventionally housed group. Mice that had IgAN and were housed in conventional conditions had higher levels of TLR9 and MyD88 transcripts than mice that had IgAN and were housed in specific pathogen-free conditions. Furthermore, nasal challenge with CpG-oligodeoxynucleotides, which are ligands for TLR9, aggravated renal injury, led to strong Th1 polarization, and increased serum and mesangial IgA. For investigation of whether these results may be generalizable to humans, single-nucleotide polymorphisms in the TLR9 and MyD88 genes were analyzed in two cohorts of patients with IgAN; an association was observed between TLR9 polymorphisms and disease progression. In summary, these findings suggest that activation of the TLR9/MyD88 pathway by common antigens may affect the severity of IgAN.

Several clinical markers correlate well with the diagnosis and prognosis of IgA nephropathy (IgAN). In the present study, we re-evaluated the usefulness of these four clinical markers for prediction of the diagnosis of patients with IgAN through a comparison between many more patients with IgAN and those with other types of renal diseases. 364 patients with IgAN and 289 with other types of renal disease were examined. An analysis was performed prior to renal biopsy, using clinical markers including, serum IgA, serum IgA/C3 ratio, number of red blood cells in urinary sediments, and urinary protein. Patients with IgAN were divided into four groups according to histopathological findings. Presence of microscopic hematuria, persistent proteinuria, high serum IgA levels, and the serum IgA/C3 ratios are useful for prediction of diagnosis of IgAN and distinguishing it from other renal diseases. Blood pressure, urinary protein, serum uric acid, renal function, and urinary sediment findings may be useful for prediction of prognostic grading in patients with IgAN., ((Copyright ) 2008 Wiley-Liss, Inc.)

IgA nephropathy (IgAN) is the most common form of chronic glomerulonephritis. Although glomerular deposition of complement components is well known, the evidence of serological complement activation in IgAN is inconclusive. We hypothesized that serum levels of complement components and regulatory proteins in patients with IgAN are correlated with its pathogenesis. In the present study we measured complement components in 50 patients with IgAN and 50 healthy volunteers. C5, C1 inhibitor, factor B, C4 binding protein, factor H, and factor I were measured with the use of single radial immunodiffusion. Mannose-binding lectin (MBL) and properdin (P) were measured by enzyme-linked immunosorbent assay (ELISA). The correlations among complements in the sera of patients with clinical gradings for IgAN (i.e., the good prognosis group, relatively good prognosis group, relatively poor prognosis group, and poor prognosis group) were evaluated. CH50, C4, factor B, P, factor I, and factor H were significantly higher in IgAN patients than in healthy controls. There were significant correlations between C5 and C4 binding protein, between C3 and C5, or between C4 and factor B in patients with IgAN. In the poor prognosis group, C4 binding protein was significantly higher than in the other groups of IgAN patients. hypercomplementemia occurs in IgAN and is associated with an increase in complement regulatory protein (CRP). C4 binding protein analyses can be used to predict disease prognosis., (2007 Wiley-Liss, Inc.)

Previous studies indicated that bone marrow cells may contribute to the pathogenesis of IgA nephropathy (IgAN). However, the cell types and mechanisms responsible remain unclear. Our recent study showed that 'grouped ddY mice' is a useful model to approach the pathogenesis of IgAN. Moreover, we also reported that bone marrow transplantation (BMT) from the onset mice of this model reconstituted IgAN in healthy recipients with strong Th1-polarization. We aimed to examine the roles of bone marrow (BM) cells, mucosa and lymphoid tissues in IgAN. We employed onset ddY mice and mutant mice lacking all systemic lymph nodes, Payer's patch, isolated lymphoid follicles in the lamina propria (LP) and IgA producing cells. BM cells from the onset mice were transplanted into the mutant and wild type (C57BL/6:B6). After BMT, serum elevation of IgA and IgA(+)B220(-) plasma cells in BM, but not IgA producing cells in LP, were observed in the mutant mice. Although both transplanted mice showed mesangial IgA deposition, glomerular lesions with IgG2a co-deposition were detected only in B6 mice. The present results suggest that glomerular IgA deposition, but not glomerular damage, can be induced by BM-derived or -primed IgA-producing cells independently of priming in mucosa and secondary lymphoid tissues.

Background: Fcgamma receptors (FcgammaRs) may play an important role in positive and negative regulation of immune cell responses and immune complex (IC) clearance. Mesangial IgG deposition and circulating IgG/IgA-IC in sera are observed in patients with IgA nephropathy (IgAN). Therefore, the pathological roles of IgG-IC in IgAN have been discussed. On the other hand, several studies have identified FcgammaR polymorphisms (FcgammaRIIa, FcgammaRIIIa and FcgammaRIIIb) that determine susceptibility to autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. The objective of the present study was to clarify whether FcgammaR polymorphisms influence susceptibility to IgAN, clinical features or severity in patients with IgAN., Methods: Japanese patients with IgAN (n = 124) and healthy controls (n = 100) were genotyped for FcgammaR polymorphisms (FcgammaRIIa-131H or R, FcgammaRIIIa-176F or V and FcgammaRIIIb-NA1 or -NA2). The genotyping of these polymorphisms was performed using allele-specific polymerase chain reaction (PCR) methods. Associations among FcgammaR polymorphisms and susceptibility, age of onset, levels of serum immunoglobulins, intensity of glomerular IgG deposition and pathological severity were analysed., Results: These three FcgammaR polymorphisms showed no significant differences in genotype and allele frequencies between the IgAN patients and healthy controls. Each FcgammaR polymorphism had no influence on age of onset, serum levels of IgG and glomerular IgG deposition in IgAN. However, FcgammaRIIa-131R (R/R or H/R) or FcgammaRIIIa-176V homozygous carriers (V/V) showed significantly more severe injury than FcgammaRIIa-131H homozygous (H/H) (P < 0.03) or FcgammaRIIIa-176F carriers (F/F or F/V) (P < 0.03), respectively., Conclusion: The present study shows that polymorphisms of FcgammaRIIa and FcgammaRIIIa influence the severity of IgAN in Japanese patients but not the incidence, suggesting that IgG-IC may play important roles in the progression and prognosis of this disease via FcgammaRs.

Genetic factors are considered to be involved in the initiation and progression of IgA nephropathy (IgAN) on the basis of racial differences in the prevalence and familial aggregation. The ddY mouse is a spontaneous animal model of human IgAN, with a highly variable incidence and extent of glomerular injury as a result of the heterogeneous background, resembling the human situation. It was hypothesized that susceptibility genes for IgAN can be detected by a genome-wide scan using this model. First, serial renal biopsies were performed at 20, 40, and 60 wk of age in 361 ddY mice. The ddY mice were classified into three groups on the basis of the onset of glomerular injury: Early onset at 20 wk (31.9%), late onset at 40 wk (37.9%), and quiescent even at 60 wk (30.2%). The severity of glomerular lesions in both onset groups correlated with the intensity of glomerular IgA deposition but not with serum IgA level. The genome-wide scan with 270 microsatellite markers identified three chromosomal regions on chromosomes 1, 9, and 10, which were significantly associated with the glomerular injuries. Surprisingly, the peak marker D10MIT86 on chromosome 10 is located on the region syntenic to human 6q22-23 with IGAN1, which is the responsible candidate of familial IgAN. In addition, D1MIT16 on chromosome 1 was very closely located at the locus of selectin gene, which is a known candidate of human IgAN. In conclusion, the three-group ddY mouse model can be a useful tool for identifying the susceptibility genes and also to examine their roles in the pathogenesis of IgAN.

In 2002, the Joint Committee of the Special Study Group on Progressive Glomerular Diseases, Ministry of Health, Labor and Welfare of Japan newly revised the clinical guidelines for IgA nephropathy (Sakai et al.: Jpn J Nephrol 37:417-421, 1995; Tomino and Sakai: Clin Exp Nephrol, 7, 93-97, 2003). The prognostic stages were classified into four groups: the good prognosis group (Group I), relatively good prognosis group (Group II), relatively poor prognosis group (Group III), and poor prognosis group (Group IV). The relationship between the levels of Hb, Ht, and RBC in peripheral blood and the renal prognostic stages was determined in 62 patients with IgA nephropathy in the present study. The mean levels of Hb, Ht, and RBC were significantly lower in Group IV than in Group I (P<0.05). However, there were no significant changes in the levels of serum creatinine (s-Cr) or creatinine clearance (CCr) among these four groups. It appears that the levels of Hb, Ht, and RBC in peripheral blood may be important clinical parameters for the evaluation of prognostic stages in patients with IgA nephropathy.

Because type IV collagen is synthesized by podocytes and mesangial cells, we investigated the relationship between levels of urinary type IV collagen (uIV) and renal injuries in patients with IgA nephropathy. uIV was measured by a highly sensitive one-step sandwich enzyme immunoassay prior to renal biopsy. Patients with IgA nephropathy were classified into four grades (grade 1 = good prognosis, grade 2 = relatively good prognosis, grade 3 = relatively poor prognosis, and grade 4 = poor prognosis) by the prognostic criteria of the Ministry of Health, Labor, and Welfare of Japan. Levels of uIV in grade 4 were significantly higher than those in grades 1-3. These levels tended to increase gradually due to progression of renal injuries. The grades were further divided into two groups: group I (good or relatively good prognoses) and group II (relatively poor or poor prognoses). Patients with proteinuria of <1.0 g/day were defined as groups Ip and IIp. The levels of uIV in group II were significantly higher than those in group I, and those in group IIp were significantly higher than those in group Ip. It appears that the level of uIV can be a useful marker for detection of renal injuries in IgA nephropathy., (Copyright 2004 Wiley-Liss, Inc.)

Diagnostic analysis of clinical markers including serum IgA levels and serum IgA/C3 ratio in patients with IgA nephropathy is described. One hundred patients with IgA nephropathy (IgA nephropathy group) and 100 patients with other primary glomerular diseases (non-IgA nephropathy group) were examined. The analysis was performed to distinguish between these two groups using four clinical markers: 1) more than five red blood cells in urinary sediments, 2) persistent proteinuria (urinary protein of more than 0.3 g/day), 3) serum IgA levels of more than 315 mg/dl, and 4) a serum IgA/C3 ratio of more than 3.01. Patients with three or four clinical markers were easily diagnosed as having IgA nephropathy in this study. Furthermore, there was a significant difference in these clinical markers between the good prognosis and relatively good prognosis groups (Groups I and II) and the relatively poor prognosis and poor prognosis groups (Groups III and IV) of IgA nephropathy patients. It appears that the presence of microscopic hematuria and/or persistent proteinuria, high serum IgA levels, and the serum IgA/C3 ratio are useful for distinguishing IgA nephropathy from other primary renal diseases. It is postulated that these clinical markers are also useful for diagnosis of IgA nephropathy without renal biopsy., (Copyright 2003 Wiley-Liss, Inc.)

Recently, the authors reported that the ratio of serum IgA to C3 (serum IgA/C3 ratio) is a good marker to distinguish patients with IgA nephropathy from non-IgA nephropathy patients together with serum IgA levels using an international reference preparation (IFCC/CRM470). In this study, the authors investigated whether the serum IgA/C3 ratio might be an indicator of prognostic grading in patients with IgA nephropathy. Two hundred and thirteen patients with IgA nephropathy and 96 other glomerular diseases including diffuse or focal mesangial proliferative glomerulonephritis without mesangial IgA deposition (non-IgA PGN), membranous nephropathy and thin basement membrane syndrome were examined. The levels of serum IgA and C3 in these patients were adjusted by the specified formula to those using international standard serum (IFCC/CRM470) in this study. The results of this study showed the highest levels of IgA/C3 ratio in patients with IgA nephropathy. The serum IgA/C3 ratio appears to gradually increase according to the prognostic grading of this disease. Therefore, measurement of the serum IgA/C3 ratio may be useful for prediction of diagnosis and prognostic grading in patients with IgA nephropathy., (Copyright 2002 S. Karger AG, Basel)