Elevated serum secretory IgA in patients with IgA nephropathy

Serum secretory IgA was measured to elucidate the significance of secretory IgA in patients with IgA nephropathy. The levels of serum secretory IgA and IgA were, respectively, 6.8 +/- 3.5 micrograms/ml and 231.0 +/- 69.2 mg/dl in the controls and 11.8 +/- 3.2 micrograms/ml and 385.3 +/- 78.7 mg/dl in the patients. The levels of serum secretory IgA and IgA in the patients were significantly higher than those in controls (p less than 0.01). Elevated serum secretory IgA may reflect the excessive state of the IgA-secreting system in IgA nephropathy patients.     

Circulating and mesangial secretory component-binding IgA-1 in primary IgA nephropathy

In a prospective study of 38 patients who presented with hematuria of renal origin, 15 patients were found to have primary IgA nephropathy and 23 had other renal disorders. Sera and renal biopsy specimens of these patients were studied for the presence of macromolecular IgA1 and IgA2 using monoclonal antibodies, and the presence of J-chain as demonstrated either by immunofluorescence or its capacity to bind free secretory component. Circulating macromolecular IgA was found exclusively in the sera of patients (80%) with primary IgA nephropathy. In these sera the polymer/monomer ratio for IgA1 (0.64 +/- 0.13) was significantly higher than for normal human serum (0.39 +/- 0.01) (P less than 0.001), while no differences were found for IgA2. The polymeric IgA1 was isolated from serum by gel chromatography and was shown to have the capacity to bind free secretory component. Direct two-color immunofluorescence studies revealed the presence of only IgA1 in the mesangial deposits and also its capacity to bind free secretory component. We conclude (1) that demonstration of circulating macromolecular IgA in patients with renal hematuria is of diagnostic value and (2) that antigenetic similarities between the circulating and the mesangial macromolecular IgA suggest that dimeric IgA1 is deposited in the mesangium of patients with primary IgA nephropathy.     

A pathogenic role for secretory IgA in IgA nephropathy

IgA nephropathy (IgAN) is characterized by deposits of IgA in the renal mesangium. It is thought that deposits of IgA mainly involve high molecular weight (HMW) IgA1. However, there is limited information on the exact composition of HMW IgA in these deposits. In this study, we investigated the presence of secretory IgA (SIgA) in human serum and in the glomerular deposits of a patient with IgAN. Furthermore, we analyzed the interaction of SIgA with mesangial cells. With enzyme-linked immunosorbent assay, SIgA concentrations in the serum of IgAN patients and healthy controls were measured. Both patients and controls had circulating SIgA that was restricted to the HMW fractions. Patients tended to have higher levels of SIgA, but this difference was not significant. However, in patients with IgAN, high serum SIgA concentrations were associated with hematuria. Binding of size-fractionated purified serum IgA and SIgA to mesangial cells was investigated with flow cytometry. These studies showed stronger binding of SIgA to primary mesangial cells compared to binding of serum IgA. Importantly, after isolation and elution of glomeruli from a nephrectomized transplanted kidney from a patient with recurrent IgAN, we demonstrated a 120-fold accumulation of SIgA compared to IgA1 in the eluate. In conclusion, we have demonstrated that SIgA strongly binds to human mesangial cells, and is present in significant amounts in serum. Furthermore, we showed that SIgA is accumulated in the glomeruli of an IgAN patient. These data suggest an important role for SIgA in the pathogenesis of IgAN.     

The level of serum secretory IgA of patients with IgA nephropathy is elevated and associated with pathological phenotypes.

BACKGROUND: Mucosal infection associated episodic macroscopic haematuria is observed in many patients with IgA nephropathy (IgAN), however, the mechanism has not been elucidated. Recent study suggested that secretory IgA (SIgA) might play an important role in the pathogenesis of IgAN. The aim of this study is to investigate the level of serum SIgA and the deposition of SIgA in glomeruli in IgAN patients with different pathological phenotypes. METHODS: The levels of serum SIgA were detected in 57 patients with IgAN and 48 normal controls. The associations between the levels of SIgA and the pathological phenotypes of IgAN as well as clinical parameters were investigated. Frozen renal sections from 34 of the 57 patients without IgM deposition were immunofluorescence stained and examined by confocal microscopy to detect the co-deposition of IgA and secretory component (SC). The association between deposition of SIgA and the level of serum SIgA was analysed. RESULTS: The level of serum SIgA in patients with IgAN was significantly higher than that of normal controls. The level of serum SIgA in patients with focal proliferative sclerosing IgAN (fpsIgAN) was much higher than that in patients with mild mesangial proliferative IgAN (mIgAN) (P<0.001). The level of serum SIgA correlated with the level of serum creatinine (R=0.509, P<0.001), degree of proteinuria (R=0.643, P<0.001) and creatinine clearance (R= -0.454, P=0.002) in patients with IgAN. Significant co-deposition of SC and IgA were found in 11 of the 34 patients. Although the level of serum SIgA in patients with SC deposits was higher than those without SC deposits, the difference was not significant. CONCLUSIONS: It was concluded that mesangial IgA, at least partly, was originated from mucosal immune sites. The levels of serum SIgA were significantly increased in patients with IgAN and were closely associated with pathological phenotypes.     

Urinary liver-type fatty acid-binding protein: discrimination between IgA nephropathy and thin basement membrane nephropathy

BACKGROUND: Microscopic hematuria without proteinuria is a common clinical finding in cases of immunoglobulin A (IgA) nephropathy and of thin basement membrane nephropathy. Liver-type fatty acid-binding protein (L-FABP) is expressed in renal proximal tubules and is reported to be a useful marker of the progression of chronic glomerulonephritis. AIM: To assess urinary L-FABP levels for differential diagnosis in patients with microscopic hematuria but without proteinuria. METHODS: This was a multi-center retrospective study. Thirty adult patients who underwent renal biopsy for microscopic hematuria and 20 healthy adult volunteers were included in this study. Urinary L-FABP levels were measured by enzyme-linked immunosorbent assay and compared, particularly between those diagnosed with IgA nephropathy and those diagnosed with thin basement membrane nephropathy. RESULTS: Twelve (40%) patients had IgA nephropathy, 6 (20%) had thin basement membrane nephropathy and 12 (40%) had normal biopsy findings. The urinary L-FABP level was significantly higher in patients with IgA nephropathy (38.4 +/- 26.8 microg/g Cr) than in healthy subjects (5.8 +/- 4.0 microg/g Cr) (p < 0.01); however, the level in patients with thin basement membrane nephropathy or normal biopsy results was comparable to that in healthy subjects. Follow-up data were available for 11 of the 12 patients with IgA nephropathy who initially had no proteinuria. After 24 months, 4 of the 11 were found to have proteinuria, and the urinary L-FABP level had increased from 40.6 +/- 30.5 microg/g Cr to 58.8 +/- 40.5 microg/g Cr (p < 0.01). CONCLUSIONS: Our data suggest that the urinary L-FABP level can be used to discriminate between IgA nephropathy and thin basement membrane nephropathy in patients with microscopic hematuria.     

Demonstration of secretory IgA in kidneys of patients with IgA nephropathy.

BACKGROUND: Recently we reported a possible role for secretory IgA (SIgA) in IgA nephropathy (IgAN), as suggested by increased serum levels in patients with active disease and accumulation of SIgA in a glomerular eluate. Therefore, we attempted to find support for these findings by analysis of the presence of SIgA in biopsies of IgAN patients. METHODS: Renal biopsies of 26 patients with biopsy-proven IgAN were analysed for the presence of SIgA and complement proteins. RESULTS: In 15% mesangial deposition of SIgA was demonstrated, using a specific staining for secretory component (SC) and colocalization with IgA. The presence of SIgA in these biopsies showed a strong correlation with deposition of mannose-binding lectin (MBL) and C4d. Moreover, we observed a strong colocalization between SIgA and MBL or C4d. This local complement activation has previously been linked to more severe renal disease. CONCLUSIONS: Therefore, these data provide additional evidence for a pathogenic role for SIgA in IgA nephropathy.     

Specificity of IgA antibodies in sera from patients with IgA nephropathy.

A study was undertaken on the specificity of circulating IgA antibodies in patients with IgA nephropathy detected by immunofluorescence using avidin-biotin complexes. Renal biopsy specimens and serum samples were obtained from 33 patients with IgA nephropathy, 14 other glomerular diseases and 3 normal renal tissues. These renal specimens were treated with citrate buffer (pH 3.2), and then incubated with serum samples obtained from the same and other patients with IgA nephropathy, other glomerular diseases or healthy adults at 37 degrees C for 30 min. The specimens were incubated with biotin conjugated gout F(ab')2 anti-human IgA antiserum at 37 degrees C for 30 min, and then with fluorescein-labeled avidin at 37 degrees C for 30 min. It was found that IgA antibodies in the sera from patients with IgA nephropathy specifically combined with the autologous glomerular mesangial areas, but only 25.7% of them combined with allogeneic renal tissues of IgA nephropathy patients. Confirmatory findings were obtained using an automatic image analyzer. However, these IgA antibodies did not combine with the renal tissues from patients with other glomerular diseases or normal renal tissues. In parallel studies, in order to distinguish IgA nephropathy from other glomerular diseases before renal biopsy, the renal specimens from patients with IgA nephropathy were also incubated with serum samples obtained from 42 patients with proteinuria and/or hematuria before renal biopsy. It was demonstrated that the incidence of IgA binding in IgA nephropathy was significantly higher than that in other glomerular diseases prior to renal biopsy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Association of secretory IgA with clinical pathological characteristics and complement activation in IgA nephropathy

Objective To further investigate the association among clinical pathology, complement activation and renal secretory IgA (SIgA) deposition in patients with IgA nephropathy (IgAN). Methods The activation of serum complements were detected by immunoturbidimetry and ELISA. Renal deposition of SIgA and activation of complements were detected by immunofluorescence. Then the association among clinical pathology, complement activation and renal SIgA deposition were analyzed in IgAN patients. Results In all 201 patients with IgAN,59 patients had SIgA deposition with higher incidences of mucosal infection history and hematuria (P＜0.05), lower levels of serum cystatin C, β2 microglobulin and lower tubulointerstitial lesion grades and T?grade in the Oxford classification (P＜0.05), when compared with patients without SIgA deposition. Both alternative and mannose binding lectin (MBL) pathways were activated in patients with or without SIgA deposition. Patients with MBL pathway activation had lower estimate glomerular filtration rate (P＜0.01), higher serum creatinine, higher proportion of glomerulosclerosis and S?grade in the Oxford classification, more severe tubulointerstitial lesion (P＜0.05). Conclusions Compared with patients without SIgA deposition, patients with SIgA deposition have a stronger link to mucosal immune. The deposition of SIgA is associated with different clinical and pathological manifestations; however, the complement activation is similar in both groups of patients. Patients with MBL pathway activation show more severe kidney injury.     

Predominant synthesis of IgA with lambda light chain in IgA nephropathy

The nature of the light chains in mesangial IgA deposits and serum IgA was studied in patients with IgA nephropathy. Immunofluorescence (IF) studies using murine monoclonal antibodies, rabbit and goat anti-human monospecific antisera were performed in kidney sections from 15 IgA nephritic patients with only IgA isotype detected in the renal biopsy. Lambda light chain IF was demonstrated in all biopsy specimens and kappa light chain IF in 11 renal biopsy specimens. The majority of renal biopsies showed a predominance of lambda light chain IF staining in the mesangial deposits. The concentration of individual immunoglobulins and their light chain fractions, and the kappa/lambda ratio were determined in the serum and the supernate from peripheral blood mononuclear cells culture of 30 IgA nephritic patients and 30 age-matched healthy controls. The IgA nephritic patients had a higher serum concentration of total IgA (P less than 0.001) and a significantly lower IgA kappa/lambda ratio (P less than 0.001) compared with the controls. The kappa/lambda ratio of supernatant IgA from IgA nephritic patients (N = 20) was also significantly lower than that of the normal subjects (N = 14), both in the unstimulated (P less than 0.01) and pokeweed mitogen stimulated, peripheral blood mononuclear-cell culture (P less than 0.05). Our results showed that patients with primary IgA nephropathy displayed a unique immunologic response characterized by a predominance of IgA with lambda light chain in circulation.     

Study on anti-IgA antibody in patients with IgA nephropathy.

Serum IgG antibodies to polyclonal IgA, IgA1 and IgA2 were evaluated by enzyme-linked immunosorbent assay in 50 patients with IgA nephropathy and 30 healthy controls to elucidate the relationship between IgA and IgG in IgA nephropathy. Anti-IgA antibody was considered positive if the titer exceeded the mean value in normal controls by greater than 2 SD. In patients with IgA nephropathy, 18 cases (36%) demonstrated anti-IgA antibody, 19 cases (38%) anti-IgA1 antibody and 7 cases (14%) anti-IgA2 antibody. Western blots confirmed the existence of anti-IgA antibody in these patients. There were no significant differences in serum IgA concentration, serum creatinine concentration, degree of hematuria, amount of urinary protein, and rate of glomerular IgG deposition between the "positive" group and "negative" group. Although the mechanism of production and the role of this antibody remain unknown, it may represent one of the diverse immune abnormalities of IgA nephropathy and may be involved in the pathogenesis of IgA nephropathy.     

穿通支原体感染与IgA肾病临床病理的关系

目的 研究穿通支原体（Mycoplasma penetrans,Mpe）感染与IgA肾病（IgAN）患者临床病理改变的关系。 方法 采集经病理检查确诊的IgAN患者118例、健康体检者89例和慢性肾脏病（CKD）90例的血液标本,用试剂盒方法提取血清DNA。用PCR技术检测Mpe p35脂蛋白,对阳性标本采用Southern 印迹方法进行验证。根据IgAN患者Mpe感染情况分为阳性组和阴性组,结合患者的临床病理资料进行分析。 结果 89例健康体检者中仅1例Mpe p35脂蛋白为阳性,阳性率为1.1%。90例CKD患者中2例阳性,阳性率为2.2%。118例IgAN患者中19例阳性,阳性率为16.0%,显著高于健康组及CKD组,差异均有统计学意义（均P ＜ 0.01）。Mpe阳性组42.1%患者临床表现为肉眼血尿,显著高于Mpe阴性组（P ＜ 0.01）。Mpe阴性组24 h尿蛋白量、Scr、Lee病理分级显著高于阳性组,差异均有统计学意义（均P ＜ 0.05）。两组间肾小管、肾间质及肾血管积分差异无统计学意义。 结论 IgAN患者的Mpe检出率显著高于健康体检者和CKD患者。Mpe阳性患者更多表现为发作性肉眼血尿。Mpe感染可能与IgAN的发病有关。     

Serum levels of soluble Fas and disease activity in patients with IgA nephropathy

Using a sandwich ELISA, we studied 48 patients with IgA nephropathy and 10 patients with diffuse mesangial proliferative glomerulonephritis without IgA deposition (non-IgA PGN) to determine if levels of serum soluble Fas (s-Fas) might reflect the disease activity. The levels of serum s-Fas in patients with the advanced stage of IgA nephropathy were significantly higher than those in patients with the mild stage of the disease, in non-IgA PGN or in healthy controls. The results showed that advanced stage IgA nephropathy patients who showed heavy proteinuria and the presence of urinary casts revealed high levels of serum s-Fas. It was thus suggested that the measurement of serum s-Fas is useful in evaluating the degree of renal injury in patients with IgA nephropathy.     

Eosinophil cationic protein in Henoch-Schönlein purpura and in IgA nephropathy

In order to identify the relationship between eosinophil activation in Henoch-Sch?nlein purpura (HSP) and IgA nephropathy, serum eosinophil cationic protein (ECP) was analyzed in both conditions. The soluble interleukin-2 receptor (sIL-2R) was also analyzed. The levels of ECP were significantly higher in HSP patients (mean 9.7±1.8 μg/l) than in a control group (mean 4.6±0.7 μg/l). When the HSP patients were classified into two groups, one with normal urine and one with abnormal urine, the latter showed higher levels of ECP than the former. Levels of ECP were not significantly higher in IgA nephropathy patients than in a control group. The sIL-2R levels were elevated in the serum of HSP and IgA nephropathy patients compared with controls. In conclusion, eosinophil activation may be involved in the pathogenesis of HSP but not in IgA nephropathy. Received May 14, 1996; received in revised form and accepted March 26, 1997     

The clinical use of serum beta-2-microglobulin and fractional beta-2-microglobulin excretion in IgA nephropathy

We measured serum beta-2-microglobulin (B2-m) and fractional beta-2-microglobulin excretion in 29 patients with IgA nephropathy. The mean serum B2-m in IgA nephropathy patients was significantly higher than that of healthy controls (p less than 0.025). The serum B2-m correlated well with serum creatinine and endogenous creatinine clearance (p less than 0.01). Patients with diffuse mesangial proliferation and glomerulosclerosis had a significantly higher level of B2-m than those with minor glomerular pathology (p less than 0.01). Patients with hypertension had significantly different levels of serum B2-m from normotensive patients (p less than 0.01). The mean fractional B2-m excretion in IgA nephropathy patients was significantly higher than that of healthy controls (p less than 0.001). Patients with moderate tubulo-interstitial involvement had significantly higher fractional B2-m excretion than those with mild tubulo-interstitial changes (p less than 0.01). Our study suggests that serum B2-m and fractional B2-m excretion may be useful indicators in the long-term prognosis of patients with IgA nephropathy.     

Discriminant analysis of clinical markers before renal biopsy in patients with IgA nephropathy

Discriminant analysis of clinical markers before renal biopsy in patients with IgA nephropathy is described. Sixty eight patients with IgA nephropathy (IgA nephropathy group) and 66 patients with other chronic glomerulonephritis (non-IgA nephropathy group) were examined. The discriminant analysis was applied to separate those two groups by using twenty clinical parameters as well as binding capacity of serum IgA to the glomeruli of renal specimens. Binding of serum IgA of patients to the glomeruli obtained from patients with IgA nephropathy was performed using avidin-biotin immunofluorescence. Among twenty clinical markers, the levels of serum IgA and creatinine, and degree of microhematuria in IgA nephropathy group were significantly higher than those in non-IgA nephropathy group Furthermore, the positive incidence of serum IgA binding of IgA nephropathy group was significantly higher than that of serum IgA binding of non-IgA nephropathy group. The correct classification rate were 79.10% using five clinical markers including serum IgA, microhematuria, serum C4, quantitation of proteinuria and degree of proteinuria. It is indicated that the levels of serum IgA and the binding of serum IgA to the glomeruli were considered to be major markers for clinical diagnosis of patients with IgA nephropathy It was concluded that the discriminant analysis before renal biopsy was useful for diagnosis of IgA nephropathy.     

The role of IgA and IgG immune complexes in IgA nephropathy

The presence of circulating immune complexes in 54 patients with IgA nephropathy has been studied by two different techniques. 64% of the patients had IgG immune complexes and 37% had IgA immune complexes, both determined with the Raji cell assay, and 48% of patients had IgA immune complexes with the anti-IgA inhibition binding assay (anti-IgA Inh BA). In sequential sera from individual patients, immune complexes remained persistently positive or negative in more than 50% of the cases being intermittently in the rest. The immune complexes detected by the Raji cell assay were mostly of 7-13S in size, while those detected by anti-IgA Inh BA were bigger. There was a good correlation between the serum levels of polymeric IgA and the presence of IgA complexes (Raji cell assay). A certain correlation (p less than 0.05) was found between these IgA immune complexes and the clinical activity assessed by the hematuria. A similar correlation (p less than 0.05) was found with specific polymeric IgA immune complexes studied by a method recently described. No relationship was observed between the presence of any HLA antigens and the existence of circulating immune complexes. These results support the contention that IgA immune complexes, especially those composed of polymeric IgA, may have a role in the pathogenesis of IgA nephropathy. Moreover, the high serum levels of polymeric IgA observed in these patients could contribute to the slow clearance and long persistence in the circulation of IgA immune complexes with their subsequent deposition at the glomerular mesangium.     

IgA1-containing immune complexes in IgA nephropathy differentially affect proliferation of mesangial cells

BACKGROUND: Sera of patients with IgA nephropathy (IgAN) contain circulating immune complexes (CIC) composed of galactose-deficient IgA1 complexed with antiglycan antibodies. The role of these CIC in the pathogenesis of IgAN is not known. METHODS: We studied how proliferation of cultured mesangial cells (MC) is affected by CIC prepared from sera of IgAN patients and healthy control subjects using size-exclusion chromatography. CIC-containing fractions were added to serum-starved MC in culture, and cell proliferation was measured using (3)H-thymidine incorporation. The results were confirmed by staining MC using an antibody against proliferating cell nuclear antigen. RESULTS: The incubation of starved MC with serum fractions with M(r) 800 to 900 kD, rich with galactose-deficient IgA1, stimulated proliferation, while fractions with smaller complexes were inhibitory. Furthermore, CIC-containing larger molecular mass fractions isolated from serum of an IgAN patient collected during an episode of macroscopic hematuria stimulated MC proliferation more than CIC obtained during a subsequent quiescent phase. To examine the role of IgA, we removed IgA1 from serum before fractionation. The resultant IgA1-depleted fractions were devoid of stimulatory IgA-CIC. Sera of IgAN patients were also fractionated after addition of desialylated galactose-deficient polymeric IgA1 to form additional immune complexes. Supplementation with a small quantity of this IgA1 increased cellular proliferation in assays using serum fractions of M(r)>/=800 to 900 kD; uncomplexed IgA1 did not affect MC proliferation significantly. In contrast, supplementation with a larger quantity of this IgA1 inhibited cellular proliferation in assays using serum fractions of M(r) 700 to 800 kD. CONCLUSION: Overall, these findings suggest that CIC containing aberrantly glycosylated IgA1 affect proliferation of MC in vitro and, thus, likely play a role in the pathogenesis of IgAN.     

Serum complement proteins in IgA nephropathy

Immunohistologic studies in IgA nephropathy which have suggested activation of the alternative complement pathway prompted us to study serum complement components and control proteins in 28 patients with IgA nephropathy. Thirteen patients, 12 of whom were men, had or developed chronic renal failure (CRF) during 34 +/- 5 months of follow-up. These patients were more hypertensive and had heavier proteinuria than those with stable renal function. Their serum IgA concentrations were not different from patients with normal renal function. The prevalence of HLA antigens was similar to that for the reference population and BW35 was not associated with CRF. Serum C3, B, H and I concentrations in patients with stable normal renal function were higher than they were in patients with CRF. Four patients studied--two with normal renal function and two with CRF--had partial familial deficiencies of single complement proteins. Our data suggest that high serum levels of C3, B, H and I may be associated with stable normal glomerular filtration rate and that complement deficiencies are not infrequent in IgA nephropathy. How these findings relate to the pathogenesis and progression of IgA nephropathy requires further study. We also conclude that higher serum IgA concentrations and the presence of BW35 are not necessarily associated with progressive renal insufficiency in IgA nephropathy.     

原发性IgA肾病与非IgA系膜增生性肾小球肾炎的临床病理分析

目的 比较原发性IgA肾病与非IgA系膜增生性肾小球肾炎（non-IgA mesangial proliferative glomerulonephritis,non-IgA MsPGN）的临床及肾脏病理改变特点.方法 选择我科经肾活检确诊的原发性IgA肾病患者（A组）和non-IgA MsPGN患者（B组）进行临床与病理资料对比分析.结果 A、B组的性别、前驱上呼吸道感染诱因、起病时伴发高血压、镜下血尿、血肌酐无统计学差异（P＞0.05）.B组较A组起病年龄小,起病时伴发肉眼血尿比率低,肾病综合征发生率高,血IgG水平低,差异均有统计学意义（P＜0.05）.A组肾小球、肾小管间质、肾小动脉病理改变发生率高于B组（P＜0.05）,IgM、C3沉积、系膜区电子致密物沉积、大块状致密物、足细胞微绒毛化、肾小球基底膜分层发生率均较B组高（P＜0.01）.结论 IgA肾病与non-IgA MsPGN在临床表现、病理改变上存在明显差异,IgA肾病较non-IgA MsPGN病理损伤重.     

Sequential study of the IgA system in relapsing IgA nephropathy

Cellular and immunochemical parameters of the IgA system were studied in 15 subjects with IgA nephropathy (IgAN) and 15 agematched controls. In IgAN remission no abnormalities of the IgA system were detectable by the methods used. In IgAN relapse, [macroscopic hematuria associated with upper respiratory tract infection (URTI) (N = 6)] there were rises in IgA-bearing B-lymphocytes (three of six), T helper/suppressor cell ratio (six of six) and pokeweed mitogen-induced IgA production (four of six). Total serum and salivary IgA were unchanged. Serum IgA profile (HPLC-ELISA) showed increases in polymer IgA (three of six). No such changes were found during URTI in controls. These findings support the view that an exaggerated IgA response to mucosal antigen challenge initiates glomerular damage and hematuria in IgAN.