Mesangial deposition of J chain-linked polymeric IgA in IgA nephropathy

Renal biopsy specimens from 8 patients with IgA nephropathy (Berger's disease) were examined immunocytochemically at the light and electron microscopic levels with peroxidase-labeled antibodies to IgA, IgM, J chain and secretory component. In 2 of the 8 specimens heavy deposits of IgA, but no IgM, were found in the mesangium. After acid-urea treatment of these tissue sections, J chain, a subunit of polymeric immunoglobulins, was identified in a distribution similar to that of IgA. In the remaining 6 specimens, small amounts of IgM in addition to denser deposits of IgA and J chains were found. We conclude that the IgA deposits in at least some patients with Berger's disease consist of IgA polymers linked by J chain.     

Mesangial C3 deposition and decreased serum C3levels in patients with IgA nephropathy

Objective To explore theclinical significance of complementactivation in IgA nephropathy (IgAN) patients and provide new potential therapy targets. Methods Biopsy-proven IgAN patients admitted in our renal center were retrospectively recruited. Demographic, baseline clinical and pathological data were recorded as well as the follow-up results. Patients were divided into three groups, negative, weak positive and strong positive group, according to the intensity of C3 deposition in mesangial area of glomurili. Decreased serum C3 level was defined as C3＜85 mg/dl. Results In this study, 528 IgAN patients were recruited and meanfollow-up time was3 years. There were 119 (22.5%), 164(31.1%), 245(46.4%) patients in the negative, weak positive and strong positive group respectively; 93(21.7%) patients had decreased serum C3 level and 335(78.3%) patients had normal serum C3 level; Significant negative correlation was found between mesangial area of C3 deposition and serum level of C3(r＝-0.209, P＜0.01). Theage or sex were similar among different groups of mesangial C3 deposition. In univariate analysis, higher baselineserum creatinine,uric acid and IgAlevels, and lower estimated glomerular filtration rate(eGFR), body mass index (BMI) levels were associated with a higher grade of mesangial C3 deposition (P＜0.05). Endocapillary hypercellularity and tubular atrophy or interstitial fibrosis were more prominent in patients with higher grade mesangial deposition of C3. Compared with the patients with normal serum C3 level, patients with decreased serum C3 level had lowerwhite blood cells,hemoglobin,triglyceride, cholesterol, eGFR level and higher serum creatinine level(P＜0.05). During the follow-up,a total of 54 patients developed to end stage renal disease (ESRD), the incidence of ESRD was 23.7% in patients with decreased serum C3 level and 8.4% with normal C3 level.Kaplan-Meieranalysis showed that median outcome-free survival timeof patients with decreased serum C3 levelwas significantshorter than patients with normal serum C3 level [(145.0±22.5) months vs (150.8±17.0) months, P＜0.01]. Cox regression proportional hazards models showed that after adjusting by sex, ageand clinical indicators (MAP, eGFR, serum albumin, urine protein and hemoglobin level), decreased serum C3level (HR＝0.97, 95%CI 0.96, 0.99, P＜0.01) remained be an independent riskfactor of ESRD. Conclusions There are different levels of complement activation in patients with IgAN. Complement activation is associated with baseline renal function and clinical outcomes, and decreased serum C3level is an independent riskfactor of ESRD in IgAN patients. Complement activation may be involved in the progression of IgAN.     

Mesangial IgA in IgA nephropathy arises from the mucosa

Numerous studies have attempted to elucidate the pathogenetic mechanisms of IgA nephropathy, analyzing kidney, serum, lymphocytes, and lymphoid tissue of patients with this glomerulonephritis. Based on studies of the molecular characteristics of the mesangial IgA, clinical features, and immunologic analysis of the mucosal tissue, a wide array of findings suggest that mesangial IgA indeed arises from the mucosa. These three areas of research are discussed, as well as the hypothesis of a systemic origin for the mesangial IgA.     

Mesangial changes in IgA nephropathy in children

The mesangial changes in 92 renal biopsy specimens from 81 children with IgA nephropathy were correlated with the clinical and the other renal biopsy findings. Three types of mesangial changes were identified: mesangial hypercellularity was predominant compared with the increase in matrix in 34 biopsy specimens (type A), the degrees of mesangial hypercellularity and matrix increase were similar in 36 (type B) and matrix increase was predominant in 22 (type C). The interval between the onset of disease and biopsy was significantly shorter in biopsies with type A mesangial changes (P less than 0.01) and significantly longer in those with type C (P less than 0.01). Serial pathologic observations revealed that predominant mesangial hypercellularity was almost exclusively seen in the initial biopsy but predominant matrix increase was usually seen in the follow-up biopsy. The percentage of glomeruli showing sclerosis was significantly higher in biopsies with type C mesangial changes (P less than 0.05). At the latest follow-up, 58% of the patients showing type A and 57% showing type B lost their proteinuria, whereas only 9% showing type C lost their proteinuria (P less than 0.01). These findings suggest that predominant mesangial hypercellularity is characteristic of the early lesion of childhood IgA nephropathy, and progression of disease leads to gradual decrease of mesangial cellularity and increase of matrix with sclerosis.     

Mesangial IgA nephropathy and idiopathic nephrotic syndrome

A 17-year-old male presented with nephrotic syndrome associated with microscopic hematuria. Renal biopsy showed only minor glomerular abnormalities (light microscopy). Immunohistology demonstrated strong mesangial deposition of IgA. Electronmicroscopy disclosed widespread effacement of foot processes in combination with isolated osmiophilic mesangial deposits. The patient responded to standard corticosteroid therapy with complete disappearance of proteinuria. Microscopic hematuria, however, persisted. Five months after steroid therapy was stopped, the nephrotic syndrome relapsed. It was again steroid-responsive with persisting microhematuria. From clinical and morphological data we conclude that the patient has concomitant idiopathic nephrotic syndrome (minimal change glomerulonephritis) and mesangial IgA glomerulonephritis. The simultaneous presence of these two diseases may give some hint as to their pathogenesis. In both, abnormalities in T cell regulation have been found. If these were indeed involved in the pathogenesis of the two glomerular diseases, a higher than expected probability for the two entities to coexist in the same patient is to be expected.     

Mesangial C3 deposition and serum C3 levels predict renal outcome in IgA nephropathy

Clinical and Experimental Nephrology - Complement activation plays an important role in the pathogenesis of IgA nephropathy (IgAN). We aimed to evaluate the relationship between mesangial C3...     

Mesangial expression of angiotensin II receptor in IgA nephropathy and its regulation by polymeric IgA1

BACKGROUND: Enhanced gene expression for the renin-angiotensin system (RAS) is detected in glomerular mesangial cells in IgA nephropathy (IgAN). Preliminary studies showed a reduced glomerular gene expression of angiotensin II subtype 1 receptor (AT1R), suggesting a regulatory response to high intrarenal angiotensin II (Ang II) concentration in IgAN. METHODS: We examined the effect of polymeric IgA1 (pIgA1) from patients with IgAN on the expression of Ang II receptors in cultured human mesangial cells (HMC). RESULTS: Polymeric IgA1 from patients with IgAN down-regulated the expression of AT1R in HMC in a dose-dependent manner. When similar experiments were conducted with addition of an angiotensin-converting enzyme inhibitor (captopril) or an AT1R antagonist (losartan), there was a significant increase in the expression of AT1R. Blockade of Ang II with captopril or losartan alone resulted in a stepwise increase of AT1R in cultured HMC. Down-regulation of Ang II subtype 2 receptor (AT2R) was not observed in HMC cultured with pIgA1 from patients with IgAN. The acute suppressive effect of pIgA1 from IgAN on the expression of AT1R was confirmed in HMC incubated with IgA isolated from 15 IgAN patients, 15 healthy subjects, and other glomerulonephritides control subjects. Reduced glomerular expression of AT1R (but not AT2R) was also demonstrated in renal biopsies from patients with IgAN. CONCLUSION: Our findings demonstrate an altered AT1R expression in HMC in response to raised intrarenal Ang II in IgAN. Our in vitro studies also support that an imbalance of AT1R and AT2R activity in HMC following exposure to pIgA plays a significant pathogenetic role in the inflammatory injury in IgAN.     

Clinicopathological significance of monoclonal IgA deposition in patients with IgA nephropathy

Background

Clinicopathological significance of monoclonal IgA deposition and its relation to bone marrow abnormalities in IgA nephropathy (IgAN) remains unclear.

Methods

We retrospectively investigated the prevalence and clinicopathological significance of monoclonal IgA deposition in 65 patients with IgAN. Serum-free light chain ratio, and urinary Bence Jones protein were also measured.

Results

Thirty-nine percent of patients were men, median age was 40 and median observation period was 31 months. Five patients (Group M) showed monoclonal IgA lambda deposition and one showed monoclonal IgA kappa deposition. Fifty-nine patients (Group P) showed polyclonal IgA deposition. There were no significant differences in the degree of proteinuria, hematuria and renal function between Group M and Group P. Total protein and albumin were significantly lower in Group M than in Group P. According to the Oxford classification, the percentage of patients with M1 was significantly higher in Group M than in Group P. One patient in Group P showed serum monoclonal IgG lambda. No patient showed abnormal serum-free light chain ratio. Seventy-five percent in Group M and 42 % in Group P were treated with steroid. Three patients in Group P progressed to end-stage renal disease (ESRD). The frequency of disappearance of proteinuria or hematuria and progression to ESRD was not different between the groups.

Conclusions

The prevalence of monoclonal IgA deposition was 9.2 %. Although some parameters differed between the groups, renal outcome were similar. Thus, IgAN with monoclonal IgA deposition seems not to be different entity from those with polyclonal IgA deposition.

     

The glomerular response to IgA deposition in IgA nephropathy

Compelling evidence points to a role for IgA receptors in the pathogenesis of IgA nephropathy. The soluble form of the type I IgA receptor (FcalphaRI or CD89) forms complexes with IgA that can be found in patients' serum and that initiate the disease in CD89 transgenic mice. A nonclassic IgA receptor, identified as the transferrin receptor (TfR), is highly expressed in patients' mesangium and colocalizes with IgA deposits. TfR preferentially binds polymeric IgA1 complexes, but not monomeric IgA1 or IgA2. The TfR-IgA1 interaction is dependent on carbohydrate moieties because hypoglycosylated IgA1 has superior binding to TfR than normally glycosylated IgA1. Polymeric IgA1 binding enhances mesangial cell TfR expression and results in cell proliferation and inflammatory and profibrogenic cytokine and chemokine production, suggesting a pivotal role in mesangial cell proliferation, matrix expansion, and recruitment of inflammatory cells. We propose that, as a second event, activation of the classic, FcRgamma-associated transmembrane FcalphaRI expressed on circulating myeloid leukocytes takes place. FcalphaRI/gamma2 cross-linking in human FcalphaRI transgenic animals promotes disease progression by enhancing leukocyte chemotaxis and cytokine production, and IgA immune complexes from IgA nephropathy patients induce FcalphaRI-dependent cell activation. This review therefore details the functional consequences of IgA/receptor interactions and discusses proposed mechanisms to explain the development and chronicity of the disease.     

Mesangial IgA1 in IgA nephropathy exhibits aberrant O-glycosylation: observations in three patients

BACKGROUND: In IgA nephropathy (IgAN), circulating IgA1 molecules display an abnormal pattern of O-glycosylation. This abnormality may potentially contribute to mesangial IgA1 deposition, but this is unproven because the O-glycosylation of mesangial IgA1 has not been analyzed. METHODS: IgA1 was eluted from glomeruli isolated from the kidneys of three IgAN patients obtained after nephrectomy or at postmortem. Serum from these patients, other patients with IgAN, and controls was subjected to the same treatment as the glomerular eluates. The O-glycosylation of eluted and serum IgA1 was measured by lectin binding using an enzyme-linked immunosorbent assay-based system. RESULTS: In all three cases, the lectin binding of IgA1 eluted from the glomeruli of IgAN patients was markedly higher than that of the serum IgA1 of the same individual, and also all but one of a series of serum IgA1 samples from other patients and controls. CONCLUSIONS: The higher lectin binding of glomerular compared with serum IgA1 suggests that O-glycosylated IgA1 molecules abnormally and selectively deposit in the kidney. These results provide the first evidence that mesangial IgA1 is abnormally O-glycosylated, and support a direct role for abnormal IgA1 O-glycosylation in the mechanism of mesangial IgA deposition in IgAN.     

Mesangial IgA nephropathy: detection of defective reticulophagocytic function in vivo

The splenic component of the reticulophagocytic system (RPS) was studied in 20 patients with primary mesangial IgA nephropathy and 15 healthy controls. Eight patients were hypertensive, seven had renal failure and six had significant proteinuria. RPS function was assessed by the measurement of T1/2 clearance of altered, radio-labelled autologous erythrocytes. Three different methods were used to alter the red cells - thermal stress, sulfhydryl inhibition with N-ethylmaleimide (NEM) and antibody-coating - and in 12 patients two of these methods were used simultaneously in double-isotope-labelled studies. Impaired clearance was demonstrated in 16 of the 20 patients. T1/2 of NEM-altered cells was abnormal in 12 of 19 studies in 17 patients (i.e. T1/2 greater than 22.5 mins) while T1/2 of IgG-coated cells was abnormal in 8 of 10 patients (i.e. T1/2 greater than 62 mins). The clearance of thermally-damaged cells was not significantly different from that observed in controls (normal range: 10.5-17 mins). In the double-isotope studies, the clearance of NEM-altered cells correlated with the clearance of IgG-coated cells (P less than 0.05). There was no correlation between T1/2 clearance times and circulating immune complexes. These abnormalities of splenic function suggest there is a primary reticulophagocytic defect in patients with mesangial IgA nephropathy. This finding could bear relevance to the pathogenesis of the disease.     

Mesangial deposition of IgA2 subclass and lectin pathway-mediated complement activation in IgA glomerulonephritis

Three pathways are recognized in the complement activation cascade. The aim of our study was to elucidate immunohistologically which complement pathway is associated with the activation in IgA glomerulonephritis (GN) and the relation of IgA subclass to the complement activation. Immunohistological staining was performed on biopsied renal specimens from 36 patients with IgA GN, 10 with systemic lupus erythematosus (SLE) and 16 with other glomerulonephritides using polyclonal antibodies of IgG, IgA, IgM, C3c, C4, C1q and monoclonal antibodies of IgA1, IgA2, mannose-binding lectin (MBL) and MBL-associated serine protease-1 (MASP-1). Mesangial deposits of IgA1, IgA2, C3c, C4, MBL and MASP-1 were detected in 19 of the 36 patients with IgA GN, and IgA2 and MBL/MASP-1 were colocalized in the mesangium in these 19 patients. The remaining 17 patients showed mesangial deposition of IgA1 alone. Twelve of these 17 patients presented mesangial deposition of C3c without deposition of C4, MBL and MASP-1. No deposition of C1q was evident in IgA GN patients. Three of the 10 SLE patients showed glomerular deposition of MBL and MASP-1 without deposition of IgA2. No patient with other glomerulonephritides showed glomerular deposition of IgA1, IgA2, MBL and MASP-1. There was no correlation in clinical and pathological indicators between IgA2-positive and IgA2-negative patients with IgA GN. In conclusion, alternative pathway-mediated complement activation is associated in patients with mesangial deposition of IgA1 alone in IgA GN. In those with the deposition of both IgA1 and IgA2, both alternative and lectin pathways are activated, and mesangial deposition of IgA2 is associated with the lectin pathway-mediated complement activation in IgA GN.     

IgA nephropathy: immune mechanisms beyond IgA mesangial deposition

IgA nephropathy is attributable to mesangial IgA immune complex deposition. The pathogenic potential of frequently colocalized IgG deposits may depend on polarized T-helper cytokines that modulate Fcgamma receptors of infiltrating macrophages, leading to either activation or inhibition that determines glomerular injury.     

Macroscopic hematuria and proteinuria preceding renal IgA deposition in patients with IgA nephropathy

Although the clinical onset of IgA nephropathy is frequently impossible to define, macroscopic hematuria apparently heralds the onset of the disease in some patients. We describe the clinical course and renal histologic findings of four adults with IgA nephropathy who were diagnosed by the characteristic immunohistologic features in a second renal biopsy specimen. IgA was not detected in the initial renal biopsy specimens obtained 9 months to 4 years earlier. The first renal biopsy had been performed to evaluate macroscopic hematuria (recurrent in three patients), accompanied by pathologic proteinuria in two patients. Our observations suggest that the pathognomonic immunohistologic findings of IgA nephropathy may follow the clinical onset and raise questions about the presumed pathogenetic role of IgA in the early stages of this disease.     

血小板活化因子与IgA肾病

IgA肾病是一种多发病,常见病,早期不予重视.最终将发展成为肾功能衰竭.给社会造成了很大的负担,研究探索IgA肾病的发病机制及治疗依然显得相当重要,本文将论述血小板活化因子在IgA肾病免疫损伤、治疗中的相关性,进一步明确血小板活化因子在IgA肾病发病中的重要作用.