Pathogenesis Of Membranoproliferative Glomerulonephritis Research Articles

The Association of Class I and II Human Leukocyte Antigen Serotypes With End-Stage Kidney Disease Due to Membranoproliferative Glomerulonephritis and Dense Deposit Disease

Membranoproliferative glomerulonephritis (MPGN), encompassing several distinct diseases, is a rare but significant cause of kidney failure in the United States. The potential etiologies of MPGN are unclear, but prior studies have suggested dysregulation of the alternative complement pathway and, recently, autoimmunity as potential mechanisms driving MPGN pathogenesis. In this study, we examined HLA associations with end-stage kidney disease (ESKD) due to MPGN and dense deposit disease (DDD) in a large racially and ethnically diverse US-based cohort. Case-control study. Using US Renal Data System (USRDS) and United Network for Organ Sharing (UNOS) data, we identified 3,424 patients with kidney failure due to MPGN and 263 due to DDD. We matched patients to kidney donor controls on designated race and ethnicity in a 1:15 ratio. 58 class I and II HLA serotypes. Case-control status. For each disease cohort, univariable and multivariable logistic regression analyses were used to investigate associations between the disease and 58 HLA serotypes. In subgroup analyses, we investigated HLA associations in White and Black patients. We also studied antiglomerular basement membrane (anti-GBM) nephritis as a positive-control outcome. We applied a Bonferroni correction to account for multiple comparisons. Eighteen serotypes were significantly associated with the odds of having MPGN in univariable analyses, with DR17 having the strongest association (odds ratio [OR], 1.55 [95% CI, 1.44-1.68], P=4.33e-28). No significant associations were found between any HLA serotype and DDD. Designated race-specific analyses showed comparable findings. We recapitulated known HLA associations in anti-GBM nephritis. Reliance on HLA serotypes (rather than genotype), lack of biopsy-confirmed diagnoses. HLA-DR17 is associated with ESKD due to MPGN in a racially and ethnically diverse cohort. The strength of association was similar in White and Black patients, suggesting a role in the pathogenesis of MPGN. No HLA associations were observed in patients with DDD. Prior studies have suggested dysregulation of the alternative complement pathway as a potential etiology of membranoproliferative glomerulonephritis (MPGN), but recent evidence from a British White population has implicated an autoimmune mechanism in MPGN pathogenesis. We investigated HLA associations between MPGN and dense deposit disease (DDD) in a large racially and ethnically diverse cohort of patients. We found that HLA-DR17 is associated with end-stage kidney disease (ESKD) due to MPGN in both White and Black patients. By contrast, no significant HLA associations with ESKD due to DDD were identified. These results suggest a role for autoimmunity in some cases of MPGN and highlight differences in the disease etiology of MPGN compared with DDD.

Clinical features and pathogenesis of membranoproliferative glomerulonephritis: a nationwide analysis of the Japan renal biopsy registry from 2007 to 2015

BackgroundThe incidence and age distribution of membranoproliferative glomerulonephritis (MPGN) vary throughout the world by race and ethnicity. We sought to evaluate the clinical features, pathogenesis, and age distribution of MPGN among a large nationwide data from the Japan Renal Biopsy Registry (J-RBR).MethodsA cross-sectional survey of 593 patients with MPGN (types I and III) registered in the J-RBR between 2007 and 2015 was conducted. Clinical parameters, and laboratory findings at diagnosis were compared between children (< 20 years), adults (20–64 years), and elderly patients (≥ 65 years).ResultsThe median age of the patients was 59.0 years and mean proteinuria was 3.7 g/day. The rate of nephrotic syndrome was significantly higher in adults (40.4%) and elderly patients (54.0%) than in children (14.9%), whereas the rate of chronic glomerulonephritis was significantly higher in children (66.2%) than in adults (34.4%) and elderly patients (31.2%). According to the CGA risk classification, high-risk (red zone) cases accounted for 3.4% of children, 52.5% of adults and 84.1% of elderly patients with MPGN. As for pathogenesis, primary MPGN was most frequent (56.0%). Lupus nephritis was the most common disease among adult patients with secondary MPGN, whereas infectious disease was more common in elderly patients. Multiple regression analysis revealed that high systolic blood pressure and high proteinuria were independent factors associated with decreased estimated glomerular filtration rate (eGFR) in adults and elderly patients with MPGN.ConclusionsIn Japan, adults and elderly patients with MPGN had a lower eGFR and severer proteinuria than children.

Understanding the complement-mediated glomerular diseases: focus on membranoproliferative glomerulonephritis and C3 glomerulopathies.

An enhanced understanding of the role of complement in the pathogenesis of membranoproliferative glomerulonephritis has led to reclassification of the latter into immunoglobulin-mediated and non-immunoglobulin-mediated disease. The new classification schema resulted in improved diagnostic clinical algorithms, while it brought into light again the diseases, which are characterized by the presence of glomerular deposits, composed predominantly by C3, in the absence of significant amounts of immunoglobulins in renal biopsy, namely, C3 glomerulopathies (dense deposit disease and C3 glomerulonephritis). Despite the lack of randomized controlled trials following the advances in the understanding of the pathogenetic pathways involved in membranoproliferative glomerulonephritis, it is important that the new mechanistic approach has opened new roads for the exploration and discovery of targeted therapies.

Interleukin 17 signaling drives Type I Interferon induced proliferative crescentic glomerulonephritis in lupus-prone mice

Crescentic glomerulonephritis (cGN) is a severe clinical manifestation in a subset of patients with Systemic lupus erythematosus. Lack of understanding of the pathogenesis of cGN act as a major constraint in treating these patients. Emerging evidence suggest a critical role of IL-17 in the pathogenesis of membranoproliferative glomerulonephritis in lupus. However, the role of IL-17 receptor (IL-17RA) signaling in cGN is unknown. Here, we developed a model of poly I:C-induced Type I Interferon (IFN-I)-dependent cGN in B6.MRL-Faslpr/J (B6.lpr) mice. B6.lpr mice deficient in IL-17RA were protected from IFN-I-dependent cGN. While systemic response was unabated, renal infiltration of alternatively activated macrophages was severely impaired in IL-17RA−/− mice. Finally, we show that IL-17 differentially regulates the expression of macrophage chemo-attractant genes in renal tubular epithelial cells and macrophages in association with IFN-I. These results suggest that neutralization IL-17 may confer better protection in SLE patients with high IFN-I gene signature and cGN.

Expression of macrophage markers in cryoglobulinemic glomerulonephritis - a possible role of CXCL9

Cryoglobulinemic glomerulonephritis (CGGN) is a type of membranoproliferative glomerulonephritis (MPGN) that develops in patients with systemic cryoglobulinemia. To date the exact pathogenesis of CGGN remains unclear. It has been suggested that macrophages may be significant contributors to the glomerular injury in this disease. In our study we attempt to characterize the macrophages in human CGGN using classical activation and regulatory macrophage markers. We searched our database for renal biopsy cases of CGGN. Macrophages were detected using a monoclonal anti-CD68 antibody. Two groups of macrophage markers were used: classical activation markers, including iNOS, CXCL9 and CCL20, and regulatory markers: SPHK1 and LIGHT. The stains were performed using immunohistochemical method. Five patients with CGGN were identified. Four patients had systemic cryoglobulinemia and two had a serological evidence of hepatitis C virus infection. In all cases the glomeruli contained numerous macrophages. Staining for activatory macrophage markers revealed a strong nuclear staining for CXCL9 in numerous cells, including those corresponding to the macrophage location. Staining for the other activatory markers, as well as staining for regulatory markers, was not significant. In this study of human CGGN we showed a striking expression of cytokine CXCL9, a classical macrophage activation marker, by the macrophages and possibly other cell types within the glomeruli. This observation points to the possible role of classically activated macrophages in the pathogenesis of MPGN. If this observation is confirmed on a larger group of patients, the cytokine CXCL9 could become a potential therapeutic target for human CGGN.

Pathogenesis of the C3 glomerulopathies and reclassification of MPGN

Until recently, membranoproliferative glomerulonephritis (MPGN) was clinically classified as either primary, idiopathic MPGN or as secondary MPGN when an underlying aetiology was identifiable. Primary MPGN was further classified into three types--type I, type II, and type III--based principally on the ultrastructural appearance and location of electron-dense deposits. Both the clinical and histopathologic schemes presented problems, however, as neither was based on disease pathogenesis. An improved understanding of the role of complement in the pathogenesis of MPGN has led to a proposed reclassification into immunoglobulin-mediated disease (driven by the classical complement pathway) and non-immunoglobulin-mediated disease (driven by the alternative complement pathway). This reclassification has led to improved diagnostic clinical algorithms and the emergence of a new grouping of diseases known as the C3 glomerulopathies, best represented by dense deposit disease and C3 glomerulonephritis. In this Review, we re-examine the previous and current classification schemes of MPGN, focusing on the role of complement. We survey current data about the pathogenesis of the C3 glomerulopathies, including familial studies and patient cohorts from the USA and Europe. In addition, we discuss the diagnosis, treatment, and prognosis of the C3 glomerulopathies.

Positive C1q staining associated with poor renal outcome in membranoproliferative glomerulonephritis

Pathogenesis and clinical prognosis of membranoproliferative glomerulonephritis (MPGN) has not yet been established. We conducted a retrospective study of 41 patients with MPGN (type I and III) and examined the renal survival. In addition, factors contributing to survival time were analyzed. Fourteen patients (34 %) were classified into the renal death group. Patients with nephrotic syndrome and positive C1q staining of glomerular deposits showed a particularly poor prognosis. Significantly higher frequency of nephrotic syndrome and higher urinary protein excretion were observed in the renal death group (p = 0.0002, p = 0.0002) than in the renal survival group. The intensity of C1q staining was positively correlated with the severity of the proteinuria (p = 0.004). Factors that influenced the survival time were positive C1q staining of glomerular deposits (p = 0.003), presence of nephrotic syndrome (p = 0.004), serum albumin (p = 0.02), and proteinuria (p = 0.04). C1q staining in glomerular deposits and nephrotic syndrome were important factors influencing the prognosis and outcome in MPGN patients. C1q deposition may play a key role in the pathogenesis of MPGN, as evidenced by numerous observations, such as induction of proteinuria.

The pathogenesis of membranoproliferative glomerulonephritis in KwaZulu-Natal, South Africa is unrelated to hepatitis C virus infection.

Idiopathic membranoproliferative glomerulonephritis (MPGN) is a well-defined clinicopathological entity with a poor prognosis, with 50% of patients progressing to end stage renal disease (ESRD) within 10 years. It was reported in about 36% of adult Black patients with nephrotic syndrome in our center previously [Seedat et al. 1988]. Hepatitis C virus (HCV) infection has been shown to be associated with cryoglobulinemic as well as non-cryoglobulinemic (or idiopathic glomerulonephritis). The aim of this study was to determine whether an association exists between HCV infection and idiopathic MPGN in a population with a relatively high prevalence of MPGN. We studied adult patients referred with glomerular disease over a two-year period, 104 patients had primary glomerulonephritis. All 23 (22%) patients with idiopathic MPGN were enrolled, as well as 32 age-matched patients presenting with other primary glomerular diseases. We examined serum from all 55 patients for evidence of HCV antibodies and HCV RNA. None of the 55 patients showed evidence of HCV infection. Chronic renal failure was present in 82.6% of the patients with idiopathic MPGN and it was advanced in 52,2%, who either were dialysis-requiring at presentation or progressed to ESRD soon thereafter; 30.4% had moderate chronic renal failure, while only 17.4% had normal renal function. HCV infection is not associated with idiopathic MPGN in our patients. Idiopathic MPGN remains an idiopathic disease, possibly with a poor prognosis in our population.

Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H.

The alternative pathway of complement is activated continuously in vivo through the C3 'tick-over' pathway. This pathway is triggered by the hydrolysis of C3, resulting in the formation of C3 convertase. This, in turn, generates C3b, which mediates many of the biological functions of complement. Factor H, the main regulator of this activation, prevents formation and promotes dissociation of the C3 convertase enzyme, and, together with factor I, mediates the proteolytic inactivation of C3b. Factor H deficiency, described in 29 individuals from 12 families and in pigs, allows unhindered activation of fluid-phase C3 and severe depletion of plasma C3 (ref. 11). Membranoproliferative glomerulonephritis (MPGN) occurs in factor H-deficient humans and pigs. Although MPGN has been reported in other conditions in which uncontrolled activation of C3 occurs, the role of C3 dysregulation in the pathogenesis of MPGN is not understood. Here we show that mice deficient in factor H (Cfh(-/-) mice) develop MPGN spontaneously and are hypersensitive to developing renal injury caused by immune complexes. Introducing a second mutation in the gene encoding complement factor B, which prevents C3 turnover in vivo, obviates the phenotype of Cfh(-/-) mice. Thus, uncontrolled C3 activation in vivo is essential for the development of MPGN associated with deficiency of factor H.

A Study of Membranoproliferative Glomerulonephritis in Iran

The aim of this study was to review the morphologic patterns of membranoproliferative glomerulonephritis (MPGN) in 100 Iranian patients using light microscopy (LM) and electron microscopy (EM), and to compare the treatment and outcome in 13 patients with two biopsies. A retrospective study of 713 kidney biopsies of Iranian patients received between 1981 to 1994 was carried out. Of the 713 kidney biopsies, MPGN (n=106) and membranous glomerulopathy (n=112) made up the highest numbers of cases. Among 100 MPGN patients, 55 (55%) were MPGN type I, 10 were type II (10%), and 35 type III (35%). Eighty-three (83%) had nephrotic proteinuria, 39 (39%) had hematuria, and 52 (52%) were hypertensive. Complement levels were estimated in 58, with low C3 in 10. The glomerular involvement was irregular, with focal hypercellularity in 47 patients (47%), widely patent capillaries in 50 (50%), arteriosclerosis in 48 (48%), and with hyaline change in 25 (25%). Follow-up data (22-130 months) was available in 61 (61%) patients: 6 (10%) died after 14-56 months, 27 (44%) were on maintenance hemodialysis for 15-110 months, and three received transplants. Thirteen patients had detailed follow-up and a second biopsy after 24-120 months. All 13 presented with edema and nephrotic range proteinuria, with hematuria and hypertension in five and azotemia in four. Seven of the 13 patients received initial steroids, followed by antiplatelet or antihypertensive drugs. Four (type III) patients received antiplatelet and antihypertension drugs, and two (type III) received only antihypertensive drugs. In the first biopsy, glomerular changes by light microscopy were non-uniform in 7 of 10 (70%) type III MPGN cases. Vascular changes were absent or mild in 11, and moderate in two. In the second biopsies, 10 showed decrease in cellularity, with many open capillaries, persistence of deposits by EM in all, and progression of vascular sclerosis in eight, and tubulointerstitial changes in 10. Among the 13, six were clinically stable, another six received dialysis followed by transplant in three, and one had relapses with episodes of cryoglobulinemia. Three patients died. There is a high incidence of MPGN in Iranian patients, with a substantial number of type III MPGN cases. Second biopsies showed decreased cellularity, but increase in chronic tubulointerstitial and vascular cases. Steroids did not appear to benefit the outcome in types I and III MPGN patients compared to patients who received antihypertensive and antiplatelet treatment without steroids.

Hepatitis C virus-related proteins in kidney tissue from hepatitis C virus-infected patients with cryoglobulinemic membranoproliferative glomerulonephritis.

Membranoproliferative glomerulonephritis (MPGN) may be a component of a generalized vasculitis as well as a component of the clinical expression of type-II mixed cryoglobulinemia (MC). Several studies have established a striking association between hepatitis C virus (HCV) infection and MC. The potential role of HCV in the pathogenesis of MPGN, which occurs in almost half of the cases of MC patients, has not been fully investigated, and the demonstration of HCV proteins as the antigenic constituent of the glomerular immune deposits has remained elusive. Kidney biopsy specimens were obtained from 12 HCV RNA, antibody to HCV (anti-HCV)-positive patients with MPGN and type-II MC, and from 8 controls (3 HCV RNA, anti-HCV-negative patients with MPGN and MC and 5 with noncryoglobulinemic "idiopathic" MPGN). Murine monoclonal antibodies developed against c22-3, E2/NS1, c33c, c100-3, and NS5 proteins were used to detect HCV-related antigens by indirect immunohistochemistry. Acid electroelution of tissue sections was performed to enhance the sensitivity of the immunohistochemical method. Specific HCV-related proteins were detected in glomerular and tubulo-interstitial vascular structures in 8 (66.7%) HCV-positive MC patients and in none of the HCV RNA, anti-HCV-negative controls. HCV immunoreactive deposits displayed the following two major patterns: 1) a linear, homogeneous deposition along glomerular capillary walls, including endothelial cells and sub-endothelial spaces; and 2) a granular bead-like appearance with distinct deposits in mesangial and paramesangial cells. Immunoglobulin G (IgG) and M (IgM) and C3 fraction deposition in adjacent kidney sections displayed features comparable with those found for HCV deposits. Patients with granular deposits showed more pronounced renal impairment and severe proteinuria. These findings indicate that in MC patients with HCV-associated MPGN, kidney deposits consist of HCV-containing immune complexes that are likely to play a direct pathogenetic role in the renal damage.

IgG subclasses in patients with membranoproliferative glomerulonephritis, membranous nephropathy, and lupus nephritis

Primary glomerulopathy can be classified into seven essential patterns based on histopathological studies. The pathogenesis of membranoproliferative glomerulonephritis (MPGN), and membranous nephropathy (MN), which show glomerular IgG deposition and induce mainly nephrotic syndrome, is not known. To clarify the role of IgG subclass in glomerulonephritis, we compared serum concentrations of IgG subclasses, the ratio of serum IgG subclasses to total IgG (%IgG subclass), and glomerular deposition of IgG subclasses between 7 MPGN patients, 21 MN patients, and 9 lupus nephritis (LN) patients. Serum IgG subclasses and %IgG in all groups were almost within normal range based on the values in Japanese healthy adults. In the MPGN and MN groups, the IgG1 concentration was significant lower than that of the LN group (P < 0.001, P < 0.0001, respectively). The IgG2 concentration in the MPGN group decreased significantly compared with that in the LN group (P < 0.05). The %IgG2 of the LN group decreased significantly compared with that of the MN group (P < 0.05). The %IgG3 of the MPGN group was significantly higher that that of the MN group (P < 0.05). The glomerular immunofluorescent intensity of IgG1 and IgG2 were significantly stronger in the LN group than in the MPGN and MN groups (IgG1, P < 0.001, P < 0.01, respectively; IgG2, P < 0.0001, P < 0.0001, respectively). IgG3 in the MPGN and LN groups deposited significantly compared with that in the MN group (P < 0.0001, P < 0.01, respectively). The intensity of IgG4 in the MN group showed a significant difference compared with that in the MPGN and LN groups (P < 0.0001, P < 0.01, respectively). IgG3 is an important factor in the pathogenesis of primary MPGN, while IgG4 relates to glomerular IgG deposition in MN.

Nephritic factors predispose to chronic glomerulonephritis.

Chronic glomerulonephritis has been reported in three rare conditions in which factor H of the complement system does not function normally. Factor H is essential for the inactivation of the C3b-dependent convertase, C3b,Bb, which is constantly being formed in vivo. With factor H dysfunction, this convertase accumulates and produces hypocomplementemia. Twenty-two individuals have been reported with the three forms of H dysfunction, and 12 have displayed evidence of chronic glomerulonephritis. In addition, matings of certain Yorkshire pigs result in offspring that are homozygous deficient in factor H and have a high incidence of a severe hypocomplementemic glomerulonephritis closely resembling membranoproliferative glomerulonephritis type II. The hypothesis proposed is that the nephritis that develops with these forms of H dysfunction is in some way the result of circulating convertase. The corollary is that nephritic factors, also producing H dysfunction and higher than normal circulating levels of the C3b-dependent convertase, are responsible for the glomerulonephritides with which they are associated, mainly membranoproliferative glomerulonephritis types II and III. Nephritic factors are autoantibodies that bind to the C3b-dependent convertase and render it resistant to dissociation by factor H. Although nephritic factors are currently considered epiphenomena, their role in the pathogenesis of membranoproliferative glomerulonephritis should be reconsidered based on the evidence that circulating convertase is nephritogenic.

A renal biopsy study of hepatitis B virus-associated nephropathy in Korea

The pathogenic role of the hepatitis B virus (HBV) infection for glomerulonephritis (GN) is not clear. The frequency of HBsAg has been studied in sera of 732 consecutive patients who have glomerular diseases by using radioimmunoassay. The frequency of HBs antigenemia was 11.9%, which was not different from that in the general population of South Korea. Of the 87 HBsAg seropositive patients with GN, 29 cases with membranoproliferative GN (MPGN) and eighteen with membranous nephropathy (MN) were diagnosed as having HBV-associated nephropathy. Eighty-seven and one-half percent of the adults with MPGN and 80% of the children with MN were HBsAg carries. The morphologic findings and laboratory data in cases with HBV-associated MPGN and MN did not differ significantly from those observed in patients with MPGN and MN without circulating HBsAg. Yet mesangial deposits were more frequently noted in patients with HBV-associated MN when compared to others with idiopathic MN. Glomerular deposits of HBsAg were not detected using indirect immunofluorescence technique. Even though HBsAg was not demonstrable within the glomeruli, HBV infection seems to play an important role in the pathogenesis of MPGN in Korean adults and MN in children.