The impact of reclassification of C3 predominant glomerulopathies on diagnostic accuracy, outcome and prognosis in patients with C3 glomerulonephritis.

BACKGROUND: C3 glomerulonephritis is a recently described entity with heterogeneous histopathological features. This study was conducted to assess the effect of reclassification of C3 glomerulopathies on renal outcomes, mortality, and response to therapy. METHODS: We undertook a retrospective analysis of 857 renal biopsies collected at The Canberra Hospital. Samples with predominant C3 staining were reviewed by a renal histopathologist. Of 31 biopsies with predominant C3 staining, 10 fulfilled histological criteria for C3 glomerulonephritis, while the remaining 21 cases were used as C3 Controls. RESULTS: Aside from a higher incidence of C3 glomerulonephritis in Torres Strait islanders (40% vs 5% C3 Controls, p = 0.04), presentation demographics were similar between the two groups. Median creatinine at diagnosis was higher in patients with C3 glomerulonephritis (253 umol/L IQR 103-333 vs 127 umol/L C3 Controls, IQR 105-182, p = 0.01). Prior to reclassification, a majority of C3 glomerulonephritis cases were diagnosed as membranoproliferative glomerulonephritis (60% vs 5% (C3 Controls) p < 0.01). Electron microscopy demonstrated all C3 glomerulonephritis patients had C3 deposition (100% vs 38% p = 0.02), these deposits were amorphous in nature (50% vs 5% respectively p = 0.007). C3 glomerulonephritis patients had shorter median follow-up (405 days IQR 203-1197 vs 1822 days respectively, IQR 1243-3948, p = 0.02). Mortality was higher in C3 glomerulonephritis patients (30% vs 14% in C3 Controls (log rank p = 0.02)). CONCLUSION: We have devised a diagnostic and treatment algorithm based on the results of literature review and our current study. Further prospective assessment is required to review diagnostic and treatment outcomes for this disease in Australian centres.

Characteristics of membranoproliferative glomerulonephritis based on a new classification at a single center.

BACKGROUND: Recently, a new classification has been established for membranoproliferative glomerulonephritis (MPGN). However, the effect of the new classification on MPGN treatment is not fully understood. METHODS: We conducted a retrospective study of 87 patients with biopsies diagnosed as MPGN. We reclassified 87 MPGN patients diagnosed between 1977 and 2014 at our hospital, according to the new classification, and analyzed both primary immune complex (IC)- and Alternative pathway (AP)-mediated MPGN [corrected] in terms of clinicopathological features, treatment, and renal prognosis. RESULTS: Proteinuria was abundant in the IC-mediated MPGN group (p = 0.0063), and the serum albumin level was significantly lower in the IC-mediated MPGN group (p = 0.0186). The serum C3 value was significantly lower in the CP-mediated MPGN group (p = 0.0317). Serum CH50 values were also lower in the CP-mediated MPGN group (p = 0.0404). However, glomerular deposition of C3 showed no significant differences in immunofluorescence findings. The 148.6-month renal survival rate was similar in both groups (p = 0.445). CONCLUSION: These results suggested no significant differences in complement activation of the solid phase in local glomeruli and therefore equivalent in renal prognosis [corrected].

Clinical and histological features of patients with membranoproliferative glomerulonephritis classified by immunofluorescence findings / Características clínicas e histológicas de pacientes com glomerulonefrite membranoproliferativa classificados por achados de imunofluorescência

Abstract Background: New classification for membranoproliferative glomerulonephritis has been proposed in the literature. The aim of this study was to compare the clinical, biochemical, etiology and renal biopsy findings of these patients grouped by immunofluorescence as proposed by the new classification. Methods: Patients with renal biopsy-proven membranoproliferative glomerulonephritis unrelated to systemic lupus erythematosus, diagnosed between 1999 and 2014. The patients were divided according to immunofluorescence: Immunoglobulin positive group, C3 positive only and negative immunofluorescence group. Results: We evaluated 92 patients, the majority of which were in the immunoglobulin positive group. Infectious diseases, hepatitis C virus and schistosomiasis, were the most frequent etiology. A negative immunofluorescence group had more vascular involvement in renal biopsy compare with others groups. Conclusions: The only difference between the groups was higher vascular involvement in renal biopsy in negative immunofluorescence group. These new classification was satisfactory for the finding of etiology in one part of the cases.

Resumo Introdução: Uma nova classificação para glomerulonefrite membranoproliferativa foi proposta na literatura. O objetivo deste estudo foi comparar os achados clínicos, bioquímicos, etiológicos e da biópsia renal desses pacientes agrupados por imunofluorescência, conforme proposto pela nova classificação. Métodos: Pacientes com glomerulonefrite membranoproliferativa comprovada por biópsia renal, não relacionada ao lúpus eritematoso sistêmico, diagnosticados entre 1999 e 2014. Os pacientes foram divididos de acordo com a imunofluorescência: grupo positivo por imunoglobulina, grupo positivo por C3 apenas e grupo com imunofluorescência negativa. Resultados: avaliamos 92 pacientes, a maioria dos quais estava no grupo de imunoglobulina positiva. Doenças infecciosas, o vírus da hepatite C e a esquistossomose, foram as etiologias mais frequentes. Um grupo com imunofluorescência negativa apresentou maior comprometimento vascular na biópsia renal quando comparado com os outros grupos. Conclusões: a única diferença entre os grupos foi o maior envolvimento vascular na biópsia renal no grupo de imunofluorescência negativa. Esta nova classificação foi satisfatória para a descoberta de etiologia em uma parte dos casos.

Clinical and histological features of patients with membranoproliferative glomerulonephritis classified by immunofluorescence findings.

BACKGROUND: New classification for membranoproliferative glomerulonephritis has been proposed in the literature. The aim of this study was to compare the clinical, biochemical, etiology and renal biopsy findings of these patients grouped by immunofluorescence as proposed by the new classification. METHODS: Patients with renal biopsy-proven membranoproliferative glomerulonephritis unrelated to systemic lupus erythematosus, diagnosed between 1999 and 2014. The patients were divided according to immunofluorescence: Immunoglobulin positive group, C3 positive only and negative immunofluorescence group. RESULTS: We evaluated 92 patients, the majority of which were in the immunoglobulin positive group. Infectious diseases, hepatitis C virus and schistosomiasis, were the most frequent etiology. A negative immunofluorescence group had more vascular involvement in renal biopsy compare with others groups. CONCLUSIONS: The only difference between the groups was higher vascular involvement in renal biopsy in negative immunofluorescence group. These new classification was satisfactory for the finding of etiology in one part of the cases.

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.

[Clinical approach to primary membranoproliferative glomerulonephritis]. / Approche clinique des glomérulonéphrites membranoprolifératives primitives.

Membranoproliferative glomerulonephritis represent a heterogeneous group of nephropathies. During the last five years, our understanding of membranoproliferative glomerulonephritis has greatly improved. Animal models and the study of complement genetics led to the dissection of the physiopathology of membranoproliferative glomerulonephritis, to the individualization of a new entity, C3 glomerulopathy, and to a new classification of these nephropathies. The study of large cohorts has also changed the clinical picture of membranoproliferative glomerulonephritis that has been long dominated by the severity of a single type of dense deposits disease. Finally, the rediscovery of complement through the study of the atypical haemolytic uremic syndrome and the availability in clinical practice of complement inhibitors have paved the way for new therapeutic approaches of membranoproliferative glomerulonephritis.

Manifestations of Complement-Mediated and Immune Complex-Mediated Membranoproliferative Glomerulonephritis: A Comparative Consecutive Series.

PURPOSE: Membranoproliferative glomerulonephritis (MPGN) recently was reclassified to reflect the underlying cause as a complement-mediated and immune complex-mediated disease. This classification is based on renal biopsy immunofluorescence examination, making the former electron-microscopy classification obsolete. In this report, we describe related eye findings in patients with MPGN based on the new classification. DESIGN: Retrospective case series. PARTICIPANTS: All Mayo Clinic Rochester patients with pathology-confirmed complement- and immune complex-mediated MPGN who had available ophthalmology records from 1997 through 2014 were included in this study. METHODS: The medical and pathologic records of patients with MPGN and eye examination results were reviewed from years 1997 through 2014. MAIN OUTCOME MEASURES: The number of patients and the number of eyes with MPGN-related pathologic features were examined. Visual acuity also was considered. RESULTS: There were 23 patients with complement-mediated MPGN and available eye examination results. Of these, 9 patients (39%) and 17 eyes (37%) had retinal pathologic features that likely were related to the same underlying pathophysiologic process as their renal disease. Five patients (22%) and 6 eyes (13%) had significant vision loss. There were 23 patients with immune complex-mediated MPGN and available eye examination results. Only 2 (9%) of these patients (4 eyes) had retinal pathologic features that potentially could be related to the same underlying pathophysiologic process as their renal disease, and neither had vision loss. CONCLUSIONS: Retinal abnormalities are more prominent among patients with complement-mediated MPGN when compared with patients with immune complex-mediated MPGN. It is critical for ophthalmologists to recognize the updated MPGN classification system, and all patients with complement-mediated MPGN require screening eye examinations.

Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome.

BACKGROUND: Membranoproliferative glomerulonephritis (MPGN) is an uncommon cause of chronic nephropathy recently reclassified into immunoglobulin-associated MPGN (Ig-MPGN) and C3 glomerulopathy (C3G). In this study we aimed: (1) to evaluate the complement genetic and biochemical profile in patients with Ig-MPGN/C3G; (2) to investigate whether genetic variants and different patterns of complement activation (i.e., fluid versus solid phase) correlate with disease manifestations and outcomes. METHODS: In 140 patients with idiopathic Ig-MPGN or C3G we performed complement biochemical and genetic screening and correlated genetic, biochemical and histology data with clinical features. RESULTS: Mutations in genes encoding alternative pathway complement proteins were found in both Ig-MPGN and C3G, and mutations in the two components of the C3 convertase are the most prevalent. We also report a mutation in THBD encoding thrombomodulin in a C3G patient. The presence of mutations alone does not significantly increase the risk of Ig-MPGN or C3G, but it does so when combined with common susceptibility variants (CD46 c.-366A in Ig-MPGN; CFH V62 and THBD A473 in C3G). Finally, patients without complement gene mutations or C3NeFs--autoantibodies that stabilize the alternative pathway C3 convertase--have a higher risk of progressing to end-stage renal disease than patients with identified mutations and/or C3NeFs, suggesting the existence of different pathogenetic mechanisms that lead to renal disease. CONCLUSIONS: We provide new insights into the pathogenesis of Ig-MPGN/C3G that underscore the complex nature of these diseases and suggest that the current C3G classification may miss many cases associated with abnormalities of the complement alternative pathway.

Membranoproliferative glomerulonephritis recurrence after kidney transplantation: using the new classification.

BACKGROUND: Membranoproliferative glomerulonephritis (MPGN) is an uncommon glomerular disorder that may lead to end stage renal disease (ESRD). With new understanding of the disease pathogenesis, the classical classification as MPGN types I, II, III has changed. Data on post-transplant MPGN, in particular with the newly refined classification, is limited. We present our center's experience of MPGN after kidney transplantation using the new classification. METHODS: This is a retrospective study of 34 patients with ESRD due to MPGN who received 40 kidney transplants between 1994 and 2014. We reviewed the available biopsies' data using the new classification. We assessed post transplantation recurrence rate, risk factors of recurrence, the response to therapy and allografts' survival. RESULTS: Median time of follow up was 5.3 years (range 0.5-14 years). Using the new classification, we found that pre-transplant MPGN disease was due to immune complex-mediated glomerulonephritis (ICGN) in 89 % of cases and complement-mediated glomerulonephritis (CGN) in 11 %. Recurrence was detected in 18 transplants (45 %). Living related allografts (P = 0.045), preemptive transplantations (P = 0.018), low complement level (P = 0.006), and the presence of monoclonal gammopathy (P = 0.010) were associated with higher recurrence rate in ICGN cases. Half of the patients with recurrence lost their allografts. The use of ACEi/ARB was associated with a trend toward less allograft loss. CONCLUSIONS: MPGN recurs at a high rate after kidney transplantation. The risk of MPGN recurrence increases with preemptive transplantation, living related donation, low complement level, and the presence of monoclonal gammopathy. Recurrence of MPGN leads to allograft failure in half of the cases.

Clinicopathological features of membranoproliferative glomerulonephritis under a new classification.

BACKGROUND: A recent classification of membranoproliferative glomerulonephritis (MPGN) utilizes the presence of immunoglobulin and complements to simplify diagnosis and point towards disease etiology. Here, we evaluate a historic cohort of patients with idiopathic MPGN using the new classification system and correlate it with clinical outcome. METHODS: We identified 281 patients diagnosed with MPGN at Stanford from 2000 to 2012. Patients with hepatitis, systemic lupus erythematosis, lymphomas, and plasma cell dyscrasias were excluded. The clinicopathologic findings of the remaining 71 patients were further analyzed and differences between immunoglobulin dominant (IM) and complement dominant (CM) disease were evaluated. RESULTS: Using the new classification system, 51 subjects were characterized as CM MPGN and 20 as IM MPGN. In the CM MPGN group, there was a non-significant trend towards lower proteinuria but higher serum creatinine values. At biopsy, most subjects had less than 50% global sclerosis or cortical scarring. The majority of subjects in the CM MPGN group (41%) had C3 nephropathy while 60% of subjects in IM MPGN group had C3 dominant disease. Treatment and outcomes: During follow-up (median 2 years), 20 patients reached a clinical end point of dialysis or death. The mean creatinine was significantly higher while the baseline proteinuria also trended slightly higher. Prednisone use was statistically higher in the survivor group. CONCLUSIONS: Our study highlights the clinicopathological features of patients with biopsy proven MPGN with no known etiological factors and sheds some light on the incidence and outcomes of various categories of MPGN under the new criteria, including MPGN with "dominant C3" deposits, rapidly becoming a descriptive diagnosis.

Histopathology of MPGN and C3 glomerulopathies.

'Membranoproliferative' describes glomerular injury characterized by capillary wall thickening and mesangial expansion owing to increased matrix deposition and hypercellularity. The presence of immune deposits is indicative of membranoproliferative glomerulonephritis (MPGN). Historically, MPGN was further classified into three types according to the appearance and site of the electron-dense deposits seen by electron microscopy, but it is now recognized that many cases show only deposition of the complement component C3, owing to abnormal control of the alternative pathway of complement activation-these cases are now classified as C3 glomerulopathies. Not all cases of C3 glomerulopathy, however, show an MPGN pattern. C3 glomerulopathies include dense deposit disease, which shows dense osmiophilic deposits, and C3 glomerulonephritis, which shows isolated deposits. In many cases, the genetic mutations or autoantibodies responsible for C3 deposition have been identified. Some patients in whom complement control is abnormal will accumulate small amounts of immunoglobulin in their glomeruli and so, in everyday practice, the morphological diagnosis of 'glomerulonephritis with dominant C3' is useful for identifying patients who require investigation of the complement pathway. The recognition that many cases of MPGN are C3 glomerulopathies and that the underlying cause can often be identified in immunoglobulin-associated cases means that the diagnosis of idiopathic MPGN is now very uncommon.

Toward a working definition of C3 glomerulopathy by immunofluorescence.

Precise immunofluorescence criteria for C3 glomerulopathy remain to be defined. Here we tested hierarchical immunofluorescence criteria with varying stringency for C3 glomerulopathy in a cohort with dense deposit disease as the gold standard and then applied these criteria to analyze the incidence of C3 glomerulopathy in membranoproliferative glomerulonephritis (MPGN) types 1 and 3. Among 319 archived cases of primary MPGN types 1-3, immunofluorescence reports were retrospectively coded as glomerular deposits of the following: C3 only; C3 dominant with trace or 1+ immunoglobulin (Ig)M only; and C3 dominant and at least two orders of intensity stronger than any combination of IgG, IgM, IgA, and C1q. The most restrictive criteria of 'C3 only' captured only half of the cases with dense deposit disease (compared with 8% of type 1 and 10% of type 3). Adding the most liberal definition identified 88% of those with dense deposit disease (compared with 31% of type 1 and 39% of type 3). The unaccounted 12% had stronger intensity of Ig staining, but it never exceeded the intensity of C3. Among MPGN type 3, 90% of C3 glomerulopathy cases were the Strife and Anders variant. Repeat biopsies in C3 glomerulopathy revealed a change in immunofluorescence pattern in 10 of 23 biopsies. The prevalence of low serum C3 and/or low C4 did not significantly differ among the three immunofluorescence criteria. Thus, 'C3 only' is an impractical definition of C3 glomerulopathy, and we propose a definition of C3 dominant and at least two orders of magnitude more intense than any other immune reactant, which requires validation by alternative pathway evaluation. These criteria provide a framework for identifying patients most likely to benefit from investigations of alternative complement pathway dysregulation.

Re-evaluation of the classification system for membranoproliferative glomerulonephritis.

In recent years, significant advances have been made in understanding the pathogenesis and etiology of membranoproliferative glomerulonephritis (MPGN). A new classification system based on pathological immunofluorescence findings has been proposed to replace the traditional clinical classification system in order to better identify the underlying causes of MPGN and to provide guidance for more individualized treatment. We conducted a retrospective survey of the MPGN patients treated in our hospital from 2000 to 2012 and report here the validation of this new classification system in this cohort. A total of 34 patients were diagnosed with MPGN, including 25 males and 9 females. There were 3 cases of secondary MPGN, including 1 case due to monoclonal gammopathy of undetermined significance (MGUS) and 2 cases related to hepatitis B virus (HBV) infection. Clinical presentations included nephrotic syndrome (76.5%), microscopic hematuria (79.4%), hypocomplementemia (58.8%), renal insufficiency (82.4%), hypertension (100%), and peripheral edema (100%). All patients were treated with prednisone and immunosuppressive agents, mainly cyclophosphamide. During follow-up (median 6 months, range 3-47 months), 4 patients were lost to follow-up and 2 patients progressed to end-stage renal disease. In Western countries the main cause of secondary MPGN was hepatitis C virus or HBV infection, here however we report 2 cases related to HBV infection. MGUS-associated MPGN was less frequent in the Chinese cohort. Future studies should be designed to evaluate the association of the new classification system and clinical outcomes of MPGN.

C3 glomerulopathies. A new perspective on glomerular diseases.

Membranoproliferative glomerulonephritis denotes a general pattern of glomerular injury that is easily recognised by light microscopy. With additional studies, MPGN subgrouping is possible. For example, electron microscopy resolves differences in electron-dense deposition location, while immunofluorescence typically detects the composition of electron-dense deposits. A C3 glomerulopathy (C3G) is a recently described entity, a proliferative glomerulonephritis (usually but not always), with a MPGN pattern on light microscopy, with C3 staining alone on immunofluorescence, implicating hyperactivity of the alternative complement pathway. The evaluation of C3G in a patient should focus on the complement cascade, as deregulation of the alternative pathway and terminal complement cascade underlies pathogenesis. Although there are no specific treatments currently available for C3G, a better understanding of their pathogenesis would set the stage for the possible use of anti-complement drugs, as eculizumab. In this review, we summarise the pathogenesis of the C3 glomerulopathies, focusing on the role of complement, the patient cohorts recently reported and options of treatment up to the current moment.

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.

Idiopathic membranoproliferative glomerulonephritis: does it exist?

When membranoproliferative glomerulonephritis (MPGN) was first delineated as a discrete clinico-pathological entity more than a half-century ago, most cases were regarded as idiopathic (or primary) in nature. Advances in analysis of pathogenetic mechanisms and etiologies underlying the lesion of MPGN have radically altered the prevalence of the truly idiopathic form of MPGN. In addition, MPGN as a category among renal biopsies showing glomerulonephritis has diminished over time. In the modern era, MPGN is mainly classified morphologically on the basis of immunoglobulin (Ig; monoclonal or polyclonal) and complement (C3 only or combined with Ig) deposition and secondarily on the basis of its appearance on ultra-structural examination. Idiopathic MPGN is a diagnosis of exclusion, at least in many adults and a portion of children, and a systematic approach to evaluation will often uncover a secondary cause, such as an infection, autoimmune disease, monoclonal gammopathy, neoplasia, complement dysregulation or a chronic thrombotic microangiopathy. Idiopathic MPGN remains an 'endangered species' after its separation from these known causes.

Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion.

Membranoproliferative glomerulonephritis (MPGN) denotes a general pattern of glomerular injury that is easily recognized by light microscopy. With additional studies, MPGN subgrouping is possible. For example, electron microscopy resolves differences in electron-dense deposition that are classically referred to as MPGN type I (MPGN I), MPGN II, and MPGN III, while immunofluorescence typically detects immunoglobulins in MPGN I and MPGN III but not in MPGN II. All three MPGN types stain positive for complement component 3 (C3). Subgrouping has led to unnecessary confusion, primarily because immunoglobulin-negative MPGN I and MPGN III are more common than once recognized. Together with MPGN II, which is now called dense deposit disease, immunoglobulin-negative, C3-positive glomerular diseases fall under the umbrella of C3 glomerulopathies (C3G). The evaluation of immunoglobulin-positive MPGN should focus on identifying the underlying trigger driving the chronic antigenemia or circulating immune complexes in order to begin disease-specific treatment. The evaluation of C3G, in contrast, should focus on the complement cascade, as dysregulation of the alternative pathway and terminal complement cascade underlies pathogenesis. Although there are no disease-specific treatments currently available for C3G, a better understanding of their pathogenesis would set the stage for the possible use of anti-complement drugs.