Reclassification of membranoproliferative glomerulonephritis: Identification of a new GN: C3GN

Abstract

This review revises the reclassification of the membranoproliferative glomerulonephritis (MPGN) after the consensus conference that by 2015 reclassified all the glomerulonephritis basing on etiology and pathogenesis, instead of the histomorphological aspects. After reclassification, two types of MPGN are to date recognized: The immunocomplexes mediated MPGN and the complement mediated MPGN. The latter type is more extensively described in the review either because several of these entities are completely new or because the improved knowledge of the complement cascade allowed for new diagnostic and therapeutic approaches. Overall the complement mediated MPGN are related to acquired or genetic cause. The presence of circulating auto antibodies is the principal acquired cause. Genetic wide association studies and family studies allowed to recognize genetic mutations of different types as causes of the complement dysregulation. The complement cascade is a complex phenomenon and activating factors and regulating factors should be distinguished. Genetic mutations causing abnormalities either in activating or in regulating factors have been described. The diagnosis of the complement mediated MPGN requires a complete study of all these different complement factors. As a consequence, new therapeutic approaches are becoming available. Indeed, in addition to a nonspecific treatment and to the immunosuppression that has the aim to block the auto antibodies production, the specific inhibition of complement activation is relatively new and may act either blocking the C5 convertase or the C3 convertase. The drugs acting on C3 convertase are still in different phases of clinical development and might represent drugs for the future. Overall the authors consider that one of the principal problems in finding new types of drugs are both the rarity of the disease and the consequent poor interest in the marketing and the lack of large international cooperative studies.

The role of the alternative pathway of complement activation in glomerular diseases

“…The activation of immune complexes by the CP led to the assumption that other complement pathways are not involved in the disease pathogenesis. However, glomerular co-deposition of CFHR5, CFH, and FP has been found in MPGN I, LN and IgAN cases, indicating the AP involvement in these diseases [7,8,32,110,111]. In MPGN I patients, Servais et al reported low AP proteins levels, such as C3, CFB, CFH, and CFI (in 46.3, 34.1, 4.9, and 7.3% of cases, respectively) and the prevalence of the C3NeF (in 53.6% cases), what suggested the AP activation [62].…”

Complement related kidney diseases: Recurrence after transplantation

“…Similarly, the role of complement in C3G has been better defined[9], thus allowing us to move from a histologically based classification of the MPGNs to a new classification based on pathophysiology[10,11]. …”

“…The latter have clear signs of C3 staining with little or no immunoglobulin deposition evident on renal biopsy. C3Gs are further divided into dense deposit diseases (DDD) and the recently recognized entity C3GN[11]. …”

“…For example Shiga toxin-related HUS combined with aHUS in many registries. Additionally, the vast majority of registries or networks report data by using the classification of MPGNs, which precedes the results of the consensus report on C3G[14] and the recent consensus report and reclassification of GNs[10,11]. …”

“…After the reclassification[10,11], the most interesting and recent data on C3G recurrence are those reported by Zand et al[27]. According to these data, the recurrence rate of C3GN is 66.7%, and graft failure occurs in 50% of patients with recurrence.…”