The role of the complement system in primary membranous nephropathy: A narrative review in the era of new therapeutic targets

Abstract

Primary membranous nephropathy (MN) is an important cause of nephrotic syndrome and chronic kidney disease (CKD) in the adult population. Although the discovery of different autoantibodies against glomerular/podocytic antigens have highlighted the role of B cells in the pathogenesis of MN, suboptimal response or even resistance to B cell-directed therapies occurs, suggesting that other pathophysiological mechanisms are involved in mediating podocyte injury. The complement system plays an important role in the innate immune response to infection, and dysregulation of the complement system has been observed in various kidney diseases. There is compelling evidence of complement cascade activation in primary MN, with the mannose-binding lectin (MBL) and alternative pathways particularly implicated. With appropriate validation, assays of complements and associated activation products could hold promise as adjunctive tools for non-invasive disease monitoring and prognostication. While there is growing interest to target the complement system in MN, there is concern regarding the risk of infection due to encapsulated organisms and high treatment costs, highlighting the need for clinical trials to identify patients most likely to benefit from complement-directed therapies.

A nomogram prediction model for treatment failure in primary membranous nephropathy

“…High immunofluorescence intensity of C3 deposits was associated with increased risk of kidney failure [ 26 ]. In the present study, C3 deposition on immunofluorescence staining negatively correlated with the study outcome, again reflecting the potential role of C3 being a therapeutic target or prognostic adjunctive tool [ 25 ]. It should be noted the significance of the correlation between C3 deposition and treatment failure was quite marginal, making further investigation necessary.…”

“…The positive correlation between interstitial inflammation infiltration and treatment failure in the final model is consistent with previous literature, further confirming the negative effect of interstitial inflammation on prognosis of PMN. Deposition of complement(s) of the mannose-binding lectin (MBL) pathway is observed in MN [ 25 ]. High immunofluorescence intensity of C3 deposits was associated with increased risk of kidney failure [ 26 ].…”

Pathological mechanism of immune disorders in diabetic kidney disease and intervention strategies

“…There are three common complement pathways[ 88 , 89 ]: Classical (CP), lectin (LP) and alternative (AP) pathways. Article 3 of the downstream activation pathway is C3 convertase and under the action of C5 invertase, it produces toxic effects, such as C5a- and C3a-mediated tissue injury, and simultaneously forms the membrane attack complex (MAC)-mediated effect of soluble cell (Figure 3 ).…”

Use of Chinese Herbal Medicine to Inhibit Podocyte Damage as Therapeutic Strategy for Membranous Nephropathy

“…C5b and other complement proteins, including C6, C7, C8, and C9, interact to form a C5b-9 complex called the MAC. [18–20]…”

“…C5b and other complement proteins, including C6, C7, C8, and C9, interact to form a C5b-9 complex called the MAC. [18][19][20] In MN, a nonspecific autoimmune disease, overproduced antiphospholipase A2 receptors in the glomerulus bind to relevant antigens on podocytes, and immune complexes are formed that activate the complement system, damaging podocytes. [21] C5b-9 is a multimeric protein complex that forms pores in the outer membrane of the target cells, causing cell damage or lysis.…”