Kidney Diseases Associated With Alternative Complement Pathway Dysregulation and Potential Treatment Options

Abstract

Atypical hemolytic uremic syndrome and C3 glomerulopathy (dense deposit disease and C3 glomerulonephritis) are characterized inappropriate activation of the alternative complement pathway (AP). Genetic mutations affecting the AP regulating proteins (complement factor H, I, membrane co-factor protein, complement factor H related proteins) and triggers (such as infection, surgery, pregnancy, and autoimmune disease flares) result in the clinical manifestation of these diseases. A decade ago prognosis of these disease states was quite poor with the majority of patients developing end-stage renal disease. Furthermore, renal transplantation in these conditions was associated with poor outcomes due to graft loss to recurrent disease. Recent advances in targeted complement inhibitor therapy resulted in significant improvement in disease remission, renal recovery, health-related quality of life and allograft survival.

Complement Inhibitors in Clinical Trials for Glomerular Diseases

“…Numerous approaches are being used to limit complement activation in the transplant in order to block complement inflammation and complement terminal pathway action (66). Involved in renal transplant as the new, foreign surface and under resourced tissue provide a platform for complement activation (67).…”

Complement-mediated renal diseases after kidney transplantation - current diagnostic and therapeutic options in de novo and recurrent diseases

“…Improved kidney function was observed in two patients; one patient showed partially improved proteinuria, while another patient showed better histological and laboratory findings[ 62 ]. Notably, elevated serum membrane attack complex (MAC) levels were associated with clinical improvement[ 63 ]. Duration of therapy is not yet defined.…”

“…CP40 can prevent in vitro complement-mediated hemolysis induced by C3GN patient sera. Moreover, it can abort dysregulated AP activation induced by autoantibodies and genetic mutations[ 63 ]. Since C3d is the major complement fragment deposited in C3GN and DDD, CP40 represents a promising therapeutic agent.…”

European Society for Immunodeficiencies (ESID) and European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN RITA) Complement Guideline: Deficiencies, Diagnosis, and Management

“…The complement system is a highly conserved part of the innate immune system, which can be traced back as far as the sea urchin [6]. It comprises over 30 membrane-bound and soluble components and has three major functions: (1) host defense by opsonisation, chemotaxis, induction of inflammation and lysis of targets [7][8][9][10] (2) interfacing between innate and adaptive immunity by augmenting the antibody response and immunological memory [11,12] and (3) the disposal of waste through the clearance of apoptotic cells and immune complexes [13][14][15][16][17].…”