The complement as therapeutic target in kidney diseases

DIMAS G. GRIGORIOS, MD, PhD  – Senior Lecturer in Nephrology

Head of Outpatient Clinic of Nephrology & Hypertension and related Research Laboratory of 1st Propaedeutic Medical Department of Internal Medicine, AHEPA University Hospital, Medical School of Aristotle University of Thessaloniki

Chairman of the Scientific Committee of International Cardiothoracic – Renal Academy (ICRA)

Researcher of National Institute of Health and Medical Research (INSERM) Paris – France

General Secretary of Hellenic College of Nephrology and Hypertension (EKONY)

& Chairman of the Scientific Committee of 26th Conference

Dysregulation of the Complement Alternative Pathway (AP), genetic or acquired, may cause kidney diseases that are traditionally classified based on clinical presentation (atypical hemolytic uremic syndrome as thrombotic microangiopathy), occurrence at biopsy (Dense Deposit Disease, DDD & C3 Glomerulonephritis, GN) or clinical path (atypical postinfectious GN).

However, we argue that these diseases should be grouped as disorders of the AP and classified on a causal basis. Accurate identification of the underlying AP abnormality is the key to predicting response to immunosuppression, plasma infusion and use of complement inhibitors, as well as post-transplant outcome. There is no standardized treatment regimen that fits a particular clinical phenotype. Based on current perceptions, treatment strategies and their underlying pathophysiology include: (1) Nonspecific treatment (control of Blood Pressure, proteinuria reduction and use of lipid-lowering agents). In C3 glomerulopathy cohort studies, the use of renin-angiotensin-aldosteron (RAAS) blocking agents was associated with better renal survival, and the combined use of RAAS blockade and immunosuppression was better than either of the two. (2) Replacement of deficient gene products through plasma infusion and liver transplantation, (3) Elimination of autoantibodies and / or mutant proteins (plasma exchange, immunosuppression and treatment of plasma cell dyscrasia) and (4) Inhibition of complement activation (eculizumab and inhibition of C3 convertase). As CFH (Complement Factor H), CFI, CFB and C3 are mainly synthesized by the liver, concomitant liver-kidney transplantation can correct the genetic abnormality.

In the absence of controlled trials, support for immunosuppression in C3 glomerulopathy is based on case reports and case series presenting varying results. Approximately, 20 agents of Complement Inhibition are, nowadays, in a prospective phase II and III trials.

Eculizumab (Soliris, Alexion Pharmaceuticals) is a recombinant, fully humanized mAb that binds with high affinity to retain the human complement protein C5 and effectively prevent the cleavage of C5. About 15% of patients with aHUS are resistant to eculizumab.

Recent advances in the availability of biomarkers and genetic tests on complement cascade have unveiled the pathophysiological heterogeneity of glomerular disease caused by AP deregulation.