The Complement System in Renal Diseases

Abstract

The complement system has long been recognized as having a role in immune glomerular disease. This review provides an update on this association, some strategies for the clinical testing of complement in disease, and a brief commentary on current research directions. Evidence of complement activation in glomerulonephritis comes from characteristic patterns of a decrease in the serum concentrations of specific components, some of which are virtually diagnostic of certain nephritides. These patterns are often accompanied by the presence of complement components in the glomeruli and the detection of complement breakdown products in the circulation. In certain diseases, circulating complement-activating substances can be detected. Although there are over 20 complement proteins, clinical analysis is most often directed at C3 and C4, with occasional measurement of B and C5. Recently, a variety of mechanisms for complement-induced injury has been recognized. These mechanisms go far beyond simple passive lysis of erythrocytes, the earliest functional effect of complement studied. The role of such mechanisms in renal disease is just beginning to be studied. Local synthesis of complement components in the kidney may play a role both in host defense and in the promotion of interstitial inflammation and scarring. Such mechanisms will likely be defined more precisely with the availability of animals with specific complement deficiencies. Ultimately, an understanding of the role of complement in renal disease may permit specific targeted inhibition of one or more complement functions as a form of therapy.

Complement and the Kidney

“…In human lupus nephritis, there is a large amount and diversity of immune reactants in glomeruli, including IgG, IgM, IgA, C1q, C4, C3, and C5b-9 (18), leading to the designation "full house" pattern. In addition, there is systemic consumption of C and the appearance of C activation products in sera (19). Altogether, these observations would suggest, but not prove, an important role for C in lupus nephritis.…”

Chronic Progression of Tubulointerstitial Damage in Proteinuric Renal Disease Is Mediated by Complement Activation

“…Similarly, phospholipid anchored and transmembrane versions of either DAF or the structurally related C3/C5 convertase inhibitor MCP (CD46), show equal efficiency in protection from complement mediated cell damage (61). Welch has argued that using one of the several naturally occurring complement inhibitors (sCR1, DAF, MCP, or CD59) is likely to be therapeutically successful in the treatment of human proteinuric glomerulonephritis (62). Thus far, AVANT Immunotherapeutics has developed TP-10, a recombinant soluble sCR1, which has been shown to be well tolerated in phase I clinical trials in adults at risk for adult respiratory distress syndrome and in adults with first-time myocardial infarction and in myocardial infarction (63).…”

Complement 3 is involved in changing the phenotype of human glomerular mesangial cells

“…Complement components, particularly C3, have been detected in glomeruli of patients with a variety of renal diseases (Welch, 2001). It is generally accepted that the complement system is associated with the development of glomerulopathy, and the beneficial effects of complement inhibition have been investigated in cases of acute and chronic renal injury (Johnson, 1997).…”