<p>Although the complement cascade is a crucial antimicrobial defense, inappropriate or uncontrolled activation can drive tissue injury and lead to primary glomerulopathies. Complement dysregulation was discussed in a session at the <strong>National Kidney Foundation (NKF) 2024 Spring Clinical Meetings</strong> (SCM24).</p> <p> </p> <p><em>Following this session, featured expert Samir V. Parikh, MD, FASN, was interviewed by </em>Conference Reporter <em>Associate Editor-in-Chief Rick Davis. Dr Parikh’s clinical perspectives are presented here. </em></p>

After years of speculation that complement participates in the inflammation and injury that we see in primary glomerular diseases, we now have more evidence to support it. Complement is activated and contributes to kidney damage across the spectrum of glomerular disorders, from C3 glomerulopathy (C3G) to immune complex glomerulonephritis such as IgA nephropathy (IgAN) and systemic diseases such as lupus nephritis and ANCA vasculitis. There is evidence of alternative and lectin pathway activation in IgAN, and studies have found genetic changes that may be protective or pathogenic. In C3G, dysregulation of the alternative pathway appears to be the primary mechanism of injury. However, in other forms of glomerular diseases, complement dysregulation may not be the primary mechanism but adds to injury in the glomerulus.

 

In a general session at SCM24 titled “Complement Cascade: The System You Wanted to Forget After Medical School Is Back,” complement experts reviewed the role of the complement cascade across kidney diseases. They noted that the kidney is particularly susceptible to complement-mediated injury and that the complement system is activated in both immune complex– and nonimmune complex–mediated glomerular diseases. The mechanism of complement activation varies across diseases. We also learned that C3a may promote podocyte injury and that factor H is crucial to controlling complement at the glomerular basement membrane. Further, complement activation participates in the development of chronic kidney damage, and chronic kidney disease promotes complement activation, creating a cycle for continued injury. During the session, it was also noted that there is no evidence-based guideline for genetic testing in C3G. Genetic testing is not widely available but should be considered in patients with a family history of glomerular diseases or when transplant is being considered.

 

In immune complex glomerulonephritis, the classical pathway is activated and then, downstream, the alternative pathway becomes activated. In a disease such as C3G, it is fairly evident that the dysregulation occurs in the alternative pathway. The alternative pathway has numerous regulators that ensure it stays on at a low level, commonly called “tick over”; however, if any of the regulators are inhibited, the pathway becomes unchecked.

 

If that happens, there is an increased generation of C3b that can go to the glomeruli and cause damage. Additionally, if C5 convertases get activated, downstream activation of the terminal pathway can lead to endothelial injury and thrombotic microangiopathy, as is seen in atypical hemolytic uremic syndrome. Mutations in alternative pathway genes, especially in regulators such as factor H or factor I, and autoantibodies that target those factors can also prevent those regulators from working. This leads to overactivation of the alternative pathway.

 

In addition, there are gain-of-function C3 mutations that can lead to alternative pathway overactivity. The rate-limiting step of the alternative pathway is the cleavage of factor B by factor D; therefore, targeting those factors are of interest, and we now have factor B and factor D inhibitors. To decrease inflammation, targeting the proinflammatory molecules C3a and C5a might be helpful, and a C5a receptor inhibitor is now available for ANCA vasculitis. Overall, there is a breadth of complement involvement in glomerular diseases, and targeting complement may help control kidney damage across glomerular diseases.