Complement System and the Kidney: Its Role in Renal Diseases, Kidney Transplantation and Renal Cell Carcinoma

Abstract

The crosstalk among the complement system, immune cells, and mediators of inflammation provides an efficient mechanism to protect the organism against infections and support the repair of damaged tissues. Alterations in this complex machinery play a role in the pathogenesis of different diseases. Core complement proteins C3 and C5, their activation fragments, their receptors, and their regulators have been shown to be active intracellularly as the complosome. The kidney is particularly vulnerable to complement-induced damage, and emerging findings have revealed the role of complement system dysregulation in a wide range of kidney disorders, including glomerulopathies and ischemia-reperfusion injury during kidney transplantation. Different studies have shown that activation of the complement system is an important component of tumorigenesis and its elements have been proved to be present in the TME of various human malignancies. The role of the complement system in renal cell carcinoma (RCC) has been recently explored. Clear cell and papillary RCC upregulate most of the complement genes relative to normal kidney tissue. The aim of this narrative review is to provide novel insights into the role of complement in kidney disorders.

Keywords: complement system; complosome; ischemia-reperfusion injury; kidney; kidney transplantation; nephropathy; renal cell carcinoma; therapy.

Figure 1

Complement system pathways. MBL: mannose-binding lectin; FI: factor I; FH: factor H; CR1: complement receptor 1; MAC: membrane-attack complex.

Figure 2

Putative complement network in ccRCC TME. Tumor-associated macrophages (TAM) secrete C1q, which then assemble with C1r and C1s to form functionally active C1 complex. The cascade initiation depends on IgG deposition on tumor cells or PTX-3. Anaphylotoxins C3a and C5a support MDSCs’ recruitment and T cells’ exhaustion. Besides promoting modulating neoangiogenesis and immunoglogosis, the complement system can directly promote tumor growth.