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The role of complement in kidney disease

Nature Reviews Nephrology volume 19, pages 771–787 (2023)Cite this article

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Abstract

The complement cascade comprises soluble and cell surface proteins and is an important arm of the innate immune system. Once activated, the complement system rapidly generates large quantities of protein fragments that are potent mediators of inflammatory, vasoactive and metabolic responses. Although complement is crucial to host defence and homeostasis, its inappropriate or uncontrolled activation can also drive tissue injury. For example, the complement system has been known for more than 50 years to be activated by glomerular immune complexes and to contribute to autoimmune kidney disease. Notably, the latest research shows that complement is also activated in kidney diseases that are not traditionally thought of as immune-mediated, including haemolytic–uraemic syndrome, diabetic kidney disease and focal segmental glomerulosclerosis. Several complement-targeted drugs have been approved for the treatment of kidney disease, and additional anti-complement agents are being investigated in clinical trials. These drugs are categorically different from other immunosuppressive agents and target pathological processes that are not effectively inhibited by other classes of immunosuppressants. The development of these new drugs might therefore have considerable benefits in the treatment of kidney disease.

Key points

  • The complement system is activated in kidney diseases of different aetiologies, including diseases involving immune complex formation, thrombotic microangiopathy, C3 glomerulopathy, glomerulosclerosis and acute kidney injury.

  • Experimental and clinical evidence suggests that the complement cascade contributes to injury in diseases that are not traditionally regarded as immune mediated, including diabetic kidney disease and focal segmental glomerulosclerosis.

  • The mechanisms of complement activation, including the activation pathways involved, vary among different kidney diseases, as do their downstream pathological effects.

  • Deposition of immune complexes in the glomerular capillaries, the high local concentration of complement proteins and the delicate system of complement regulation within the kidney might all contribute to its unique susceptibility to complement-mediated injury.

  • Many complement-inhibiting drugs have been approved, and additional agents targeting different components along the complement cascade are being investigated in clinical trials.

  • Complement-inhibiting drugs target immune system pathways that are not directly blocked by other immunosuppressive agents.

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Fig. 1: Mechanisms of complement activation in glomerular disease.
Fig. 2: Complement fragments mediate multiple downstream effects.
Fig. 3: Complement regulators in the kidney.
Fig. 4: Complement-inhibiting drugs for the treatment of kidney diseases.

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  1. Institute for Clinical and Experimental Medicine, Prague, Czech Republic

    Vojtech Petr

  2. University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

    Vojtech Petr & Joshua M. Thurman

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J.M.T. is a consultant for Q32 Bio, Inc., which is a company developing complement inhibitors. He holds stock and will receive royalty income from Q32 Bio, Inc. He co-founded and holds stock in Compsit3, a company developing complement diagnostics. V.P. declares no competing interests.

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Petr, V., Thurman, J.M. The role of complement in kidney disease. Nat Rev Nephrol 19, 771–787 (2023). https://doi.org/10.1038/s41581-023-00766-1

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