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

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Nov 25

PMID 38003705

Authors

Francesco Lasorsa

Monica Rutigliano

Martina Milella

Matteo Ferro

Savio Domenico Pandolfo

Felice Crocetto

Simona Simone

Loreto Gesualdo

Michele Battaglia

Pasquale Ditonno

Giuseppe Lucarelli

Affiliations

Soon will be listed here.

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.

Citing Articles

Comprehensive profiling of cell type-specific expression and distribution of complement genes in mouse and human kidneys: insights into normal physiology and response to kidney transplantations.

Li X, Zhu L Ren Fail. 2025; 47(1):2471568.

PMID: 40015727 PMC: 11869339. DOI: 10.1080/0886022X.2025.2471568.

Glycogen metabolism genes as a molecular signature for subtyping, prognostic prediction, and immunotherapy selection in clear cell renal cell carcinoma.

Ni F, Tan X, Zhang J, Guo T, Yuan Z, Wang X Clin Exp Med. 2025; 25(1):61.

PMID: 39961952 PMC: 11832626. DOI: 10.1007/s10238-025-01592-4.

Inhibition of complement system-related gene ITGB2 attenuates epithelial-mesenchymal transition and inflammation in diabetic nephropathy.

Peng J, Zhao W, Zhou L, Ding K Eur J Med Res. 2025; 30(1):87.

PMID: 39920798 PMC: 11806615. DOI: 10.1186/s40001-025-02323-x.

Potential prognostic and immunologic significances of ADAM8 in clear cell renal cell carcinoma.

Chu M, Zhang Z, Wang Z, Li Z, Guo Y Medicine (Baltimore). 2025; 104(5):e41375.

PMID: 39889162 PMC: 11789870. DOI: 10.1097/MD.0000000000041375.

Complement C3 of tumor-derived extracellular vesicles promotes metastasis of RCC via recruitment of immunosuppressive myeloid cells.

Zhang Y, Wang X, Gu Y, Liu T, Zhao X, Cheng S Proc Natl Acad Sci U S A. 2025; 122(4):e2420005122.

PMID: 39847320 PMC: 11789090. DOI: 10.1073/pnas.2420005122.

References

Roumenina L, Daugan M, Petitprez F, Sautes-Fridman C, Fridman W . Context-dependent roles of complement in cancer. Nat Rev Cancer. 2019; 19(12):698-715. DOI: 10.1038/s41568-019-0210-0. View

Lalli P, Strainic M, Yang M, Lin F, Medof M, Heeger P . Locally produced C5a binds to T cell-expressed C5aR to enhance effector T-cell expansion by limiting antigen-induced apoptosis. Blood. 2008; 112(5):1759-66. PMC: 2518884. DOI: 10.1182/blood-2008-04-151068. View

Kaabak M, Babenko N, Shapiro R, Zokoyev A, Dymova O, Kim E . A prospective randomized, controlled trial of eculizumab to prevent ischemia-reperfusion injury in pediatric kidney transplantation. Pediatr Transplant. 2018; 22(2). DOI: 10.1111/petr.13129. View

Medjeral-Thomas N, Cook H, Pickering M . Complement activation in IgA nephropathy. Semin Immunopathol. 2021; 43(5):679-690. PMC: 8551128. DOI: 10.1007/s00281-021-00882-9. View

Cho M, Rupaimoole R, Choi H, Noh K, Chen J, Hu Q . Complement Component 3 Is Regulated by TWIST1 and Mediates Epithelial-Mesenchymal Transition. J Immunol. 2016; 196(3):1412-8. PMC: 4724537. DOI: 10.4049/jimmunol.1501886. View

De Marco S, Torsello B, Minutiello E, Morabito I, Grasselli C, Bombelli S . The cross-talk between Abl2 tyrosine kinase and TGFβ1 signalling modulates the invasion of clear cell Renal Cell Carcinoma cells. FEBS Lett. 2022; 597(8):1098-1113. DOI: 10.1002/1873-3468.14531. View

Fremeaux-Bacchi V, Dragon-Durey M, Blouin J, Vigneau C, Kuypers D, Boudailliez B . Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J Med Genet. 2004; 41(6):e84. PMC: 1735822. DOI: 10.1136/jmg.2004.019083. View

de Weers M, Tai Y, van der Veer M, Bakker J, Vink T, Jacobs D . Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2010; 186(3):1840-8. DOI: 10.4049/jimmunol.1003032. View

Arbore G, West E, Rahman J, Le Friec G, Niyonzima N, Pirooznia M . Complement receptor CD46 co-stimulates optimal human CD8 T cell effector function via fatty acid metabolism. Nat Commun. 2018; 9(1):4186. PMC: 6180132. DOI: 10.1038/s41467-018-06706-z. View

10.

Vavallo A, Simone S, Lucarelli G, Rutigliano M, Galleggiante V, Grandaliano G . Pre-existing type 2 diabetes mellitus is an independent risk factor for mortality and progression in patients with renal cell carcinoma. Medicine (Baltimore). 2014; 93(27):e183. PMC: 4602816. DOI: 10.1097/MD.0000000000000183. View

11.

Daina E, Cortinovis M, Remuzzi G . Kidney diseases. Immunol Rev. 2022; 313(1):239-261. PMC: 10099622. DOI: 10.1111/imr.13167. View

12.

Huang E, Vo A, Choi J, Ammerman N, Lim K, Sethi S . Three-Year Outcomes of a Randomized, Double-Blind, Placebo-Controlled Study Assessing Safety and Efficacy of C1 Esterase Inhibitor for Prevention of Delayed Graft Function in Deceased Donor Kidney Transplant Recipients. Clin J Am Soc Nephrol. 2019; 15(1):109-116. PMC: 6946080. DOI: 10.2215/CJN.04840419. View

13.

Trambas I, Coughlan M, Tan S . Therapeutic Potential of Targeting Complement C5a Receptors in Diabetic Kidney Disease. Int J Mol Sci. 2023; 24(10). PMC: 10218149. DOI: 10.3390/ijms24108758. View

14.

Lucarelli G, Ferro M, Battaglia M . Multi-omics approach reveals the secrets of metabolism of clear cell-renal cell carcinoma. Transl Androl Urol. 2016; 5(5):801-803. PMC: 5071207. DOI: 10.21037/tau.2016.06.12. View

15.

Ronco P, Plaisier E, Debiec H . Advances in Membranous Nephropathy. J Clin Med. 2021; 10(4). PMC: 7915386. DOI: 10.3390/jcm10040607. View

16.

Hoxha E, Reinhard L, Stahl R . Membranous nephropathy: new pathogenic mechanisms and their clinical implications. Nat Rev Nephrol. 2022; 18(7):466-478. DOI: 10.1038/s41581-022-00564-1. View

17.

Nauser C, Farrar C, Sacks S . Complement Recognition Pathways in Renal Transplantation. J Am Soc Nephrol. 2017; 28(9):2571-2578. PMC: 5576943. DOI: 10.1681/ASN.2017010079. View

18.

Garlanda C, Bottazzi B, Magrini E, Inforzato A, Mantovani A . PTX3, a Humoral Pattern Recognition Molecule, in Innate Immunity, Tissue Repair, and Cancer. Physiol Rev. 2018; 98(2):623-639. PMC: 5985957. DOI: 10.1152/physrev.00016.2017. View

19.

Fremeaux-Bacchi V, Fakhouri F, Garnier A, Bienaime F, Dragon-Durey M, Ngo S . Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol. 2013; 8(4):554-62. PMC: 3613948. DOI: 10.2215/CJN.04760512. View

20.

Merle N, Noe R, Halbwachs-Mecarelli L, Fremeaux-Bacchi V, Roumenina L . Complement System Part II: Role in Immunity. Front Immunol. 2015; 6:257. PMC: 4443744. DOI: 10.3389/fimmu.2015.00257. View