De novo thrombotic microangiopathy (TMA) is associated with poor kidney graft survival, and as we previously described, it is a recipient driven process with suspected genetic background. Direct Sanger sequencing was performed in 90 KTR with de novo TMA and 90 corresponding donors on selected regions in CFH, CD46, C3, and CFB genes that involve variations with a functional effect or confer a risk for aHUS. Additionally, 37 recipients of paired kidneys who did not develop TMA were analyzed for the MCPggaac haplotype. Three-years death-censored graft survival was assessed using Kaplan-Meier and Cox regression models. The distribution of haplotypes in all groups was in the Hardy-Weinberg equilibrium and there was no clustering of haplotypes in any group. In the TMA group, we found that MCPggaac haplotype carriers were at a significantly higher risk of graft loss compared to individuals with the wild-type genotype. Worse 3-year death-censored graft survival was associated with longer cold ischemia time (HR 1.20, 95% CI 1.06, 1.36) and recipients' MCPggaac haplotype (HR 3.83, 95% CI 1.42, 10.4) in the multivariable Cox regression model. There was no association between donor haplotypes and kidney graft survival. Similarly, there was no effect of the MCPggaac haplotype on 3-year graft survival in recipients of paired kidneys without de novo TMA. Kidney transplant recipients carrying the MCPggaac haplotype with de novo TMA are at an increased risk of premature graft loss. These patients might benefit from therapeutic strategies based on complement inhibition.

1st Faculty of Medicine Charles University Prague Czechia

Department of Clinical and Transplant Pathology Institute for Clinical and Experimental Medicine Prague Czechia

Department of Immunogenetics Institute for Clinical and Experimental Medicine Prague Czechia

Department of Nephrology Institute for Clinical and Experimental Medicine Prague Czechia

Research Laboratory Department of Internal Medicine and Hematology Semmelweis University Budapest Hungary

Transplant Laboratory Institute for Clinical and Experimental Medicine Prague Czechia

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Petr V, Hruba P, Kollar M, Krejci K, Safranek R, Stepankova S, et al. . Rejection-associated phenotype of de novo thrombotic microangiopathy represents a risk for premature graft loss. Transplant Direct (2021) 7(11):e779. doi: 10.1097/TXD.0000000000001239 PubMed DOI PMC

Brocklebank V, Wood KM, Kavanagh D. Thrombotic microangiopathy and the kidney. CJASN (2018) 13(2):300–17. doi: 10.2215/CJN.00620117 PubMed DOI PMC

Garg N, Rennke HG, Pavlakis M, Zandi-Nejad K. De novo thrombotic microangiopathy after kidney transplantation. Transplant Rev (2018) 32(1):58–68. doi: 10.1016/j.trre.2017.10.001 PubMed DOI

Jodele S, Zhang K, Zou F, Laskin B, Dandoy CE, Myers KC, et al. . The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy. Blood (2016) 127(8):989–96. doi: 10.1182/blood-2015-08-663435 PubMed DOI PMC

Quintrec ML, Lionet A, Kamar N, Karras A, Barbier S, Buchler M, et al. . Complement mutation-associated De novo thrombotic microangiopathy following kidney. Am J Transplant (2008) 8:1694–1701. doi: 10.1111/j.1600-6143.2008.02297.x. PubMed DOI

Loupy A, Haas M, Roufosse C, Naesens M, Adam B, Afrouzian M, et al. . The banff 2019 kidney meeting report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection. Am J Transplant (2020) 20(9):2318–31. doi: 10.1111/ajt.15898 PubMed DOI PMC

Esparza-Gordillo J, de Jorge EG, Buil A, Berges LC, López-Trascasa M, Sánchez-Corral P, et al. . Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32. Hum Mol Genet (2005) 14(5):703–12. doi: 10.1093/hmg/ddi066 PubMed DOI

Liszewski MK, Post TW, Atkinson JP. Membrane cofactor protein (MCP or CD46): Newest member of the regulators of complement activation gene cluster. Annu Rev Immunol (1991) 9(1):431–55. doi: 10.1146/annurev.iy.09.040191.002243 PubMed DOI

Liszewski MK, Kemper C, Price JD, Atkinson JP. Emerging roles and new functions of CD46. Springer Semin Immun (2005) 27(3):345–58. doi: 10.1007/s00281-005-0002-3 PubMed DOI

Cattaneo R. Four viruses, two bacteria, and one receptor: Membrane cofactor protein (CD46) as pathogens’ magnet. J Virol (2004) 78(9):4385–8. doi: 10.1128/JVI.78.9.4385-4388.2004 PubMed DOI PMC

West EE, Kolev M, Kemper C. Complement and the regulation of T cell responses. Annu Rev Immunol (2018) 36(1):309–38. doi: 10.1146/annurev-immunol-042617-053245 PubMed DOI PMC

Jodele S, Medvedovic M, Luebbering N, Chen J, Dandoy CE, Laskin BL, et al. . Interferon-complement loop in transplant-associated thrombotic microangiopathy. Blood Adv (2020) 4(6):1166–77. doi: 10.1182/bloodadvances.2020001515 PubMed DOI PMC

Frimat M, Roumenina LT, Tabarin F, Halbwachs-Mecarelli L, Fremeaux-Bacchi V. Membrane cofactor protein (MCP) haplotype, which predisposes to atypical hemolytic and uremic syndrome, has no consequence on neutrophils and endothelial cells MCP levels or on HUVECs ability to activate complement. Immunobiology (2012) 217(11):1187–8. doi: 10.1016/j.imbio.2012.08.168 DOI

Fremeaux-Bacchi V. The development of atypical haemolytic-uraemic syndrome is influenced by susceptibility factors in factor h and membrane cofactor protein: evidence from two independent cohorts. J Med Genet (2005) 42(11):852–6. doi: 10.1136/jmg.2005.030783 PubMed DOI PMC

Ermini L, Goodship THJ, Strain L, Weale ME, Sacks SH, Cordell HJ, et al. . Common genetic variants in complement genes other than CFH, CD46 and the CFHRs are not associated with aHUS. Mol Immunol (2012) 49(4):640–8. doi: 10.1016/j.molimm.2011.11.003 PubMed DOI PMC

Park MS, Kim SK, Lee TW, Lee SH, Moon JY, Ihm CG, et al. . A promoter polymorphism in the CD46 complement regulatory protein gene is associated with acute renal allograft rejection. Transplant Proc (201) 48(3):809–12. doi: 10.1016/j.transproceed.2015.12.126 PubMed DOI