#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Polymorphisms in vasoactive eicosanoid genes of kidney donors affect biopsy scores and clinical outcomes in renal transplantation


Autoři: Sonia Mota-Zamorano aff001;  Luz M. González aff001;  Enrique Luna aff002;  José J. Fernández aff003;  Áurea Gómez aff003;  Alberto Nieto-Fernández aff003;  Nicolás R. Robles aff002;  Guillermo Gervasini aff001
Působiště autorů: Department of Medical and Surgical Therapeutics, Division of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain aff001;  Service of Nephrology, Badajoz University Hospital, Badajoz, Spain aff002;  Service of Anatomical Pathology, Infanta Cristina University Hospital, Badajoz, Spain aff003
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0224129

Souhrn

Cytochrome P450 (CYP) enzymes metabolize arachidonic acid to vasoactive eicosanoids such as epoxyeicosatrienoic acids (EETs) and 20-Hydroxyeicosatetraenoic acid (20-HETE), whilst soluble epoxide hydrolase, encoded by the EPHX2 gene, is in charge of EETs degradation. We aimed to analyze the influence of common, functional polymorphisms in four genes of the donor on the renal biopsy scores independently assigned by pathologists. Additionally, we examined whether this score or the presence of these SNPs were independent risk factors of clinical outcomes in the first year after grafting. A cohort of 119 recipients and their corresponding 85 deceased donors were included in the study. Donors were genotyped for the CYP4F2 V433M, CYP2C8*3, CYP2J2*7, EPHX2 3’UTR A>G, EPHX2 K55R and EPHX2 R287Q polymorphisms. The association of the donors’ SNPs with the biopsy scores and clinical outcomes was retrospectively evaluated by multivariate regression analysis. The CYP2C8*3 polymorphism in the donor was significantly associated with higher scores assigned to pretransplant biopsies [OR = 3.35 (1.03–10.93), p = 0.045]. In turn, higher scores were related to an increased risk of acute rejection [OR = 5.28 (1.32–21.13), p = 0.019] and worse glomerular filtration rate (eGFR) (45.68±16.05 vs. 53.04±16.93 ml/min in patients whose grafts had lower scores, p = 0.010) one year after transplant. Patients whose donors carried the CYP4F2 433M variant showed lower eGFR values (48.96±16.89 vs. 55.94±18.62 ml/min in non-carriers, p = 0.038) and higher risk of acute rejection [OR = 6.18 (1.03–37.21), p = 0.047]. The CYP2J2*7 SNP in the donor was associated with elevated risk of delayed graft function [OR = 25.68 (1.52–43.53), p = 0.025]. Our results taken together suggest that donor genetic variability may be used as a predictor of tissue damage in the graft as well as to predict clinical outcomes and graft function in the recipient.

Klíčová slova:

Biopsy – Genetic polymorphism – Glomerular filtration rate – Histology – Kidneys – Renal system – Renal transplantation – Transplant rejection


Zdroje

1. Wu DA, Watson CJ, Bradley JA, Johnson RJ, Forsythe JL, Oniscu GC. Global trends and challenges in deceased donor kidney allocation. Kidney Int. 2017;91(6):1287–99. doi: 10.1016/j.kint.2016.09.054 28320531

2. Dahmane D, Audard V, Hiesse C, Pessione F, Bentaarit B, Barrou B, et al. Retrospective follow-up of transplantation of kidneys from 'marginal' donors. Kidney Int. 2006;69(3):546–52. doi: 10.1038/sj.ki.5000102 16407884

3. Anglicheau D, Loupy A, Lefaucheur C, Pessione F, Letourneau I, Cote I, et al. A simple clinico-histopathological composite scoring system is highly predictive of graft outcomes in marginal donors. Am J Transplant. 2008;8(11):2325–34. doi: 10.1111/j.1600-6143.2008.02394.x 18785957

4. Philosophe B, Malat GE, Soundararajan S, Barth RN, Manitpisikul W, Wilson NS, et al. Validation of the Maryland Aggregate Pathology Index (MAPI), a pre-implantation scoring system that predicts graft outcome. Clin Transplant. 2014;28(8):897–905. doi: 10.1111/ctr.12400 24931144

5. Gervasini G, Garcia M, Macias RM, Benitez J, Caravaca F, Cubero JJ. CYP2C8*3 Polymorphism and Donor Age are Associated With Allograft Dysfunction in Kidney Transplant Recipients Treated With Calcineurin Inhibitors. J Clin Pharmacol. 2013;53(4):427–34. doi: 10.1002/jcph.15 23426640

6. Lee SH, Lee J, Cha R, Park MH, Ha JW, Kim S, et al. Genetic variations in soluble epoxide hydrolase and graft function in kidney transplantation. Transplant Proc. 2008;40(5):1353–6. doi: 10.1016/j.transproceed.2008.03.137 18589104

7. Sharma M, McCarthy ET, Reddy DS, Patel PK, Savin VJ, Medhora M, et al. 8,9-Epoxyeicosatrienoic acid protects the glomerular filtration barrier. Prostaglandins Other Lipid Mediat. 2009;89(1–2):43–51. 19480064

8. Node K, Huo Y, Ruan X, Yang B, Spiecker M, Ley K, et al. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science. 1999;285(5431):1276–9. doi: 10.1126/science.285.5431.1276 10455056

9. Dolegowska B, Blogowski W, Domanski L. Is it possible to predict the early post-transplant allograft function using 20-HETE measurements? A preliminary report. Transpl Int. 2009;22(5):546–53. doi: 10.1111/j.1432-2277.2008.00829.x 19175563

10. Gervasini G, Garcia-Cerrada M, Vergara E, Garcia-Pino G, Alvarado R, Fernandez-Cavada MJ, et al. Polymorphisms in CYP-mediated arachidonic acid routes affect the outcome of renal transplantation. Eur J Clin Invest. 2015;45(10):1060–8. doi: 10.1111/eci.12507 26214067

11. Gervasini G, Garcia-Cerrada M, Coto E, Vergara E, Garcia-Pino G, Alvarado R, et al. A 3'-UTR Polymorphism in Soluble Epoxide Hydrolase Gene Is Associated with Acute Rejection in Renal Transplant Recipients. PLoS One. 2015;10(7):e0133563. doi: 10.1371/journal.pone.0133563 26230946

12. Gervasini G, Garcia-Pino G, Vergara E, Mota-Zamorano S, Garcia-Cerrada M, Luna E. CYP3A genotypes of donors but not those of the patients increase the risk of acute rejection in renal transplant recipients on calcineurin inhibitors: a pilot study. Eur J Clin Pharmacol. 2018;74(1):53–60. doi: 10.1007/s00228-017-2353-9 29043387

13. Dai D, Zeldin DC, Blaisdell JA, Chanas B, Coulter SJ, Ghanayem BI, et al. Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics. 2001;11(7):597–607. 11668219

14. Smith HE, Jones JP 3rd, Kalhorn TF, Farin FM, Stapleton PL, Davis CL, et al. Role of cytochrome P450 2C8 and 2J2 genotypes in calcineurin inhibitor-induced chronic kidney disease. Pharmacogenet Genomics. 2008;18(11):943–53. doi: 10.1097/FPC.0b013e32830e1e16 18769365

15. King LM, Ma J, Srettabunjong S, Graves J, Bradbury JA, Li L, et al. Cloning of CYP2J2 gene and identification of functional polymorphisms. Mol Pharmacol. 2002;61(4):840–52. doi: 10.1124/mol.61.4.840 11901223

16. Stec DE, Roman RJ, Flasch A, Rieder MJ. Functional polymorphism in human CYP4F2 decreases 20-HETE production. Physiol Genomics. 2007;30(1):74–81. doi: 10.1152/physiolgenomics.00003.2007 17341693

17. Ward NC, Tsai IJ, Barden A, van Bockxmeer FM, Puddey IB, Hodgson JM, et al. A single nucleotide polymorphism in the CYP4F2 but not CYP4A11 gene is associated with increased 20-HETE excretion and blood pressure. Hypertension. 2008;51(5):1393–8. doi: 10.1161/HYPERTENSIONAHA.107.104463 18391101

18. Przybyla-Zawislak BD, Srivastava PK, Vazquez-Matias J, Mohrenweiser HW, Maxwell JE, Hammock BD, et al. Polymorphisms in human soluble epoxide hydrolase. Mol Pharmacol. 2003;64(2):482–90. doi: 10.1124/mol.64.2.482 12869654

19. Imig JD. Epoxide hydrolase and epoxygenase metabolites as therapeutic targets for renal diseases. Am J Physiol Renal Physiol. 2005;289(3):F496–503. doi: 10.1152/ajprenal.00350.2004 16093425

20. Seron D, Anaya F, Marcen R, del Moral RG, Martul EV, Alarcon A, et al. [Guidelines for indicating, obtaining, processing and evaluating kidney biopsies]. Nefrologia. 2008;28(4):385–96. 18662146

21. Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant. 2008;8(4):753–60. doi: 10.1111/j.1600-6143.2008.02159.x 18294345

22. Perico N, Cattaneo D, Sayegh MH, Remuzzi G. Delayed graft function in kidney transplantation. Lancet. 2004;364(9447):1814–27. doi: 10.1016/S0140-6736(04)17406-0 15541456

23. Joosten SA, Sijpkens YW, van Kooten C, Paul LC. Chronic renal allograft rejection: pathophysiologic considerations. Kidney Int. 2005;68(1):1–13. doi: 10.1111/j.1523-1755.2005.00376.x 15954891

24. Lundblad MS, Stark K, Eliasson E, Oliw E, Rane A. Biosynthesis of epoxyeicosatrienoic acids varies between polymorphic CYP2C enzymes. Biochem Biophys Res Commun. 2005;327(4):1052–7. doi: 10.1016/j.bbrc.2004.12.116 15652503

25. Mota-Zamorano S, Luna E, Garcia-Pino G, Gonzalez LM, Gervasini G. Variability in the leptin receptor gene and other risk factors for post-transplant diabetes mellitus in renal transplant recipients. Ann Med. 2019:1–30. doi: 10.1080/07853890.2019.1614656 31046466

26. Gervasini G, Luna E, Garcia-Cerrada M, Garcia-Pino G, Cubero JJ. Risk factors for post-transplant diabetes mellitus in renal transplant: Role of genetic variability in the CYP450-mediated arachidonic acid metabolism. Mol Cell Endocrinol. 2016;419:158–64. doi: 10.1016/j.mce.2015.10.009 26483195

27. Gonzalez JR, Armengol L, Sole X, Guino E, Mercader JM, Estivill X, et al. SNPassoc: an R package to perform whole genome association studies. Bioinformatics. 2007;23(5):644–5. doi: 10.1093/bioinformatics/btm025 17267436

28. Fan F, Muroya Y, Roman RJ. Cytochrome P450 eicosanoids in hypertension and renal disease. Curr Opin Nephrol Hypertens. 2015;24(1):37–46. doi: 10.1097/MNH.0000000000000088 25427230

29. Zeldin DC, Moomaw CR, Jesse N, Tomer KB, Beetham J, Hammock BD, et al. Biochemical characterization of the human liver cytochrome P450 arachidonic acid epoxygenase pathway. Arch Biochem Biophys. 1996;330(1):87–96. doi: 10.1006/abbi.1996.0229 8651708

30. Sánchez-Escuredo A, Sagasta A, Revuelta I, Rodas LM, Paredes D, Musquera M, et al. Histopathological evaluation of pretransplant donor biopsies in expanded criteria donors with high kidney donor profile index: a retrospective observational cohort study. Transpl Int. 2017;30(10):975–86. doi: 10.1111/tri.12966 28403541

31. Zeier M, Döhler B, Opelz G, Ritz E. The effect of donor gender on graft survival. J Am Soc Nephrol. 2002;13(10):2570–6. doi: 10.1097/01.asn.0000030078.74889.69 12239247

32. Øien CM, Reisaeter AV, Leivestad T, Dekker FW, Line PD, Os I. Living donor kidney transplantation: the effects of donor age and gender on short- and long-term outcomes. Transplantation. 2007;83(5):600–6. doi: 10.1097/01.tp.0000255583.34329.dd 17353781

33. Fernandez-Fresnedo G, Palomar R, Escallada R, Martin de Francisco AL, Cotorruelo JG, Zubimendi JA, et al. Hypertension and long-term renal allograft survival: effect of early glomerular filtration rate. Nephrol Dial Transplant. 2001;16 Suppl 1:105–9. doi: 10.1093/ndt/16.suppl_1.105 11369835

34. Yilmaz S, Tomlanovich S, Mathew T, Taskinen E, Paavonen T, Navarro M, et al. Protocol core needle biopsy and histologic Chronic Allograft Damage Index (CADI) as surrogate end point for long-term graft survival in multicenter studies. J Am Soc Nephrol. 2003;14(3):773–9. doi: 10.1097/01.asn.0000054496.68498.13 12595515

35. Nyberg SL, Matas AJ, Rogers M, Harmsen WS, Velosa JA, Larson TS, et al. Donor scoring system for cadaveric renal transplantation. Am J Transplant. 2001;1(2):162–70. 12099365

36. Kahu J, Kyllonen L, Raisanen-Sokolowski A, Salmela K. Donor risk score and baseline biopsy CADI value predict kidney graft outcome. Clin Transplant. 2011;25(3):E276–83. doi: 10.1111/j.1399-0012.2011.01401.x 21303414

37. Zhang W, Yi Z, Wei C, Keung KL, Sun Z, Xi C, et al. Pretransplant transcriptomic signature in peripheral blood predicts early acute rejection. JCI Insight. 2019;4(11). doi: 10.1172/jci.insight.127543 31167967

38. Menon MC, Keung KL, Murphy B, O'Connell PJ. The Use of Genomics and Pathway Analysis in Our Understanding and Prediction of Clinical Renal Transplant Injury. Transplantation. 2016;100(7):1405–14. doi: 10.1097/TP.0000000000000943 26447506

39. Krajewska M, Koscielska-Kasprzak K, Weyde W, Drulis-Fajdasz D, Madziarska K, Mazanowska O, et al. Impact of donor-dependent genetic factors on long-term renal graft function. Transplant Proc. 2009;41(8):2978–80. doi: 10.1016/j.transproceed.2009.08.027 19857655

40. Park JI, Yang SH, Lee JP, Yoo SH, Kim YS. Genetic predisposition of donors affects the allograft outcome in kidney transplantation: Single-nucleotide polymorphism of aquaporin-11. Kidney Res Clin Pract. 2015;34(1):47–52. doi: 10.1016/j.krcp.2015.01.002 26484019


Článek vyšel v časopise

PLOS One


2019 Číslo 10
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

KOST
Koncepce osteologické péče pro gynekology a praktické lékaře
nový kurz
Autoři: MUDr. František Šenk

Sekvenční léčba schizofrenie
Autoři: MUDr. Jana Hořínková

Hypertenze a hypercholesterolémie – synergický efekt léčby
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Svět praktické medicíny 5/2023 (znalostní test z časopisu)

Imunopatologie? … a co my s tím???
Autoři: doc. MUDr. Helena Lahoda Brodská, Ph.D.

Všechny kurzy
Kurzy Podcasty Doporučená témata Časopisy
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se

#ADS_BOTTOM_SCRIPTS#