Clinical and pathological features of thrombotic microangiopathy influencing long-term kidney transplant outcomes

English version

Autoři: Cínthia Montenegro Teixeira ^aff001; Hélio Tedesco Silva Junior ^aff001; Luiz Antônio Ribeiro de Moura ^aff002; Henrique Machado de Sousa Proença ^aff002; Renato de Marco ^aff003; Maria Gerbase de Lima ^aff003; Marina Pontello Cristelli ^aff001; Laila Almeida Viana ^aff001; Cláudia Rosso Felipe ^aff001; José Osmar Medina Pestana ^aff001
Působiště autorů: Nephrology Division, Federal University of São Paulo, São Paulo, Brazil ^aff001; Pathology Division, Hospital do Rim, Federal University of São Paulo, São Paulo, Brazil ^aff002; Immunogenetics Institute, AFIP, São Paulo, Brazil ^aff003
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0227445

Souhrn

Introduction

Thrombotic microangiopathy (TMA) in post-transplant setting has heterogeneous clinical manifestations.

Methods

We retrospectively studied data of 89 patients with post-transplant TMA, which was characterized by thrombi in at least one glomerulus and/or arteriole. Systemic TMA was defined by thrombocytopenia and microangiopathic anemia and early onset TMA, when occurred less than 90 days post transplant.

Results

The cumulative incidence was 0.93%. The majority of the recipients were young (mean age 39 years), female (52%) and Caucasian (48%) with primary kidney disease of unknown etiology (37%). Early TMA occurred in 51% of the patients and systemic TMA, in 25%. Underlying precipitating factors were: infection (54%), acute rejection (34%), calcineurin inhibitor toxicity (13%) and pregnancy (3%). 18% of the patients had several triggers. Glomerular TMA was observed in 50% of the biopsies and endothelial cell activation, in 61%. The 1-year patient survival was 97% and corresponding graft survival, 66%. Allograft survival was inferior when acute antibody mediated rejection (ABMR) occurred (with 41%; without 70%, p = 0.01), however no differences were determined by hemolysis, time of onset, thrombi location or endothelial cell activation.

Conclusions

Our results suggest that post-transplant TMA is a rare but severe condition, regardless of its clinical and histological presentation, mainly when associated to ABMR.

Klíčová slova:

Kidneys – Renal transplantation – Endothelial cells – Glomerular filtration rate – Histology – Biopsy – Graft survival – Arterioles

Zdroje

1. Noris M and Remuzzi G. Thrombotic microangiopathy after kidney transplantation. Am J Transplant 2010;10(7):1517–23. doi: 10.1111/j.1600-6143.2010.03156.x 20642678

2. Satoskar AA, Pelletier R, Adams P, Nadasdy GM, Brodsky S, Pesavento T et al. De novo thrombotic microangiopathy in renal allograft biopsies—role of antibody-mediated rejection. Am J Transplant 2010;10(8):1804–11. doi: 10.1111/j.1600-6143.2010.03178.x 20659088

3. Schwimmer J1, Nadasdy TA, Spitalnik PF, Kaplan KL, Zand MS. De novo thrombotic microangiopathy in renal transplant recipients: a comparison of hemolytic uremic syndrome with localized renal thrombotic microangiopathy. Am J Kidney Dis 2003;41(2):471–9. doi: 10.1053/ajkd.2003.50058 12552512

4. Reynolds JC, Agodoa LY, Yuan CM, Abbott KC. Thrombotic microangiopathy after renal transplantation in the United States. Am J Kidney Dis 2003;42(5):1058–68. doi: 10.1016/j.ajkd.2003.07.008 14582050

5. Zarifian A1, Meleg-Smith S, O'donovan R, Tesi RJ, Batuman V. Cyclosporine-associated thrombotic microangiopathy in renal allografts. Kidney Int 1999;55(6):2457–66. doi: 10.1046/j.1523-1755.1999.00492.x 10354295

6. Sreedharanunni S1, Joshi K, Duggal R, Nada R, Minz M, Sakhuja V. An analysis of transplant glomerulopathy and thrombotic microangiopathy in kidney transplant biopsies. Transpl Int 2014;27(8):784–92. doi: 10.1111/tri.12331 24684170

7. Le Quintrec M, Lionet A, Kamar N, Karras A, Barbier S, Buchler M et al. Complement Mutation-associated de novo thrombotic microangiopathy following kidney transplantation. Am J Transplant 2008;8(8):1694–701. doi: 10.1111/j.1600-6143.2008.02297.x 18557729

8. Le Quintrec M, Zuber J, Moulin B, Kamar N, Jablonski M, Lionet A et al. Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome. Am J Transplant 2013;13(3):663–75. doi: 10.1111/ajt.12077 23356914

9. Zuber J, Le Quintrec M, Sberro-Soussan R, Loirat C, Frémeaux-Bacchi V, Legendre C. New insights into postrenal transplant hemolytic uremic syndrome. Nat Rev Nephrol 2011;7(1):23–35. doi: 10.1038/nrneph.2010.155 21102542

10. Chiurchiu C, Ruggenenti P and Remuzzi G. Thrombotic microangiopathy in renal transplantation. Ann Transplant 2002;7(1):28–33. 12221901

11. Garg N, Rennke HG, Pavlakis M, Zandi-Neja K. De Novo Thrombotic Microangiopathy after Kidney Transplantation. Transplant Rev (Orlando) 2018;32(1):58–68.

12. Caires RA, Marques ID, Repizo LP, Sato VA, Carmo LP, Machado DJ et al. De novo thrombotic microangiopathy after kidney transplantation: clinical features, treatment and long-term patient and graft survival. Transplant Proc 2012;44(8):2388–90. doi: 10.1016/j.transproceed.2012.07.039 23026601

13. Hollenbeck M, Kutkuhn B, Aul C, Leschke M, Willers R, Grabensee B. Haemolytic-uraemic syndrome and thrombotic-thrombocytopenic purpura in adults: clinical findings and prognostic factors for death and end-stage renal disease. Nephrol Dial Transplant 1998;13(1):76–81. doi: 10.1093/ndt/13.1.76 9481719

14. Argyle JC, Hogg RJ, Pysher TJ, Silva FG, Siegler RL. A clinicopathological study of 24 children with hemolytic uremic syndrome. Pediatr Nephrol 1990;4(1):52–8. doi: 10.1007/bf00858440 2206882

15. Laszik ZG, Kambham N, Silva FG. Thrombotic microangiopathies. In: Jennette JC, ed. Heptinstall's Pathology of the Kidney- Seventh Edition. Wolters Kluwer Health/Lippincott Williams & Wilkins, Philadelphia, US: 2015; 753–766.

16. Matsumae T, Takebayashi S, Naito S. The clinico-pathological characteristics and outcome in hemolytic-uremic syndrome of adults. Clin Nephrol 1996;45(3):153–62. 8706355

17. Tostivint I, Mougenot B, Flahault A, Vigneau C, Costa MA, Haymann JP et al. Adult haemolytic and uraemic syndrome: causes and prognostic factors in the last decade. Nephrol Dial Transplant 2002;17(7):1228–34. doi: 10.1093/ndt/17.7.1228 12105245

18. Yu XJ, Yu F, Song D, Wang SX, Song Y, Liu G et al. Clinical and Renal Biopsy Findings Predicting Outcome in Renal Thrombotic Microangiopathy: A Large Cohort Study from a Single Institute in China. ScientificWorldJournal 2014;2014:680502. doi: 10.1155/2014/680502 25184151

19. Nadasdy T. Thrombotic microangiopathy in renal allografts: the diagnostic challenge. Curr Opin Organ Transplant 2014;19(3):283–92. doi: 10.1097/MOT.0000000000000074 24811438

20. Meehan SM, Kremer J, Ali FN, Curley J, Marino S, Chang A et al. Thrombotic microangiopathy and peritubular capillary C4d expression in renal allograft biopsies. Clin J Am Soc Nephrol 2011;6(2):395–403. doi: 10.2215/CJN.05870710 20966124

21. Haas M, Sis B, Racusen LC, Solez K, Glotz D, Colvin RB et al. Banff 2013 meeting report: inclusion of C4d-negative antibody-mediated rejection and antibody-associated arterial lesions. Am J Transplant 2014;14(2):272–83. doi: 10.1111/ajt.12590 24472190

22. Ardalan MR, Shoja MM, Tubbs RS, Etemadi J, Esmaili H, Khosroshahi HT. Thrombotic Microangiopathy in the Early Post-Renal Transplant Period. Ren Fail 2008;30(2):199–203. doi: 10.1080/08860220701810547 18300121

23. LeArdalan MR, Shoja MM, Tubbs RS, Etemadi J, Esmaili H, Khosroshahi HT. A New Equation to Estimate Glomerular Filtration Rate. Ann Intern Med 2009;150(9):604–12. doi: 10.7326/0003-4819-150-9-200905050-00006 19414839

24. El-Zoghby ZM, Stegall MD, Lager DJ, Kremers WK, Amer H, Gloor JM et al. Identifying Specific Causes of Kidney Allograft Loss. Am J Transplant 2009;9(3):527–35. doi: 10.1111/j.1600-6143.2008.02519.x 19191769

25. Karthikeyan V, Parasuraman R, Shah V, Vera E, Venkat KK. Outcome of Plasma Exchange Therapy in Thrombotic Microangiopathy After Renal Transplantation. Am J Transplant 2003;3(10):1289–94. doi: 10.1046/j.1600-6143.2003.00222.x 14510703

26. Wu K, Budde K, Schmidt D, Neumayer HH, Lehner L, Bamoulid J R et al. The inferior impact of antibody-mediated rejection on the clinical outcome of kidney allografts which develop de novo thrombotic microangiopathy. Clin Transplant 2016;30(2):105–17. doi: 10.1111/ctr.12645 26448478

27. Gareau AJ, Wiebe C, Pochinco D, Gibson IW, Ho J, Rush DN et al. Pre-transplant AT1R antibodies correlate with early allograft rejection. Transpl Immunol 2018;46:29–35. doi: 10.1016/j.trim.2017.12.001 29217423

28. Taniguchi M, Rebellato LM, Cai J, Hopfield J, Briley KP, Haisch CE et al. Higher risk of kidney graft failure in the presence of anti-angiotensin II type-1 receptor antibodies. Am J Transplant 2013;13(10):2577–89. doi: 10.1111/ajt.12395 23941128

29. Banasik M, Boratyńska M, Kościelska-Kasprzak K, Kamińska D, Bartoszek D, Zabińska M et al. The influence of non-HLA antibodies directed against angiotensin II type 1 receptor (AT1R) on early renal transplant outcomes. Transpl Int 2014;27(10):1029–38. doi: 10.1111/tri.12371 24909812

30. Nava F, Cappelli G, Mori G, Granito M, Magnoni G, Botta C et al. Everolimus, Cyclosporine, and Thrombotic Microangiopathy: Clinical Role and Preventive Tools in Renal Transplantation. Transplant Proc 2014;46(7):2263–8. doi: 10.1016/j.transproceed.2014.07.062 25242766

31. Bayer G1, von Tokarski F, Thoreau B, Bauvois A, Barbet C, Cloarec S et al. Etiology and Outcomes of Thrombotic Microangiopathies. Clin J Am Soc Nephrol 2019.

32. Riedl M, Fakhouri F, Le Quintrec M, Noone DG, Jungraithmayr TC, Fremeaux-Bacchi V et al. Spectrum of Complement- Mediated Thrombotic Microangiopathies: Pathogenetic Insights Identifying Novel Treatment Approaches. Semin Thromb Hemost 2014;40(4):444–64. doi: 10.1055/s-0034-1376153 24911558

33. Suarez MLG, Thongprayoon C, Mao MA, Leeaphorn N, Bathini T, Wisit Cheungpasitporn W. Outcomes of Kidney Transplant Patients with Atypical Hemolytic Uremic Syndrome Treated with Eculizumab: A Systematic Review and Meta-Analysis. J Clin Med 2019; 8(7).

34. Zuber J, Frimat M, Caillard S, Kamar N, Gatault P, Petitprez F et al. Use of Highly Individualized Complement Blockade Has Revolutionized Clinical Outcomes after Kidney Transplantation and Renal Epidemiology of Atypical Hemolytic Uremic Syndrome. J Am Soc Nephrol 2019. doi: 10.1681/ASN.2019040331 31575699

35. CONITEC, Eculizumabe para o tratamento da Hemoglobinúria Paroxística Noturna, C.N.d.I.d.T.n. SUS, Editor. 2018. Available from: http://conitec.gov.br/index.php/consultas-publicas-2019-encerradas

36. CONITEC, Eculizumabe para o tratamento Síndrome Hemolítico Urêmica atípica C.N.d.I.d.T.n. SUS, Editor. 2018. Available from: http://conitec.gov.br/index.php/consultas-publicas-2019-encerradas

37. Baid-Agrawal S, Farris AB 3rd, Pascual M, Mauiyyedi S, Farrell ML, Tolkoff-Rubin N et al. Overlapping pathways to transplant glomerulopathy: chronic humoral rejection, hepatitis C infection, and thrombotic microangiopathy. Kidney Int 2011;80(8):879–85. doi: 10.1038/ki.2011.194 21697808

38. Drachenberg CB, Papadimitriou JC. Endothelial injury in renal antibody- mediated allograft rejection: a schematic view based on pathogenesis. Transplantation 2013;95(9):1073–83. doi: 10.1097/TP.0b013e31827e6b45 23370711