Bastos, M

Figueiredo, A

Furtado, AL

Mota, A

Pratas, J

Xavier da Cunha, MF

Name not available

Risk factors for acute rejection in 806 cyclosporine-treated renal transplants: a multivariate analysis

Repositório Institucional dos Hospitais da Universidade de Coimbra

OUTCOMESRisk Factors for Acute Rejection in 806 Cyclosporine-Treated RenalTransplants: A Multivariate AnalysisA. Mota, A. Figueiredo, M.F.X. Cunha, M. Bastos, J. Pratas, and L. FurtadoIT is known that acute rejection (AR) is responsible forserious graft injury, causing parenchymal deteriorationthat can end in early graft failure1 or in long-term develop-ment of chronic dysfunction.2 Both mechanisms contributenegatively to graft survival.3,4 The aim of this study was toinvestigate the incidence, the causes, and the effects of ARon the outcome of transplants under cyclosporine (CyA)-based therapy.PATIENTS AND METHODSWe analyzed 866 renal transplants performed between December1985 and December 1999: of these, 854 (98.6%) were fromcadaveric (834 primary transplants and 20 retransplants) and 12(1.4%) were from living related donors. Acute rejection wasbiopsy-proven in 35%; in 65% it was diagnosed by clinical andlaboratory elements, among which the most relevant was a serumcreatinine (SCr) increase of at least 0.4 mg/dL. Sixty transplantswere not included, either because the diagnosis of AR was notavailable or because nonimmunologic causes, such as vascularthrombosis or death, were responsible for the early graft loss.Therefore, 806 renal transplants (794 from cadaveric and 12 fromliving donor) remained eligible for the study. Steroid-based therapywas the AR treatment of choice. Antibody therapy was used forsteroid-resistant AR. A diagnosis of chronic dysfunction (CD) wasbased on a progressive decline of renal function with a SCr 2.5mg/dL.We investigated the following parameters: namely in the donor(age, cause of death, perfusion solution, cold ischemia time [CIT],and SCr before retrieval), in the recipient (age, weight, associatedpathology, HLA mismatches, and immunosuppression), and in thetransplant course (delayed graft function [DGF], SCr at the end ofthe first year, and CD). Evaluation of transplant variables includedthe influence of DGF on AR incidence and, in contrast, theinfluence of AR on the SCr in the first year and on CD occurrence.We did not consider sensitization because the panel reactiveantibody (PRA) rate proved to be irrelevant (2%). The cytomeg-alovirus status was not available. From database constructed withthe records of all donors and recipients, a multivariate analysis wasperformed using logistic regression and univariate techniques withthe Fisher Exact Test. We used the Kaplan-Meier method tocalculate survival and the log-rank test to compare survival ratesbetween the two groups (with AR or without AR). For all tests a Pvalue .05 was considered significant (two-tailed).RESULTSAcute rejection was diagnosed in 300 (37%) of the 806renal transplants. A multivariate analysis showed that therisk factors for AR were cerebrovascular stroke as a causeof death in the cadaver donor (54% vs 35%), graft perfusionwith Euro-Collins solution (42% vs 33%), cold ischemiatime (CIT)24 hours (44% vs 34%), and recipient age45years (42% vs 30%) (Table 1). The difference in theincidence of AR between the groups with 6, 5, 4 versus 3, 2,1 HLA mismatches was not significant (39% vs 35%). Thequadruple immunosuppressive regimen of antilymphocyteglobulin (ALG)  azathioprine (Aza)  prednisone (Pred) CyA was associated with the highest (46%) incidence ofAR, and micophenolate mofetil (MMF) CyA Pred, thelowest (30%) risk. Acute rejection was more frequentamong patients with DGF (48% vs 35%), and AR wasresponsible for 4.7% of graft losses (11 grafts of 236).From the Department of Urology and Transplantation, Coim-bra University Hospital, Coimbra, Portugal.Address reprint requests to Alfredo Mota, Department ofUrology and Transplantation, Coimbra University Hospital, 3049Coimbra Codex, Portugal.© 2003 by Elsevier Science Inc. 0041-1345/03/$–see front matter360 Park Avenue South, New York, NY 10010-1710 doi:10.1016/S0041-1345(03)00306-3Transplantation Proceedings, 35, 1061–1063 (2003) 1061Regarding the influence of AR on transplant evolution(Table 2), we observed significantly worse renal function at1 year evaluated as a SCr 1.2 mg/dL, namely 46% vs 27%,and a higher CD incidence, namely 40% vs 12%. Thishigher CD incidence is particularly important because CDemerged as the second cause of graft failure, with a rate of30.5%, after death with a functioning graft (DWFG),namely 41.5%.Graft survival rates at 1, 3, 5, 10, and 15 years were 94%,85%, 74%, 49%, and 37% in the AR group, respectively,and 97%, 91%, 88%, 77%, and 68% in the group withoutAR, respectively. The differences in graft survival werestatistically significant (P  .000) (Fig 1). Acute rejectiondid not influence patient survival (P  .914). These survivalresults did not include grafts and patients who had been lostdue to nonimmunologic causes (vascular thrombosis anddeath), before reaching 6 months’ survival.DISCUSSIONThe progress of immunosuppression has dramatically changedthe incidence and consequences of AR. Therefore, graft losssecondary to AR has become quite uncommon. Despite thisprogress, the role of AR in the development of CD isincontrovertible,1 and CD appears to be one of the principalcauses of graft failure. Ferguson et al5 showed that the numberof AR episodes was the most relevant factor for long-termcadaver kidney allograft outcome, and Matas6 emphasizedthat one AR episode is enough to decrease long-term graftsurvival. In the present study, AR was responsible for only4.7% of graft loss, but CD emerged as the second cause ofgraft failure, with a 30.5% rate. Our results (Table 2) clearlyshow that AR was the most important factor for CD (12%without AR vs 40% with AR). The AR immunological dam-age promotes a local cytokine release, inducing progressivenephron damage and renal mass destruction, with develop-ment of a fibrotic repair that ends in CD.2 Hyperfiltration inthe remnant nephrons, leading to glomerulosclerosis, alsoplays a role in the evolution to organ failure.2,4 Basadonna etal7 showed a CD occurrence of less than 1% at 5 years withoutAR and about 50% with previous AR.Concerning the increase in AR among grafts from ca-daver donors whose cause of death was cerebrovascularstroke with a prolonged history of arterial hypertension,Guidi et al8 reported that a grafted kidney from a hyper-tensive donor could transmit not only chronic hypertension,but also more severe kidney impairment after an acuteinsult (Table 1). It has been reported that perfusion withEuro-Collins solution and prolonged cold ischemia timesare associated with an easier development of ischemia-reperfusion lesions that increase both graft immunogenicityand the rate of AR.4The higher AR rate that we observed in younger recipi-ents (45 years) probably indicates a stronger innateimmune responsiveness in these patients.3 Confirming thishypothesis, Cecka observed that, in young patients, immu-nologic graft failures were more frequent.1 Like others9 wedid not find any statistically significant difference (P .292)between the two groups based upon the number of HLAmismatches (6, 5, 4 vs 3, 2, 1) under CyA-based therapy.The immunosuppressive protocol that showed a higher ARincidence was the association of ALG  Aza  Pred CyA, a protocol that sought to decrease DGF incidence byavoiding early CyA nephrotoxicity. Therefore, CyA admin-istration was delayed until onset of diuresis. However, whenCyA was initiated and ALG was stopped, we noted a highAR incidence (46%), despite 2 days of concomitant ther-apy. Another finding in our study was the increase of ARamong patients with DGF (Table 1) an observation attrib-uted to the increase graft immunogenicity, caused by DGFTable 1. Risk Factors for Acute RejectionFactors P Value Odds Ratio CI 95%Donor age NSDonor cause of death (CVS) .018 1.813 1.108–2.966Perfusion with Euro-Collins solution .007 1.508 1.118–2.033CIT .039 1.398 1.017–1.922Recipient age 45 years .000 1.871 1.366–2.562Recipient weight NSRecipient-associated pathology NSHLA mismatches NSALG  Aza  Pred  CyA .004 2.017 1.248–3.258DGF .008 1.714 1.162–2.527Abbreviations: CVS, cerebrovascular stroke; CIT, cold ischemia time; ALG,antilymphocyte globulin; Aza, azathioprine; Pred, prednisone; CyA, cyclospor-ine; DGF, delayed graft function.Table 2. Influence of Acute Rejection on the Evolutionof the TransplantFactors P Value Odds Ratio CI 95%SCr at 1 year 1.2 mg/dL .000 2.358 1.742–3.191Chronic dysfunction .000 4.819 3.360–6.912Abbreviations: SCr, serum creatinine.Fig 1. Comparison of graft actuarial survival without AR andwith AR (Kaplan-Meier method).1062 MOTA, FIGUEIREDO, CUNHA ET ALwherein the ischemic tubular cells10 upregulate foreign histo-compatibility antigen expression. Furthermore, graft functionat 1 year evaluated as a SCr 1.2 mg/dL was significantlyworse (46% vs 27%) among patients with AR (Table 2).We conclude that acute rejection persists as an importantand complex factor leading to chronic allograft dysfunction,being the second cause of kidney graft loss following deathwith a functioning graft. In this study the most relevantfactors for AR were recipient age 45 years, immunosup-pressive therapy without CyA, delayed graft function, per-fusion with Euro-Collins solution, and prolonged coldischemia times (24 hours). The worse graft function at 1year in patients with AR episodes heralds the later devel-opment of chronic dysfunction.REFERENCES1. Cecka M: Surg Clin North Am 78:133, 19982. Almond PS, Matas A, Gillingham K, et al: Transplantation55:752, 19933. Koyama H, Cecka JM: In Terasaki PI, Cecka JM (eds):Clinical Transplants 1992. Los Angeles, Calif: UCLA Tissue Typ-ing Laboratory; 1993, p 3914. Gjertson DW: In Terasaki PI, Cecka JM (eds): ClinicalTransplants 2000. Los Angeles, Calif: UCLA ImmunogeneticsCenter; 2001, p 4675. Ferguson RM, Henry M, Elkhammas EA, et al: Presented atthe American Society of Transplant Surgeons, 18th Annual Scien-tific Meeting, Chicago, 1992 (Abstract) p 836. Matas AJ: Transpl Immunol 6:1, 19987. Basadonna GP, Matas AJ, Gillingham KJ, et al: Transplan-tation 55:993, 19938. Guidi E, Cozzi MG, Minetti E, et al: J Am Soc Nephrol9:2102, 19989. Kerman RH, Kimball PM, Lindholm A, et al: Transplantation56:1242, 199310. Shoskes DA, Halloran PF: Transplant Proc 23:599, 1991ACUTE REJECTION IN RENAL TRANSPLANTS 1063

http://rihuc.huc.min-saude.pt/bitstream/10400.4/517/1/RID402%20Transplant%20Proc%201061.pdf

Risk factors for acute rejection in 806 cyclosporine-treated renal transplants: a multivariate analysis

Abstract

Similar works

Full text

Available Versions

Name not available

Repositório Institucional dos Hospitais da Universidade de Coimbra