Contribution of Late Acute Rejection to Long-Term Renal Allograft Survival in Patients With Chronic Allograft Nephropathy S. Sezer, F.N. Ozdemir, A. Akcay, T. Colak, A. Kut, and M. Haberal C HRONIC allograft nephropathy (CAN) is the primary cause of late renal allograft loss, but the pathogenesis of this condition is not fully understood. 1–3 A previous episode of acute rejection (AR) is a major alloantigen- dependent risk factor for later development of CAN. 1–6 Several studies have shown that kidney recipients who do not experience AR have better long-term survival than those with a history of this problem. 1–8 Although AR is principally a feature of the early posttransplant period, it may also occur in the late (1 year) stage. Late-onset AR may contribute to the development of CAN 3–6 and graft loss. 1–6 In this study, we aimed to assess how the timing of AR onset impacts the development of CAN and late renal allograft loss. PATIENTS AND METHODS We retrospectively reviewed data from 210 first renal transplant patients including 153 men and 57 women of mean age 36.5  11.8 years who received 156 living-related and 54 cadaveric organs between January 1992 and December 1996. All recipients had been followed for a minimum of 5 years postsurgery. The initial immu- nosuppressive therapy regimen consisted of cyclosporine (CsA), azathioprine, and prednisolone. CsA was initiated at 8 to 10 mg/kg/d PO in two divided doses and then adjusted to maintain whole-blood trough levels between 100 and 200 ng/mL. AR was suspected on the basis of clinical and biochemical parameters. All acute and chronic rejection diagnoses were confirmed by percuta- neous kidney allograft biopsy. The initial treatment was IV pulses of methylprednisolone; steroid-resistant episodes were treated with OKT3. To determine the effect of the timing of the first AR episode on CAN and late graft loss, the recipients were categorized into three groups: no AR episode; an early first episode (1 year posttrans- plant); and only a late first episode (1 year posttransplant). The fractions of 54 cadaveric transplants were identically distributed among these groups, suggesting that these groups did not distinctly affect graft survival rates. Patients with multiple AR episodes were excluded from the study. Graft loss was defined as transplant nephrectomy, retransplantation, or return to chronic dialysis ther- apy. Patients who had functioning grafts at the time of death were excluded from the analysis. We also investigated the relationship between the timing of AR onset and noncompliance with medications. Unfortunately, there is no gold standard method for measuring noncompliance. 9,10 In our study, we defined noncompliance with CsA therapy as an unexpect- edly low blood CsA level based on prior levels and/or dosage level. The mean CsA levels and doses after 1 year posttransplant in patients with early and late AR were compared. CsA levels were determined using a monoclonal antibody enzyme immunoassay system (CEDIA-Cyclosporin Assay, Roche Diagnostic Corp., Indi- anapolis, Ind, USA) and a modular ISE 900 machine. The chi-square and unpaired student t-tests were used to identify statistically significant differences. One-way ANOVA was used to compare group mean values. Normally distributed continuous variables were presented as mean values  SD with two-sided test. P values .05 considered to indicate statistical significance. A statistical software package (SPSS 10.0 for Windows, SPSS Inc.) was used to perform the calculations. RESULTS One hundred seventeen patients (55.7%) never had an AR episode, whereas 93 (44.3%) had a treated AR episode. In the latter group, 60 patients had had an early first AR episode (1 year posttransplantation) and 33 had a late first AR episode (1 year posttransplantation). Indepen- dent of the timing, the occurrence of an AR had a signifi- cant negative impact on the development of CAN, namely CAN rates 64% vs 33% for those with and without AR, respectively, (P  .0001) and on the 5-year allograft sur- vival, namely, 61.2% vs 85.9%; (P  .001). There was no significant difference in the development of CAN among patients with early versus late AR onset namely 69% vs 61%, respectively (P  .05). Similarly, the timing of AR onset did not influence the period of progression to chronic rejection; 808.5  547.5 days vs 921.8  416.2 days in the early- and late-onset groups (P  .05). In contrast, the early- and late-onset groups differed significantly with respect to the duration of graft function and the rate of graft loss after CAN. The mean time to graft loss after development of CAN was 258.5  255.0 days in the early AR group versus 94.0  59.4 days in the late AR group (P  .02). Fifty-two percent of the patients with late-onset AR lost their grafts compared with 30% of those with early onset (P  .001) (Fig 1). There was a significant relationship between a late onset From the Baskent University Faculty of Medicine, Depart- ments of Nephrology (S.S., F.N.O., A.A., T.C., A.K.) and General Surgery (M.H.), Ankara, Turkey. Address reprint requests to F.N. Ozdemir, Fevzi Cakmak Caddesi, 10. Sokak No: 45 Bahcelievler, 06490 Ankara, Turkey. E-mail: foz310@hotmail.com © 2003 by Elsevier Inc. All rights reserved. 0041-1345/03/$–see front matter 360 Park Avenue South, New York, NY 10010-1710 doi:10.1016/j.transproceed.2003.09.037 Transplantation Proceedings, 35, 2637–2638 (2003) 2637