SELECTED ABSTRACTS. All (n) % 3-year GS 88% 82% 86% 85% 88% 80% % 3-year DC-GS 95% 87% 94% 89% 96% 80%

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1 SELECTED ABSTRACTS The following are summaries of selected posters presented at the American Transplant Congress on May 5 9, 2007, in San Humar A, Gillingham KJ, Payne WD, et al. Review of >1000 kidney transplants over 10 years shows that acute rejection remains a significant risk factor for 3-year graft loss. Presented at: American Transplant Congress; May 5-9, 2007; San Acute rejection (AR) has been known for decades to be the major risk factor for biopsy-proven chronic rejection and chronic allograft nephropathy. In recent years, protocols aimed at early withdrawal or avoidance of immunosuppressive agents such as calcineurin inhibitors (CNIs) have been considered as a way to avoid drug side effects that diminish long-term outcomes. The trade-off for reduced side effects is the possibility of increased acute rejection, which clinicians using the newer CNI-sparing/avoidance protocols attempt to manage with early detection and treatment. Thus, the incidence and impact of acute rejection with current immunosuppressive regimens remains a relevant question. This study evaluated trends in acute rejection over a 10-year period (Jan 1996 Dec 2005) in one institution where 1199 first kidney transplants were performed. The question asked was: have current immunosuppressive protocols modified the longer term risk associated with AR? Graft survival (GS) at 3 years was evaluated in those with and without AR (Table). This AR impact on outcome was evaluated overall and also when recipients were divided by era (1/96 12/00 and 1/01 12/05) and by donor source as either deceased donor or living donor (DD and LD, respectively). Overall, 23% of recipients had 1 AR (1/96 12/00, 26%; 1/01 12/05, 20%). Actuarial GS and death censored (DC) GS was significantly lower for those with (vs without) AR (P <.001). As shown in the Table, this was true for both DDs and LDs, and for both those transplanted 1/96 to 12/00 and those transplanted 1/01 to 12/05. There was no difference in patient survival. Cox regression showed that AR (hazard ratio [HR] = 2.1; P <.0001) and donor source (HR = 1.8; P =.0001) were independent risk factors for graft loss; for DC-graft loss, AR (HR = 3.9; P <.0001) and donor source (HR = 1.7; P =.002) were again significant factors. Era (1/96 12/00 vs 1/01 12/05) was not significant. Repeating the analyses comparing 0 versus 1 AR showed similar results. One AR was associated with significant decrease in actuarial GS and DC-GS for both LDs and DDs in both eras (P <.001; data not shown). Similarly, Cox regression showed that 1 AR (HR = 1.6; P =.002) and donor source (HR = 1.8; P =.0001) were independent risk factors for graft loss, and for DC-graft loss (AR, HR = 2.7, P <.0001; donor source, HR = 1.8, P =.005). The authors concluded that although the rate of AR has decreased, 1 or more AR episodes remains a significant risk factor for kidney transplant outcome. Ongoing efforts are necessary to further lower AR rates. Table. Percent 3-Year Survival ALL 1/96 12/00 1/01 12/05 No AR 1 AR No AR 1 AR No AR 1 AR All (n) % 3-year GS 88% 82% 86% 85% 88% 80% % 3-year DC-GS 95% 87% 94% 89% 96% 80% DD (n) % 3-year GS 83% 78% 78% 80% 89% 78% % 3-year DC-GS 93% 85% 92% 86% 95% 83% LD (n) % 3-year GS 91% 84% 92% 87% 89% 74% % 3-year DC-GS 96% 88% 96% 91% 97% 79% AR = acute rejection. 286 Vol. 7, No. 9 n August 2007

2 Flechner S, Glyda M, Steinberg S, Harler MB (ORION Trial Investigators). Comparison of immunosuppressive regimens shows higher rate of acute rejection with a sirolimus-based regimen (vs tacrolimus-based). Presented at: American Transplant Congress; May 5-9, 2007; San The main objective of this ongoing study was to compare the safety and efficacy of 2 calcineurin inhibitor-sparing and avoidance strategies used in attempts to improve long-term renal allograft function. This 2-year multinational open-label study randomly assigned 450 kidney recipients to 1 of 3 groups SRL + TAC Elim (n = 154): sirolimus (SRL; 8 15 ng/ml) plus tacrolimus (TAC; 6 15 ng/ml) through week 13 after which TAC was eliminated and SRL increased to 12 to 20 ng/ml; SRL + MMF (n = 156): SRL (10 15 ng/ml through week 26, 8 15 ng/ml thereafter) plus mycophenolate mofetil (MMF; up to 2 g/day); or TAC + MMF (n = 140; control): TAC (8 15 ng/ml through week 26, 5 15 ng/ml thereafter) plus MMF (up to 2 g/day). All patients received 2 doses of daclizumab (2 mg/kg) and corticosteroids. This 18-month interim analysis showed excellent patient and graft survival in all groups and similar levels of overall renal function (eg, creatinine clearance and serum creatinine). However, the rates of biopsyconfirmed acute rejection (AR), graded using Banff criteria by a local pathologist blinded to treatment group, were significantly different between the SRL + MMF and TAC + MMF groups (P <.0001), but not between SRL + TAC Elim and TAC + MMF groups (P =. 0998; Table). All of the events were mild to moderate in severity and the vast majority occurred in the first 6 months post-transplant. Approximately 43% of rejectors on SRL + MMF therapy had subtherapeutic SRL trough concentrations at the time of AR. Table. Acute Rejection by Severity: Banff Score Group 1A 1B 2A 2B 3 SRL + TAC Elim SRL + MMF TAC + MMF In June 2006, based on the higher than expected AR rates reported here, the ORION Investigators terminated the SRL + MMF arm of the study. Rao AVR, Gilg JA, Ansell D, et al. UK Registry data confirm lower survival in diabetic transplant recipients, suggest risk factors. Presented at: American Transplant Congress; May 5-9, 2007; San Diabetes is particularly dangerous in renal transplant recipients, with a negative influence on graft function, graft survival rates, infection rates, and patient mortality. Nephrologists and nephrology nurses have increasingly focused on appropriate diabetes care for their kidney transplantation patients, but the exact and potentially modifiable risk factors contributing to this elevated mortality risk remain unclear. This analysis used UK Renal Registry data to compare quality of care, various laboratory measures, and outcomes after renal transplantation in diabetic and nondiabetic incident patients with a first transplant recorded by the end of Eleven percent of the 3860 incident patients had diabetes mellitus (DM). Researchers collected electronic quarterly reports on hemoglobin, blood pressures, calcium, phosphate, parathyroid hormone (ipth), bicarbonate, and creatinine. Estimated means for these variables were analyzed using ANOVA after adjusting for age, gender, ethnicity, time on dialysis, year of transplantation, and estimated glomerular filtration rate (egfr). The rate of decline in egfr and survivals (patient and graft) were also compared. The 1-, 3-, and 5-year death-censored graft survival for diabetic and nondiabetic patients were 91%, 88%, 81% and 91%, 88%, 85%, respectively. Five-year transplant survival (graft survival not censored for death) was 69% for diabetic patients and 78% for nondiabetic patients (P =.003). Five-year patient survival was 85% for the DM group and 91% for the non-dm group (P <.0001). Throughout the 5-year observational period, DM transplant recipients had higher systolic blood pressure (5 mm Hg; P <.001) and lower cholesterol (0.5 mmol/l; P <.001). Importantly, there were no differences in hemoglobin, corrected calcium, ipth, or bicarbonate levels between the groups. Estimated median egfr at 1, 3, and 5 years for DM and non-dm patients were 47.1, 44.4, 39.2 and 45.6, 43.7, 41 ml/min/1.73 m 2, respectively. The authors concluded that the overall quality of care after renal transplantation in the UK is similar in diabetic and nondiabetic patients. They point Johns Hopkins Advanced Studies in Medicine n 287

3 out that although the death-censored graft survival is similar in the 2 groups, a higher proportion of renal allografts are lost in diabetic patients through all-cause deaths, resulting in significantly lower transplant survival. Patel A, Goggins M, Hani A, Sandhu A. Female renal transplant recipients have more graft failure and higher panel reactive antibody. Presented at: American Transplant Congress; May 5-9, 2007; San Renal allograft outcomes are inferior in younger patients, African Americans, deceased donor transplant recipients, older donors, and those with delayed graft function and longer duration of dialysis. Little is known about renal allograft failure in female renal transplant recipients. This study used data (n = ) from the United Network of Organ Sharing database ( ) to identify factors associated with death censored allograft failure in female renal allograft recipients. A Cox regression model was used to delineate factors associated with graft failure in this population of patients. Median follow-up was 4 years. There was a 7.5 % increase in allograft failure in female renal transplant recipients (P <.0001) compared to males after adjusting for all variables. Median time to graft failure was 13 years. Most factors for increased risk of graft failure, including human leukocyte antigen-dr mismatch, were no different between females and males. However, both the peak panel of reactive antibodies (PRA) and most recent PRA were higher in females (Table). This high immunological risk needs to be further characterized to clarify the difference between male and female recipients. Kumar MS, Khan SM, Malat GE, et al. Outcomes after early steroid withdrawal in African American recipients. Presented at: American Transplant Congress; May 5-9, 2007; San To avoid the wide-ranging side effects associated with chronic steroid therapy, renal transplant recipients are sometimes placed on steroid-avoidance immunosuppressive regimens. The 2 studies described in these presentations tracked long-term outcomes after early steroid withdrawal in the highrisk African American (AA) population. The first study analyzed safety outcomes of early steroid withdrawal in 200 kidney recipients (100 AA and 100 non-aa) transplanted between June 2000 and March Steroid was withdrawn 2 days after transplantation in all recipients. The data show that AA recipients had comparable 5-year patient and graft survival (Figure) with similar rates of biopsy-proven acute rejection (BPAR) in the first year and chronic allograft nephropathy (CAN) at 5 years. The AA recipients had a significantly higher subclinical acute rejection (SCAR) at 1 month (23% vs 11%; P =.04) and serum creatinine (2.1 vs 1.8; P =.019) at 5 years post-transplant compared to the non-aa group. However, their serum creatinine clearance was comparable to that seen in the non- Figure. 5-Year Patient and Graft Survival Rate Table. Percentage of Panel of Reactive Antibodies in Females and Males Variable Females Males Peak PRA, mean ±SD 15.7 ± ± 15.9 Most recent PRA, mean ±SD 8.0 ± ± Vol. 7, No. 9 n August 2007

4 AA group. BPAR and SCAR were treated by shortcourse intravenous steroid therapy and all recipients remained free of chronic steroid therapy. The second study compared 3-year outcomes of early steroid withdrawal (after 2 doses on day 0 and day 1) in 90 AA kidney recipients with outcomes of chronic oral steroid therapy in 90 AA patients. All recipients were given interleukin-2 receptor blocking antibody induction and maintained on a calcineurin inhibitor and mycophenolate mofetil or sirolimus. BPAR was treated by methylprednisolone and/or thymoglobulin. Threeyear patient and graft survival rates in the 2 groups were comparable as were all measures of kidney function, including incidence of acute rejection, SCAR, CAN, serum creatinine, and creatinine clearance at 3 years. However, early steroid withdrawal resulted in significantly lower increases in body mass index (2.1% vs 8.3%) and significantly lower incidence of new-onset diabetes mellitus (6% vs 19%) at 3 years. Johns Hopkins Advanced Studies in Medicine n 289

5 NOTES 290 Vol. 7, No. 9 n August 2007