Cumulative Incidence Of Acute Rejection Research Articles

Pre-transplant history of mental health concerns, non-adherence, and post-transplant outcomes in kidney transplant recipients

ObjectiveThe association between pre-transplant mental health concerns and non-adherence and post-transplant outcomes after kidney transplantation is not fully established. We examined the relationship between a pre-transplant history of mental health concerns and non-adherence and post-transplant outcomes among kidney transplant recipients. MethodsIn this retrospective single center cohort study of adult kidney transplant recipients (n=955) the associations between the history of mental health concerns or non-adherence and the time from kidney transplant to biopsy proven acute rejection; death-censored graft failure and total graft failure were examined using Cox proportional hazards models. ResultsMean (SD) age was 51 (13) years, 61% were male and 27% had a history of diabetes. Twenty-two and 11% of patients had mental health concerns and non-adherence, respectively. Fifteen percent of the patients had acute rejection, 5.6% had death-censored graft failure and 13.0% had total graft failure. The history of mental health concerns was not associated with acute rejection, death-censored graft failure or total graft failure. Patients with versus without a history of non-adherence tended to have higher cumulative incidence of acute rejection (23.3% [95% CI: 16.1, 33.2] vs. 13.6% [95% CI: 11.4, 16.2]) and death-censored graft failure (15.0% [95% CI: 6.9, 30.8] vs. 6.4% [95% CI: 4.7, 8.7]) (log rank p=0.052 and p=0.086, respectively). These trends were not significant after multivariable adjustment. ConclusionIn summary, a history of pre-transplant mental health concerns or non-adherence is not associated with adverse outcomes in patients who completed transplant workup and received a kidney transplant.

The Impact of Protease Inhibitor-Based Antiretroviral Regimens On Renal Transplant Outcomes in HIV-Infected Recipients.

Background: Protease inhibitors (PI) pose a challenge post-transplant due to significant drug interactions with calcineurin inhibitors (CNI), leading to altered CNI dosing and the potential for increased CNI exposure. This has prompted many clinicians to convert patients to newer, non-CNI interacting antiretroviral (ARV) agents prior to transplant. The purpose of this study was to examine the impact of PI-based regimens on graft outcomes in HIV-infected renal transplant recipients. Methods: Retrospective study of renal allograft recipients transplanted between 2003-2013 with ≥6 months of follow-up. Maintenance IS included CNI/MMF ± steroids. Results: During this period, 45 renal transplants were performed in HIV-infected individuals.Table: No Caption available.There was no difference in mean tacrolimus trough levels at days 30, 60, 90, and 180 post-transplant. Rejection-free survival at 6 and 12 months was 63.5% and 59.3% in the PI group and 50.5% and 37.9% in the non-PI group, respectively. The cumulative incidence of acute rejection was lower in the PI group (p=0.08). There was no difference between groups in the degree of IF/TA in available biopsies (p=0.687). Patients who received a PI-based regimen had significantly reduced graft failure rates, independent of the induction regimen (HR=0.24, p=0.023).Figure: No Caption available.Conclusions: In HIV-infected renal transplant recipients, PI-based ARV regimens are associated with a lower rate of rejection and better graft survival. Our data suggests that converting patients to non-PI regimens is not warranted.

Acute Rejection in the First Year in Heart Transplant Recipients in the United States.

Background: Othotopic heart transplantation(OHT) is the preferred treatment for patients with end-stage heart disease. Here we studied the incidence and risk factors of acute rejection in heart recipients by using data from the Organ Procurement and Transplant Network/United Network for Organ Sharing. Methods: Adult ( ≥18 years) who received OHT from 2006-2010 were included. We studied overall incidence and risk factors of acute rejection both at discharge and up to 1 year follow-up. To find the effect of induction agents on acute rejection, we then stratified recipients by using induction therapy and its type including rabbit anti-thymocyte globulin(rATG) and interleukin 2 receptor antagonist (IL2RA). Results: Acute rejection was reported in 1,345(15.37%) out of 8,750 recipients before discharge from hospital and at least once in 3,067 (35.05%) recipients during the first year of follow up. Age≤45, female gender, higher DR-mismatch and higher panel reactive antibody(PRA) were associated with a higher risk of rejection at both discharge and 1-year follow-up. The cyclosporine-prednisone-mycophenolate mofetil regimen was associated with a higher risk of rejection at 1-year follow-up. Compared to the no induction group, the rATG group had a lower risk of acute rejection both at discharge and at 1 year while the ILRA2 group had a lower risk of that only at discharge.Among donor factors, receiving heart from male donor was associated with a lower risk of acute rejection.Table: No Caption available.Conclusions:The cumulative incidence of acute rejection was 15.36% at discharge and 35.05% at one year. The maintenance therapy comprising of tacrolimus, prednisone, and MMF was associated with a lower acute rejection rate at 1 year. The use of rATG and IL2RA as induction therapy was associated with a lower risk of acute rejection rate at discharge and the protective effect of rATG lasted at least 1 year after transplantation.

Kidney transplantation in HIV-positive adults: the UK experience

HIV-positive patients are at increased risk of end-stage kidney disease (ESKD). Kidney transplantation (KT) is an established treatment modality for ESKD in the general population. Recent data have confirmed the feasibility of kidney transplantation in HIV-positive patients, and kidney transplantation is increasingly offered to ESKD patients with well-controlled HIV infection. We report clinical outcomes in a national cohort study of kidney transplantation in HIV-positive patients. In all, 35 HIV-positive KT recipients who had undergone KT up to December 2010 (66% male, 74% black ethnicity) were identified; the median CD4 cell count was 366, all had undetectable HIV RNA levels at kidney transplantation, and 44% received a kidney from a live donor. Patient survival at 1 and 3 years was 91.3%, and graft survival 91.3% and 84.7%, respectively. At one-year post-kidney transplantation, the cumulative incidence of acute rejection was 48%, and the median (IQR) eGFR was 64 (46, 78) mL/min/1.73 m(2). Although HIV viraemia and HIV disease progression were uncommon, renal complications were relatively frequent. Our study corroborates the feasibility of kidney transplantation in HIV-positive patients. The high rates of acute rejection suggest that the optimal immune suppression strategy in this population remains to be refined.

Outcomes of kidney transplantation in HIV-positive patients: the UK experience

BackgroundHIV infection is an independent risk factor for end-stage kidney disease in HIV-positive patients of black ethnicity. Highly effective antiretroviral therapy has allowed these patients to be considered for kidney transplantation (KT). We report the outcomes of KT in a national observational cohort study. MethodsWe retrospectively identified HIV-positive patients who had undergone KT up to December, 2010, through all 25 UK KT centres and major HIV clinics, and included follow-up until December, 2011. Patient characteristics, treatments, and complications were described. Patient and graft survival rates and cumulative incidence of acute rejection were estimated with Kaplan-Meier and Nelson-Aalen analyses. Findings35 HIV-positive KT recipients (median age 40 years, 66% male, 74% black ethnicity) were identified. At the time of KT, all patients were stable on antiretroviral therapy with undetectable HIV RNA and median CD4 cell count of 366 cells per mL. Patient survival at both 1 and 3 years was 91·3%, and graft survival was 91·3% and 84·7%, respectively. In the first year after KT, blood concentrations of calcineurin inhibitors (CNI) were frequently outside the therapeutic reference range. At 1 year after KT, the cumulative incidence of acute allograft rejection was 48%, and the median estimated glomerular filtration rate 61 mL/min/1·73 m2 (IQR 46–78). Although HIV viraemia and HIV disease progression were uncommon, renal complications were relatively frequent. InterpretationOur study corroborates the feasibility of KT in HIV-positive patients. Co-administration of antiretroviral therapy and CNI is challenging, and sub-therapeutic CNI concentrations may contribute to the high rate of acute allograft rejection. The optimum immune suppression strategy in this population remains to be refined. FundingKing's College London.

Indoleamine, 2-3 Dioxygenase Activity Could Be an Early Marker of Graft Rejection in Heart Transplantation

BackgroundThe indoleamine, 2-3 dioxygenase (IDO) is an inducible intracellular enzyme with immunosuppressive effects mainly on lymphocyte populations. It has been postulated that indirect determination of IDO serum activity may be a marker of renal graft rejection, but its potential usefulness in heart transplantation (HT) is unknown. MethodsThis longitudinal study included 98 HT patients (83% males) who survived ≥1 year. Mean age was 54.14 ± 11.57 years. Serum IDO activity was analyzed one month after HT by means of high performance liquid chromatography and correlated with the cumulative incidence of acute rejection (AR) during one-year follow-up. AR was defined as biopsy-proven ≥ ISHLT grade 2R rejection or empirically treated non-biopsy-proven rejection. The study sample was divided into two groups: AR group (n = 51), including patients who experienced at least one AR episode during the first year after HT; No-AR group (N = 47), including the remaining patients. ResultsMean serum IDO activity one month after HT was significantly higher (P = .021) in the AR group (3.32 ± 1.56) than in the no-AR group (2.62 ± 1.35). No significant association between serum IDO activity and gender (male: 3.1 ± 1.56, women: 2.43 ± 0.99, P = .092), recipient age (r = −.07, P = .943) or donor age (r = 0.108, P = 0.293) was observed. By means of binary logistic regression, an odds ratio of 1.4 [CI 95%: 1.033-1.876, P = .03] per unit increase of act-IDO was estimated, with no significant modification upon forced adjustment for age and sex. Mean glomerular filtration rate 1 month after HT was 67.01 ± 28.51 mL/min/m2. No significant correlation between this parameter and serum IDO activity was observed (r = .160, P = .117). ConclusionsOur study suggests that serum IDO activity one month after HT might be associated with a higher risk of AR during one-year follow-up. This association seems to be independent of recipient gender, age or renal function.

Tacrolimus and cyclosporine have differential effects on the risk of development of bronchiolitis obliterans syndrome: Results of a prospective, randomized international trial in lung transplantation

Chronic lung allograft dysfunction, which manifests as bronchiolitis obliterans syndrome (BOS), is recognized as the primary cause of morbidity and mortality after lung transplantation. In this study we assessed the efficacy and safety of two de novo immunosuppression protocols to prevent BOS. Our study approach was a multicenter, prospective, randomized (1:1) open-label superiority investigation of de novo tacrolimus vs cyclosporine, with both study arms given mycophenolate mofetil and prednisolone after lung transplantation. Cytolytic induction therapy was not employed. Patients were stratified at entry for cystic fibrosis. Primary outcome was incidence of BOS 3 years after transplant (intention-to-treat analysis). Secondary outcomes were survival and incidence of acute rejection, infection and other adverse events. Group demographic data were well matched: 110 of 124 tacrolimus vs 74 of 125 cyclosporine patients were treated per protocol (p < 0.01 by chi-square test). Cumulative incidence of BOS Grade ≥1 at 3 years was 11.6% (tacrolimus) vs 21.3% (cyclosporine) (cumulative incidence curves, p = 0.037 by Gray's test, pooled over strata). Univariate proportional sub-distribution hazards regression confirmed cyclosporine as a risk for BOS (HR 1.97, 95% CI 1.04 to 3.77, p = 0.039). Three-year cumulative incidence of acute rejection was 67.4% (tacrolimus) vs 74.9% (cyclosporine) (p = 0.118 by Gray's test). One- and 3-year survival rates were 84.6% and 78.7% (tacrolimus) vs 88.6% and 82.8% (cyclosporine) (p = 0.382 by log-rank test). Cumulative infection rates were similar (p = 0.91), but there was a trend toward new-onset renal failure with tacrolimus (p = 0.09). Compared with cyclosporine, de novo tacrolimus use was found to be associated with a significantly reduced risk for BOS Grade ≥1 at 3 years despite a similar rate of acute rejection. However, no survival advantage was detected.

Influence of African-American Ethnicity on Acute Rejection after Early Steroid Withdrawal in Primary Kidney Transplant Recipients

Background and Purpose The influence of African-American ethnicity on outcomes of kidney transplant recipients subjected to early steroid withdrawal remains controversial. Recent studies that suggest no higher risk among African Americans may be biased by recruitment of relatively small number of African Americans or by patient selection. We compared outcomes of African Americans to non-African Americans in a center in which early steroid withdrawal has become the standard of practice. Methods This was a single-center prospective study of 133 consecutive patients receiving primary kidney transplants between January 2006 and December 2008, followed for ≥3 months, and managed with a similar immunosuppression regimen that included induction antibody therapy, tacrolimus, mycophenolate mofetil, and withdrawal of steroids on postoperative day 5. Acute rejection and other outcomes were compared in African-American patients (n = 55) and compared with those of non-African-American patients (n = 78). Results During the first 12 months after early steroid withdrawal, African-American patients experienced a significantly higher cumulative incidence of acute rejection than non-African Americans (23.6% vs 7.7%; P = .020). Using multivariate logistic regression, ethnicity (odds ratio 3.33; P = .047) and HLA mismatch (odds ratio 1.44; P = .041) were significantly correlated with acute rejection independent of recipient age, gender, historical peak panel reactive antibody level (PRA) or PRA at time of transplant, time on dialysis, or donor source. Conclusions African Americans are at increased risk of acute rejection after early steroid withdrawal, particularly when they receive kidneys from poorly matched donors.

Randomized trial of cyclosporine and tacrolimus therapy with steroid withdrawal in living-donor renal transplantation: 5-year follow-up

The aim of this study was to compare the long-term safety and efficacy of immunosuppressive regimens consisting of cyclosporine (CsA) plus mycophenolate mofetil (MMF) or tacrolimus (TAC) plus MMF after steroid withdrawal 6 months after kidney transplantation in low-risk patients. One hundred and thirty-one patients were randomized to receive either CsA (n = 63) or TAC (n = 68). Of these, 117 patients satisfied the criteria for steroid withdrawal (no biopsy-proven rejection episode and serum creatinine level <2.0 mg/dl 6 months after transplantation). Fifty-five recipients were of the CsA group, and 62 were of the TAC group. The 5-year graft survival rate did not differ between groups (90.5% vs. 93.3% respectively; P = 0.55). The cumulative incidence of acute rejection 5 years after transplantation was 16.4% and 8.1% for the CsA and TAC groups respectively (P = 0.15). Post-transplantation diabetes mellitus was more frequent in the TAC group than in the CsA group (P = 0.05), but the incidence of other side-effects did not differ between groups. In conclusion, CsA- and TAC-based regimens in conjunction with MMF have similar patient- and graft survival rates in low-risk patients who underwent steroid withdrawal 6 months after kidney transplantation.

Sirolimus‐based triple immunosupression with antithymocyte globulin induction in expanded criteria donor kidney transplantation

Target of rapamycin inhibitors have presented similar graft and patient outcomes with no evidence of drug-induced nephrotoxicity when compared with calcineurin inhibitors. The principal aim of this study is to demonstrate the efficacy of sirolimus-based triple immunosuppression with antithymocyte globulin induction in expanded donor kidney transplantation. Twenty-seven primary expanded criteria donor kidney transplant recipients were recruited. The severity of kidney damage was qualified by zero-hour biopsies. Protocol biopsies were performed at 1 year to assess the chronic allograft damage. Death, graft function, proteinuria and adverse events were systematically analysed during the study period. The mean follow up was 20.2 months. Patient and graft survival was 100% with a mean glomerular filtration rate (GFR) of 53.1+/-4.9 mL/min at last follow up. The cumulative incidence of acute rejection was 11% at the last follow up. At 1 year, mean creatinine, GFR and proteinuria were 1.84 mg/dL, 52.3 mL/min, 651.5 mg/day, respectively. Four patients required surgical intervention due to urinary complications and recovered successfully. Two patients developed acute graft dysfunction due to acute tubular necrosis which was presumably drug related. Ten patients developed relapsing urinary tract infections and three patients had pneumonia. No infectious death occurred throughout the study period. Baseline renal structure was preserved in 13 biopsies at 1 year post transplant. Five patients demonstrated progressive but mild tubular atrophy or interstitial fibrosis in their protocol biopsies. The mean chronic allograft damage index scores at baseline and at 1 year from biopsy were 2.57+/-0.23 and 2.83+/-0.23, respectively (P=0.046). Low-dose sirolimus-based triple immunosuppression with antibody induction offered a safe clinical outcome in expanded criteria donor kidneys with the achievement of stable renal function and favourable recipient outcomes throughout the short term. However, mild progression of histological damage and increased risk of bacterial infection are a major concern. Additionally, the benefit (if any) of the low acute rejection rate on long-term graft outcome is still undetermined.

Regimen of Tacrolimus-Based Immunosuppression With Basiliximab, Mycophenolate Mofetil, and Low-Dose Steroid Reduces Acute Rejection in Kidney Transplants

Background Acute rejection is a major problem in kidney transplantation. To reduce its likelihood, we investigated the efficacy and safety of an immunosuppressive regimen including tacrolimus, basiliximab, mycophenolate mofetil, and low-dose steroids. Methods Fifty-seven patients, including 14 pediatric patients, were enrolled in this study. The mean age at the time of transplantation was 33.5 years, and the mean observation period was 8.2 months. The mean trough concentrations of FK at 1, 6, and 12 months posttransplant were 10.2, 6.6, and 6.0 ng/mL, respectively. Results All recipients survived without graft loss. The cumulative incidence of acute rejection in adults was 2.3% and 8.4% at 6 and 12 months posttransplant, respectively. Of the adverse events, 11 recipients (19.3%) were positive for CMV antigenemia or had CMV infections. Four recipients (7.0%) exhibited mild hyperglycemia. Conclusions Our immunosuppressive regimen demonstrated favorable results, reducing the incidence of acute rejection without causing severe adverse events, especially in adults.

REDUCED INCIDENCE OF ACUTE REJECTION IN HBV-INFECTED LIVER TRANSPLANT RECIPIENTS MAY BE DUE TO INHIBTION OF DENDRITIC CELL FUNCTION BY ANTI-HBS IMMUNOGLOBULIN TREATMENT

O303* Aims: To establish the effect of intravenous polyclonal immunoglobulins (ivig) on the incidence of acute rejection after liver transplantation and on dendritic cell (dc) function. Methods: As a model to study the influence of ivig on acute rejection, we analyzed a group of liver transplant recipients treated with prophylactic intravenous infusions of an anti-hepatitis b surface immunoglobulin preparation (anti-Hbs Ig, Hepatect®, Biotest Pharma GmbH, Germany) to prevent infection of the liver graft with hbv. Of the 216 recipients of a primary liver graft transplanted in our center between 1989 and 2002, forty were treated with anti-hbs Ig. In a retrospective analysis, the cumulative incidence of acute rejection of these patients was compared to recipients with hcv-infection (n=29), and to recipients without viral hepatitis (n=147), which both were not treated with any polyclonal Ig. Morever, immature dc were isolated by immunomagnetic selection from the blood of liver transplant recipients treated with anti-hbs Ig, or with hcv-infection, and of healthy individuals, and their capacity to stimulate allogeneic t-cell proliferation was determined. In addition, the influence of anti-HBs Ig on in vitro maturation of dc from healthy individuals was determined. Results: The cumulative incidence of acute rejection in hbv-infected liver transplant recipients treated with anti-hbs Ig was significantly lower (13%; p=0.01) as compared to recipients without viral hepatitis (34%). In contrast, hcv-infected recipients had a similar incidence of acute rejection (31%) as compared to recipients without viral hepatitis in multivariate Cox-regression analysis, treatment with anti-HBs Ig was, independently of other risk factors, associated with a reduced incidence of acute rejection (Relative Risk compared to recipients without viral hepatitis = 0.36; 95% ci=0.14-0.91; p=0.03). During the first two weeks after transplantation, the patients treated with anti-HBs Ig had high anti-HBs Ig concentrations in their serum (median peak levels: 3.5 mg/ml; range: 1.9 - 10.6). Therefore, we postulated that the reduced incidence of acute rejection in these patients might be due to a suppressive effect of anti-HBs Ig on dc-function. We found that DC obtained from HBV-infected recipients during anti-HBs Ig treatment had a strongly reduced capacity to stimulate allogeneic T-cell proliferation as compared to dc isolated from HCV-infected liver transplant recipients or from healthy individuals. In addition, the presence of anti-HBs Ig, in concentrations similar to the peak serum concentrations reached in the patients, during in vitro DC-maturation resulted in DC with a significantly reduced capacity to stimulate allogeneic T-cell proliferation as compared to DC maturated in the absence of anti-HBs Ig (n=5; p<0.05). Flow-cytometric analysis revealed that the expression of the co-stimulatory molecule CD80 on DC maturated in the presence of anti-HBs Ig was significantly reduced (p=0.02), while induction of HLA-DR and CD86-expresion were unaffected. Conclusions: Immediate post-transplant treatment with a specific IVIG-preparation (anti-HBs Ig) is associated with a significantly reduced incidence of acute rejection in liver transplant recipients. This may be due to inhibition of the acquirement of allogeneic t-cell stimulatory capacity in their DC by the anti-HBs Ig. This type of ivig-preparations may be applicable as immusuppressive agents after organ transplantation.

Silent acute rejection during prolonged delayed graft function reduces kidney allograft survival.

The relationship between the effects of early, silent, acute rejection (AR) and delayed graft function (DGF) on kidney allograft survival remain controversial, and the role of protocol biopsies during DGF is unclear. We hypothesized that protocol biopsies during DGF would reveal a high incidence of silent AR that may adversely affect long-term allograft survival. We routinely carried out protocol biopsies in patients requiring dialysis 7 to 10 days posttransplant. We retrospectively examined the extent to which silent AR, diagnosed by protocol biopsies during prolonged DGF, may mediate the adverse effects of DGF on graft survival in 410 consecutive transplants using Cox proportional hazards analysis. By 40 days posttransplant, the cumulative incidence of AR was 57.2% among 65 patients who had a protocol biopsies during DGF, while it was only 15.1% among the 345 who did not need a protocol biopsy. Mild DGF (n=30) requiring one or two dialysis treatments had no effect on graft survival, but the unadjusted risk ratio (and 95% confidence interval) associated with more prolonged DGF (n=104) was 3.08 (2.09-4.52, P<0.0001). The risk for graft failure from AR detected on protocol biopsy was 2.91 (1.60-5.27, P=0.0004) and was similar to the risk from early AR in patients without DGF, 2.95 (1.72-5.07, P<0.0001). After taking the effects of AR into account, the risk of graft failure attributable to prolonged DGF was reduced to 1.76 (1.06-2.94, P=0.0294), suggesting that much of the risk of DGF was because of the risk of AR. Silent AR is common during DGF. Prolonged DGF is associated with reduced graft survival after kidney transplantation, and much of this association can be explained by silent AR. In the absence of data from randomized trials, protocol biopsies and treatment of silent AR during prolonged DGF appear to be warranted.

Analysis of a single-center experience with mycophenolate mofetil based immunosuppression in renal transplantation.

Acute rejection continues to be a major clinical issue in renal transplantation. Three large multicenter trials have demonstrated a 50% decline in biopsy-proven rejection when mycophenolate mofetil (MMF) was given to renal transplant recipients with corticosteroids and cyclosporine. The purpose of this study was to compare the 6-month outcome of renal transplant recipients using MMF and non-MMF based immunosuppression protocols over a 4-year period at a single center. This retrospective study analyzed three patient groups defined by their immunosuppression protocol. The first group included patients who received a quadruple immunosuppression regimen of anti-lymphocyte induction (ATG), cyclosporine (CYA), azathioprine (AZA), and corticosteroids (CCS), and were transplanted between October 1993 and May 1995 (AZA group). The second group included patients who received a triple immunosuppression regimen of CYA, MMF, and CCS, and were transplanted between June 1995 and May 1996 (MMF group). The third group included patients who were transplanted between January 1997 and December 1997, and received an immunosuppression regimen of CYA and MMF with a reduced CCS dosing schema (reduced steroid group (RST)). Data were collected from a retrospective review of inpatient and outpatient clinical records. A total of 325 patients were included in the study (106 AZA, 106 MMF, 113 RST). The demographic characteristics of the three groups were similar; however, the mean donor age for the AZA group was 40+/-15.1 years versus 33+/-14.1 years and 34+/-13.1 years for the MMF and RST groups, respectively (p<0.043). The incidence of acute, biopsy-proven rejection at 6 months was significantly less in the MMF group when compared with the AZA group [16 (15.1%) versus 35 (33%) patients, p = 0.002]. However, the incidence of acute, biopsy-proven rejection in the RST group (35 patients, 31%) was similar to that of the AZA group. Kaplan-Meier estimates for the cumulative incidence of acute rejection demonstrated a significant difference between the MMF group and the other two groups (p = 0.0059). The AZA group had more severe rejection as demonstrated by the more frequent use of antilymphocyte therapy for rejection treatment (68.4% episodes) compared with the MMF (38.9%) and RST (47.6%) groups. After 6 months of follow-up, 11 patients had lost their grafts (8, AZA; 1, MMF; 2, RST). One patient died in each of the AZA and RST groups due to hemorrhage and a pulmonary embolus, respectively. Four AZA patients were diagnosed with a malignancy (three post-transplant lymphoproliferative disorder, one squamous skin cell carcinoma) compared with 2 MMF patients (prostate cancer, basal skin cell carcinoma) and no RST patients. Herpes zoster was the only infection that occurred more frequently in the MMF group (p = 0.03). No other differences in infection rates were noted among the three groups. The initial length of hospital stay declined significantly over the 4-year study period [11+/-4.3 d (AZA), 7.0+/-4.0 d (MMF), 6.2+/-3.3 d (RST), p<0.001]. Total number of hospital days for the first 6 months also followed a similar declining pattern. Despite using intravenous cyclosporine immediately post-transplant in the MMF and RST groups, the incidence of delayed graft function was similar among the three groups. Average serum creatinine at 1 month was significantly lower in the MMF group (p = 0.008), but no difference was noted at 3 and 6 months when compared with the AZA and RST groups. This retrospective analysis indicates that MMF is an effective immunosuppressant. Decreased length of stay and less steroid resistant rejections with MMF is favorable for decreased hospital costs. However, the rebound in rejection rate with the RST group suggests that further study is needed to define the optimal use of this agent in combination with others to maximize effectiveness and minimize negative side effects.

CYCLOSPORINE WITHDRAWAL IN RENAL TRANSPLANT RECIPIENTS

12 In randomized controlled trials, elective Cyclosporine A (CsA) withdrawal(WDL) has not affected short-term graft survival. We retrospectively compared late, conditional graft survival (CGS), i.e., conditional on survival at 1 year, in 751 consecutive patients transplanted between 1/1/85 and 12/31/96 who had: 1) conventional immunosuppression without CsA (n=177, 24%), 2) elective CsA WDL after 1 year (n=394, 52%), 3) elective continuation of CsA) at the request of the patient or private nephrologist (n=107, 14%), 4) CsA WDL due to failure or toxicity of CsA (n=29, 4%), or 5) CsA continuation because of rejection or intolerance to azathioprine (n=44, 6%). All patients received prednisone and, if possible, azathioprine. The 3- and 6-year (Kaplan Meier) CGS were very low in groups 4 (68% and 37%) and 5 (59% and 37%), illustrating the potential fallacy of using registry data that includes patients with non-elective CsA WDL or non-elective CsA continuation to judge the effects of elective CsA WDL on CGS. The 3- and 6-year CGS in groups 1, 2 and 3, respectively, were: 87% and 76% (n=145 and 100), 94% and 76% (n=313 and 161), and 95% and 87% (n=67 and 26), p=0.16 by Log Rank. After adjusting for differences in multiple risk factors in a Cox proportional hazards model, there was a trend for reduced CGS with conventional immunosuppression without CsA (p=0.062), and a trend for reduced CGS with elective CsA WDL (p=0.065). The cumulative incidence of acute rejection between 1 and 6 years post-transplant was 28%, 28%, and 13% in groups 1, 2 and 3, respectively(p=0.014). Nevertheless, according to the 1997 UNOS Center Specific Report for kidney transplants from 1/1/88 through 4/30/92, 3-year CGS was 88.1% at our center, which was comparable to the expected (adjusted) 87.6% 3-year CGS. We conclude that the use of CsA vs. conventional immunosuppression, and elective CsA WDL, have had either no effect or a small effect (p>0.05) on late graft failure at out center. The rate of late acute rejection is the same after CsA WDL as it was before the introduction of CsA, challenging the notion that WDL actually causes acute rejection. A trend (p>0.05) toward improved CGS among patients who elected to continue CsA may be due to chance, may be the result of selection bias, or may be due to improved CGS from continued CsA(suggesting the need for additional long-term follow-up). We speculate that newer adjunctive immunosuppression may reduce the incidence of acute rejection after CsA WDL and enhance long-term CGS in the future.