All-cause Graft Failure Research Articles

Characteristics and Performance of Unilateral Kidney Transplants from Deceased Donors.

The fraction of kidneys procured for transplant that are discarded is rising in the United States. Identifying donors from whom only one kidney was discarded allows us to control for donor traits and better assess reasons for organ discard. We conducted a retrospective cohort study using United Network for Organ Sharing Standard Transplant Analysis and Research file data to identify deceased donors from whom two kidneys were procured and at least one was transplanted. Unilateral pairs were defined as kidney pairs from a single donor from whom one kidney was discarded ("unilateral discard") but the other was transplanted ("unilateral transplant"). Organ quality was estimated using the Kidney Donor Risk Index and Kidney Donor Profile Index (KDPI). We compared all-cause graft failure rates for unilateral transplants to those for bilateral transplant Kaplan-Meier methods, and life table methodology was used to evaluate 1-, 2-, 3-, and 5-year survival rates of transplants from bilateral and unilateral donors. Compared with bilateral donors (i.e., both kidneys transplanted) (n=80,584), unilateral donors (i.e., only one kidney transplanted) (n=7625) had higher mean terminal creatinine (1.3±2.1 mg/dl versus 1.1±0.9 mg/dl) and KDPI (67%±25% versus 42%±27%), were older, and were more likely to have hypertension, diabetes, hepatitis C, terminal stroke, or meet Centers for Disease Control and Prevention high-risk donor criteria. Unilateral discards were primarily attributed to factors expected to be similar in both kidneys from a donor: biopsy findings (22%), no interested recipient (13%), and donor history (7%). Anatomic abnormalities (14%), organ damage (11%), and extended ischemia (6%) accounted for about 30% of discards, but were the commonest reasons among low KDPI kidneys. Among kidneys with KDPI≥60%, there was an incremental difference in allograft survival over time (for unilateral versus bilateral transplants, 1-year survival: 83% versus 87%; 3-year survival: 69% versus 73%; 5-year survival: 51% versus 58%). A large number of discarded kidneys were procured from donors whose contralateral kidneys were transplanted with good post-transplant outcomes.

Antidepressant medication use before and after kidney transplant: implications for outcomes - a retrospective study.

We examined a novel database wherein national US transplant registry identifiers were linked to records from a large pharmaceutical claims warehouse (2008-2015) to characterize antidepressant use before and after kidney transplantation, and associations [adjusted hazard ratio (aHR) 95% CI] with death and graft failure. Among 72 054 recipients, 12.6% filled antidepressant medications in the year before transplant, and use was more common among women and patients who were white, unemployed, and had limited functional status. Pre-transplant antidepressant use was associated with 39% higher 1-year mortality (aHR 1.39, 95% CI 1.18-1.64) and 15% higher all-cause graft loss risk (aHR 1.15, 95% CI 1.02-1.30). More than 50% of patients who filled antidepressants pre-transplant continued fill post-transplant. Antidepressant use in the first year after transplant was associated with twofold higher risk of death (aHR 1.94, 95% CI 1.60-2.35), 38% higher risk of death-censored graft failure, and 61% higher risk of all-cause graft failure in the subsequent year. Pre-listing antidepressant use was also associated with increased mortality, but transplantation conferred a survival benefit regardless of prelisting antidepressant use status. While associations may in part reflect underlying behaviors or comorbidities, kidney transplant candidates and recipients treated with antidepressant medications should be monitored and supported to reduce the risk of adverse outcomes.

High serum PCSK9 is associated with increased risk of new-onset diabetes after transplantation in renal transplant recipients

OBJECTIVE New-onset diabetes after transplantation (NODAT) is a major complication in renal transplant recipients (RTRs). Cholesterol metabolism has been linked to diabetes development. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is crucial in LDL receptor regulation. Its association with NODAT is unknown. We prospectively determined the association between serum PCSK9 levels and NODAT development and then with all-cause mortality, cardiovascular mortality, and renal graft failure. RESEARCH DESIGN AND METHODS In a university setting, nondiabetic RTRs recruited between 2001 and 2003 with a functional graft for ≥1 year were eligible. Serum PCSK9 was measured by ELISA. Cox proportional hazards analysis was used to assess the association of PCSK9 with the development of NODAT, all-cause mortality, cardiovascular mortality, and graft failure. RESULTS In 453 RTRs (age 51 ± 12 years, 56% male; 6.1 [2.7–11.7] years after transplantation), serum PCSK9 was 107.1 ± 43.4 μg/L. During a median follow-up of 10 years, 70 RTRs developed NODAT, 123 died, and 59 developed graft failure. NODAT occurred more frequently in the upper PCSK9 tertile (23%) versus the lowest two PCSK9 tertiles (12%; P CONCLUSIONS Circulating PCSK9 is associated with NODAT in RTRs. The PCSK9 pathway may contribute to the pathogenesis of NODAT.

High Serum PCSK9 Is Associated With Increased Risk of New-Onset Diabetes After Transplantation in Renal Transplant Recipients.

New-onset diabetes after transplantation (NODAT) is a major complication in renal transplant recipients (RTRs). Cholesterol metabolism has been linked to diabetes development. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is crucial in LDL receptor regulation. Its association with NODAT is unknown. We prospectively determined the association between serum PCSK9 levels and NODAT development and then with all-cause mortality, cardiovascular mortality, and renal graft failure. In a university setting, nondiabetic RTRs recruited between 2001 and 2003 with a functional graft for ≥1 year were eligible. Serum PCSK9 was measured by ELISA. Cox proportional hazards analysis was used to assess the association of PCSK9 with the development of NODAT, all-cause mortality, cardiovascular mortality, and graft failure. In 453 RTRs (age 51 ± 12 years, 56% male; 6.1 [2.7-11.7] years after transplantation), serum PCSK9 was 107.1 ± 43.4 μg/L. During a median follow-up of 10 years, 70 RTRs developed NODAT, 123 died, and 59 developed graft failure. NODAT occurred more frequently in the upper PCSK9 tertile (23%) versus the lowest two PCSK9 tertiles (12%; P < 0.001). In crude Cox regression analyses, PCSK9 was significantly associated with development of NODAT (hazard ratio 1.34 [95% CI 1.10-1.63]) per SD change (P = 0.004). This association remained independent of adjustment for potential confounders, including statin use. PCSK9 was not associated with all-cause mortality, cardiovascular mortality, or graft failure. Circulating PCSK9 is associated with NODAT in RTRs. The PCSK9 pathway may contribute to the pathogenesis of NODAT.

Effects of Dopamine Donor Pretreatment on Graft Survival after Kidney Transplantation: A Randomized Trial.

Donor dopamine improves initial graft function after kidney transplantation due to antioxidant properties. We investigated if a 4 µg/kg per minute continuous dopamine infusion administered after brain-death confirmation affects long-term graft survival and examined the exposure-response relationship with treatment duration. Five-year follow-up of 487 renal transplant patients from 60 European centers who had participated in the randomized, multicenter trial of dopamine donor pretreatment between 2004 and 2007 (ClinicalTrials.gov identifier: NCT00115115). Follow-up was complete in 99.2%. Graft survival was 72.6% versus 68.7% (P=0.34), and 83.3% versus 80.4% (P=0.42) after death-censoring in treatment and control arms according to trial assignment. Although infusion times varied substantially in the treatment arm (range 0-32.2 hours), duration of the dopamine infusion and all-cause graft failure exhibited an exposure-response relationship (hazard ratio, 0.96; 95% confidence interval [95% CI], 0.92 to 1.00, per hour). Cumulative frequency curves of graft survival and exposure time of the dopamine infusion indicated a maximum response rate at 7.10 hours (95% CI, 6.99 to 7.21), which almost coincided with the optimum infusion time for improvement of early graft function (7.05 hours; 95% CI, 6.92 to 7.18). Taking infusion time of 7.1 hours as threshold in subsequent graft survival analyses indicated a relevant benefit: Overall, 81.5% versus 68.5%; P=0.03; and 90.3% versus 80.2%; P=0.04 after death-censoring. We failed to show a significant graft survival advantage on intention-to-treat. Dopamine infusion time was very short in a considerable number of donors assigned to treatment. Our finding of a significant, nonlinear exposure-response relationship disclosed a threshold value of the dopamine infusion time that may improve long-term kidney graft survival.

Serum free sulfhydryl status is associated with patient and graft survival in renal transplant recipients

Oxidative stress contributes significantly to graft failure, morbidity and mortality in renal transplant recipients (RTR). In cells, free sulfhydryl groups (reduced thiols, R-SH) are the transducers of redox-regulated events; their oxidation status is modulated by interaction with reactive oxygen and nitrogen oxide species and thought to be in equilibrium with the circulating pool. We hypothesized that high levels of serum free thiols are a reflection of a favorable redox status and therefore positively associated with cardiovascular risk parameters, patient and graft survival in RTR.To test this, reactive free thiol groups (R-SH; corrected for total protein) were quantified in serum of 695 RTR (57% male, 53±13yr, functioning graft ≥1yr) using Ellman's Reagent, and R-SH determinants were evaluated with multivariable linear regression models. Associations between R-SH and mortality or graft failure were assessed using multivariable Cox regression analyses.In multivariable models, male gender, estimated glomerular filtration rate and serum thiosulfate positively associated with R-SH while BMI, HbA1c, corrected calcium and NT-pro-BNP inversely associated with R-SH (model R2=0.26). During follow-up (3.1 [2.7–3.9] yrs), 79 (11%) patients died and 45 (7%) patients developed graft failure. R-SH correlated inversely with all-cause mortality (HR 0.58 [95% CI 0.45–0.75] per SD increase) and graft failure (HR 0.42 [0.30–0.59]; both P<0.001), independent of parameters with which R-SH significantly associated in the multivariable regression analyses, except for NT-pro-BNP.Serum R-SH are associated with a beneficial cardiovascular risk profile and better patient and graft survival in RTR, suggesting potential usefulness as low-cost, high-throughput screening tool for whole-body redox status in translational studies. Whether R-SH modification improves long-term outcome of RTR warrants further exploration.

Pancreas.

Even though pancreas transplant numbers have steadily declined over the past decade, new listings increased in 2014 compared with the previous year, notably for pancreas transplant alone (PTA) and simultaneous pancreas-kidney transplant. The number of new PTAs also increased over the past two years. Whether this is a sustainable trend remains to be seen. Significant events in 2014 included implementation of a new pancreas allocation system and development of a proposed uniform definition of pancreas graft failure. Meanwhile, overall pancreas transplant rates and outcomes continued to improve. Substantial decline in pancreas after kidney transplants remains a serious concern. SRTR has not published pancreas graft failure data in the program-specific reports for the past two years. While this will not change in the near future, the acceptance of a uniform definition of graft failure is a crucial first step toward resuming graft failure reporting. Continued improvements and innovation, both surgical and immunological, will be critical to keep pancreas transplant as a viable option for treatment of insulin-dependent diabetes. As alternative therapies for diabetes such as islet transplant and artificial pancreas are evolving, improved outcomes with minimizations of complications are more important than ever.

High urinary homoarginine excretion is associated with low rates of all-cause mortality and graft failure in renal transplant recipients

Renal transplant recipients (RTR) have an increased cardiovascular risk profile. Low levels of circulating homoarginine (hArg) are a novel risk factor for mortality and the progression of atherosclerosis. The kidney is known as a major source of hArg, suggesting that urinary excretion of hArg (UhArg) might be associated with mortality and graft failure in RTR. hArg was quantified by mass spectrometry in 24-h urine samples of 704 RTR (functioning graft ≥1 year) and 103 healthy subjects. UhArg determinants were identified with multivariable linear regression models. Associations of UhArg with all-cause mortality and graft failure were assessed using multivariable Cox regression analyses. UhArg excretion was significantly lower in RTR compared to healthy controls [1.62 (1.09-2.61) vs. 2.46 (1.65-4.06) µmol/24 h, P < 0.001]. In multivariable linear regression models, body surface area, diastolic blood pressure, eGFR, pre-emptive transplantation, serum albumin, albuminuria, urinary excretion of urea and uric acid and use of sirolimus were positively associated with UhArg, while donor age and serum phosphate were inversely associated (model R (2) = 0.43). During follow-up for 3.1 (2.7-3.9) years, 83 (12 %) patients died and 45 (7 %) developed graft failure. UhArg was inversely associated with all-cause mortality [hazard risk (HR) 0.52 (95 % CI 0.40-0.66), P < 0.001] and graft failure [HR 0.58 (0.42-0.81), P = 0.001]. These associations remained independent of potential confounders. High UhArg levels are associated with reduced all-cause mortality and graft failure in RTR. Kidney-derived hArg is likely to be of particular importance for proper maintenance of cardiovascular and renal systems.

Calcification Propensity and Survival among Renal Transplant Recipients.

Calciprotein particle maturation time (T50) in serum is a novel measure of individual blood calcification propensity. To determine the clinical relevance of T50 in renal transplantation, baseline serum T50 was measured in a longitudinal cohort of 699 stable renal transplant recipients and the associations of T50 with mortality and graft failure were analyzed over a median follow-up of 3.1 years. Predictive value of T50 was assessed for patient survival with reference to traditional (Framingham) risk factors and the calcium-phosphate product. Serum magnesium, bicarbonate, albumin, and phosphate levels were the main determinants of T50, which was independent of renal function and dialysis vintage before transplant. During follow-up, 81 (12%) patients died, of which 38 (47%) died from cardiovascular causes. Furthermore, 45 (6%) patients developed graft failure. In fully adjusted models, lower T50 values were independently associated with increased all-cause mortality (hazard ratio, 1.43; 95% confidence interval, 1.11 to 1.85; P=0.006 per SD decrease) and increased cardiovascular mortality (hazard ratio, 1.55; 95% confidence interval, 1.04 to 2.29; P=0.03 per SD decrease). In addition to age, sex, and eGFR, T50 improved prognostication for all-cause mortality, whereas traditional risk factors or calcium-phosphate product did not. Lower T50 was also associated with increased graft failure risk. The associations of T50 with mortality and graft failure were confirmed in an independent replication cohort. In conclusion, reduced serum T50 was associated with increased risk of all-cause mortality, cardiovascular mortality, and graft failure and, of all tested parameters, displayed the strongest association with all-cause mortality in these transplant recipients.

Comparison of Longer-Term Outcomes After Kidney Transplantation Between Hispanic and Non-Hispanic Whites in the United States

Little is known about the longer-term kidney transplant outcomes in the rapidly growing Hispanic population. Using the United States Renal Data System, we identified 105 250 Caucasian patients who received a first kidney transplant between January 1, 1996 and December 31, 2010. We tested for differences between Hispanic and non-Hispanic patients in the outcomes of (1) mortality, (2) all-cause graft failure, and (3) graft failure excluding death with a functioning graft. We used Cox regression to estimate (with 95% confidence intervals) multivariable-adjusted cause-specific hazard ratios (aHRCS ) for mortality and all-cause graft failure and subdistribution hazard ratios (aHRSD ) accounting for death as a competing risk for graft failure excluding death with a functioning graft. Both mortality [aHRCS = 0.69 (0.65-0.73)] and all-cause graft failure [aHRCS = 0.79 (0.75-0.83)] were lower in Hispanics. The association between Hispanic ethnicity and graft failure excluding death was modified by age (p < 0.003). Compared with non-Hispanic whites, graft failure excluding death with a functioning graft did not differ in Hispanics aged 18-39 years [aHRSD = 0.96 (0.89-1.05)] or aged 40-59 years [aHRSD = 1.08 (1.00-1.16)], but was 13% lower in those aged ≥60 years [aHRSD = 0.87 (0.78-0.98)]. In conclusion, once accounting for differences in overall survival, better graft survival was found in older Hispanic patients, but among not those aged <60 years.

New Quality Monitoring Tools Provided by the Scientific Registry of Transplant Recipients: CUSUM

The Scientific Registry of Transplant Recipients (SRTR) has been providing data on transplant program performance through semi-annual release of program-specific reports (PSRs). A consensus conference held in February 2012 recommended that SRTR also supply transplant programs with tools such as the cumulative sum (CUSUM) technique to facilitate quality assessment and performance improvement. SRTR developed the process, methodologies, programming code and web capabilities necessary to bring the CUSUM charts to the community, and began releasing them to all liver, kidney, heart and lung programs in July 2013. Observed-minus-expected CUSUM charts provide a general picture of a program's performance (all-cause graft failure and mortality within the first-year posttransplant) over a 3-year period; one-sided charts can determine when performance appears to be sufficiently worrisome to warrant action by the program. CUSUM charts are intended for internal quality improvement by allowing programs to better track performance in near-real time and day to day, and will not be used to indicate whether a program will be flagged for review. The CUSUM technique is better suited for real-time quality monitoring than the current PSRs in allowing monthly outcomes monitoring and presenting data recorded as recently as 2 months before the release of the CUSUM charts.

Increased Recipient Body Mass Index Is Associated With Acute Rejection and Other Adverse Outcomes After Kidney Transplantation

Outcomes of kidney transplant recipients with increased body mass index (BMI) remain controversial. We studied the relationship between BMI and clinically relevant outcomes among kidney transplant recipients at a large center. We performed an observational cohort study of all recipients of kidney transplants at our center from January 1, 2000 to December 31, 2010 to determine if increased BMI at transplantation is associated with adverse outcomes, including delayed graft function and biopsy-proven acute rejection (BPAR). Recipient BMI was categorized as <20, 20 to 24.9 (reference), 25 to 29.9, 30 to 34.9, and ≥35 kg/m. Potential confounders were included in logistic and Cox proportional hazards models. A total of 1151 patients were studied. Recipient BMI of 30 to 34.9 and ≥35 kg/m were associated with an increased risk of delayed graft function (odds ratio [95% confidence interval [CI], 1.92 [1.16-3.19] and 4.49 [2.24-9.00], respectively). BMI≥35 kg/m was also associated with an increased risk of BPAR (hazard ratio [HR; 95% CI], 2.43 [1.48-3.99]), all-cause graft failure (HR [95% CI], 1.97 [1.09-3.56]), and death-censored graft failure (HR [95% CI], 2.43 [1.07-5.51]). Adjustment for acute rejection as a time-varying covariate significantly attenuated the association with graft failure endpoints. There was no significant relation between BMI and death with graft function. Increased BMI at kidney transplantation is a predictor of adverse outcomes, including BPAR. The role of pretransplantation weight reduction in improving graft and patient outcomes requires further study.

Outcomes After Kidney Transplantation of Patients Previously Diagnosed With Atrial Fibrillation

Little is known about the prevalence and outcomes of patients with atrial fibrillation/flutter (AF) who receive a kidney transplant. We identified all patients who had >1 year of uninterrupted Medicare A+B coverage before receiving their first kidney transplant (1997-2009). The presence of pretransplant AF was ascertained from diagnosis codes in Medicare physician claims. We studied the posttransplant outcomes of death, all-cause graft failure, death-censored graft failure and stroke using multivariable Cox regression. Of 62 706 eligible first kidney transplant recipients studied, 3794 (6.4%) were diagnosed with AF prior to kidney transplant. Over a mean follow up of 4.9 years, 40.6% of AF patients and 24.9% without AF died. All-cause and death-censored graft failure were 46.8% and 16.5%, respectively, in the AF group and 36.4% and 19.5%, respectively, in those without AF. Ischemic stroke occurred in 2.8% of patients with and 1.6% of patients without AF. In patients with AF, multivariable-adjusted hazard ratios (95% confidence intervals) for death, graft failure, death-censored graft failure and ischemic stroke were 1.46 (1.38-1.54), 1.41 (1.34-1.48), 1.26 (1.15-1.37) and 1.36 (1.10-1.68), respectively. Pre-existing AF is associated with poor posttransplant outcomes. Special attention should be paid to AF in pretransplant evaluation, counseling and risk stratification of kidney transplant candidates.

Health-Related Quality of Life and Long-Term Survival and Graft Failure in Kidney Transplantation

Although the prognosis of kidney transplantation is generally good, long-term survival varies substantially between patients. This study examined whether health-related quality of life (HRQOL) predicts long-term mortality in kidney transplantation after adjustment for known risk factors. A cohort of 347 (46.77 ± 13.96 years) kidney transplant recipients was followed up for 12 years after enrolment (1999-2001). Patients completed measures of HRQOL and medical records were reviewed to document clinical and cardiovascular risk factors and comorbidities at study entry (mean [SD], 8.57 [6.55] years after transplantation). The primary outcomes were ensuing all-cause mortality and all-cause graft failure (a composite endpoint consisting of return to dialysis therapy, preemptive retransplantation, or death with function). Cox proportional hazards multivariate models were developed to identify predictors of long-term patient and graft survival. During the 12-year follow-up, 86 (24.8%) patients died, 64 (18.3%) died with a functioning graft, and 35 (11.1%) were placed back to dialysis. Physical QOL impairment increased the risk of mortality and graft failure during the follow-up period. The risk remained significant after adjusting for sociodemographic and clinical risk factors (adjusted hazard ratio, 1.89; 95% confidence interval, 1.09-2.95; P=0.022 and adjusted hazard ratio, 1.68; 95% confidence interval, 1.12-2.52; P=0.012 for patient and graft survival, respectively). Other significant risk factors were older age, time elapsed since transplantation, and Charlson comorbidity index. Risk of graft failure was also associated with glomerular filtration rate. Physical HRQOL predicts long-term mortality and graft failure independently of sociodemographic and clinical risk factors in renal transplant patients. Future research should identify the determinants of HRQOL and refine interventions to improve it.

The Relationship Between Kidney Function and Long-term Graft Survival After Kidney Transplant

Whether chronic kidney disease (CKD) staging provides a useful framework for predicting outcomes after kidney transplant is unclear. Retrospective cohort study. We used data from the Patient Outcomes in Renal Transplantation (PORT) Study, including 13,671 transplants from 12 centers during 10 years of follow-up. Estimated glomerular filtration rate (eGFR; in milliliters per minute per 1.73 m(2)) at 12 months posttransplant. All-cause graft failure (a composite end point consisting of return to dialysis therapy, pre-emptive retransplant, or death with function), death-censored graft failure, and death with a functioning graft. The relationship between 12-month eGFR and subsequent graft outcomes through 10 years posttransplant was assessed using Cox proportional hazards analyses. Stage 3 included 63% of patients and was subdivided into stages 3a (eGFR, 45-59 mL/min/1.73 m(2); 34%) and 3b (eGFR, 30-44 mL/min/1.73 m(2); 29%). Compared with stage 2 (eGFR, 60-89 mL/min/1.73 m(2); 24%), adjusted Cox proportional HRs for graft failure were 1.12 (95% CI, 1.01-1.24; P = 0.04) for stage 3a, 1.50 (95% CI, 1.35-1.66; P < 0.001) for stage 3b, 2.86 (95% CI, 2.53-3.22; P < 0.001) for stage 4 (eGFR, 15-29 mL/min/1.73 m(2); 9%), and 13.2 (95% CI, 10.7-16.4; P < 0.001) for stage 5 (eGFR <15 mL/min/1.73 m(2); 1%). For stage 1 (eGFR ≥ 90 mL/min/1.73 m(2); 3%), risk of graft failure was increased (1.41 [95% CI, 1.13-1.75]; P < 0.001), likely due to serum creatinine associations independent of kidney function. Similar associations were seen between CKD stages and mortality. Retrospective study; lack of gold-standard measurements of true GFR; lack of measures of comorbidity, inflammation, muscle mass, proteinuria, and other noncreatinine markers of eGFR. CKD stages validated in the general population provide a useful framework for predicting outcomes after kidney transplant.

Educational Level as a Determinant of Access to and Outcomes After Kidney Transplantation in the United States

Disparities in access to kidney transplantation exist, yet few studies investigated educational level as a determinant of access to and outcomes after kidney transplantation. Prospective cohort study. Nationally representative sample of incident US dialysis patients, in which 3,245 patients reported their educational level. Educational level, categorized as some high school, high school graduate, some college, and college graduate. Access to kidney transplantation was defined as time from first dialysis treatment to: (1) the day of being wait-listed and (2) first kidney transplantation. Outcomes after kidney transplantation were: (3) all-cause mortality and graft failure ([4] all-cause and [5] death censored). Using Cox regression, we studied the relationship between predialysis educational level and access to and outcomes after kidney transplantation. During follow-up, 692 patients were wait-listed and 670 underwent kidney transplantation. Of those, 164 died and 241 lost their allograft (121 from nondeath causes). After multivariate adjustment, college graduates experienced 3 times greater rates of wait-listing (hazard ratio, 2.81; 95% confidence interval, 2.21 to 3.58) or kidney transplantation (hazard ratio, 3.06; 95% confidence interval, 2.38 to 3.92) compared with patients without a high school degree (P for trend across educational level for both outcomes < 0.001). Although mortality was not associated with educational level, increased rates of death-censored allograft loss were observed with less education (P for trend = 0.03). Not a randomized study. The latter finding is novel and important and requires confirmation. Its possible mechanisms (eg, adherence to immunosuppressants) warrant additional study.

Results of PREVENT III: A multicenter, randomized trial of edifoligide for the prevention of vein graft failure in lower extremity bypass surgery

The PREVENT III study was a prospective, randomized, double-blinded, multicenter phase III trial of a novel molecular therapy (edifoligide; E2F decoy) for the prevention of vein graft failure in patients undergoing infrainguinal revascularization for critical limb ischemia (CLI). From November 2001 through October 2003, 1404 patients with CLI were randomized to a single intraoperative ex vivo vein graft treatment with edifoligide or placebo. After surgery, patients underwent graft surveillance by duplex ultrasonography and were followed up for index graft and limb end points to 1 year. A blinded Clinical Events Classification committee reviewed all index graft end points. The primary study end point was the time to nontechnical index graft reintervention or major amputation due to index graft failure. Secondary end points included all-cause graft failure, clinically significant graft stenosis (>70% by angiography or severe stenosis by ultrasonography), amputation/reintervention-free survival, and nontechnical primary graft patency. Event rates were based on Kaplan-Meier estimates. Time-to-event end points were compared by using the log-rank test. Demographics, comorbidities, and procedural details reflected a population with CLI and diffuse atherosclerosis. Tissue loss was the presenting symptom in 75% of patients. High-risk conduits were used in 24% of cases, including an alternative vein in 20% (15% spliced vein and 5% non-great saphenous vein) and 6% less than 3 mm in diameter; 14% of the cases were reoperative bypass grafts. Most (65%) grafts were placed to infrapopliteal targets. Perioperative (30-day) mortality occurred in 2.7% of patients. Major morbidity included myocardial infarction in 4.7% and early graft occlusion in 5.2% of patients. Ex vivo treatment with edifoligide was well tolerated. There was no significant difference between the treatment groups in the primary or secondary trial end points, primary graft patency, or limb salvage. A statistically significant improvement was observed in secondary graft patency (estimated Kaplan-Meier rates were 83% edifoligide and 78% placebo; P = .016) within 1 year. The reduction in secondary patency events was manifest within 30 days of surgery (the relative risk for a 30-day event for edifoligide was 0.45; 95% confidence interval, 0.27-0.76; P = .005). For the overall cohort at 1 year, the estimated Kaplan-Meier rate for survival was 84%, that for primary patency was 61%, that for primary assisted patency was 77%, that for secondary patency was 80%, and that for limb salvage was 88%. In this prospective, randomized, placebo-controlled clinical trial, ex vivo treatment of lower extremity vein grafts with edifoligide did not confer protection from reintervention for graft failure.

Controlling treatment allocation bias in a registry analysis when comparing calcineurin inhibitors

Previous analyses of outcomes between immunosuppressive regimens included data from the early years of tacrolimus use and frequently included all Tacrolimus- or cyclosporine-based regimens. We now evaluate clinical outcomes associated with only the two most commonly prescribed regimens—Tacrolimus (Tac)-mycophenylate mofetil (MMF) and cyclosporine (CsA)-MMF—using recent data reported to the UNOS Scientific Renal Transplant Registry. Data from living donor kidney transplants was chosen to minimize selection bias between treatment groups. Outcomes are reported only for recent years (1998 to 1999 with 3-year follow-up) because acute rejection rates were markedly higher in 1995 to 1997 compared to 1998 to 2000 (38% to 68% vs 21% to 32%) and clinical practice has evolved since 1995, which would have biased results in favor of more recent immunosuppressive regimens. Three-year graft survival for patients transplanted from 1998 to 1999 was significantly higher in living donor kidney transplant patients receiving CsA-MMF (91.1%, n = 4686) versus Tac-MMF (88.1%, n = 2393) ( P = .0006). After adjustment for potential confounding variables, risk of graft failure at 3 years was significantly higher in patients receiving Tac-MMF versus CsA-MMF for both all-cause graft failure (hazard ratio 1.28, 95%CI 1.09 to 1.49, P = .002) and death-censored graft failure (hazard ratio 1.25, 95%CI 1.05 to 1.49, P = .013). In view of the reduced rejection rate that has been reported using Tac-MMF versus CsA-MMF in clinical trials, it is possible that the nonimmunologic effects of calcineurin inhibitors may now play an increasingly important role in determining graft survival rates. In conclusion, this large-scale registry analysis demonstrates that graft survival in living donor kidney transplant patients is significantly improved using CsA-MMF compared to Tac-MMF.

Study 1: graft survival after living donor renal transplantation: a comparison between tacrolimus and cyclosporine microemulsion with mycophenolate mofetil and steroids

C ontrolled clinical trials provide essential comparative data on safety and short-term surrogate end points such as rejection rates, but they are rarely powered to detect significant differences in graft survival or other “hard” end points. Registry analyses provide sufficient patient numbers to identify differences in graft outcomes between interventions, and they are conducted over the long term in a standard-risk patient population managed in routine clinical practice. We undertook a comparative intent-to-treat analysis of 3-year graft survival with use of either cyclosporine (CsA) or tacrolimus (TAC) in combination with mycophenolate mofetil (MMF) and steroids among renal transplant patients registered with the United Network for Organ Sharing Renal Transplant Registry. We selected a 2-year time frame to minimize the impact of concurrent improvements in patient management that were unrelated to immunosuppression. The most recent year for which full 3-year follow-up data are available is 1999, and, therefore, patients who underwent kidney transplants during 1998-1999 were selected for analysis. Univariate analysis was used to identify potential confounding factors including original disease, recipient age, body mass index, race, sex and panel reactive antibody status, previous transplant, previous pregnancy, waiting time on dialysis, and pretransplant blood transfusion; donor type, age, body mass index, race, sex, serum creatinine level, and mode of death; cold ischemia time, year of transplant, human leukocyte antigen compatibility, calcineurin inhibitor switch, cytomegalovirus status, and hepatitis B and C status. Cox regression analysis was utilized to adjust graft survival for known confounding factors that were found to differ significantly between treatment groups. A total of 21,267 patients were included in the analysis, 8038 of whom were treated with TAC-MMF and 13,229 of whom were given CsA-MMF. Approximately one third (7079) received a graft from a living donor. Three-year graft survival (KaplanMeier estimate) was significantly higher with CsAMMF than with TAC-MMF (86.6% vs 84.5%, respectively; P .0002) (Table 1). Twenty-one confounding factors varied significantly between treatment groups among the entire 1998-1999 cohort. After adjustment for confounding variables, the hazards ratio (HR) for graft failure with TAC-MMF versus CsA-MMF was 1.10, a difference that was statistically significant (95% confidence interval [CI], 1.03-1.20; P .007). When we repeated the analysis and excluded patients who died with a functioning graft, there was again a significantly higher risk of graft loss in the TACMMF treatment group when compared with the CsA-MMF treatment group (HR, 1.20, 95% CI 1.091.32, P .001). Fewer confounding factors (n 11) varied significantly between the CsA-MMF and TAC-MMF groups among living-donor patients, so we repeated the analysis using only living-donor recipients to further reduce risk of selection bias. Among living-donor recipients, 3-year graft survival was significantly higher with CsA-MMF than TACMMF (91.1% vs 88.1%, respectively; P .001), as was death-censored graft survival (94.5% vs 91.5%, respectively; P .0001). Estimated graft half-life was 20.8 1.2 years for the CsA-MMF group and 16.1 1.2 years for the TAC-MMF group (P .001). When graft survival was adjusted for confounding variables, the HR for all-cause graft failure with TAC-MMF compared with CsA-MMF was 1.27 (95% CI, 1.08-1.48; P .003); for death-censored graft failure, it was 1.48 (95% CI, 1.22-1.80; P .001). From the Multiorgan Transplant Program, Cedars-Sinai Medical Center, Los Angeles, CA; and Dumont Transplant Program & Immunogenetics Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA. © 2003 Elsevier Inc. All rights reserved. 0955-470X/03/1704-0000$30.00/0 doi:10.1016/j.trre.2003.10.022