Time for reform in transplant program-specific reporting: AST/ASTS transplant metrics taskforce.

In accordance with the National Organ Transplant Act and Department of Health and Human Services' Final Rule, the Scientific Registry of Transplant Recipients (SRTR) publicly releases biannual program-specific reports that include analyses of transplant centers' risk-adjusted waitlist mortality, organ acceptance ratios, transplant rates, and graft and patient survival. Since the inception of these center metrics, 1-year posttransplant graft and patient survival have improved, and center variation has decreased, casting uncertainty on their clinical relevance. The SRTR has recently modified center evaluations by ranking centers into 5 tiers rather than 3 tiers in an attempt to discriminate between programs performing within a tight range, further exacerbating this uncertainty. The American Society of Transplantation/American Society of Transplant Surgeons convened an expert taskforce to examine both the utility and unintended consequences of transplant center metrics. Estimates of center variation in outcomes in adjacent tiers are imprecise and fleeting, but can result in consequential changes in clinician and center behavior. The taskforce has concerns that current metrics, based principally on 1-year graft and patient survival, provide minimal if any benefit in informing patient choice and access to transplantation, with the untoward effect of decreased utilization of organs and restriction of research and innovation.

Donor-specific antibodies require preactivated immune system to harm renal transplant.

BACKGROUND: It is an unresolved issue why some kidney transplant recipients with pretransplant donor-specific HLA antibodies (DSA) show a high transplant failure rate, whereas in other patients DSA do not harm the graft. We investigated whether help from preactivated T-cells might be necessary for DSA to exert a deleterious effect. METHODS: The impact of pretransplant DSA and immune activation marker soluble CD30 (sCD30) on 3-year graft survival was analyzed in 385 presensitized kidney transplant recipients. FINDINGS: A deleterious influence of pretransplant DSA on graft survival was evident only in patients who were positive for the immune activation marker sCD30. In the absence of sCD30 positivity, 3-year graft survival was virtually identical in patients with or without DSA (83.1±3.9% and 84.3±2.8%, P=0.81). A strikingly lower 3-year graft survival rate of 62.1±6.4% was observed in patients who were both sCD30 and DSA positive (HR 2.92, P<0.001). Even in the presence of strong DSA with ≥5000 MFI, the 3-year graft survival rate was high if the recipients were sCD30 negative. INTERPRETATION: Pretransplant DSA have a significantly deleterious impact on graft survival only in the presence of high pretransplant levels of the activation marker sCD30.

Hypercoagulability in Kidney Transplant Recipients.

Thrombosis remains an important complication after kidney transplantation. Outcomes for graft and deep vein thrombosis are not favorable. The majority of early kidney transplant failure in adults is due to allograft thrombosis. Risk stratification, early diagnosis, and appropriate intervention are critical to the management of thrombotic complications of transplant. In patients with end-stage renal disease, the prevalence of acquired risk factors for thrombosis is significantly high. Because of hereditary and acquired risk factors, renal transplant recipients manifest features of a chronic prothrombotic state. Identification of hereditary thrombotic risk factors before transplantation may be a useful tool for selecting appropriate candidates for thrombosis prophylaxis immediately after transplantation. Short-term anticoagulation may be appropriate for all patients after kidney transplantation.

Association of Kidney Graft Loss With De Novo Produced Donor-Specific and Non-Donor-Specific HLA Antibodies Detected by Single Antigen Testing.

BACKGROUND: The association of donor-specific HLA antibodies (DSA) with kidney graft failure has been addressed previously; however, the majority of studies were based on small numbers of patients with graft failure. METHODS: We investigated 83 patients with failed kidney transplants for a possible association of de novo development and persistence or loss of pre-existing DSA with graft failure. Single Antigen Bead assay-detected DSA and non-DSA antibodies were compared between patients with graft loss and matched controls with functioning grafts. RESULTS: The incidence of weak de novo DSA or non-DSA at a mean fluorescence intensity of 500 or higher was higher in the graft loss than in the nonrejector group (76% vs 40%, P < 0.001). Because of the low number of patients developing de novo DSA, the DSA results did not reach statistical significance (only 22% of patients with graft loss developed de novo DSA). However, at all cutoffs, there was a significantly higher rate of graft loss in patients with de novo non-DSA. The incidence of strong pretransplant DSA that persist after transplantation was higher in the graft loss group (10% vs 1%, P = 0.034). When C1q-binding ability in sera of rejectors and nonrejectors with posttransplant de novo or persistent DSA was compared, none of the nonrejectors demonstrated C1q positivity, whereas 43% of patients with graft loss showed C1q-positive antibodies, although not necessarily donor-specific (P < 0.001). CONCLUSIONS: Our data show that the posttransplant presence of persisting or de novo HLA antibodies, especially if C1q binding, is associated with graft loss, even if the antibodies are not specific for mismatched donor HLA.

Tacrolimus exposure in the real world: an analysis from the Mycophenolic acid Observational REnal transplant study.

Tacrolimus exposure and renal function data to 36 months post-transplant were analyzed from the prospective, observational Mycophenolic acid Observational REnal transplant (MORE) registry in which de novo kidney transplant patients were managed according to local practice. Tacrolimus trough (C0 ) concentration at month 12 was stratified as low (<6 ng/mL), moderate (6-8 ng/mL), or high (>8 ng/mL) in 724 patients. Estimated glomerular filtration rate (eGFR) was stratified as low (<60 mL/min/1.73 m(2) ) or high (≥60 mL/min/1.73 m(2) ). High tacrolimus C0 (>8 ng/mL) was observed in 47.7%, 34.1%, 26.8%, and 26.7% of patients at baseline and months 12, 24, and 36, respectively. Biopsy-proven acute rejection was similar to month 36 regardless of tacrolimus C0 category at month 12. Tacrolimus C0 >8 ng/mL vs. <6 ng/mL at month 12 was predictive of low eGFR at month 24 (p = 0.023) with a nonsignificant trend at month 36 (p = 0.085). Infections (p < 0.013) and BK virus infection (p < 0.001) were most frequent in the low tacrolimus C0 cohort. Neutropenia was most frequent in the high tacrolimus C0 category (p = 0.010). In conclusion, over a quarter of patients were exposed to high tacrolimus C0 to 36 months post-transplant. Tacrolimus exposure did not affect rejection risk, but tacrolimus C0 >8 ng/mL at month 12 was predictive of subsequent low eGFR compared to C0 <6 ng/mL.

An update on the impact of pre-transplant transfusions and allosensitization on time to renal transplant and on allograft survival.

BACKGROUND: Blood transfusions have the potential to improve graft survival, induce sensitization, and transmit infections. Current clinical practice is to minimize transfusions in renal transplantation candidates, but it is unclear if the evidence continues to support pre-transplant transfusion avoidance. Changes in the Medicare prospective payment system may increase transfusion rates. Thus there is a need to re-evaluate the literature to improve the management options for renal transplant candidates. METHODS: A review applying a systematic approach and conducted using MEDLINE(®), Embase(®), and the Cochrane Library for English-language publications (timeframe: 01/1984-03/2011) captured 180 studies and data from publically available registries and assessed the impact of transfusions on allosensitization and graft survival, and the impact of allosensitization on graft survival and wait time. RESULTS: Blood transfusions continued to be a major cause of allosensitization, with allosensitization associated with increased rejection and graft loss, and longer wait times to transplantation. Although older studies showed a beneficial effect of transfusion on graft survival, this benefit has largely disappeared in the post-cyclosporine era due to improved graft outcomes with current practice. Recent data suggested that it may be the donor-specific antibody component of allosensitization that carried the risk to graft outcomes. CONCLUSIONS: Results of this review indicated that avoiding transfusions whenever possible is a sound management option that could prevent detrimental effects in patients awaiting kidney transplantation.

African American living-kidney donors should be screened for APOL1 risk alleles.

The adjusted rate of end-stage kidney disease (ESKD) among African Americans is markedly increased relative to European Americans. African Americans are overrepresented on the kidney transplantation waiting list and experience longer wait times. In aggregate, these pressures drive recommendations for living donor transplantation. Genovese et al. recently implicated the APOL1 gene in ESKD risk among African Americans (Genovese et al. Science 2010; 329: 841). The presence of two APOL1 risk alleles doubles the relative risk for ESKD; moreover, the alleles are prevalent among African Americans. We propose a strategy for screening for the presence of APOL1 risk alleles among African American living kidney donors and for living-related donors for African American recipients.

Late steroid withdrawal and cardiovascular events in kidney transplant recipients.

INTRODUCTION: Cardiovascular events (CVE) are the leading cause of mortality in kidney transplant recipients. The adverse effects of long-term therapy with steroids on cardiovascular risk have motivated increasing interest in steroid withdrawal (SW). The objective of this study was to compare the incidences of CVE and all-cause mortality between patients who had undergone SW at 1 year posttransplant and control patients who continued on steroids. METHODS: A cohort of 400 consecutive adult recipients of a kidney transplant between 1993 and 1998 who qualified for late SW was studied. At 1 year posttransplant 188 patients underwent SW, whereas 212 patients continued on steroids. Cox proportional-hazards analysis was used to estimate CVE (cardiac and cerebrovascular events) and all-cause mortality hazard ratios (HR) for patients who had undergone SW versus controls who continued on steroids beyond 1 year. RESULTS: The average follow-up was 61 months. There were 44 (11%) cardiac events, 18 (4.5%) cerebrovascular events, and 41 deaths (10.3%). The composite outcome of CVE and all-cause mortality was reached in 26 (13.8%) subjects who had undergone SW and 50 (23.6%) controls (P=0.013). In adjusted analyses, SW was associated with decreased risk for the composite outcome (HR 0.46, 95% confidence interval [CI] 0.28-0.76), cardiac events (HR 0.48, 95% CI 0.28-0.84), and all-cause mortality (HR 0.27, 95% CI 0.12-0.59). There was no association of SW with the risk for cerebrovascular events (HR 1.76, 95% CI 0.45-7.01). CONCLUSION: In this retrospective analysis, SW at 1 year posttransplant was associated with decreased risk for future CVE and all-cause mortality.

Long-term kidney regraft survival from deceased donors: risk factors and outcomes in a single center.

BACKGROUND: Although survival of kidney regrafts is similar to that of primary grafts, risk factors associated with regraft survival have not been defined clearly. The aim of this study was to investigate risk factors for regraft outcome, including characteristics of the previous and current transplant, and time to retransplant. METHODS: In a historical cohort study, 966 primary and 176 repeat deceased donor kidney graft recipients transplanted between January 1, 1990 and December 31, 2004 were studied. Cox regression analysis was used to estimate graft loss hazard ratios (HR) for regrafts versus primary grafts. Adjustments were made for recipient and donor demographics, transplant-related factors (transplant era, panel reactive antibodies, human leukocyte antigens mismatches, immunosuppression, delayed graft function, acute rejection [AR]), previous transplant characteristics (graft survival, graft loss because of AR), and time to retransplant. RESULTS: A total of 508 kidney grafts were lost in the period between January 1990 and May 2007: 427 primary grafts and 81 regrafts. Regraft recipients had a covariate-adjusted 6% increase in graft loss (HR=1.06; P=0.69). Regraft loss was significantly associated with previous graft survival less than or equal to 1 year (HR=2.01; P=0.004), previous graft loss because of AR (HR=2.26; P=0.017) and time to retransplant more than 1 year (HR=2.42; P=0.002). Other significant predictors of regraft loss were diabetes (HR=1.81), donor age more than 50 years (HR=1.86) and delayed graft function after retransplant (HR=1.95). CONCLUSIONS: Kidney regrafts seem to have similar long-term outcome as primary grafts. However, additional risk factors significantly associated with regraft survival are previous graft survival, graft loss because of rejection, and time to retransplant.

Living unrelated donor renal transplantation: a single center experience.

PURPOSE: Living, genetically unrelated donor renal transplantation (LURT) is being performed with increasing frequency. We evaluated our single center experience with LURT and compared this to a cohort of living related donor renal transplants (LRT) to evaluate the short-term success of LURT at our center. MATERIALS AND METHODS: We identified 99 consecutive patients who underwent LURT at our center and had at least 1 year of followup data. A control cohort of 99 patients who underwent LRT at our center matched for age, number of transplants and date of transplant was also identified. One-year graft and patient survival, and serum creatinine levels at 1, 3, 6 and 12 months were compared between the groups. Our data were compared with national and international data. RESULTS: At our center 1-year graft survival was 95% in the LURT and LRT cohorts. One-year LURT patient survival was 99% compared with 97% in the LRT group and the serum creatinine levels were not significantly different. CONCLUSIONS: Patients undergoing LURT at our center have excellent 1-year graft and patient survival compared with LRT performed at our center, and national and international LURT. Genetically unrelated kidney donors should continue to be used to expand the kidney donor pool.

Factors associated with improvement in deceased donor renal allograft function in the 1990s.

The decade of the 1990s saw an improvement in cadaveric renal graft function and dramatic reduction in the acute rejection (AR) rate. The purpose of this study was to determine whether the reduction in rejection rate was the primary cause of the improvement in graft function seen and whether this improved long-term graft survival. All adult patients who received a cadaver renal transplant between 1991 and 2000 and had graft survival of at least 6 mo and complete data for creatinine at 6 mo, HLA mismatch, delayed graft function, and acute rejection (AR) were identified in the United Network for Organ Sharing database. A total of 40,164 cases that met the inclusion criteria were identified. The mean Modification of Diet in Renal Disease GFR at 6 mo improved from 49.94 ml/min per 1.73 m2 in 1991 to 54.59 ml/min per 1.73 m2 in 2000 (P < 0.001). The improvement in GFR was not gradual but occurred over a 4-yr period between 1994 and 1997, coinciding with the introduction of new immunosuppressive agents mycophenolate mofetil and tacrolimus into maintenance immunosuppression regimens. The improvement was seen in all subgroups of patients, even patients without clinical AR or delayed graft function. The magnitude of improvement in patients without clinical AR was similar to that seen in patients with AR. The drop in clinical AR rate accounted for a minority of the improvement in graft function in the 1990s. Other factors, such as reduced drug toxicity and improved control of subclinical rejection, seem to account for the majority of the improvement. This improvement in graft function at 6 mo did not translate into improved long-term graft survival, however.

Autosomal-dominant polycystic kidney disease as a risk factor for diabetes mellitus following renal transplantation.

BACKGROUND: Posttransplant diabetes mellitus is an important complication of renal transplantation that is associated with a significant impact on quality of life and an increase in long-term morbidity and mortality. Autosomal-dominant polycystic kidney disease (ADPKD) is a hereditary disease that commonly leads to end-stage renal disease (ESRD) in adulthood. The association between ADPKD and posttransplant diabetes mellitus has not been previously studied in a large cohort of patients. METHODS: To address this question, we studied a cohort of 135 patients with ADPKD who received a first renal-only transplant between January 1985 and December 1999. An age, race, and date of transplant-matched cohort of 135 non-ADPKD subjects were used as the control population. RESULTS: The cohorts were similar at baseline for gender distribution, body mass index (BMI), proportion of obese subjects (BMI greater than 30 kg/m(2)), family history of diabetes mellitus, and type of donor (deceased or living). At 12 months, the incidence of posttransplant diabetes mellitus was significantly higher in patients with ADPKD when compared to the controls (17% vs. 7.4%) (P= 0.016), despite no significant differences in the BMI, percent increase in BMI, number of acute rejections, prednisone dose at 3 and 6 months, use of diuretics or beta blockers, delayed graft function, or serum creatinine levels. The proportion of subjects requiring insulin was significantly higher in the ADPKD group (11.1% vs. 3%) (P= 0.009). Variables significantly associated with posttransplant diabetes mellitus at 1 year by bivariate analyses were the diagnosis of ADPKD (P= 0.02), BMI at transplant (P= 0.04), obesity at 12 months (P= 0.01), and delayed graft function (P= 0.02). Gender of recipient (P= 0.9), family history of diabetes (P= 0.3), prednisone dose at 3 months (P= 0.9) and 6 months (P= 0.7), acute rejection (P= 0.9), use of beta blockers or tacrolimus (P= 0.8), deceased donor transplant (P= 0.2), and serum creatinine at 1 year (P= 0.5) were not associated with posttransplant diabetes mellitus. A trend toward increased incidence of posttransplant diabetes mellitus was found with the use of diuretics post transplant (P= 0.054). By multivariable analyses, in patients with ADPKD, the adjusted (by all the variables listed above) relative risk for development of posttransplant diabetes mellitus was 2.87 (95% CI = 1.24-6.65) (P= 0.014). Only the diagnosis of ADPKD (RR = 2.9) (P= 0.01), obesity at 1 year (RR 2.5) (P= 0.017), and delayed graft function (RR 2.4) (P= 0.03) contributed significantly to the fit of a stepwise logistic regression model. Patient survival was significantly worse in the cohort of patients who developed posttransplant diabetes mellitus (median survival 109.3 vs. 121 months) (P= 0.008). CONCLUSION: In our study patients with ADPKD were at a threefold increased risk for development of posttransplant diabetes mellitus within the first year following renal transplantation. Development of posttransplant diabetes mellitus was associated with a significant detrimental impact on patient survival. Further studies are needed to provide insight into the mechanisms of the association between ADPKD and posttransplant diabetes mellitus.

The kidney transplant wait-list: allocation of patients to a limited supply of organs.

The improvement of survival rates and the increasing demand for renal transplantation has resulted in tremendous growth of the deceased donor kidney waiting list. Unfortunately, over the same period, the number of deceased donor kidneys available for transplantation has only increased modestly. In this review, the rules by which deceased donor kidneys are allocated and distributed are reviewed. In addition, we discuss the ethical issues involved in the formulation of these policies and the implications for individual patients.

Renal transplantation at Oregon Health and Science University: recent results and protocols.

Renal transplants have been performed at the University Hospital, Portland, OR since 1959. In the 5-year period between January 1997 and December 2001, 736 kidney-only transplants were performed at our institution. Living donor transplants comprise an increasing proportion of the transplants performed. Our patient and graft survival rates, both short- and long-term reflect the close collaboration between the transplantation medicine and transplantation surgery faculties, and the excellent support from nurse-coordinators, histocompatibility laboratory specialists and the organ procurement organization. Since September 2001, we have used a risk-based immunosuppression algorithm. The incidence of acute rejection within the first 3 months following transplantation ranged from 7-18% in the different risk groups. We have incorporated surveillance renal allograft biopsies into our standard of care and biopsies are performed at 3 months and one year after transplantation. The incidence of subclinical rejection was 15% on the 3-month surveillance biopsies and 4% on the one-year biopsies. The majority of these rejection episodes were CCTT type I acute rejection, which responded to treatment with pulse steroids. Since 1991, we have been transplanting kidneys from blood group A2 donors into blood group B or O recipients. Graft survival is similar to that in patients receiving an ABO compatible transplant. We have recently adopted the use of intravenous immune globulin to abrogate a positive crossmatch and allow transplantation of a kidney from a living donor. Six patients have been successfully transplanted using this protocol. In an effort to speed up the work-up of recipients waiting for a deceased donor kidney transplant, we have implemented a computer-driven algorithm. By generating a list of patients who should be crossmatched, and by automating generation of work sheets and reports, this computer-driven program has expedited deceased donor workups.

Validation of an algorithm for predicting cardiac events in renal transplant candidates.

A 2-tiered noninvasive cardiac risk stratification algorithm was first evaluated in a test population with planar thallium myocardial perfusion imaging and subsequently in a validation population using single-photon emission computed tomographic (SPECT) thallium myocardial perfusion imaging. This study examines if SPECT imaging was as predictive of cardiac death as planar imaging and also if SPECT imaging predicted nonfatal cardiac events in the patient population. Renal transplant candidates were evaluated using a 2-tiered noninvasive cardiac risk stratification algorithm. The first tier of risk assessment utilized 5 variables: age >50 years, insulin-dependent diabetes mellitus, abnormal electrocardiogram, and a history of either angina or congestive heart failure. Patients without risk factors were considered low risk and underwent no further cardiac evaluation. Patients with > or =1 risk factor were considered high risk and underwent a second tier of risk assessment with planar (n = 95) or SPECT (n = 112) imaging. In the test population, 13 of 16 cardiac deaths (81%) occurred in high-risk patients with abnormal planar studies. In the validation group, all cardiac deaths (5 of 60) and nonfatal cardiac events (13 of 60) occurred in high-risk patients with abnormal SPECT studies. SPECT imaging was at least as predictive as planar imaging and also predicted nonfatal as well as fatal cardiac events. Pretransplant risk stratification by clinical variables identified low-risk patients who may not require further cardiac evaluation and high-risk patients with normal SPECT imaging who may not require angiography.