Infliximab Induction Lacks Efficacy and Increases BK Virus Infection in Deceased Donor Kidney Transplant Recipients: Results of the CTOT-19 Trial.

BACKGROUND: Ischemia-reperfusion (IR) of a kidney transplant (KTx) upregulates TNF α production that amplifies allograft inflammation and may negatively affect transplant outcomes. METHODS: We tested the effects of blocking TNF peri-KTx via a randomized, double-blind, placebo-controlled, 15-center, phase 2 clinical trial. A total of 225 primary transplant recipients of deceased-donor kidneys (KTx; 38.2% Black/African American, 44% White) were randomized to receive intravenous infliximab (IFX) 3 mg/kg or saline placebo (PLBO) initiated before kidney reperfusion. All patients received rabbit anti-thymocyte globulin induction and maintenance immunosuppression (IS) with tacrolimus, mycophenolate mofetil, and prednisone. The primary end point was the difference between groups in mean 24-month eGFR. RESULTS: There was no difference in the primary end point of 24-month eGFR between IFX (52.45 ml/min per 1.73 m 2 ; 95% CI, 48.38 to 56.52) versus PLBO (57.35 ml/min per 1.73 m 2 ; 95% CI, 53.18 to 61.52; P =0.1). There were no significant differences between groups in rates of delayed graft function, biopsy-proven acute rejection (BPAR), development of de novo donor-specific antibodies, or graft loss/death. Immunosuppression did not differ, and day 7 post-KTx plasma analyses showed approximately ten-fold lower TNF ( P <0.001) in IFX versus PLBO. BK viremia requiring IS change occurred more frequently in IFX (28.9%) versus PLBO (13.4%; P =0.004), with a strong trend toward higher rates of BKV nephropathy in IFX (13.3%) versus PLBO (4.9%; P =0.06). CONCLUSIONS: IFX induction therapy does not benefit recipients of kidney transplants from deceased donors on this IS regimen. Because the intervention unexpectedly increased rates of BK virus infections, our findings underscore the complexities of targeting peritransplant inflammation as a strategy to improve KTx outcomes.Clinical Trial registry name and registration number:clinicaltrials.gov (NCT02495077).

Prostate Cancer, Kidney Transplant Wait Time, and Mortality in Maintenance Dialysis Patients: A Cohort Study Using Linked United States Renal Data System Data.

RATIONALE & OBJECTIVE: The impact of prostate cancer on mortality in patients with end-stage kidney disease may be different from the general population. Prostate cancer may also delay the kidney transplant but has not been studied in a population-based cohort. We examined how prostate cancer influenced time to kidney transplant and death in a dialysis population. STUDY DESIGN: Retrospective population-based, risk-set propensity score-matched cohort study. SETTING & PARTICIPANTS: Men, 40-79 years old, who were dialysis-dependent Medicare beneficiaries without prior documented prostate cancer, from the United States Renal Data System. EXPOSURES: Incident prostate cancer, identified using International Classification of Disease, Ninth Revision, Clinical Modification system diagnosis code 185. OUTCOMES: Time to kidney transplant and death. ANALYTICAL APPROACH: Propensity-based risk-set matching to reduce bias between cases and controls. Cox proportional hazards model for time to death, and Fine-Gray competing risk model for time to kidney transplant. RESULTS: Among a total of 588,478 male dialysis patients who met the eligibility criteria, 18,162 had claims for prostate cancer. After propensity-based risk-set matching, 15,554 pairs of prostate cancer cases and controls were identified. Among the matched pairs, survival rates were 76%, 48%, and 30% at 1, 3, and 5 years in the prostate cancer group, compared with 80%, 51%, and 33% in the control group, with relative mortality of 95%, 94%, and 91% respectively (log-rank test P < 0.001). Prostate cancer was associated with a 22% lower likelihood of kidney transplant (HR: 0.78; 95% CI: 0.72-0.85) and 11% higher likelihood of death (HR: 1.11; 95% CI: 1.08-1.14) compared with controls. Kidney transplant was associated with a 4-fold improvement in overall survival, both in patients with and without prostate cancer (HR: 0.20; 95% CI: 0.18-0.21). LIMITATIONS: Retrospective registry study. CONCLUSIONS: Prostate cancer is associated with a modest increase in the risk of death and time to transplant in patients with end-stage kidney disease. Kidney transplant is associated with the same degree of survival benefit among those with pretransplant prostate cancer as those without.

Securing the future of kidney transplantation by addressing the challenges of transplant nephrology.

Kidney transplant is a life-changing procedure, and transplant nephrologists, as part of a larger transplant team, play an important role in the field by managing the complex medical needs of transplant patients. The subspecialty of transplant nephrology, however, faces structural challenges related to its workforce, reporting structures, compensation, research and innovation, and health care information technology. The position of transplant nephrology at the academic and operational intersection of medicine and surgery may limit its access to critical resources, hinder academic promotion, and contribute to physician burnout. The authors provide an overview of the subspecialty transplant nephrology and propose solutions. Collaborative efforts that fortify the subspecialty of transplant nephrology will ultimately improve the lives of patients suffering from kidney disease.

Peritransplant eculizumab does not prevent delayed graft function in deceased donor kidney transplant recipients: Results of two randomized controlled pilot trials.

Animal models and observational human data indicate that complement, including C5a, pathogenically participates in ischemia reperfusion (IR) injury that manifests as delayed graft function (DGF) following deceased donor kidney transplantation. We report on the safety/efficacy of anti-C5 monoclonal antibody eculizumab (Ecu) administered in the operating room prior to reperfusion, to prevent DGF in recipients of deceased donor kidney transplants in two related, investigator-sponsored, randomized controlled trials. Eight recipients from a single center were enrolled in a pilot study that led to a 19-subject multicenter trial. Together, 27 deceased donor kidney transplant recipients, 16 Ecu-treated and 11 controls, were treated with rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil with or without glucocorticoids, and followed for 6 months. Data analysis showed no epidemiological or transplant-related differences between study arms. Ecu was well tolerated with a similar severe adverse event incidence between groups. The DGF rate did not differ between Ecu-treated (44%) and control (45%, P = 1.0) subjects. Serum creatinine reduction in the first week after transplantation, and graft function up to 180-days post-transplant, were also similar. Ecu administration was safe but did not reduce the rate of DGF in a high-risk population of deceased donor recipients.

Analysis of Biomarkers Within the Initial 2 Years Posttransplant and 5-Year Kidney Transplant Outcomes: Results From Clinical Trials in Organ Transplantation-17.

BACKGROUND: An early posttransplant biomarker/surrogate marker for kidney allograft loss has the potential to guide targeted interventions. Previously published findings, including results from the Clinical Trials in Organ Transplantation (CTOT)-01 study, showed that elevated urinary chemokine CXCL9 levels and elevated frequencies of donor-reactive interferon gamma (IFNγ)-producing T cells by enzyme-linked immunosorbent spot (ELISPOT) assay associated with acute cellular rejection within the first year and with lower 1-year posttransplant estimated glomerular filtration rate (eGFR). How well these biomarkers correlate with late outcomes, including graft loss, is unclear. METHODS: In CTOT-17, we obtained 5-year outcomes in the CTOT-01 cohort and correlated them with (a) biomarker results and (b) changes in eGFR (Chronic Kidney Disease Epidemiology Collaboration formula) over the initial 2 years posttransplant using univariable analysis and multivariable logistic regression. RESULTS: Graft loss occurred in 14 (7.6%) of 184 subjects 2 to 5 years posttransplant. Neither IFNγ ELISPOTs nor urinary CXCL9 were informative. In contrast, a 40% or greater decline in eGFR from 6 months to 2 years posttransplant independently correlated with 13-fold odds of 5-year graft loss (adjusted odds ratio, 13.1; 95% confidence interval, 3.0-56.6), a result that was validated in the independent Genomics of Chronic Allograft Rejection cohort (n = 165; adjusted odds ratio, 11.2). CONCLUSIONS: We conclude that although pretransplant and early posttransplant ELISPOT and chemokine measurements associate with outcomes within 2 years posttransplant, changes in eGFR between 3 or 6 months and 24 months are better surrogates for 5-year outcomes, including graft loss.

Costimulatory Blockade and Use of Mammalian Target of Rapamycin Inhibitors: Avoiding Injury Part 1.

Although calcineurin inhibitor drugs have been the mostly used therapy in modern immunosuppression in kidney transplantation, their effect on kidney allograft dysfunction has been suboptimal as far as preservation of kidney function is concerned. Additionally, there are metabolic and other nonmetabolic effects including increased risk of malignancy that has necessitated the use of mammalian target of rapamycin inhibitors to reduce exposure to calcineurin inhibitors. Mammalian target of rapamycin inhibitors, both sirolimus and everolimus, have been studied in several trials to facilitate preservation of kidney function with variable effects on kidney allograft function and immunogenicity. Preservation of kidney function is increasingly becoming the mainstay of immunosuppression not only in kidney transplantation, but also in extrakidney transplantation. The best kidney outcomes have been reported in calcineurin inhibitor withdrawal studies using mammalian target of rapamycin inhibitors, in kidney transplant recipients with stable kidney function. This review article summarizes data from several studies in which mammalian target of rapamycin inhibitors have been used to reduce exposure to or withdraw calcineurin inhibitors in an attempt to preserve kidney function.

Adverse Outcomes of Tacrolimus Withdrawal in Immune-Quiescent Kidney Transplant Recipients.

Concerns about adverse effects of calcineurin inhibitors (CNIs) have prompted development of protocols that minimize their use. Whereas previous CNI withdrawal trials in heterogeneous cohorts showed unacceptable rates of acute rejection (AR), we hypothesized that we could identify individuals capable of tolerating CNI withdrawal by targeting immunologically quiescent kidney transplant recipients. The Clinical Trials in Organ Transplantation-09 Trial was a randomized, prospective study of nonsensitized primary recipients of living donor kidney transplants. Subjects received rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil, and prednisone. Six months post-transplantation, subjects without de novo donor-specific antibodies (DSAs), AR, or inflammation at protocol biopsy were randomized to wean off or remain on tacrolimus. The intended primary end point was the change in interstitial fibrosis/tubular atrophy score between implantation and 24-month protocol biopsies. Serially collected urine CXCL9 ELISA results were correlated with outcomes. The study was terminated prematurely because of unacceptable rates of AR (4 of 14) and/or de novo DSAs (5 of 14) in the tacrolimus withdrawal arm. Positive urinary CXCL9 predated clinical detection of AR by a median of 15 days. Analyses showed that >16 HLA-DQ epitope mismatches and pretransplant, peripheral blood, donor-reactive IFN-γ ELISPOT assay results correlated with development of DSAs and/or AR on tacrolimus withdrawal. Although data indicate that urinary CXCL9 monitoring, epitope mismatches, and ELISPOT assays are potentially informative, complete CNI withdrawal must be strongly discouraged in kidney transplant recipients who are receiving standard-of-care immunosuppression, including those who are deemed to be immunologically quiescent on the basis of current clinical and laboratory criteria.

Fever, infection, and rejection after kidney transplant failure.

BACKGROUND: Patients returning to dialysis therapy after renal transplant failure have high morbidity and retransplant rates. After observing frequent hospitalizations with fever after failure, it was hypothesized that maintaining immunosuppression for the failed allograft increases the risk of infection, while weaning immunosuppression can lead to symptomatic rejection mimicking infection. METHODS: One hundred eighty-six patients with failed kidney transplants were analyzed for rates of hospitalization with fever within 6 months of allograft failure. Patients were stratified by the presence of full immunosuppression versus minimal (low-dose prednisone) or no immunosuppression, before hospital admission. Subsequent rates of documented infection and nephrectomy, as well as patient survival, were ascertained. RESULTS: Hospitalization with fever within 6 months of allograft failure was common, occurring in 44% of patients overall. However, among febrile hospitalized patients who had been weaned off of immunosuppression before admission, only 38% had documented infection. In contrast, 88% of patients maintained on immunosuppression had documented infection (P<0.001). In both groups, dialysis catheter-related infections were the most common infection source. Allograft nephrectomy was performed in 81% of hospitalized patients with no infection, compared to 30% of patients with documented infection (P<0.001). Mortality risk was significantly higher in patients with concurrent pancreas transplants or who were hospitalized with documented infection. CONCLUSIONS: Maintenance immunosuppression after kidney allograft failure was associated with a greater incidence of infection, while weaning of immunosuppression commonly resulted in symptomatic rejection with fever mimicking infection on presentation. Management of the failed allograft should include planning to avoid both infection and sensitizing events.

Urinary-cell mRNA profile and acute cellular rejection in kidney allografts.

BACKGROUND: The standard test for the diagnosis of acute rejection in kidney transplants is the renal biopsy. Noninvasive tests would be preferable. METHODS: We prospectively collected 4300 urine specimens from 485 kidney-graft recipients from day 3 through month 12 after transplantation. Messenger RNA (mRNA) levels were measured in urinary cells and correlated with allograft-rejection status with the use of logistic regression. RESULTS: A three-gene signature of 18S ribosomal (rRNA)-normalized measures of CD3ε mRNA and interferon-inducible protein 10 (IP-10) mRNA, and 18S rRNA discriminated between biopsy specimens showing acute cellular rejection and those not showing rejection (area under the curve [AUC], 0.85; 95% confidence interval [CI], 0.78 to 0.91; P<0.001 by receiver-operating-characteristic curve analysis). The cross-validation estimate of the AUC was 0.83 by bootstrap resampling, and the Hosmer-Lemeshow test indicated good fit (P=0.77). In an external-validation data set, the AUC was 0.74 (95% CI, 0.61 to 0.86; P<0.001) and did not differ significantly from the AUC in our primary data set (P=0.13). The signature distinguished acute cellular rejection from acute antibody-mediated rejection and borderline rejection (AUC, 0.78; 95% CI, 0.68 to 0.89; P<0.001). It also distinguished patients who received anti-interleukin-2 receptor antibodies from those who received T-cell-depleting antibodies (P<0.001) and was diagnostic of acute cellular rejection in both groups. Urinary tract infection did not affect the signature (P=0.69). The average trajectory of the signature in repeated urine samples remained below the diagnostic threshold for acute cellular rejection in the group of patients with no rejection, but in the group with rejection, there was a sharp rise during the weeks before the biopsy showing rejection (P<0.001). CONCLUSIONS: A molecular signature of CD3ε mRNA, IP-10 mRNA, and 18S rRNA levels in urinary cells appears to be diagnostic and prognostic of acute cellular rejection in kidney allografts. (Funded by the National Institutes of Health and others.).

Effects of cellular sensitization and donor age on acute rejection and graft function after deceased-donor kidney transplantation.

BACKGROUND: Allografts from older donors may be more immunogenic than those from younger donors. Pretransplantation cellular sensitization may interact with advanced donor age to increase the risk of immune injury after deceased-donor kidney transplantation. METHODS: The outcomes of 118 consecutive deceased-donor kidney transplant recipients with available pretransplantation donor-stimulated enzyme-linked immunosorbent spot (ELISPOT) assays for interferon gamma were analyzed retrospectively to determine the impact of cellular sensitization and other clinical variables, including donor age, on the incidence of acute rejection (AR) in the first year after deceased-donor transplantation and on estimated glomerular filtration rate 12 months after transplantation. RESULTS: The incidence of AR was higher in patients with positive pretransplantation ELISPOT assays versus those with negative assays (36% vs. 14%, P=0.009). Logistic regression indicated that the combination of donor age 50 years or older and a positive pretransplantation ELISPOT assay was more strongly associated with AR (odds ratio, 12.1; confidence interval, 1.1-133) than either variable alone. Estimated glomerular filtration 12 months after transplantation was highest in ELISPOT-negative patients receiving kidneys from donors younger than 50 years and lowest in ELISPOT-positive recipients with donors 50 years or older. CONCLUSION: The combination of advanced donor age and pretransplantation cellular sensitization increases the risk of AR and poor graft function after deceased-donor kidney transplantation beyond the risk associated with each factor alone.

Independent of nephrectomy, weaning immunosuppression leads to late sensitization after kidney transplant failure.

BACKGROUND: Patients returning to dialysis therapy after renal transplant failure have a high rate of human leukocyte antigen antibody sensitization, and sensitization has been linked to allograft nephrectomy. We hypothesized that nephrectomy for cause is a consequence of weaning immunosuppression and that weaning leads to sensitization even in the absence of nephrectomy. METHODS: We examined outcomes in 300 consecutive patients with kidney allograft failure and survival of more than 30 days after failure. We analyzed a subset of 119 patients with a low panel reactive antibody (PRA) before transplantation and follow-up PRA testing at 6 to 24 months after failure (late PRA). RESULTS: By late PRA testing, 56% of patients were highly sensitized (class I or II PRA ≥80%). On multivariate analysis controlling for human leukocyte antigen matching, allograft nephrectomy, and other variables, weaning of immunosuppression predicted high sensitization (odds ratio, 14.34; P=0.004). In a subset of patients, the percentage of those who were highly sensitized increased from 21% at the time of failure on immunosuppressive therapy to 68% by late PRA after weaning (P<0.001). Conversely, patients who maintained immunosuppression showed minimal sensitization after failure. Transplant nephrectomy was required in 41% of patients who weaned immunosuppression versus 0% of the 24 patients who maintained immunosuppression with calcineurin inhibitor therapy after failure (P<0.001). CONCLUSIONS: Weaning immunosuppression was a triggering event leading to late rejection and allograft nephrectomy and was an independent predictor of alloantibody sensitization after kidney allograft failure.

Impact of navigators on completion of steps in the kidney transplant process: a randomized, controlled trial.

BACKGROUND AND OBJECTIVES: Many patients with ESRD, particularly minorities and women, face barriers in completing the steps required to obtain a transplant. These eight sequential steps are as follows: medical suitability, interest in transplant, referral to a transplant center, first visit to center, transplant workup, successful candidate, waiting list or identify living donor, and receive transplant. This study sought to determine the effect of navigators on completion of steps. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Cluster randomized, controlled trial at 23 Ohio hemodialysis facilities. One hundred sixty-seven patients were recruited between January 2009 and August 2009 and were followed for up to 24 months or until study end in February 2011. Trained kidney transplant recipients met monthly with intervention participants (n=92), determined their step in the transplant process, and provided tailored information and assistance in completing the step. Control participants (n=75) continued to receive usual care. The primary outcome was the number of transplant process steps completed. RESULTS: Starting step did not significantly differ between the two groups. By the end of the trial, intervention participants completed more than twice as many steps as control participants (3.5 versus 1.6 steps; difference, 1.9 steps; 95% confidence interval, 1.3-2.5 steps). The effect of the intervention on step completion was similar across race and sex subgroups. CONCLUSIONS: Use of trained transplant recipients as navigators resulted in increased completion of transplant process steps.

T-cell immune monitoring by the ELISPOT assay for interferon gamma.

The enzyme-linked immunosorbent spot (ELISPOT) assay for interferon gamma has been available for more than twenty years and has been used for a number of applications, including the monitoring of T cell immunity in solid organ transplant recipients. Studies from single centers indicate that heightened T cell alloreactivity measured with this assay correlates with acute and chronic rejection and with poor long-term allograft function. The assay has been used not only to assess T cell reactivity after transplantation, but also as a tool for assessing immune risk prior to transplantation. Additional work is needed to validate the assay in larger multicenter clinical trials.

Nephrology quiz and questionnaire: transplantation.

Presentation of the Nephrology Quiz and Questionnaire (NQQ) has become an annual "tradition" at the meetings of the American Society of Nephrology. It is a very popular session judged by consistently large attendance. Members of the audience test their knowledge and judgment on a series of case-oriented questions prepared and discussed by experts. They can also compare their answers in real time, using audience response devices, to those of program directors of nephrology training programs in the United States, acquired through an Internet-based questionnaire. Topics presented here include transplantation issues. These cases, along with single best answer questions, were prepared by Dr. Hricik. After the audience responses, the "correct" and "incorrect" answers were then briefly discussed and the results of the questionnaire were displayed. This article aims to recapitulate the session and reproduce its educational value for a larger audience-that of the readers of the Clinical Journal of the American Society of Nephrology. Have fun.

Immune factors influencing ethnic disparities in kidney transplantation outcomes.

An influence of ethnicity on the outcomes of kidney transplant recipients has been recognized for several decades. Both immune and nonimmune factors have been explored as potential explanations. Most studies have focused on the inferior outcomes of African-Americans. As a group, African-Americans differ from Caucasians with respect to a number of measurable components of the alloimmune response, including the T-cell repertoire and the expression and function of costimulatory molecules and various cytokines and chemokines. In general, these differences suggest that African-Americans may be high immune responders. However, no single difference in any of these components of alloimmunity satisfactorily explains the disparities in outcomes. It seems probable that some combination of immune factors interacts with nonimmune factors, such as socioeconomic resources, to influence transplant outcomes in a complex manner.