Comparing the prognostic performance of iBOX and biopsy-proven acute rejection for long-term kidney graft survival.

Biopsy-proven acute rejection (BPAR) occurs in approximately 10% of kidney transplant recipients in the first year, making superiority trials unfeasible. iBOX, a quantitative composite of estimated glomerular filtration rate, proteinuria, antihuman leukocyte antigen donor-specific antibody, and + full/- abbreviated kidney histopathology, is a new proposed surrogate endpoint. BPAR's prognostic ability was compared with iBOX in a pooled cohort of 1534 kidney transplant recipients from 4 data sets, including 2 prospective randomized controlled trials. Discrimination analyses showed mean c-statistic differences between both iBOX compared with BPAR of 0.25 (95% confidence interval: 0.17-0.32) for full iBOX and 0.24 (95% confidence interval: 0.16-0.32) for abbreviated iBOX, indicating statistically significantly higher c-statistic values for the iBOX prognosis of death-censored graft survival. Mean (± standard error) c-statistics were 0.81 ± 0.03 for full iBOX, 0.80 ± 0.03 for abbreviated iBOX, and 0.57 ± 0.03 for BPAR. In calibration analyses, predicted graft loss events from both iBOX models were not significantly different from those observed. However, for BPAR, the predicted events were significantly (P < .01) different (observed: 64; predicted: 70; full iBOX: 76; abbreviated iBOX: 173 BPAR). IBOX at 1-year posttransplant is superior to BPAR in the first year posttransplant in graft loss prognostic performance, providing valuable additional information and facilitating the demonstration of superiority of novel immunosuppressive regimens.

Qualifying a Novel Clinical Trial Endpoint (iBOX) Predictive of Long-Term Kidney Transplant Outcomes.

New immunosuppressive therapies that improve long-term graft survival are needed in kidney transplant. Critical Path Institute's Transplant Therapeutics Consortium received a qualification opinion for the iBOX Scoring System as a novel secondary efficacy endpoint for kidney transplant clinical trials through European Medicines Agency's qualification of novel methodologies for drug development. This is the first qualified endpoint for any transplant indication and is now available for use in kidney transplant clinical trials. Although the current efficacy failure endpoint has typically shown the noninferiority of therapeutic regimens, the iBOX Scoring System can be used to demonstrate the superiority of a new immunosuppressive therapy compared to the standard of care from 6 months to 24 months posttransplant in pivotal or exploratory drug therapeutic studies.

Qualifying a novel clinical trial endpoint (iBOX) predictive of long-term kidney transplant outcomes.

New immunosuppressive therapies that improve long-term graft survival are needed in kidney transplant. Critical Path Institute's Transplant Therapeutics Consortium received a qualification opinion for the iBOX Scoring System as a novel secondary efficacy endpoint for kidney transplant clinical trials through European Medicines Agency's qualification of novel methodologies for drug development. This is the first qualified endpoint for any transplant indication and is now available for use in kidney transplant clinical trials. Although the current efficacy failure endpoint has typically shown the noninferiority of therapeutic regimens, the iBOX Scoring System can be used to demonstrate the superiority of a new immunosuppressive therapy compared to the standard of care from 6 months to 24 months posttransplant in pivotal or exploratory drug therapeutic studies.

Belatacept and Long-Term Outcomes in Kidney Transplantation.

BACKGROUND: In previous analyses of BENEFIT, a phase 3 study, belatacept-based immunosuppression, as compared with cyclosporine-based immunosuppression, was associated with similar patient and graft survival and significantly improved renal function in kidney-transplant recipients. Here we present the final results from this study. METHODS: We randomly assigned kidney-transplant recipients to a more-intensive belatacept regimen, a less-intensive belatacept regimen, or a cyclosporine regimen. Efficacy and safety outcomes for all patients who underwent randomization and transplantation were analyzed at year 7 (month 84). RESULTS: A total of 666 participants were randomly assigned to a study group and underwent transplantation. Of the 660 patients who were treated, 153 of the 219 patients treated with the more-intensive belatacept regimen, 163 of the 226 treated with the less-intensive belatacept regimen, and 131 of the 215 treated with the cyclosporine regimen were followed for the full 84-month period; all available data were used in the analysis. A 43% reduction in the risk of death or graft loss was observed for both the more-intensive and the less-intensive belatacept regimens as compared with the cyclosporine regimen (hazard ratio with the more-intensive regimen, 0.57; 95% confidence interval [CI], 0.35 to 0.95; P=0.02; hazard ratio with the less-intensive regimen, 0.57; 95% CI, 0.35 to 0.94; P=0.02), with equal contributions from the lower rates of death and graft loss. The mean estimated glomerular filtration rate (eGFR) increased over the 7-year period with both belatacept regimens but declined with the cyclosporine regimen. The cumulative frequencies of serious adverse events at month 84 were similar across treatment groups. CONCLUSIONS: Seven years after transplantation, patient and graft survival and the mean eGFR were significantly higher with belatacept (both the more-intensive regimen and the less-intensive regimen) than with cyclosporine. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00256750.).

Across all solid organs, adolescent age recipients have worse transplant organ survival than younger age children: A US national registry analysis.

Univariate analyses suggest that adolescents have worse long-term allograft survival versus younger children across different SOT. This study's objective was to determine whether multivariate analyses of a large national database recording all deceased SOT (KI; LI; HR; LU) also show worse adolescent allograft survival in the different organs. Using data from the national Scientific Registry for Transplant Recipients in the USA for pediatric primary SOT from 1989 to 2010, we calculated median half-lives and constructed K-M graft survival curves. Recipient age at transplant (<12 or adolescent 12-17 yr) was fitted with other identical covariates into multivariate Cox proportional hazards models. In all SOT recipients, unadjusted graft survival curves demonstrated better graft survival for adolescents initially, followed by crossing of the lines, such that adolescent SOT recipients had worse survival after one yr (KI), 4.6 yr (LI), 4.4 yr (HR), and 1.6 yr (LU). Multivariate models of the post-cross period showed a significantly higher AHR for worse graft survival in adolescent age across all four SOTs: AHR 1.400 (KI), 1.958 (LI), 1.414 (HR), and 1.576 (LU). Improving adolescent long-term outcomes across all four organs will be a defining issue in the future.

Lack of significant improvements in long-term allograft survival in pediatric solid organ transplantation: A US national registry analysis.

Improvements across many facets of transplantation have led to better 1-yr outcomes of transplanted organs. In this study, we assessed whether longer-term attrition rates improved in pediatric kidney (KI), liver (LI), heart (HR) and lung (LU) transplant (TX) survival. We analyzed data between 1989 and 2008 from 5747 KI, 7348 LI, 5103 HR, and 715 LU TXs (under 18 yr of age at transplant, first solitary transplant only), from the National Scientific Registry of Transplant Recipients database in the USA. Kaplan-Meier (K-M) or ordinary least square (OLS) estimates were used to calculate median and projected survival half-lives. Attrition rates, defined as percent failing within a given time period, were stratified by year of TX. Median half-lives from 1989 TX year to 2005 TX year have shown a major improvement only in LI TX, remaining unchanged in HR and KI TX, or remaining very low in LU TX. All four organ TX types have shown a dramatic drop in first-year attrition rates from 1989 to 2008. However, longer-term attrition rates (1-3, 3-5, 5-10 yr) have remained largely unchanged for all four organ TX types. Further progress in long-term survival will need targeting end-points beyond first-year rejection and survival rates.

Prolonged immunosuppression preserves nonsensitization status after kidney transplant failure.

BACKGROUND: When kidney transplants fail, transplant medications are discontinued to reduce immunosuppression-related risks. However, retransplant candidates are at risk for allosensitization which prolonging immunosuppression may minimize. We hypothesized that for these patients, a prolonged immunosuppression withdrawal after graft failure preserves nonsensitization status (PRA 0%) better than early immunosuppression withdrawal. METHODS: We retrospectively examined subjects transplanted at a single center between July 1, 1999 and December 1, 2009 with a non-death-related graft loss. Subjects were stratified by timing of immunosuppression withdrawal after graft loss: early (≤3 months) or prolonged (>3 months). Retransplant candidates were eligible for the main study where the primary outcome was nonsensitization at retransplant evaluation. Non-retransplant candidates were included in the safety analysis only. RESULTS: We found 102 subjects with non-death-related graft loss of which 49 were eligible for the main study. Nonsensitization rates at retransplant evaluation were 30% and 66% for the early and prolonged immunosuppression withdrawal groups, respectively (P=0.01). After adjusting for cofactors such as blood transfusion and allograft nephrectomy, prolonged immunosuppression withdrawal remained significantly associated with nonsensitization (adjusted odds ratio=5.78, 95% CI [1.37-24.44]). No adverse safety signals were seen in the prolonged immunosuppression withdrawal group compared to the early immunosuppression withdrawal group. CONCLUSIONS: These results suggest that prolonged immunosuppression may be a safe strategy to minimize sensitization in retransplant candidates and provide the basis for larger or prospective studies for further verification.

Clinical characteristics and outcomes in 303 HIV-infected patients with invasive fungal infections: data from the Prospective Antifungal Therapy Alliance registry, a multicenter, observational study.

This analysis aimed to characterize the epidemiology, diagnosis, treatment, and outcomes of invasive fungal infections (IFIs) in patients with human immunodeficiency virus (HIV). Data were examined for HIV patients enrolled in the Prospective Antifungal Therapy (PATH) Alliance registry, a multicenter, observational study of patients with IFIs in North America from 2004 to 2008. Patient demographics, clinical characteristics, comorbidities, antifungal therapies, and survival were assessed. In total, 320 fungal isolates were identified from 303 HIV patients with IFIs in the PATH Alliance® registry. These included Cryptococcus (50.0%), Candida (33.1%), Histoplasma (9.1%), and Aspergillus (4.4%). Candida infection occurred mainly as candidemia (86.0%); Cryptococcus as central nervous system infection (76.7%); Histoplasma as disseminated infection (74.1%); and Aspergillus as pulmonary infection (81.8%). The CD4 cell count was ≤200 cells/µL in 91.2% of patients with available data. The majority of patients with Cryptococcus (77.9%), Histoplasma (100.0%), and Aspergillus (71.4%) infections had CD4 cell counts <50 cells/µL compared with 48.9% of patients with Candida infections. Patients with candidiasis were more likely to have other conditions requiring medical services compared with patients with other IFIs. Survival probability was lower in patients with Aspergillus (0.58) and Candida (0.59) infection than in patients with Histoplasma (0.84) and Cryptococcus (0.81) infection. In the highly active antiretroviral therapy era, traditional opportunistic IFIs such as cryptococcosis and histoplasmosis still mainly occur in HIV patients with CD4 counts <50 cells/µL. Fungal infections remain a clinical challenge in HIV patients with severe immunosuppression. Our data also suggest that HIV patients with CD4 cell counts >200 cells/µL and other underlying conditions may be susceptible to invasive candidiasis.

Long-term follow-up of a phase III clinical trial comparing tacrolimus extended-release/MMF, tacrolimus/MMF, and cyclosporine/MMF in de novo kidney transplant recipients.

BACKGROUND: In a phase III, open-label, comparative, noninferiority study, 638 subjects receiving de novo kidney transplants were randomized to one of three treatment arms: tacrolimus extended-release (Astagraf XL) qd, tacrolimus (Prograf) bid, or cyclosporine (CsA) bid. All subjects received basiliximab induction, mycophenolate mofetil, and corticosteroids. Safety and efficacy follow-up data through 4 years are reported. METHODS: Evaluations included patient and graft survival, study drug discontinuations, laboratory values including renal function and development of new-onset diabetes after transplantation, concomitant medications, and adverse events. RESULTS: At study termination, 129 Astagraf XL, 113 Prograf, and 79 CsA patients had continued follow-up. Demographic and baseline characteristics were similar in all arms. Four-year Kaplan-Meier estimates of patient survival in the Astagraf XL, Prograf, and CsA groups were 93.2, 91.2, and 91.7%, respectively, while graft survival was 84.7, 82.7, and 83.9%, respectively. At least one serious adverse event was reported in the majority of patients in each group during the study (65.9% Astagraf XL, 69.8% Prograf, and 65.6% CsA). Renal function was not significantly different between Astagraf XL and Prograf. HgbA1c levels were collected every 6 months; the 4-year Kaplan-Meier estimate for incidence of HgbA1c levels ≥ 6.5% was significantly higher for both tacrolimus formulations compared to CsA; 41.1% (Astagraf XL), 33.6% (Prograf), and 21.3% (CsA). CONCLUSIONS: In this 4-year follow-up report, patients receiving Astagraf XL and Prograf showed comparable efficacy and safety profiles, with a higher incidence of new-onset diabetes after transplantation but superior renal function compared to patients receiving CsA.

Obesity and kidney transplantation.

Obesity confers increased risk for graft loss and death among renal transplant recipients. However the relationship of changes in body weight and composition to outcome on the transplant waitlist and post-transplantation is not straightforward. Strategies to manage weight in the waitlisted patient and after kidney transplantation must be performed in the context of a multidisciplinary approach and individualized based on risk factors in particular patients. Although retrospective studies offer considerable insights into the relationship between obesity and kidney transplant outcome, causal inferences must be made with great caution.

Best allograft survival from share-35 kidney donors occurs in middle-aged adults and young children-an analysis of OPTN data.

BACKGROUND: On October 2005, the Organ Procurement and Transplant Network implemented a new allocation policy for kidney transplants (KTX) from deceased donors (DD) ages <35 years to increase an access to transplantation from young donors for pediatric (ages <18 years) recipients, which is known as Share-35 (S35). However, many of these kidneys were allocated to adult recipients. The intent of this study was to analyze the graft outcomes from S35 kidneys in pediatric and adult recipients, stratified further by recipient age, to assess if recipient age affects the outcome from these presumably ideal kidneys. METHODS: The Organ Procurement and Transplant Network database from October 2005 to November 2010 involving 18,461 S35-KTX was used to calculate cumulative graft survival (CGS), death-censored graft survival, and patient survival using Kaplan-Meier estimates. The differences between survival curves were tested for significance by log-rank method after adjusting for various donor, recipient, and transplant-associated variables. RESULTS: With S35 implementation, children received a higher proportion of DD ages <35 years. Within the pediatric age group, adolescents (ages 13-17 years) had the worst CGS. Among adults, the highest CGS was obtained in middle-aged adults, whereas young adults (ages 18-25 years) showed worse CGS. CGS in young children (ages <12 years) was comparable with those in middle-aged adults. In older adults (ages >55 years), CGS was lowered by higher patient death rates. CONCLUSIONS: Recipient age affects allograft survival from high-quality young DD kidneys, such as S35 kidneys. Best survival occurs in middle-aged adults and in children ages <12 years, whereas adolescents and young adults do not derive an optimal benefit.

Epidemiology and outcomes of candidemia in 3648 patients: data from the Prospective Antifungal Therapy (PATH Alliance®) registry, 2004-2008.

This analysis describes the epidemiology and outcomes of candidemia in patients enrolled in the Prospective Antifungal Therapy Alliance (PATH Alliance®) registry from 2004 to 2008. Overall, 4067 Candida isolates were identified from 3648 patients. The most common Candida spp. were C. albicans (42.1%), C. glabrata (26.7%), C. parapsilosis (15.9%), C. tropicalis (8.7%), and C. krusei (3.4%). The proportion of candidemia caused by non-albicans Candida spp. (57.9%) was higher than that caused by C. albicans (42.1%). Infections with C. albicans were most common in neonatal intensive care unit (54.8%). In total, 3342 patients received antifungal therapy; fluconazole (66.0%) and echinocandins (50.5%) were most frequently administered. The 90-day survival rate for all patients was 61.3%. Among the most common Candida spp., the highest 90-day survival rate was observed for C. parapsilosis (70.0%) and the lowest for C. krusei (53.6%). In conclusion, this study expands the current knowledge of the epidemiology and outcomes of candidemia.

Clinical epidemiology of 960 patients with invasive aspergillosis from the PATH Alliance registry.

OBJECTIVES: The study investigated the epidemiology and outcome of invasive aspergillosis (IA), an important cause of morbidity and mortality in immunocompromised patients. METHODS: Cases of proven/probable IA from the Prospective Antifungal Therapy Alliance (PATH Alliance(®)) registry - a prospective surveillance network comprising 25 centers in the United States and Canada that collected data on invasive fungal infections from 2004 to 2008 - were analyzed with respect to clinical outcome. RESULTS: Nine hundred and sixty patients with IA were enrolled, the most frequent underlying disease being hematologic malignancy (n=464 [48.3%]). Two hundred and eighty patients (29.2%) received solid organ transplant; 268 patients (27.9%) underwent hematopoietic stem cell transplantation. Identified isolates included Aspergillus fumigatus (72.6%), Aspergillus flavus (9.9%), Aspergillus niger (8.7%) and Aspergillus terreus (4.3%). The lung was most frequently affected. Following diagnosis, 47% patients received monotherapy - voriconazole (70%), an amphotericin B formulation (13.8%), or an echinocandin (10.5%) - while 279 patients (29%) received combination therapy. Twelve-week overall survival was 64.4%. CONCLUSIONS: In this series of patients with IA, the lung was the predominant focus of infection, A. fumigatus was the major species isolated, and overall survival appeared slightly improved compared with previous reports.

The PATH (Prospective Antifungal Therapy) Alliance® registry and invasive fungal infections: update 2012.

The Prospective Antifungal Therapy Alliance (PATH Alliance®) performed prospective surveillance of invasive fungal infections (IFIs) among patients hospitalized at 25 medical centers in North America between 2004 and 2008, collecting information on the epidemiology, diagnosis, treatment, and mortality rates of IFIs. In total, 7526 IFIs were identified in 6845 patients. Candida spp. (73.4%) were the most common pathogens, followed by Aspergillus spp. (13.3%), and other yeasts (6.2%). Culture was the most frequently used diagnostic test in the majority of IFI categories. Most patients with invasive candidiasis were treated with fluconazole (48.3%) and the echinocandins (34.0%), while voriconazole (45.5%) was the main antifungal agent for invasive aspergillosis. The 12-week survival rate ranged from 37.5% for hematopoietic stem cell transplant recipients to ~75.0% for those with HIV/AIDS. In summary, the findings of the PATH Alliance® registry provide a better understanding of the epidemiology of a vast variety and large numbers of IFIs.

Effect of different immunosuppressive regimens on the evolution of distinct metabolic parameters: evidence from the Symphony study.

BACKGROUND: The metabolic syndrome (MS) is an important risk factor for graft dysfunction and patient death after renal transplantation. The aim of this sub-analysis of the Symphony study was to assess the progression of the laboratory parameters associated with MS in the first year after transplantation. METHODS: Data collected from the Symphony study were used; 1645 patients were randomized to receive standard-dose cyclosporine (Stand-CsA), low-dose cyclosporine (Low-CsA), tacrolimus (Low-Tac) or sirolimus (Low-SRL), in addition to mycophenolate mofetil (MMF) and corticosteroids. Data were collected for levels and progression over the first year post-transplantation of systolic and diastolic blood pressure, uric acid, triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and fasting glucose levels by treatment arm. RESULTS: The low-SRL group had significantly higher levels of triglycerides and LDL. The two CsA arms were associated with the highest uric acid levels at each time point. There were no significant differences in overall levels or changes in glucose or HDL. Patients in the standard-CsA arm had significantly higher diastolic blood pressure than those in the Low-SRL and Low-Tac arms. Systolic blood pressure was higher in the Low-CsA arm than in the Low-Tac arm. The use of antihypertensive and antidiabetic agents was similar between the treatment arms. In the Low-SRL arm, more patients were treated with lipid-lowering therapy. Mean daily steroid doses were the highest in the Low-SRL arm. CONCLUSIONS: This sub-analysis demonstrates that there is a difference in metabolic parameters between immunosuppressive groups. CsA therapy was associated with the highest values of uric acid and systolic and diastolic blood pressure. Patients on SRL therapy had the worst lipaemic control. A possible effect of Tac on new-onset diabetes could not be excluded.

Calcineurin inhibitors in kidney transplantation: friend or foe?

PURPOSE OF REVIEW: The utilization of calcineurin inhibitors (CNI) in kidney transplantation has dramatically improved short-term outcomes but significant gains in long-term outcomes have proved elusive. Nephrotoxicity is the major problem associated with CNIs and is responsible for the disappointing progress seen in long-term graft survival. In this review, we assess CNI efficacy as well as the latest strategies employed to limit long-term CNI nephrotoxicity. RECENT FINDINGS: Three CNI sparing strategies - CNI withdrawal, CNI avoidance, and CNI minimization - are evaluated with discussion of key studies such as the Efficacy Limiting Toxicity Elimination-Symphony and Spare-the-Nephron studies. Recent breakthroughs in transplant immunosuppression are discussed such as the BENEFIT and BENEFIT-EXT studies, which have led to the recent US Food and Drug Administratrion approval of belatacept, a novel T-cell costimulation blocker. SUMMARY: For now, CNIs remain the proven standard of care in modern immunosuppression. However, some novel agents may challenge the role CNIs play in kidney transplantation in the very near future.

Barriers to evaluation and wait listing for kidney transplantation.

BACKGROUND AND OBJECTIVES: Many factors have been shown to be associated with ESRD patient placement on the waiting list and receipt of kidney transplantation. Our study aim was to evaluate factors and assess the interplay of patient characteristics associated with progression to transplantation in a large cohort of referred patients from a single institution. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We examined 3029 consecutive adult patients referred for transplantation from 2003 to 2008. Uni- and multivariable logistic models were used to assess factors associated with progress to transplantation including receipt of evaluations, waiting list placement, and receipt of a transplant. RESULTS: A total of 56%, 27%, and 17% of referred patients were evaluated, were placed on the waiting list, and received a transplant over the study period, respectively. Older age, lower median income, and noncommercial insurance were associated with decreased likelihood to ascend steps to receive a transplant. There was no difference in the proportion of evaluations between African Americans (57%) and Caucasians (56%). Age-adjusted differences in waiting list placement by race were attenuated with further adjustment for income and insurance. There was no difference in the likelihood of waiting list placement between African Americans and Caucasians with commercial insurance. CONCLUSIONS: Race/ethnicity, age, insurance status, and income are predominant factors associated with patient progress to transplantation. Disparities by race/ethnicity may be largely explained by insurance status and income, potentially suggesting that variable insurance coverage exacerbates disparities in access to transplantation in the ESRD population, despite Medicare entitlement.

Mycophenolate mofetil initiation in renal transplant patients at different times posttransplantation: the TranCept Switch study.

BACKGROUND: Despite evidence of favorable long-term effects of mycophenolate mofetil (MMF) in renal transplantation, its introduction at different times posttransplant has not been studied in large cohorts. METHODS: Single-organ renal allograft recipients (n=2217) who had MMF introduced 6 months to more than 20 years posttransplantation for various reasons were included in TranCept Switch, a multicenter, noninterventional, observational 4-year study. Changes in renal function before and after the introduction of MMF were analyzed. RESULTS: MMF was introduced because of renal function decline in 43% of patients and poor tolerability with previous treatment in 23% of patients. The change in slope of the calculated glomerular filtration rate (modification of diet in renal diseases formula) regression line before and after MMF initiation was +2.01 mL/min per year (P<0.001) on average. The greatest benefit was noted in patients who received MMF because of renal function decline and in whom calcineurin inhibitor treatment was subsequently reduced or withdrawn (+3.09 mL/min per year). Time from transplantation to MMF introduction influenced the glomerular filtration rate at MMF initiation (slow progressive deterioration) but not the direction of the slope change, which was positive even for late introduction. CONCLUSION: MMF introduction may be associated with improvement or stabilization of renal function even several years after transplantation.