Long-term Outcome Of Kidney Transplantation Research Articles

Mesenchymal Stromal Cell Therapy for Solid Organ Transplantation.

Improvement of long-term outcome of kidney transplantation has reached its limits due to consequences of efficient, but nonspecific immunosuppressive drugs. Mesenchymal stromal cells (MSC) have been proposed as an alternative strategy for more refined therapy. The interest in MSCs comes from their anti-inflammatory properties on the one hand and their propensity to ameliorate tissue damage and mediate repair on the other hand. First clinical trials have demonstrated that administration of MSCs in kidney transplant recipients is safe and feasible, and follow-up studies have been initiated with the desired clinical efficacy to reduce ischemia-reperfusion injury, to prevent/reverse acute transplant rejection, and to improve long-term transplant survival with minimization of immunosuppression. To further promote wider application of MSC in renal transplantation, it is of importance to determine efficacy, to increase the understanding of the mechanism of action, and to develop tools to identify eligible patients. In addition, we should overcome challenges particularly at the transition of early phase I studies to more advanced stages of clinical development. In this review, latest insights, first clinical experiences, and future challenges of MSC in solid organ transplantation are discussed.

Long-term Outcomes of Kidney Transplantation in Patients With High Levels of Preformed DSA: The Necker High-Risk Transplant Program.

There is an increasing number of anti-HLA sensitized and highly sensitized renal transplant candidates on waiting lists, and the presence of donor-specific alloantibodies (DSAs) at the time of transplantation leads to acute and chronic antibody-mediated rejection (AMR). Acceptable short-term outcomes have been described, notably because of desensitization protocols, but mid- and long-term data are still required. Our high immunologic risk program included 95 patients with high peak or day 0 DSA levels (mean fluorescence intensity [MFI] > 3000) with a complement-dependent cytotoxicity-negative crossmatch, who received a posttransplant desensitization protocol starting at day 0 with high-dose intravenous immunoglobulin, plasma exchanges, and eventually rituximab. Their characteristics were compared with a control group including 39 patients with a lower immunologic risk (MFI between 500 and 3000 at day 0) who received the same posttransplant desensitization. The median MFI of the immunodominant class I or II DSA in the peak or day 0 serum was 9421 (interquartile range, 4959-12 610). An AMR occurred during the first posttransplant year in 31 patients (32.6%), and at one year, the rate of chronic AMR was 39.5%. The 1-, 3-, 5- and 7-year death-censored allograft survival rates were 98%, 91%, 86%, and 78%, respectively, with concomitant recipient survival rates of 97%, 93%, 85%, and 79%, respectively. These results suggest that DSA-sensitized patients with high MFI levels can receive transplantation across the HLA-barrier, with the use of an intensified posttransplant immunosuppressive therapy starting at day 0 combined with close clinical, immunologic, and histologic monitoring.

Role of Magnetic Resonance Elastography as a Noninvasive Measurement Tool of Fibrosis in a Renal Allograft: A Case Report

A major reason for poor long-term kidney transplant outcomes is the development of chronic allograft injury, characterized by interstitial fibrosis and tubular atrophy. Currently, an invasive biopsy that samples only <1% of the kidney is the gold standard for detecting kidney allograft fibrosis. We report the use of magnetic resonance elastography (MRE) to quantify tissue stiffness as a noninvasive and whole-kidney measurement tool of allograft fibrosis in a kidney transplant patient at 2 time points. The MRE whole-kidney stiffness values reflected the changes in fibrosis of the kidney allograft as assessed by histologic examination. To our knowledge, this technique is the first observation of change over time in MRE-derived whole-kidney stiffness in an allograft that is consistent with changes in histology-derived fibrosis scores in a single patient.

Impact of Hyperuricemia on Long-term Outcomes of Kidney Transplantation: Analysis of the FAVORIT Study

Elevated uric acid concentration is associated with higher rates of cardiovascular (CV) morbidity and mortality in the general population. It is not known whether hyperuricemia increases the risk for CV death or transplant failure in kidney transplant recipients. Post hoc cohort analysis of the FAVORIT Study, a randomized controlled trial that examined the effect of homocysteine-lowering vitamins on CV disease in kidney transplantation. Adult recipients of kidney transplants in the United States, Canada, or Brazil participating in the FAVORIT Study, with hyperhomocysteinemia, stable kidney function, and no known history of CV disease. Uric acid concentration. The primary end point was a composite of CV events. Secondary end points were all-cause mortality and transplant failure. Risk factors included in statistical models were age, sex, race, country, treatment assignment, smoking history, body mass index, presence of diabetes mellitus, history of CV disease, blood pressure, estimated glomerular filtration rate (eGFR), donor type, transplant vintage, lipid concentrations, albumin-creatinine ratio, and uric acid concentration. Cox proportional hazards models were fit to examine the association of uric acid concentration with study end points after risk adjustment. 3,512 of 4,110 FAVORIT participants with baseline uric acid concentrations were studied. Median follow-up was 3.9 (IQR, 3.0-5.3) years. 503 patients had a primary CV event, 401 died, and 287 had transplant failure. In unadjusted analyses, uric acid concentration was significantly related to each outcome. Uric acid concentration was also strongly associated with eGFR. The relationship between uric acid concentration and study end points was no longer significant in fully adjusted multivariable models (P=0.5 for CV events; P=0.09 for death, and P=0.1 for transplant failure). Unknown use of uric acid-lowering agents among study participants. Following kidney transplantation, uric acid concentrations are not independently associated with CV events, mortality, or transplant failure. The strong association between uric acid concentrations with traditional risk factors and eGFR is a possible explanation.

The effect of differing kidney disease treatment modalities and organ donation and transplantation practices on health expenditure and patient outcomes.

The Effect of Differing Kidney Disease Treatment Modalities and Organ Donation and Transplantation Practices on Health Expenditure and Patient Outcomes (EDITH) aims to obtain information on long-term kidney transplant outcomes, long-term health outcomes of living kidney donors and detailed outcomes and costs related to the different treatment modalities of end-stage kidney disease. Nine partners from seven European Union countries will participate in this project.

Long-term Clinical Outcomes of First and Second Kidney Transplantation in Patients With Biopsy-Proven IgA Nephropathy

IntroductionThe recurrence of IgA nephropathy (IgAN) after kidney transplantation (KT) has an effect on graft survival, but there are few reports about long-term clinical outcomes of KT with recurrent IgAN. This study shows the long-term clinical outcomes of KT in patients with IgAN. MethodsAll recipients who had biopsy-proven IgAN were followed from February 1990 to February 2016. We analyzed overall graft and patient survival rates, incidence of recurrent IgAN, factors affecting graft survival, and IgAN recurrence. ResultsThere were 88 patients with first KT. The mean follow-up duration was 82.5 months. Twenty patients went through graft loss and 1 patient died due to sepsis. IgAN recurred in 15 patients, and 11 patients experienced graft failure. Among the patients who had failed graft after first KT, 7 patients underwent retransplantation. The graft survival period, presence of rejection, and proteinuria were the relevant risk factors for recurrence of IgAN. In the first KT patients, presence of rejection and 1-year serum creatinine were the significant risk factors for graft loss. But recurrence of IgAN was not a relevant risk factor. Overall graft survival rates at 5 and 10 years were 93.8% and 73.1% in the first transplantation group and 100% and 100% in the retransplantation group, respectively. ConclusionAlthough IgAN recurrence was a significant risk factor for graft failure, the patient who underwent retransplantation showed favorable results. Retransplantation should be considered in patients who lost their first graft after recurrence of IgAN.

Graft Function and Intermediate-Term Outcomes of Kidney Transplants Improved in the Last Decade: Analysis of the United States Kidney Transplant Database.

Previous analyses of the United States transplant database regarding long-term outcomes in kidney transplantation have shown minimal improvement in the rate of long-term graft loss. This study sought to analyze intermediate-term outcomes and graft function at 6 months in kidney transplantation in adult living and deceased donor recipients in the last decade. Survival analysis was performed based on the year of transplant between 6 months and 3 years' posttransplant. The Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate (eGFR) was determined at 6 months. The unadjusted graft survival between 6 months and 3 years improved significantly in the latter half of the decade in both deceased and living donor kidney recipients. Cox analysis showed a 33% reduction in the rate of graft loss and that the improvement in graft survival was due to similar improvements in both death-censored graft and death with graft function survival. A 10% improvement in median eGFR occurred despite worsening donor demographics over time in both donor types. This improvement in eGFR and graft survival occurred in association with a consolidation of chronic discharge immunosuppression from a variety of combinations to over 85% of recipients receiving tacrolimus and mycophenolate derivative immunosuppression. In the latter half of last decade graft survival improved in adult kidney transplant recipients. The improvement in graft survival occurred in temporal association with an improvement in median eGFR at 6 months and consolidation of discharge immunosuppression in most patients to tacrolimus and mycophenolate derivatives.

Long-Term Outcomes of Kidney Transplantation From Expanded-Criteria Deceased Donors: A Single-Center Experience

BackgroundOrgan shortage has prompted the use of expanded-criteria donors (ECDs). Our objective was to compare long-term outcomes of kidney transplants from ECDs with those from concurrent standard-criteria donors (SCDs). In addition, we evaluated variables associated with graft survival in both groups. MethodsWe retrospectively reviewed all 617 deceased-donor kidney transplantations performed from 2005 to 2009 in our department. The population was divided according to donor status into ECD or SCD. Patients were followed until 5 years after transplantation, death, graft failure, or loss to follow-up. ResultsWe transplanted 150 deceased-donor kidneys from ECDs and 467 from SCDs. ECD were older, more frequently women, had a lower pre-retrieval glomerular filtration rate, and more frequently died due to cerebrovascular accident. ECD recipients were older, presented a lower proportion of black race, more frequently were on hemodialysis, and presented a higher rate of first kidney transplants. Mean glomerular filtration rate was consistently lower in the ECD group. Patient and graft survivals were lower in the ECD group, but statistical significance was present only in graft survival censored for death with a functioning graft at 3 years and graft survival noncensored for death with a functioning graft at 5 years. Younger recipient ages, longer time on dialysis, acute rejection episodes, and glomerular filtration rate at 1 year after transplantation were independent risk factors for lower graft survival. ConclusionsTransplantation with the use of ECD kidneys provide quite satisfactory patient and graft survival rates despite their poorer long-term outcomes.

Moving Biomarkers toward Clinical Implementation in Kidney Transplantation.

Long-term kidney transplant outcomes remain suboptimal, delineating an unmet medical need. Although current immunosuppressive therapy in kidney transplant recipients is effective, dosing is conventionally adjusted empirically on the basis of time after transplant or altered in response to detection of kidney dysfunction, histologic evidence of allograft damage, or infection. Such strategies tend to detect allograft rejection after significant injury has already occurred, fail to detect chronic subclinical inflammation that can negatively affect graft survival, and ignore specific risks and immune mechanisms that differentially contribute to allograft damage among transplant recipients. Assays and biomarkers that reliably quantify and/or predict the risk of allograft injury have the potential to overcome these deficits and thereby, aid clinicians in optimizing immunosuppressive regimens. Herein, we review the data on candidate biomarkers that we contend have the highest potential to become clinically useful surrogates in kidney transplant recipients, including functional T cell assays, urinary gene and protein assays, peripheral blood cell gene expression profiles, and allograft gene expression profiles. We identify barriers to clinical biomarker adoption in the transplant field and suggest strategies for moving biomarker-based individualization of transplant care from a research hypothesis to clinical implementation.

IMMUNE AND MORPHOLOGICAL PHENOTYPES OF KIDNEY ALLOGRAFT INJURY

Long-term outcome of kidney transplantation is limited by the development of allograft rejection due to activation and realization of Tand B-cell immune response as well as the effects of other types of immune reactions mediated by various mechanisms. This article is dedicated to nowadays point of view upon the different immune and morphological phenotypes of kidney transplant injury. Main focus is made on the pathways of microvascular inflammation in the case of donor-specific antibodies absence as the unique self-sustained phenotype of the kidney allograft injury.

Long-Term Outcomes in Kidney Transplantation From Expanded-Criteria Donors After Circulatory Death

The number of recipients waiting for a transplant is increasing. In Japan, there is more frequent use of organs from expanded-criteria donors (ECDs) after circulatory death. We retrospectively analyzed long-term outcomes of kidney transplantation (KT) from expanded-criteria donation after circulatory death (DCD). From 1995 to 2013, 97 cases of KT from DCD donors were performed in our department. Death-censored graft survival rates of ECD kidneys (n = 50) versus standard-criteria deceased-donor (SCD) kidneys (n = 47) for 1, 5, and 10 years after transplantation were 84.0% vs 97.9%, 74.8% vs 95.6%, and 70.2% vs 81.8%, respectively. No significant difference was found between the 2 groups (P = .102). Kidneys from donors with a history of hypertension (HTN) and cerebrovascular events (CVE) and contribution from older donors had significantly lower 10-year graft survival rates (P values of .010, .036, and .050, respectively). Cox proportional hazard regression analyses showed donor age to be significantly associated with long-term graft survival independently from other factors. These results suggest that ECD kidneys remain an acceptable alternative to dialysis under certain conditions. Increased donor age was a significant risk factor determining long-term graft function. Moreover, comorbidities of HTN and CVE could become significant risk factors, especially in older donors.

Long-term outcomes of kidney transplantation in people with type 2 diabetes: a population cohort study

Overall survival for younger patients with type 2 diabetes without kidney disease has improved substantially over time, but whether a similar pattern of improvement is observed in diabetic kidney transplant recipients remained uncertain. We aimed to compare patient outcomes between diabetic and non-diabetic transplant recipients, and to determine the effect of age and era on patient survival. This population cohort study included all primary kidney-only transplant recipients included in the Australia and New Zealand Dialysis and Transplant registry between Jan 1, 1994, and Dec 31, 2012. The primary outcomes were all-cause mortality and death with functioning graft. Associations between outcomes and diabetes status were examined using adjusted Cox regression, and interactions between diabetes status and transplant era and recipient age were examined. Of 10 714 transplant recipients, 985 (9%) had type 2 diabetes. Mortality rates in the first 10 years after transplantation were higher in recipients with diabetes (25·3 per 100 recipients) compared to those without diabetes (11·5 per 100 recipients). Compared with recipients without diabetes, the adjusted hazard ratios (HR) for all-cause mortality and death with a functioning graft in recipients with diabetes were 1·60 (95% CI 1·37-1·86; p<0·0001) and 1·54 (1·28-1·85 p<0·0001), respectively. The association between diabetes status, all-cause mortality, and death with a functioning graft was modified by recipient age (pinteraction<0·0001), with the highest risk in recipients with diabetes aged younger than 40 years (adjusted HR 5·16 [95% CI 2·84-9·35], p<0·0001; and 9·83 [4·51-21·43], p<0·0001; for all-cause mortality and death with a functioning graft, respectively). Risk was increased to a lesser extent in recipients with diabetes aged older than 55 years (adjusted HR 1·41 [95% CI 1·17-1·71; p=0·002] and 1·27 [1·02-1·59; p=0·03], for all-cause mortality and death with a functioning graft, respectively). Transplant era did not modify the association between diabetes status and mortality. Kidney transplant recipients with type 2 diabetes had substantially poorer patient survival, with 5-year mortality rates exceeding those for non-diabetic recipients by over two times. The magnitude of this survival disadvantage was greatest in recipients with diabetes aged less than 40 years. By contrast with the general population, there was no evidence of improvement in mortality over time among people with type 2 diabetes following kidney transplantation. None.

Long-Term Outcomes and Discard Rate of Kidneys by Decade of Extended Criteria Donor Age.

Extended criteria donors represent nowadays a main resource for kidney transplantation, and recovery criteria are becoming increasingly inclusive. However, the limits of this approach are not clear as well as the effects of extreme donor ages on long-term kidney transplantation outcomes. To address these issues, we performed a retrospective study on extended criteria donor kidney transplantation. In total, 647 consecutive extended criteria donor kidney transplantations performed over 11 years (2003-2013) were included. Donor, recipient, and procedural variables were classified according to donor age decades (group A, 50-59 years old [n=91]; group B, 60-69 years old [n=264]; group C, 70-79 years old [n=265]; and group D, ≥80 years old [n=27]). Organs were allocated in single- or dual-kidney transplantation after a multistep evaluation including clinical and histologic criteria. Long-term outcomes and main adverse events were analyzed among age groups and in either single- or dual-kidney transplantation. Kidney discard rate incidence and causes were evaluated. Median follow-up was 4.9 years (25th; 75th percentiles: 2.7; 7.6 years); patient and graft survival were comparable among age groups (5-year patient survival: group A, 87.8%; group B, 88.1%; group C, 88.0%; and group D, 90.1%; P=0.77; graft survival: group A, 74.0%; group B, 74.2%; group C, 75.2%; and group D, 65.9%; P=0.62) and between dual-kidney transplantation and single-kidney transplantation except for group D, with a better survival for dual-kidney transplantation (P=0.04). No difference was found analyzing complications incidence or graft function over time. Kidney discard rate was similar in groups A, B, and C (15.4%, 17.7%, and 20.1%, respectively) and increased in group D (48.2%; odds ratio, 5.1 with A as the reference group; 95% confidence interval, 2.96 to 8.79). Discard rate and long-term outcomes are similar among extended criteria donor kidney transplantation from donors ages 50-79 years old. Conversely, discard rate was strikingly higher among kidneys from octogenarian donors, but appropriate selection provides comparable long-term outcomes, with better graft survival for dual-kidney transplantation.

Mesenchymal stromal cells in clinical kidney transplantation

Progress in the improvement of short-term and long-term outcomes of kidney transplantation seems to have reached a plateau, partially due to consequences of very efficient, but nonspecific immunosuppressive drugs. In recent years, various forms of cell therapy, including the use of mesenchymal stromal cells, have been put forward as an alternative strategy for more defined therapy. It is thought that these therapies will not only allow controlled tapering of immunosuppressive medication, but might bring us also closer to the ambition of generating donor-specific immune regulation and tolerance. Different forms of alloimmunity, including direct, indirect and semi-direct alloantigen presentation have to be controlled before donor-specific immune regulation can be reached. Several mechanisms have been described how mesenchymal stromal cells can affect alloimmunity. Especially, the interaction with professional antigen presenting cells, like dendritic cells, is of critical importance. This review will discuss the current status of ongoing clinical trials with mesenchymal stromal cells in kidney transplantation and specifically concentrate on the possibilities and impossibilities of how these therapeutic strategies can contribute to control of the different forms of alloreactivity operation in organ transplantation.

Long-Term Outcome of Kidney Transplantation in Recipients with Focal Segmental Glomerulosclerosis.

FSGS can recur after kidney transplantation and is associated with poor graft outcomes. We aimed to assess the incidence of FSGS recurrence post-transplant and determine the effect of graft source on recurrence and graft survival in patients with biopsy-proven FSGS. Using the Australian and New Zealand Dialysis and Transplant Registry, we assessed incidence of FSGS, the influence of donor type on the risk of FSGS recurrence, and graft loss in recipients with ESRD caused by primary FSGS using Kaplan-Meier and logistic regression analyses. Between 1992 and 2011, 736 first kidney transplants were performed in 666 adults and 70 children (≤20 years old) with biopsy-proven primary FSGS. FSGS recurred in 76 (10.3%) patients. Younger age (P<0.001), nonwhite ethnicity (P=0.02), and having a live donor (P=0.02) were independent risk factors associated with recurrence. Median graft survival was significantly better for live donor compared with deceased donor grafts (14.8 versus 12.1 years; P<0.01). Disease recurrence predicted poor graft outcomes, with 52% (95% confidence interval, 40% to 63%) 5-year graft survival in the recurrence group compared with 83% (95% confidence interval, 79% to 86%) in the group without recurrent disease (P<0.001). FSGS recurrence after kidney transplantation was more common in live donor kidneys. Despite this, graft survival in live donor recipients was significantly better for both children and adults with FSGS. We propose that live donor transplantation should not be avoided in patients with FSGS.

A high intrapatient variability in tacrolimus exposure is associated with poor long-term outcome of kidney transplantation.

Tacrolimus is a critical dose drug with a considerable intrapatient variability (IPV) in its pharmacokinetics. We investigated whether a high IPV in tacrolimus exposure is associated with adverse long-term renal transplantation outcomes. Tacrolimus IPV was calculated from predose concentrations measured between 6 and 12 months post-transplantation of 808 renal transplant recipients (RTRs) transplanted between 2000 and 2010. One hundred and eighty-eight (23.3%) patients reached the composite end point consisting of graft loss, late biopsy-proven rejection, transplant glomerulopathy, or doubling of serum creatinine concentration between month 12 and the last follow-up. The cumulative incidence of the composite end point was significantly higher in patients with high IPV than in patients with low IPV (hazard ratio: 1.41, 95% CI: 1.06-1.89; P = 0.019). After the adjustment for several factors, the higher incidence of the composite end point for RTRs with a high IPV remained statistically significant (hazard ratio: 1.42, 95% CI: 1.06-1.90; P = 0.019). Younger recipient age at transplantation, previous transplantation, worse graft function (at month 6 post-transplantation), and low mean tacrolimus concentration at 1 year post-transplantation were additional predictors for worse long-term transplant outcome. A high tacrolimus IPV is an independent risk factor for adverse kidney transplant outcomes that can be used as an easy monitoring tool to help identify high-risk RTRs.

Kidney transplantation from deceased donors with elevated serum creatinine.

Elevated donor serum creatinine has been associated with inferior graft survival in kidney transplantation (KT). The aim of this study was to evaluate the impact of elevated donor serum creatinine on short and long-term outcomes and to determine possible ways to optimize the use of these organs. All kidney transplants from 01-2000 to 12-2012 with donor creatinine ≥ 2mg/dl were considered. Risk factors for delayed graft function (DGF) were explored with uni- and multivariate regression analyses. Donor and recipient data were analyzed with uni- and multivariate cox proportional hazard analyses. Graft and patient survival were calculated using the Kaplan-Meier method. Seventy-eight patients were considered. Median recipient age and waiting time on dialysis were 53years and 5.1years, respectively. After a median follow-up of 6.2years, 63 patients are alive. 1, 3, and 5-year graft and patient survival rates were 92, 89, and 89% and 96, 93, and 89%, respectively. Serum creatinine level at procurement and recipient's dialysis time prior to KT were predictors of DGF in multivariate analysis (p = 0.0164 and p = 0.0101, respectively). Charlson comorbidity score retained statistical significance by multivariate regression analysis for graft survival (p = 0.0321). Recipient age (p = 0.0035) was predictive of patient survival by multivariate analysis. Satisfactory long-term kidney transplant outcomes in the setting of elevated donor serum creatinine ≥2mg/dl can be achieved when donor creatinine is <3.5mg/dl, and the recipient has low comorbidities, is under 56years of age, and remains in dialysis prior to KT for <6.8years.

Kidney transplantation for end-stage renal disease secondary to familial Mediterranean fever.

Although kidney transplantation (KT) is widely used for treating renal amyloidosis secondary to familial Mediterranean fever (FMF), data concerning transplant outcome are limited and inconsistent. The aim of this study was to determine the long-term outcome of KT in patients with amyloidosis secondary to FMF. Kidney transplantation outcome in 24 patients with FMF was compared to that in 72 controls matched for age, gender of recipient, and type of the donor that underwent KT due to end-stage renal disease (ESRD) not caused by FMF. Mean follow-up time was 80.3 ± 55.1 months in the FMF group, vs. 86.5 ± 47.6 months in the control group. Death-censored graft survival at five and 10 yr in the FMF group was 95.8% and 78.4%, respectively, and was comparable to that in the control group. In the FMF group, five- and 10-yr patient survival (87.5 and 65.6%) was shorter than in the control group, but the difference was not statistically significant. The findings show that long-term outcome of KT in the patients with amyloidosis secondary to FMF was comparable to that in patients with ESRD not caused by FMF. Recurrence of amyloidosis in the allograft, gastrointestinal intolerance, and fatal infections remain as major complications during the post-transplant period.

A joint model for longitudinal and time-to-event data to better assess the specific role of donor and recipient factors on long-term kidney transplantation outcomes.

In renal transplantation, serum creatinine (SCr) is the main biomarker routinely measured to assess patient's health, with chronic increases being strongly associated with long-term graft failure risk (death with a functioning graft or return to dialysis). Joint modeling may be useful to identify the specific role of risk factors on chronic evolution of kidney transplant recipients: some can be related to the SCr evolution, finally leading to graft failure, whereas others can be associated with graft failure without any modification of SCr. Sample data for 2749 patients transplanted between 2000 and 2013 with a functioning kidney at 1-year post-transplantation were obtained from the DIVAT cohort. A shared random effect joint model for longitudinal SCr values and time to graft failure was performed. We show that graft failure risk depended on both the current value and slope of the SCr. Deceased donor graft patient seemed to have a higher SCr increase, similar to patient with diabetes history, while no significant association of these two features with graft failure risk was found. Patient with a second graft was at higher risk of graft failure, independent of changes in SCr values. Anti-HLA immunization was associated with both processes simultaneously. Joint models for repeated and time-to-event data bring new opportunities to improve the epidemiological knowledge of chronic diseases. For instance in renal transplantation, several features should receive additional attention as we demonstrated their correlation with graft failure risk was independent of the SCr evolution.

Belatacept and Long-Term Outcomes in Kidney Transplantation

BackgroundIn 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.MethodsWe 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).ResultsA 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.ConclusionsSeven 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.)