The Progression of Interstitial Fibrosis and Tubular Atrophy at 6 Months Is an Independent Predictor of Poor Graft Outcomes in Kidney Transplant Recipients.

Interstitial fibrosis and tubular atrophy (IFTA) found on 1-y surveillance biopsies has been associated with poor graft outcomes. However, its progression over time and relationship to outcomes are less well defined. Methods: We studied implantation and 6-mo surveillance biopsies and examined the association between the progression of IFTA (ΔIFTA) and a composite of censored graft loss or doubling of serum creatinine in 248 adult kidney recipients. Results: The percentage of patients with ΔIFTA of 1 or ≥2 was 35% and 22%, respectively. Positive ΔIFTA was a risk factor for the composite endpoint (hazard ratio, 1.36; 95% confidence interval, 1.03-1.79). This estimate was robust to adjustment for recipient and donor baseline characteristics, baseline IFTA, tacrolimus levels, and rejection status. ΔIFTA was associated with decreased estimated glomerular filtration rate at 3 and 5 y. IFTA+i was a predictor in the cohort; however, IFTA progression was not limited to those with a mononuclear cell interstitial inflammation (Banff "i") score above zero. Notably, donor age was a predictor of IFTA at 6 mo, but not of ΔIFTA, whereas rejection, donor diabetes, and recipient smoking status were. Conclusions: Progression of IFTA at 6 mo can predict outcomes. ΔIFTA was not related to donor age but may be linked to other risk factors influencing decision-making for donor versus recipient selection.

Factors Associated With the Use of Hypothermic Machine Perfusion in Kidney Transplant Recipients: A Multicenter Retrospective Cohort Study.

Background: Delayed graft function (DGF) is associated with an increased risk of graft loss. The use of cold hypothermic machine perfusion (HMP) has been shown to reduce the incidence of DGF in kidney transplant recipients (KTRs), especially when extended-criteria donors (ECDs) are used. HMP can also improve graft survival. However, there is a paucity of data on the determinants of HMP use in clinical practice. Objective: We aimed to determine the factors associated with the use of HMP in a cohort of donors and KTRs. Design: Multicenter retrospective cohort study. Setting: 5 transplant centers in Quebec. Patients: 159 neurologically deceased donors (NDD) and 281 KTR. Measurements: Use of HMP. Methods: We collected data on consecutive NDD admitted to a dedicated donor unit in a single university-affiliated center and their KTRs between June 2013 and December 2018 in 5 adult transplant centers across the province of Quebec, Canada. All organs were recovered in a single hospital center where a HMP device was available for every organ recovered and the decision to use HMP was left at the discretion of the procurement surgeon. Generalized estimating equations were used to predict the use of HMP. Results: The cohort included 159 NDDs and their 281 KTRs. Thirty-three percent of donors were ECDs, and 59% of KTRs received organs placed on HMP. The median cold ischemia time (CIT) was 12.5 (IQR 7.9-16.3) hours. In univariate analysis, none of the donors' characteristics were associated with the use of HMP. ECD represented 33% of KTR on HMP vs 35% of those not placed on HMP (P = .77). In univariate analysis, the use of HMP was associated with KTR race (non-Caucasian), longer CIT, use of basiliximab/alemtuzumab, year of transplant, and transplant center. The use of HMP varied largely across transplant centers, ranging from 15% to 82%. In multivariate analysis, use of HMP was associated with longer CIT (odds ratio [OR] 1.15, 95% confidence interval [CI] = 1.07-1.25), transplant center as well as transplantations performed after 2013. Limitations: One dedicated donor unit including NDD only, absence of specific data on surgeons' experience and personal or logistic reasons for using or not HMP. Conclusions: We found that use of HMP remains low and varies largely across transplant centers. The use of HMP was strongly associated with the transplant center where the surgeons practiced, suggesting that surgeon preference/training plays an important role in determining the use of HMP. Availability of HMP at the time of organ procurement might also be limited by logistic issues such as difficulty in returning the device. Further studies aimed at determining the reasons underlying the barriers precluding the use of HMP could help increasing its use and improve transplant outcomes.

Contexte: Les retards dans la reprise de fonction du greffon (RRFG) sont associés à un risque accru d'échec de la greffe. Il a été démontré que la perfusion hypothermique mécanisée (PHM) peut réduire l'incidence d'un RRFG chez les receveurs d'une greffe rénale (RGR), particulièrement dans les cas où des donneurs à critères étendus (DCÉ) sont impliqués. La PHM pourrait également améliorer la survie du greffon. Il existe cependant peu de données sur les facteurs déterminant l'utilisation de la PHM dans la pratique clinique. Objectifs: Déterminer les facteurs associés à l'utilisation de la PHM dans une cohorte de donneurs et de RGR. Type d'étude: Étude de cohorte rétrospective multicentrique. Cadre: Cinq centres de transplantation au Québec. Sujets: L'étude a inclus 159 donneurs neurologiquement décédés (DND) et 281 RGR. Mesures: L'utilisation de la PHM. Méthodologie: Nous avons recueilli les données de DND consécutifs admis entre juin 2013 et décembre 2018 dans une unité spécialisée dans le don d'organes d'un centre hospitalier universitaire, de même que les données de leurs RGR respectifs. Les sujets provenaient de cinq centres de transplantation pour adultes de la province de Québec, au Canada. Tous les organes ont été prélevés dans un centre hospitalier où un dispositif de PHM était disponible pour chaque organe prélevé, et la décision de recourir à la PHM a été laissée à la discrétion du chirurgien chargé du prélèvement. Des équations d'estimation généralisées ont été employées pour prédire l'utilisation de la PHM. Résultats: La cohorte était composée de 159 DND et de leurs 281 RGR. Les DCÉ constituaient 33 % des DND et 59 % des RGR avaient reçu un organe placé sur PHM. La durée médiane de l'ischémie froide (DmIF) était de 12,5 heures (ÉIQ: 7,9-16,3 heures). Dans l'analyse univariée, aucune des caractéristiques des donneurs n'a été associée à l'utilisation de la PHM. Des RGR de la cohorte qui avaient reçu un rein provenant d'un DCÉ, 33 % ont reçu un organe qui avait été placé sous PHM et 35 % avaient reçu un rein non perfusé à froid (p = 0,77). L'analyse univariée a également révélé une association entre l'utilisation de la PHM et l'origine ethnique du RGR (non caucasien), une DmIF prolongée, l'administration de basiliximab/alemtuzumab, l'année de la greffe et le centre de transplantation. L'utilisation de la PHM variait grandement d'un centre à un autre, allant de 15 % à 82 %. Dans l'analyse multivariée, l'utilisation de la PHM a été associée à une DmIF prolongée (rapport de cotes [RC]: 1,15; [IC95 %]: 1,07-1,25), au centre de transplantation ainsi qu'aux transplantations réalisées après 2013. Limites: Étude tenue dans une seule unité spécialisée en don d'organes et portant uniquement sur des DND. Absence de données précises sur l'expérience des chirurgiens et sur les raisons personnelles ou logistiques justifiant l'utilisation ou non de la PHM. Conclusion: Nous avons constaté que l'utilisation de la PHM demeure faible et qu'elle varie fortement d'un centre de transplantation à un autre. L'utilisation de la PHM a été fortement associée au centre de transplantation où exerçaient les chirurgiens, ce qui laisse penser que les préférences personnelles et la formation du chirurgien sont des facteurs déterminants pour son utilisation. La disponibilité de la PHM au moment du prélèvement des organes peut également être limitée par des questions logistiques telles que la difficulté de retourner l'appareil. D'autres études se penchant sur les raisons sous-jacentes aux obstacles empêchant l'utilisation de la PHM pourraient aider à en accroître l'utilisation et à améliorer les résultats de la transplantation.

Immunosuppressant Medication Use in Patients with Kidney Allograft Failure: A Prospective Multicenter Canadian Cohort Study.

BACKGROUND: Patients with kidney transplant failure have a high risk of hospitalization and death due to infection. The optimal use of immunosuppressants after transplant failure remains uncertain and clinical practice varies widely. METHODS: This prospective cohort study enrolled patients within 21 days of starting dialysis after transplant failure in 16 Canadian centers. Immunosuppressant medication use, death, hospitalized infection, rejection of the failed allograft, and anti-HLA panel reactive antibodies were determined at 1, 3, 6, and 12 months and and then twice yearly until death, repeat transplantation, or loss to follow-up. RESULTS: The 269 study patients were followed for a median of 558 days. There were 33 deaths, 143 patients hospitalized for infection, and 21 rejections. Most patients (65%) continued immunosuppressants, 20% continued prednisone only, and 15% discontinued all immunosuppressants. In multivariable models, patients who continued immunosuppressants had a lower risk of death (hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.17 to 0.93) and were not at increased risk of hospitalized infection (HR, 1.81; 95% CI, 0.82 to 4.0) compared with patients who discontinued all immunosuppressants or continued prednisone only. The mean class I and class II panel reactive antibodies increased from 11% to 27% and from 25% to 47%, respectively, but did not differ by immunosuppressant use. Continuation of immunosuppressants was not protective of rejection of the failed allograft (HR, 0.81; 95% CI, 0.22 to 2.94). CONCLUSIONS: Prolonged use of immunosuppressants >1 year after transplant failure was not associated with a higher risk of death or hospitalized infection but was insufficient to prevent higher anti-HLA antibodies or rejection of the failed allograft.

A Sequential Two-Step Cell-Based Assay Predicts Immunosuppression-Related Adverse Events.

Immunosuppressants are associated with serious and often life-threatening adverse effects. To optimize immunotherapy, a tool that measures the immune reserve is necessary. We validated that a cell-based assay that measures TNF-α production by CD14+16+ intermediate monocytes following stimulation with EBV peptides has high sensitivity for the detection of over-immunosuppression (OIS) events. To develop a sequential, two-step assay with high specificity, we used PBMCs from kidney recipients (n = 87). Patients were classified as cases or controls, according to the occurrence of opportunistic infection, recurring bacterial infections, or de novo neoplasia. Patients who tested positive in the first step were randomly allocated to a training or a testing set for the development of the second step. In the discovery phase, an assay based on the examination of early mature B (eBm5) cells was able to discriminate OIS patients from controls with a specificity of 88%. The testing set also revealed a specificity of 88%. The interassay coefficient of variability between the experiments was 6.1%. Stratified analyses showed good diagnostic accuracy across tertiles of age and time posttransplant. In the adjusted model, the risk of OIS was more than 12 times higher in patients classified as positive than in those who tested negative (adjusted hazard ratio, 12.2; 95% confidence interval: 4.3-34.6). This sequential cell-based assay, which examines the monocyte and eBm5 cell response to EBV peptides, may be useful for identifying OIS in immunosuppressed patients.

Canadian Society of Transplantation and Canadian Society of Nephrology Commentary on the 2017 KDIGO Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors.

PURPOSE OF REVIEW: To review an international guideline on the evaluation and care of living kidney donors and provide a commentary on the applicability of the recommendations to the Canadian donor population. SOURCES OF INFORMATION: We reviewed the 2017 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors and compared this guideline to the Canadian 2014 Kidney Paired Donation (KPD) Protocol for Participating Donors. METHODS: A working group was formed consisting of members from the Canadian Society of Transplantation and the Canadian Society of Nephrology. Members were selected to have representation from across Canada and in various subspecialties related to living kidney donation, including nephrology, surgery, transplantation, pediatrics, and ethics. KEY FINDINGS: Many of the KDIGO Guideline recommendations align with the KPD Protocol recommendations. Canadian researchers have contributed to much of the evidence on donor evaluation and outcomes used to support the KDIGO Guideline recommendations. LIMITATIONS: Certain outcomes and risk assessment tools have yet to be validated in the Canadian donor population. IMPLICATIONS: Living kidney donors should be counseled on the risks of postdonation outcomes given recent evidence, understanding the limitations of the literature with respect to its generalizability to the Canadian donor population.

JUSTIFICATION: Examiner une directive internationale sur l'évaluation et la prise en charge des donneurs vivants d'un rein et formuler un commentaire sur l'applicabilité de ces recommandations à la population des donneurs canadiens. SOURCES: Nous avons révisé le guide des pratiques cliniques relatives à l'évaluation et à la prise en charge des donneurs vivants d'un rein (Clinical Practice Guideline for Evaluation and Care of Living Kidney Donors) de 2017 du KDIGO (Kidney Disease: Improving Global Outcomes) et nous l'avons comparé aux recommandations canadiennes de 2014 du Protocole de don croisé d'un rein par donneurs participants (Kidney Paired Donation Protocol for Participating Donors). MÉTHODOLOGIE: Un groupe de travail réunissant des membres de la Société canadienne de transplantation et de la Société canadienne de néphrologie a été formé. Les membres ont été sélectionnés pour représenter tout le Canada et plusieurs sous-spécialisations relatives au don vivant d'un rein, notamment la néphrologie, la chirurgie, la transplantation, la pédiatrie et l'éthique. PRINCIPALES CONSTATATIONS: Plusieurs des recommandations du KDIGO s'harmonisent aux recommandations du protocole de don croisé d'un rein. Les chercheurs canadiens ont contribué en grande partie aux données sur l'évaluation des donneurs et des résultats utilisées pour appuyer les recommandations formulées dans les lignes directrices du KDIGO. LIMITES: Certains résultats et outils d'évaluation des risques doivent encore être validés dans la population des donneurs canadiens. CONCLUSION: Compte tenu des plus récentes données, les donneurs vivants d'un rein devraient être mis en garde concernant les risques sur leur santé post-don, tout en comprenant les limites de la littérature en ce qui concerne leur généralisabilité à la population de donneurs canadiens.

TNF-α Production by Monocytes Stimulated With Epstein-Barr Virus-Peptides as a Marker of Immunosuppression-Related Adverse Events in Kidney Transplant Recipients.

INTRODUCTION: Infections and cancers now outnumber rejection as a cause of morbidity in transplant recipients, likely as a result of over-immunosuppression. Currently, there is no clinical tool to detect over-immunosuppression. We recently reported that tumor necrosis factor alpha (TNF-α) production by CD14+CD16+ intermediate monocytes, following ex vivo stimulation by Epstein-Barr virus-peptides, could identify over-immunosuppressed patients. METHODS: We conducted a pilot study the assay using 142 peripheral blood mononuclear samples from a cohort of 71 kidney transplant recipients. Patients were classified as cases or controls according to the occurrence of opportunistic infection, recurring bacterial infections or de novo neoplasia in the 12 months following blood collection. We used both the classifier rule and a threshold of <73% of CD14+CD16+TNFα+ cells developed in a previous training set. RESULTS: Cases were detected with 83% sensitivity and 68% specificity. The negative predictive value of the assay was 89%. The hazard ratio for the occurrence of the endpoint was 6.8 (95% confidence interval 2.0-23.9; P = 0.003) in patients with a positive test. Multivariable linear regression analysis revealed that the association was independent of baseline clinical characteristics, renal function, and immunosuppressive regimen. CONCLUSION: These data validate this cell-based assay as a promising tool for personalizing immunotherapy. Studies are under way for a 2-step assay with improved specificity.

Organ donor management and delayed graft function in kidney transplant recipients: A multicenter retrospective cohort study.

Meeting donor management goals (DMGs) has been reported to decrease the incidence of delayed graft function (DGF) after kidney transplant, but whether this relationship is independent of cold machine perfusion is unclear. We aimed to determine whether meeting DMGs is associated with a reduced incidence of DGF, independent of the use of machine perfusion. We collected data on consecutive brain-dead donors and their KT recipients (KTRs) between June 2013 and December 2016 in 5 adult transplant centers. We evaluated whether DMGs were met at donor neurologic death (DND) and later time points. We defined a priori meeting optimal DMG as achieving ≥7 DMGs. Generalized estimating equations were used to predict DGF. Among 122 donors, 34% were extended-criteria donors (ECDs). The number of DMGs met increased over time (5.6 ± 1.4 at DND and 6.1 ± 1.3 at organ procurement [P < .001]). DGF occurred in 23% of 214 KTRs, and 55% received organs placed on machine perfusion. In multivariate analysis, ECD (odds ratio [OR] 2.24, 95% confidence interval [CI] 1.13-4.45), use of machine perfusion (OR 0.45, 95% CI 0.22-0.94), and optimal DMG at DND (OR 0.39, 95% CI 0.16-0.99) were associated with DGF. Early achievement of DMGs was associated with a reduced risk of the development of DGF, independent of the use of machine perfusion.

Comparison of the effects of standard vs low-dose prolonged-release tacrolimus with or without ACEi/ARB on the histology and function of renal allografts.

Targeting the renin-angiotensin system and optimizing tacrolimus exposure are both postulated to improve outcomes in renal transplant recipients (RTRs) by preventing interstitial fibrosis/tubular atrophy (IF/TA). In this multicenter, prospective, open-label controlled trial, adult de novo RTRs were randomized in a 2 × 2 design to low- vs standard-dose (LOW vs STD) prolonged-release tacrolimus and to angiotensin-converting enzyme inhibitors/angiotensin II receptor 1 blockers (ACEi/ARBs) vs other antihypertensive therapy (OAHT). There were 2 coprimary endpoints: the prevalence of IF/TA at month 6 and at month 24. IF/TA prevalence was similar for LOW vs STD tacrolimus at month 6 (36.8% vs 39.5%; P = .80) and ACEi/ARBs vs OAHT at month 24 (54.8% vs 58.2%; P = .33). IF/TA progression decreased significantly with LOW vs STD tacrolimus at month 24 (mean [SD] change, +0.42 [1.477] vs +1.10 [1.577]; P = .0039). Across the 4 treatment groups, LOW + ACEi/ARB patients exhibited the lowest mean IF/TA change and, compared with LOW + OAHT patients, experienced significantly delayed time to first T cell-mediated rejection. Renal function was stable from month 1 to month 24 in all treatment groups. No unexpected safety findings were detected. Coupled with LOW tacrolimus dosing, ACEi/ARBs appear to reduce IF/TA progression and delay rejection relative to reduced tacrolimus exposure without renin-angiotensin system blockade. ClinicalTrials.gov identifier: NCT00933231.

Impact of the Current Versus the Previous Diagnostic Threshold on the Outcome of Patients With Borderline Changes Suspicious for T Cell-mediated Rejection Diagnosed on Indication Biopsies.

BACKGROUND: Since the borderline changes suspicious for acute T cell-mediated rejection (BL) category was broadened, there has been a debate regarding the right threshold for tubulitis and interstitial inflammation scores. METHODS: We studied a first cohort of 111 patients with BL found on an indication biopsy between 2006 and 2016 and compared those with scores of t1i0 (BLt1i0) to those with higher scores (BL≥t1i1). A second cohort of 56 patients with BL was used for external validation. We used a composite endpoint of death-censored graft failure or doubling of the serum creatinine level postbiopsy. RESULTS: In the first cohort, 68% (75/111) of the BL cases fell in the BLt1i0 group. At 5 years, the occurrence of the composite endpoint was 5% and 14% for BLt1i0 and BL≥t1i1, respectively. In contrast, the endpoint occurred in 5% of nonrejectors and 21% of patients with T cell-mediated rejection. In the validation cohort, 8% versus 36% of BLt1i0 and BL≥t1i1 reached the endpoint, respectively. Multivariable Cox modeling revealed that BLt1i0 patients had a prognosis similar to that of nonrejectors (adjusted hazard ratio, 0.6; 95% confidence interval, 0.1-2.2; P = 0.40) but better than that of patients with BL≥t1i1 (hazard ratio, 3.8; 95% confidence interval, 1.3-11.5; P = 0.02). Sensitivity analyses restricted to death-censored graft loss or using time posttransplant as the time of reference provided similar results. CONCLUSIONS: In summary, patients with BLt1i0 have a different prognosis to that of BL≥t1i1 patients, which brings into question the current diagnostic thresholds.

Impaired Secretion of TNF-α by Monocytes Stimulated With EBV Peptides Associates With Infectious Complications After Kidney Transplantation.

BACKGROUND: The successful development of immunosuppressive agents has paradoxically led to an era in which adverse effects of immunosuppression, such as infections and cancer, are now a major concern in solid organ recipients. Nevertheless, the main focus of immune monitoring research remains the identification of rejection. There is currently no clinical tool to assess the net state of immunosuppression or to identify patients at increased risk of infectious complications. METHODS: We report a prospective, longitudinal study in which we conducted detailed phenotyping of over 300 peripheral blood mononuclear cell samples from 45 kidney recipients during the first 24 months posttransplant. Patients were classified as cases or controls according to the following events: an opportunistic infection, recurring bacterial infections, or de novo neoplasia. RESULTS: Using a training cohort, an exploratory analysis revealed that the TNFα response to synthetic Epstein-Barr virus peptides by CD14CD16 monocytes was lower in cases. A classifier rule based on 2 or greater consecutive values below a threshold of 73% of TNFα-positive cells provided a sensitivity and specificity of 83%. In the validation cohort, the assay exhibited a sensitivity of 90% and a specificity of 63%. Analysis of IFNγ responses by T cells showed no correlation with the cases' phenotype. The association between overimmunosuppression status and the monocyte response was independent of age, renal function, and immunosuppressive regimen. CONCLUSIONS: These data suggest that patients with infectious complications posttransplantation have lower CD14CD16 monocyte responses to Epstein-Barr virus peptides. This assay seems promising to help personalize the immunotherapy.

Higher calcineurin inhibitor levels predict better kidney graft survival in patients with de novo donor-specific anti-HLA antibodies: a cohort study.

The development of de novo anti-HLA donor-specific antibodies (dnDSA) is associated with poorer outcomes in kidney transplant recipients. Despite this, antibody screening post-transplant is not widespread, largely because the optimal management of patients with dnDSA remains undetermined. We hypothesized that in this population, calcineurin inhibitor blood levels would be an independent predictor of graft loss. We analyzed a cohort of unsensitized patients for whom anti-HLA antibody screening was performed prospectively post-transplant. During the screening period between January 2005 and April 2016, 42 patients developed dnDSA. There was no difference in the clinical characteristics or the histological scores of patients biopsied for clinical indication versus those biopsied solely due to detection of dnDSA. Cox modeling revealed a strong relationship between mean tacrolimus levels following dnDSA detection and graft loss, with a hazard ratio of 0.49 (95% CI, 0.33-0.75), which persisted following adjustment for established independent predictors (HR, 0.52, 95% CI, 0.30-0.89). Kaplan-Meier analysis by tertiles of tacrolimus levels and receiver operating curve analysis concurred to show that a threshold of 5.3 ng/ml could be predictive of graft loss. These data suggest that anti-HLA antibody monitoring post-transplant could guide maintenance immunosuppression and improve graft outcomes.

Donor-specific antibodies, C4d and their relationship with the prognosis of transplant glomerulopathy.

BACKGROUND: Transplant glomerulopathy (TG) is a diagnostic criterion for chronic active antibody-mediated rejection (CAABMR), with C4d, donor-specific antibodies (DSA) and other lesions of chronic tissue injury. However, TG often presents without C4d or DSA. Until recently, such cases were termed suspicious for CAABMR, and their prognosis remains unclear. METHODS: To better understand the contribution of TG, C4d, and DSA on outcomes, we retrospectively studied 61 patients with late TG for the composite endpoint of death-censored graft failure or doubling of serum creatinine. Cases were matched to controls based on age, year and number of transplant, type of donor, and the availability of an indication biopsy during the same time after transplantation. Analyses were performed using proportional hazards models. RESULTS: Compared to matched controls, patients with TG had a more than fivefold increased risk of reaching the endpoint (adjusted hazard ratio (aHR), 5.3; 95% confidence interval (95% CI), 1.5-18.4). The proportion of patients with isolated TG, TG suspicious for CAABMR (C4+/DSA- or C4d-/DSA+) and TG with definite CAABMR (C4d+/DSA+) were 63%, 20%, and 17%, respectively. Suspicious and definite CAABMR showed a similar prognosis, significantly worse than isolated TG (aHR, 4.5; 95% CI, 1.1-18.9 and aHR, 5.9, 95% CI, 1.1-31.3 respectively). CONCLUSION: Transplant glomerulopathy is associated with poor prognosis, independent of the level of graft dysfunction and other chronic histologic changes. This prognosis is similar whether there is evidence of tissue or peripheral alloantibody reactivity. These findings are relevant to the development of clinically meaningful criteria for CAABMR, for its clinical management, and in the future selection of population for clinical trials.

Impact of donor age on long-term outcomes after delayed graft function: 10-year follow-up.

Delayed graft function (DGF) has a negative impact on graft survival in donation after brain death (DBD) but not for donation after cardiac death (DCD) kidneys. However, older donor age is associated with graft loss in DCD transplants. We sought to examine the interaction between donor age and DGF in DBD kidneys. This is a single-center, retrospective review of 657 consecutive DBD recipients transplanted between 1990 and 2005. We stratified the cohort by decades of donor age and studied the association between DGF and graft failure using Cox models. The risk of graft loss associated with DGF was not significantly increased for donor age below 60 years (adjusted hazard ratio [aHR] 1.12, 1.51, and 0.90, respectively, for age <40, 41-50 and 51-60 years) but significantly increased after 60 years (aHR 2.67; P = 0.019). Analysis of death-censored graft failure yielded similar results for donor age below 60 years and showed a substantially increased risk with donors above 60 years (aHR 6.98, P = 0.002). This analysis reveals an unexpectedly high impact of older donor age on the association between DGF and renal transplant outcomes. Further research is needed to determine the best use of kidneys from donors above 60 years old, where DGF is expected.

Age-related and blood pressure-independent reduction in aortic stiffness after kidney transplantation.

OBJECTIVES: Aortic stiffness is a novel cardiovascular risk factor in patients with chronic kidney disease (CKD). The purpose of the present study is to examine whether there is a blood pressure-independent improvement in aortic stiffness 3 months after successful kidney transplantation (KTx), and whether this improvement is age-dependent. METHOD: In this prospective, longitudinal observational study, we studied hemodynamic and biological parameters prior to and 3 months after a KTx in 52 stage 5 CKD patients. Aortic stiffness was measured by carotido-femoral pulse wave velocity (c-f PWV) and enhanced central wave reflection was evaluated by the heart rate-adjusted central augmentation index (AIx) by means of arterial tonometry. Endothelin-1, L-arginine, asymmetric dimethylarginine (biomarkers of endothelial dysfunction), pentosidine (advanced glycation end-products) and mineral metabolism parameters were also measured. RESULTS: After adjusting for the reduction in mean blood pressure, c-f PWV decreased significantly from 12.1 ± 3.3 to 11.6 ± 2.3 m/s (P < 0.05). In an analysis stratified by age, this improvement was only present in patients older than 50 years of age as compared with patients younger than 50 years of age (-5.5 ± 2.2 vs. 2.1 ± 1.9%, P < 0.05). AIx decreased from 22 ± 11 to 14 ± 13% (P < 0.01), but this reduction was not age-dependent. We also observed a similar degree of improvement in the biomarker levels of endothelial dysfunction and pentosidine in both groups. CONCLUSION: This study shows for the first time that there is an age-dependent improvement in aortic stiffness after KTx. These observations suggest that older patients may have an added cardiovascular risk reduction after a successful KTx.

Dual-kidney transplants as an alternative for very marginal donors: long-term follow-up in 63 patients.

BACKGROUND: Organ shortage has led to the use of dual-kidney transplant (DKT) of very marginal donors into a single recipient to increase the use of marginal organs. To date, few data are available about the long-term outcome of DKT and its usefulness to increase the pool of available organ. METHODS: We conducted a single-center cohort study of DKTs with longitudinal follow-up over an 8-year period. Between 1999 and 2007, 63 DKTs were performed. All kidneys from donors younger than 75 years refused by all centers for single transplantation, and kidneys from donors aged 75 years or older were routinely evaluated based on preimplantation glomerulosclerosis. Renal function, patient or graft survival, and perioperative complications were compared with 66 single kidneys from expanded criteria donors (ECD) and 63 ideal kidney donors. RESULTS: After a median follow-up of 56 months, patient or graft survival was similar between the three groups. Twelve-, 36-, and 84-month creatinine clearance were similar for DKT and ECD (12 months: 58 and 59 mL/min; 36 months: 54 and 60 mL/min; and 84 months: 62 and 51 mL/min, respectively). For the study period, the routine evaluation of very marginal kidneys for DKT in our center has led to an increase of 47% in the transplants from donors aged 50 years or older, which represent 12% at the level of our organ procurement organization. CONCLUSIONS: DKT patients can expect long-term results comparable with single kidney ECD. The implementation of a DKT program in our unit safely increased the pool of organs from marginal donors.

The CLEAR study: a 5-day, 3-g loading dose of mycophenolate mofetil versus standard 2-g dosing in renal transplantation.

BACKGROUND AND OBJECTIVES: Adequate early mycophenolic acid (MPA) exposure is associated with lower rates of acute rejection in renal transplantation. The aim of this randomized controlled trial was to determine if higher initial mycophenolate mofetil (MMF) doses increased the proportion of patients reaching therapeutic MPA levels (30 to 60 mg.h/L) by day 5. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: De novo renal transplant patients were randomized to receive intensified dosing of MMF (1.5 g twice daily on days 1 to 5, then 1.0 g twice daily) or standard dosing (1.0 g twice daily). All recipients received tacrolimus and prednisone. Full MPA areas under the curve (AUCs) were completed on days 3 and 5, whereas a limited sampling strategy was utilized at four subsequent time points. RESULTS: At day 5, 47.5% of the MMF 3-g arm achieved the MPA therapeutic window versus 54.4% of the MMF 2-g arm. However, MPA AUC levels were significantly higher in the 3-g arm at day 3 and 5. This resulted in a trend for fewer treated acute rejections at 6 months. Significantly more acute rejections (treated, biopsy-proven including and excluding borderline) occurred in patients with MPA AUC levels<30 mg.h/L compared with those >or=30 mg.h/L at day 5. No significant differences were seen in common adverse events. CONCLUSIONS: A limited intensified dose of MMF increased early MPA exposure and was well tolerated. Further studies are required to determine whether limited intensified MMF dosing can reduce acute rejection.

Screening for polyomavirus associated nephropathy in renal transplantation with blood viral load measurement.

BACKGROUND: Polyomavirus associated nephropathy (PVAN) is an important cause of graft failure in the renal transplant population. It has been shown that viremia precedes PVAN, suggesting that measurement of blood viral load could be used for PVAN screening. OBJECTIVES: To verify the utility of BK virus (BKV) blood viral load measurement for PVAN screening in the renal transplant population, establish a threshold value, and determine the sensitivity and specificity of the test. STUDY DESIGN: We developed a real-time PCR assay for BKV blood viral load measurement and included this assay in the PVAN screening protocol of the renal transplant recipients of our institution. We report results for 60 patients who had a blood viral load measurement concomitantly with an allograft biopsy with immunohistochemistry for polyomavirus. RESULTS: 14 patients were found to have a PVAN on allograft biopsy together with a viral load above 3.0x10(3)copies/ml. None of the patients with a viral load under 3.0x10(3)copies/ml had a PVAN on allograft biopsy. The area under the receiver operating characteristic (ROC) curve was 0.95 (95% CI: 0.91-1.00) and using a threshold value of 3.0x10(3)copies/ml yielded a sensitivity of 100% (95% CI: 76.8-100%) and a specificity of 89.6% (95% CI: 77.3-96.5%) for PVAN screening. CONCLUSIONS: BKV blood viral load measurement is sensitive and specific for PVAN screening when a threshold value is precisely determined.

Modifiable factors predicting patient survival in elderly kidney transplant recipients.

BACKGROUND: Elderly transplant candidates represent an increasingly important group on the waiting list for kidney transplantation. Yet the factors that determine posttransplantation outcomes in this population remain poorly defined. METHODS: We performed a population-based retrospective cohort study involving all patients aged 60 years or older who received a first cadaveric kidney transplantation between 1985 and 2000 in the province of Quebec. The main outcomes were patient survival, overall graft survival, and treatment failure (patient death or graft loss within the first posttransplant year). Survival analyses were performed using a Cox proportional hazard model. Logistic regression identified factors predicting treatment failure. RESULTS: On multivariate analysis, the modifiable factors associated with patient survival were active smoking at transplantation [hazard ratio (HR) 2.09, 95% confidence interval (CI) 1.22-3.60)], body mass index (BMI) (HR 1.34 for a 5-point increase, 95% CI 1.05-1.67), and time on dialysis before transplantation (HR 1.10 for a 1-year increase, 95% CI 1.02-1.18). The only modifiable factor associated with graft survival was active smoking at transplantation (HR 2.04, 95% CI 1.24-3.30). Treatment failure was associated with time on dialysis before transplantation (odds ratio for dialysis >/=2 years 3.28, 95% CI 1.34-7.9). CONCLUSION: Our results show that active smoking, obesity, and time on dialysis before transplantation are modifiable risk factors associated with an increased risk of mortality after transplantation in elderly recipients. They represent potential targets for interventions aimed at improving patient and graft survival in elderly patients.