Impact of Preformed Donor-Specific Anti-HLA-Cw and Anti-HLA-DP Antibodies on Acute Antibody-Mediated Rejection in Kidney Transplantation.

Given the risk of rejection, the presence of preformed donor specific antibodies (DSA) contraindicates transplantation in most allocation systems. However, HLA-Cw and -DP DSA escape this censorship. We performed a multicentric observational study, in which the objective was to determinate risk factors of acute antibody-mediated rejection (aABMR) in recipients transplanted with preformed isolated Cw- or DP-DSA. Between 2010 and 2019, 183 patients were transplanted with a preformed isolated Cw- or DP-DSA (92 Cw-DSA; 91 DP-DSA). At 2 years, the incidence of aABMR was 12% in the Cw-DSA group, versus 28% in the DP-DSA group. Using multivariable Cox regression model, the presence of a preformed DP-DSA was associated with an increased risk of aABMR (HR = 2.32 [1.21-4.45 (p = 0.001)]) compared with Cw-DSA. We also observed a significant association between the DSA's MFI on the day of transplant and the risk of aABMR (HR = 1.09 [1.08-1.18], p = 0.032), whatever the DSA was. Interaction term analysis found an increased risk of aABMR in the DP-DSA group compared with Cw-DSA, but only for MFI below 3,000. These results may plead for taking these antibodies into account in the allocation algorithms, in the same way as other DSA.

Immune modulation with extracorporeal photopheresis in renal transplantation: proof of concept clinical outcomes and perspective / Immunomodulation par photo-chimiothérapie extracorporelle en transplantation rénale : preuves de concept, données cliniques et perspectives

For 30 years, photopheresis is used to treat graft versus host disease and heart or lung allograft rejection. In this review, we discuss the place of photopheresis in kidney transplantation both in prevention or treatment of rejection. Mechanisms of action in kidney transplantation are mainly based on results observed in graft versus host disease and in heart or lung transplantation. Photopheresis may induce innate and adaptive immunity changes with restauration of a favourable Th1/Th2 immune balance, an expansion of LT /LB reg subsets, and a local enrichment in IL-10. French national clinical and mechanistic studies are underway to define the place of photopheresis therapy in immunomodulation strategies in kidney transplantation.

Depuis presque 30 ans, l'utilisation de la photo-chimiothérapie (PEC) a montré son efficacité dans le contrôle de la maladie du greffon contre l'hôte et dans le traitement du rejet d'allogreffe cardiaque et pulmonaire. L'utilisation de la PEC en transplantation rénale pourrait apporter un bénéfice thérapeutique sans majoration du risque infectieux ou oncologique, tant en prévention que dans le traitement du rejet. Il existe peu de données sur les mécanismes d'action de la PEC, les principales hypothèses reposant sur les résultats observés dans la maladie du greffon contre l'hôte ou en transplantation cardiaque et pulmonaire. La PEC induirait des modifications de l'immunité innée et adaptative dont la restauration d'un équilibre de la balance Th1/Th2 et une expansion des sous-populations LT/B régulatrices ainsi qu'une modification de l'environnement cytokinique avec enrichissement en IL-10. En France, des études cliniques et mécanistiques sont en cours pour affiner la place de la PEC dans les stratégies d'immunomodulation en transplantation rénale.

The challenging follow-up of pregnancy in women with known thrombotic thrombocytopenic purpura: a single-center experience of a preemptive management protocol.

BACKGROUND: Although thrombotic thrombocytopenic purpura frequently affects women of childbearing age, there is no clear recommendation for the management of subsequent pregnancies in women with established thrombotic thrombocytopenic purpura. METHODS: This single-center, retrospective, observational study included all women with hereditary thrombotic thrombocytopenic purpura or immune thrombotic thrombocytopenic purpura who had had at least one subsequent pregnancy after thrombotic thrombocytopenic purpura diagnosis between 2003 and 2022. The strategy comprised weekly surveillance of platelet count during pregnancy (and quarterly monitoring of ADAMTS13 activity) for women with immune thrombotic thrombocytopenic purpura, without any routine prophylactic treatment. In case of thrombocytopenia < 150,000/mm3 (with or without hemolysis relapse), women with hereditary thrombotic thrombocytopenic purpura systematically received plasma infusions twice weekly until platelet count normalized. RESULTS: A total of 13 patients were included (7 with hereditary thrombotic thrombocytopenic purpura and 6 with immune thrombotic thrombocytopenic purpura, with 20 planned pregnancies (11 and 9, respectively). All pregnancies resulted in live births, and all mothers survived. There was a marked improvement in pregnancy terms in the hereditary thrombotic thrombocytopenic purpura group compared to index pregnancies (37 [35;39] versus 31 [24;38] weeks, p = 0.037) and birth weights (3265 [3029;3410] versus 2160 [1240;2705] grams, p = 0.016), with need for plasma support mostly starting during the third trimester (5/7 patients, 7/11 pregnancies). A single hereditary thrombotic thrombocytopenic purpura relapse occurred, with rapid resolution after plasma support intensification. There were no relapses in the immune thrombotic thrombocytopenic purpura group, with ADAMTS13 activity systematically above 40% during all monitored pregnancies. CONCLUSION: These real-life data support the feasibility of a preemptive approach to pregnancy monitoring in women with known thrombotic thrombocytopenic purpura who undergo active surveillance within a multidisciplinary network.

Transfused Red Blood Cell Characteristics and Kidney Transplant Outcomes Among Patients Receiving Early Posttransplant Transfusion.

Importance: Red blood cell transfusion (RBCT) is frequently required in the early post-kidney transplant period, but long-term outcomes associated with RBCT is controversial. Therefore, it may be relevant to investigate the association between RBCT characteristics and transplant outcomes. Objective: To study the association between RBC storage duration and transplant outcomes. Design, Setting, and Participants: This was a nationwide retrospective cohort study based on data linking between 2 prospective French nationwide registries. Clinical transplant parameters, outcomes, and RBCT characteristics were extracted from the CRISTAL registry of the Agence de la Biomédecine and the national database of the Etablissement Français du Sang. All 12 559 patients having received a first kidney transplant in France between January 1, 2002, and December 31, 2008, were included. Patients were followed up from transplant to graft loss, death with a functional graft, or data retrieval in June 2016. Data were analyzed from April 2019 to June 2022. Exposures: Clinical outcomes of transplant recipients who underwent early RBCT were analyzed considering transfusion characteristics. Main Outcomes and Measures: Cox proportional hazards regression models were fitted to evaluate transplant failure defined as graft loss or death with a functional graft. Results: Among 12 559 patients who underwent kidney transplant, 3483 received an RBCT during the first 14 days posttransplant. The median (IQR) age of patients was 53.0 (41.5-61.2) years, and 1929 patients (55.4%) were male. Median (IQR) follow-up was 7.8 (7.6-8.0) years. In multivariable analysis, longer (vs shorter) storage duration of transfused RBC was associated with a decrease in risk of transplant failure (hazard ratio, 0.99; 95% CI, 0.98-1.00 for each additional storage day; P = .06). Patients transfused with at least 1 RBC unit stored for more than 20 days had a 5% absolute decrease in transplant failure at 3 years and 7% at 5 years compared with those who received RBC stored for less than 20 days. Conclusions and Relevance: In this study, longer RBC storage duration was associated with a decreased risk of transplant failure among patients who received kidney transplants and RBC transfusions. Preferential use of RBC with longer storage duration might improve kidney graft survival following transplant and transfusion.

Prognostic value of complement serum C3 level and glomerular C3 deposits in anti-glomerular basement membrane disease.

Background and objectives: Activation of the complement system is involved in the pathogenesis of anti-glomerular basement membrane (anti-GBM) disease. Glomerular deposits of complement 3 (C3) are often detected on kidney biopsies. The primary objective of this study was to analyze the prognostic value of the serum C3 level and the presence of C3 glomerular deposits in patients with anti-GBM disease. Methods: We conducted a retrospective cohort study of 150 single-positive patients with anti-GBM disease diagnosed between 1997 and 2017. Patients were categorized according to the serum C3 level (forming a low C3 (C3<1.23 g/L) and a high C3 (C3≥1.23 g/L) groups) and positivity for C3 glomerular staining (forming the C3+ and C3- groups). The main outcomes were kidney survival and patient survival. Results: Of the 150 patients included, 89 (65%) were men. The median [interquartile range (IQR)] age was 45 [26-64]. At diagnosis, kidney involvement was characterized by a median [IQR] peak serum creatinine (SCr) level of 578 [298-977] µmol/L, and 106 (71%) patients required dialysis. Patients in the low C3 group (72 patients) had more severe kidney disease at presentation, as characterized by higher prevalences of oligoanuria, peak SCr ≥500 µmol/L (69%, vs. 53% in the high C3 group; p=0.03), nephrotic syndrome (42%, vs. 24%, respectively; p=0.02) and fibrous forms on the kidney biopsy (21%, vs. 8%, respectively; p=0.04). Similarly, we observed a negative association between the presence of C3 glomerular deposits (in 52 (41%) patients) and the prevalence of cellular forms (83%, vs. 58% in the C3- group; p=0.003) and acute tubulo-interstitial lesions (60%, vs. 36% in the C3- group; p=0.007). When considering patients not on dialysis at diagnosis, the kidney survival rate at 12 months was poorer in the C3+ group (50% [25-76], vs. 91% [78-100] in the C3- group; p=0.01), with a hazard ratio [95% confidence interval] of 5.71 [1.13-28.85] (p=0.04, after adjusting for SCr). Conclusion: In patients with anti-GBM disease, a low serum C3 level and the presence of C3 glomerular deposits were associated with more severe disease and histological kidney involvement at diagnosis. In patients not on dialysis at diagnosis, the presence of C3 deposits was associated with worse kidney survival.

Nonskeletal and skeletal effects of high doses versus low doses of vitamin D3 in renal transplant recipients: Results of the VITALE (VITamin D supplementation in renAL transplant recipients) study, a randomized clinical trial.

Vitamin D sufficiency is associated with a reduced risk of fractures, diabetes mellitus, cardiovascular events, and cancers, which are frequent complications after renal transplantation. The VITALE (VITamin D supplementation in renAL transplant recipients) study is a multicenter double-blind randomized trial, including nondiabetic adult renal transplant recipients with serum 25-hydroxy vitamin D (25(OH) vitamin D) levels of <30 ng/mL, which is randomized 12 to 48 months after transplantation to receive high (100 000 IU) or low doses (12 000 IU) of cholecalciferol every 2 weeks for 2 months and then monthly for 22 months. The primary outcome was a composite endpoint, including diabetes mellitus, major cardiovascular events, cancer, and death. Of 536 inclusions (50.8 [13.7] years, 335 men), 269 and 267 inclusions were in the high-dose and low-dose groups, respectively. The serum 25(OH) vitamin D levels increased by 23 versus 6 ng/mL in the high-dose and low-dose groups, respectively (P < .0001). In the intent-to-treat analysis, 15% versus 16% of the patients in the high-dose and low-dose groups, respectively, experienced a first event of the composite endpoint (hazard ratio, 0.94 [0.60-1.48]; P = .78), whereas 1% and 4% of patients in the high-dose and low-dose groups, respectively, experienced an incident symptomatic fracture (odds ratio, 0.24 [0.07-0.86], P = .03). The incidence of adverse events was similar between the groups. After renal transplantation, high doses of cholecalciferol are safe but do not reduce extraskeletal complications (trial registration: ClinicalTrials.gov; identifier: NCT01431430).

Primary Graft Function and 5 Year Insulin Independence After Pancreas and Islet Transplantation for Type 1 Diabetes: A Retrospective Parallel Cohort Study.

In islet transplantation (ITx), primary graft function (PGF) or beta cell function measured early after last infusion is closely associated with long term clinical outcomes. We investigated the association between PGF and 5 year insulin independence rate in ITx and pancreas transplantation (PTx) recipients. This retrospective multicenter study included type 1 diabetes patients who underwent ITx in Lille and PTx in Nantes from 2000 to 2022. PGF was assessed using the validated Beta2-score and compared to normoglycemic control subjects. Subsequently, the 5 year insulin independence rates, as predicted by a validated PGF-based model, were compared to the actual rates observed in ITx and PTx patients. The study enrolled 39 ITx (23 ITA, 16 IAK), 209 PTx recipients (23 PTA, 14 PAK, 172 SPK), and 56 normoglycemic controls. Mean[SD] PGF was lower after ITx (ITA 22.3[5.2], IAK 24.8[6.4], than after PTx (PTA 38.9[15.3], PAK 36.8[9.0], SPK 38.7[10.5]), and lower than mean beta-cell function measured in normoglycemic control: 36.6[4.3]. The insulin independence rates observed at 5 years after PTA and PAK aligned with PGF predictions, and was higher after SPK. Our results indicate a similar relation between PGF and 5 year insulin independence in ITx and solitary PTx, shedding new light on long-term transplantation outcomes.

[Association between controlled circulatory death donor waitlisting and waiting time before kidney transplantation in a French center]. / Association entre l'inscription sur liste d'attente de donneur à cœur arrêté contrôlé Maastricht III et le temps d'attente avant la transplantation rénale dans un centre français.

INTRODUCTION: Transplantation from controlled donation after circulatory determination of death (cDCD) is a new practice in France. An additional specific consent is required for registration on the cDCD waiting list. The aim of this study is to evaluate the impact of cDCD acceptance on the waiting time for the registered patients on the transplant list. METHODS: Patients registered on the kidney transplant waiting list for a Death Brain Donor (DBD) kidney transplant between 2018 and 2019 in our center were included. Patients who were candidates for a second kidney transplant or who had already received an organ transplant were not included. The cDCD waiting list registration was authorized by a signed consent of the patient on the day of DBD registration. The primary endpoint was time to renal transplantation. RESULTS: Of the 315 patients eligible for a cDCD graft at transplant list registration, 152 were registered on the cDCD waiting list. Time to transplantation for these patients was multiplied by 1.42 (95%CI 1.07-1.87) compared with patients not registered for a cDCD graft. The time to transplantation was 2.59 months (95%CI 0.49-4.69) shorter for a 2-year follow-up for cDCD-listed patients. This represents one additional transplant at 6 months for every seven registered patients. CONCLUSION: cDCD waiting list registration reduced the time to kidney transplantation in France.

Absence of Mortality Differences Between the First and Second COVID-19 Waves in Kidney Transplant Recipients.

Introduction: SARS-CoV-2 pandemic evolved in 2 consecutive waves during 2020. Improvements in the management of COVID-19 led to a reduction in mortality rates among hospitalized patients during the second wave. Whether this progress benefited kidney transplant recipients (KTRs), a population particularly vulnerable to severe COVID-19, remained unclear. Methods: In France, 957 KTRs were hospitalized for COVID-19 in 2020 and their data were prospectively collected into the French Solid Organ Transplant (SOT) COVID registry. The presentation, management, and outcomes of the 359 KTRs diagnosed during the first wave were compared to those of the 598 of the second wave. Results: Baseline comorbidities were similar between KTRs of the 2 waves. Maintenance immunosuppression was reduced in most patients but withdrawal of antimetabolite (73.7% vs. 58.4%, P < 0.001) or calcineurin inhibitor (32.1% vs. 16.6%, P < 0.001) was less frequent during the second wave. Hydroxychloroquine and azithromycin that were commonly used during the first wave (21.7% and 30.9%, respectively) but were almost abandoned during the second wave. In contrast, the use of high dose corticosteroids doubled (19.5% vs. 41.6%, P < 0.001). Despite these changing trends in COVID-19 management, 60-day mortality was not statistically different between the 2 waves (25.3% vs. 23.9%; Log Rank, P = 0.48) and COVID-19 hospitalization period was not associated with death due to COVID-19 in multivariate analysis (Hazard ratio 0.89, 95% confidence interval 0.67-1.17, P = 0.4). Conclusion: We conclude that changing of therapeutic trends during 2020 did not reduce COVID-19 related mortality among KTRs. Our data indirectly support the importance of vaccination and neutralizing monoclonal anti-SARS-CoV-2 antibodies to protect KTRS from severe COVID-19.

[Nephrology 2.0: Communication with connected patients and health professionals]. / La néphrologie 2.0 : communication avec les patients connectés et les professionnels de santé.

Web 2.0 is characterized by the development of the Internet from its initial static content to a dynamic and participatory content, and by the large place taken by social networks. The growing interest of health actors for information and communication via these new media is gradually but lastingly modifying the practice of nephrology. These developments require nephrologists to understand the issues, rules and risks associated with these digital tools. The present article summarizes the main practical aspects of communication with patients and health professionals and addresses the important issue of the digital identity of the caregiver in the new field of connected nephrology.

The challenge of HLA donor specific antibodies in the management of pancreatic islet transplantation: an illustrative case-series.

Islet transplantation is a unique paradigm in organ transplantation, since multiple donors are required to achieve complete insulin-independence. Preformed or de novo Donor Specific Antibodies (DSA) may target one or several donor islets, which adds complexity to the analysis of their impact. Adult patients with type 1 diabetes transplanted with pancreatic islets between 2005 and 2018 were included in a single-center observational study. Thirty-two recipients with available sera tested by solid-phase assays for anti-HLA antibodies during their whole follow-up were analyzed. Twenty-five recipients were islet-transplantation-alone recipients, and 7 islet-after-kidney recipients. Seven recipients presented with DSA at any time during follow-up (two with preformed DSA only, one with preformed and de novo DSA, 4 with de novo DSA only). Only islet-transplantation-alone recipients presented with de novo DSA. Three clinical trajectories were identified according to: 1/the presence of preformed DSA, 2/early de novo DSA or 3/late de novo DSA. Only late de novo DSA were associated with unfavorable outcomes, depicted by a decrease of the ß-score. Islet transplantation with preformed DSA, even with high MFI values, is associated with favorable outcomes in our experience. On the contrary, de novo DSA, and especially late de novo DSA, may be associated with allograft loss.

Association Between Maintenance Immunosuppressive Regimens and COVID-19 Mortality in Kidney Transplant Recipients.

BACKGROUND: Solid organ transplant recipients are at high risk for fatal forms of coronavirus disease 2019 (COVID-19). We conducted a cohort study among kidney transplant (KT) recipients from the French Solid Organ Transplant COVID-19 Registry to investigate the association between maintenance immunosuppressive drugs and 60-d mortality. METHODS: Data from all KT recipients with COVID-19 included in the French Solid Organ Transplant COVID-19 Registry between February 28, 2020, and December 30, 2020, were retrieved. We evaluated associations between immunosuppressive drugs and death within 60 d using logistic regression, with all baseline characteristics considered to influence outcome or immunosuppressive regimen. The Benjamini-Hochberg correction was used for controlling false positive rate; 40 multiple imputations were performed. Adjusted P value <0.05 was considered statistically significant. RESULTS: There were 1451 KT recipients included. Median age was 58 y, and 66.4% were men. Most frequent comorbidities were hypertension (81.9%), diabetes (34.5%), and cardiovascular disease (29.5%). Median time since transplant was 71 mo. Maintenance immunosuppression regimens included calcineurin inhibitors (1295, 89.2%), antimetabolites (1205, 83%), corticosteroids (1094, 75.4%), mammalian target of rapamycin inhibitors (144, 9.9%), and belatacept (58, 4.0%). Among 1451 transplant recipients, 201 (13.9%) died within 60 d. Older age and higher baseline serum creatinine were associated with mortality (odds ratios, 1.09 [1.07-1.11] and 1.01 [1.005-1.009], P < 0.001). Corticosteroid-free regimens were associated with a significantly lower risk of death (odds ratio, 0.48 [0.31-0.76]; P = 0.011). CONCLUSIONS: Corticosteroid-free regimens were associated with a lower risk of death in KT recipients with COVID-19. Long-term exposure to corticosteroids impairs immune functions and may predispose solid organ transplant recipients to severe forms of COVID-19.

Post-Transplantation Early Blood Transfusion and Kidney Allograft Outcomes: A Single-Center Observational Study.

The association between blood transfusion and the occurrence of de novo HLA donor specific antibodies (DSA) after kidney transplantation remains controversial. In this single-center observational study, we examined the association between early blood transfusion, i.e. before 1-month post-transplantation, and the risk of DSA occurrence, using Luminex based-methods. In total, 1,424 patients with a minimum of 1-month follow-up were evaluated between January 2007 and December 2018. During a median time of follow-up of 4.52 years, we observed 258 recipients who had at least one blood transfusion during the first month post-transplantation. At baseline, recipients in the transfused group were significant older, more sensitized against HLA class I and class II antibodies and had a higher 1-month serum creatinine. Cox proportional hazards regression analyses did not show any significant association between blood transfusion and the risk of de novo DSA occurrence (1.35 [0.86-2.11], p = 0.19), the risk of rejection (HR = 1.33 [0.94-1.89], p = 0.11), or the risk of graft loss (HR = 1.04 [0.73-1.50], p = 0.82). These data suggest then that blood transfusion may not be limited when required in the early phase of transplantation, and may not impact long-term outcomes.

Impact of kidney transplantation in obese candidates: a time-dependent propensity score matching study.

BACKGROUND: Although kidney transplantation (KT) is considered the best treatment for end-stage renal disease (ESRD), there are concerns about its benefit in the obese population because of the increased incidence of post-transplant adverse events. We compared patients who underwent KT versus patients awaiting KT on dialysis. METHODS: We estimated the life expectancy [restricted mean survival time (RMST)] for a 10-year follow-up by matching on time-dependent propensity scores. The primary outcome was time to death. RESULTS: In patients with a body mass index (BMI) ≥30 kg/m2 (n = 2155 patients per arm), the RMST was 8.23 years [95% confidence interval (CI) 8.05-8.40] in the KT group versus 8.00 years (95% CI 7.82-8.18) in the awaiting KT group, a difference of 2.71 months (95% CI -0.19-5.63). In patients with a BMI ≥35 kg/m2 (n = 212 patients per arm), we reported no significant difference [8.56 years (95% CI 7.96-9.08) versus 8.66 (95% CI 8.10-9.17)]. Hence we deduced that KT in patients with a BMI between 30 and 35 kg/m2 was beneficial in terms of life expectancy. CONCLUSION: Regarding the organ shortage, KT may be questionable for those with a BMI ≥35 kg/m2. These results do not mean that a BMI ≥35 kg/m2 should be a barrier to KT, but it should be accounted for in allocation systems to better assign grafts and maximize the overall life expectancy of ESRD patients.

Impact of targeted hypothermia in expanded-criteria organ donors on recipient kidney-graft function: study protocol for a multicentre randomised controlled trial (HYPOREME).

INTRODUCTION: Expanded-criteria donors (ECDs) are used to reduce the shortage of kidneys for transplantation. However, kidneys from ECDs are associated with an increased risk of delayed graft function (DGF), a risk factor for allograft loss and mortality. HYPOREME will be a multicentre randomised controlled trial (RCT) comparing targeted hypothermia to normothermia in ECDs, in a country where the use of machine perfusion for organ storage is the standard of care. We hypothesise that hypothermia will decrease the incidence of DGF. METHODS AND ANALYSIS: HYPOREME is a multicentre RCT comparing the effect on kidney function in recipients of targeted hypothermia (34°C-35°C) and normothermia (36.5°C-37.5°C) in the ECDs. The temperature intervention starts from randomisation and is maintained until aortic clamping in the operating room. We aim to enrol 289 ECDs in order to analyse the kidney function of 516 recipients in the 53 participating centres. The primary outcome is the occurrence of DGF in kidney recipients, defined as a requirement for renal replacement therapy within 7 days after transplantation (not counting a single session for hyperkalemia during the first 24 hours). Secondary outcomes include the proportion of patients with individual organs transplanted in each group; the number of organs transplanted from each ECD and the vital status and kidney function of the recipients 7 days, 28 days, 3 months and 1 year after transplantation. An interim analysis is planned after the enrolment of 258 kidney recipients. ETHICS AND DISSEMINATION: The trial was approved by the ethics committee of the French Intensive Care Society (CE-SRLF-16-07) on 26 April 2016 and by the competent French authorities on 20 April 2016 (Comité de Protection des Personnes-TOURS-Région Centre-Ouest 1, registration #2016-S3). Findings will be published in peer-reviewed journals and presented during national and international scientific meetings. TRIAL REGISTRATION NUMBER: NCT03098706.

Association Between Deceased Donor Acute Kidney Injury Assessed Using Baseline Serum Creatinine Back-Estimation and Graft Survival: Results From the French National CRISTAL Registry.

RATIONALE & OBJECTIVE: Deceased donor acute kidney injury (AKI) frequently leads to kidney discards, but its impact on long-term graft survival in kidney transplant recipients remains unclear. We investigated the association between deceased donor AKI assessed using back-estimation of baseline serum creatinine (Scr) and graft survival. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: Adult patients represented within the French CRISTAL registry who received a single kidney allograft from brain-dead deceased donors between January 2006 and December 2017. EXPOSURE: A back-estimated Scr baseline value was derived for an assumed glomerular filtration rate at 75mL/min/1.73m2, using the MDRD Study equation. A refined classification system for donor AKI was implemented as follows: no AKI, undetermined AKI/chronic kidney disease (CKD), recovery from AKI, and ongoing AKI. OUTCOME: Death-censored graft survival. ANALYTICAL APPROACH: Multivariable Cox models using a robust variance estimator for paired kidneys from the same donor. RESULTS: We classified 26,786 recipients as follows: no AKI (n=19,276); undetermined AKI/CKD (n=1,745); recovery from AKI (n=2,392); and ongoing AKI (n=3,373). We observed 4,458 kidney graft losses during a median follow-up period of 5.7 years. Compared with no AKI, ongoing AKI was associated with an increased risk of graft failure (hazard ratio [HR], 1.24 [95% CI, 1.13-1.35]). The HRs for graft failure in the undetermined AKI/CKD and recovery from AKI groups (1.22 [95% CI, 1.07-1.38] and 1.18 [95% CI, 1.06-1.31], respectively) were similar to those observed in the ongoing AKI group. The adverse effect of deceased donor AKI was no longer evident when relying either on the admission or the lowest Scr throughout the procurement procedure as baseline Scr. LIMITATIONS: No measurement of urine output in donors. CONCLUSIONS: Deceased donor ongoing AKI, undetermined AKI/CKD, and recovery from AKI according to back-estimated baseline Scr are associated with decreased graft survival. The definition of baseline Scr as the first value measured on admission would have led to a misclassification bias and erroneous estimates.

Impact of Tacrolimus Daily Dose Limitation in Renal Transplant Recipients Expressing CYP3A5: A Retrospective Study.

The pharmacokinetic variability of tacrolimus can be partly explained by CYP3A5 activity. Our objective was to evaluate a tacrolimus sparing policy on renal graft outcome according to CYP3A5 6986A>G genetic polymorphism. This retrospective study included 1114 recipients with a median follow-up of 6.3 years. Genotyping of the 6986A>G allelic variant corresponding to CYP3A5*3 was systematically performed. One year after transplantation, tacrolimus blood trough concentration (C0) target range was 5-7 ng/mL. However, daily dose was capped to 0.10 mg/kg/day regardless of the CYP3A5 genotype. A total 208 CYP3A5*1/- patients were included. Despite a higher daily dose, CYP3A5*1/- recipients exhibited lower C0 during follow-up (p < 0.01). Multivariate analysis did not show any significant influence of CYP3A5*1/- genotype (HR = 0.70, 0.46-1.07, p = 0.10) on patient-graft survival. Glomerular Filtration Rate (GFR) decline was significantly lower for the CYP3A5*1/- group (p = 0.02). The CYP3A5*1/- genotype did not significantly impact the risk of biopsy-proven acute rejection (BPAR) (HR = 1.01, 0.68-1.49, p = 0.97) despite significantly lower C0. Based on our experience, a strategy of tacrolimus capping is associated with a better GFR evolution in CYP3A5*1/- recipients without any significant increase of BPAR incidence. Our study raised some issues about specific therapeutic tacrolimus C0 targets for CYP3A5*1/- patients and suggests to set up randomized control studies in this specific population.