BACKGROUND Vascular complications remain a significant concern after kidney transplantation. While external iliac (EI) implantation is standard, common iliac (CI) implantation is occasionally performed in selected cases, particularly in the presence of vascular disease or anatomical constraints. We compared vascular outcomes according to the arterial anastomosis site. MATERIAL AND METHODS We conducted a bicentric retrospective study including kidney transplant recipients between 2015 and 2019. Implantation strategy differed between centers, with a preferential use of CI implantation in one center and EI implantation in the other. Patients underwent arterial anastomosis to the CI (n=157) or EI vessels (n=359). The primary endpoint was vascular complications graded according to the Clavien-Dindo classification. Secondary endpoints included ≥60% vascular stenosis, lymphocele rate, and graft failure at 2 years. RESULTS Baseline characteristics differed between groups, reflecting center-specific practices and case-mix variations. Overall vascular complication rates were similar (22.9% in CI vs 20.1% in EI; P=0.46). However, Clavien-Dindo ≥III complications were more frequent in the CI group (14.6% vs 7.5%; P=0.01). Severe vascular stenosis requiring intervention (Clavien-Dindo III) occurred more often in CI recipients (7.0% vs 0.8%; P<0.01). Lymphocele was also significantly more frequent in the CI group (27.4% vs 9.2%; P<0.01; OR 4.55, 95% CI 2.56-8.09; P<0.001). At 2 years, graft failure rates did not differ significantly (4.1% vs 5.3%; P=0.29). CONCLUSIONS In this bicentric retrospective analysis, CI implantation was associated with a higher rate of severe vascular complications, particularly stenosis, and lymphocele, without a significant impact on graft failure at 2 years. These findings should be interpreted with caution, as they likely reflect, at least in part, differences in patient selection and center-specific surgical practices.

The MTOR inhibitors have demonstrated antiviral properties, and prior non-randomized studies have suggested they may have a suppressive effect on BKPyV replication. Here, in this randomized, multicenter, controlled trial (BKEVER study), we sought to evaluate the impact of everolimus (EVR) in facilitating the clearance of BKPyV compared to simply reducing immunosuppression among kidney transplant recipients (KTRs). All together, 130 KTRs presenting with BKPyV DNAemia were randomized 1:1 into two groups. The EVR group, in which mycophenolate mofetil (MMF) was replaced by EVR along with a decrease in calcineurin inhibitor trough levels and secondly the MMF group, in which the MMF dose was decreased by half along with a similar lowering of calcineurin inhibitor levels. The primary endpoint was the proportion of patients achieving viral clearance at six months. Secondary endpoints included the kinetics of BKPyV replication over time, the incidence of BKPyV-associated nephropathy, kidney graft function, the incidence of kidney graft rejection, and medication tolerability over two years. Significantly, BKPyV clearance was achieved in 55.7% of patients in the EVR group compared to 81.3% of patients in the MMF group at six months. The reduction in BKPyV DNA load was significantly more rapid in the MMF group. Calcineurin inhibitor trough levels were within expected target ranges and did not differ meaningfully between the two groups from randomization through month six. Two grafts were lost, and four patients died. Eleven patients in the EVR group and six patients in the MMF group developed biopsy-proven BKPyV nephropathy. Thus, in KTRs with BKPyV DNAemia, replacing MMF with EVR along with lowering calcineurin inhibitor levels did not lead to more frequent or faster clearance of BKPyV.

Patients with chronic kidney disease (CKD) requiring kidney replacement therapy experience a loss in walking autonomy. This study used data from the French Renal Epidemiology and Information Network in Nephrology (REIN) registry and those from the National Health Data System [Système national des Données de Santé (SNDS)] to assess associations between walking inabilities and patient characteristics. We extracted data on all patients receiving kidney replacement therapy in France as of 31 December 2020. We used logistic regression to evaluate data associated with walking autonomy. We also created four focus groups to explore the perspectives of dialysis patients with respect to walking autonomy, and conducted a thematic analysis of qualitative data. Data were available for 50 629 adults undergoing dialysis. Among the remaining 48 243 patients without missing data, 6834 (14%) were identified as having a walking disability, defined as walking with assistance or being totally unable to walk. Walking disabilities were associated with numerous comorbidities after adjustment for age. Despite their limitations, 2117 (46%) patients requiring assistance and 730 (43%) with total inability to walk had not been reimbursed for a mobility aid through the National Health Data System (SNDS). Thematic analysis identified four major themes from the focus groups: difficulties carrying out daily tasks, impact on social life, impact on connection to the body and psychological impact. Walking disability is strongly associated with patient comorbidities. It impairs quality of life, particularly through psychological and social consequences. Dedicated interventions and improved access to assistive devices are needed to help patients with walking disabilities.

Introduction:In kidney transplantation, concerns remain about whether corticosteroids (CS) avoidance could favor interstitial fibrosis (IF) and its progression. We conducted a multicenter randomized noninferiority clinical trial to evaluate the histopathological progression of IF using an innovative automated method in patients receiving CS or not. Methods:Low immunological risk recipients of a kidney allograft for whom an analyzable biopsy was available at implantation were randomly assigned to receive a CS-free regimen (CS-) or a standard CS tapering regimen (CS+). All patients received induction therapy with basiliximab, and conventional maintenance therapy. The primary outcome was the difference in the percentage change of IF between the baseline and the 1-year protocol biopsy with a prespecified 10% noninferiority margin. Results:A total of 108 patients were analyzed in the full analysis set (FAS) population as follows: 52 patients in the CS+ group and 56 patients in the CS- group. Complete avoidance of CS was reached in 36 (64%) CS- patients (per-protocol [PP] population). In the FAS population, the mean percentage of IF at implantation was 19.5% ± 7.9% in the CS- group (n = 51) and 17.9% ± 7.8% in the CS+ group (n = 49; P = 0.3), and 25.9% ± 11% (n = 43) and 21.5% ± 11.2% (n = 39; P = 0.03) at 1 year. Considering the difference in IF change, the CS- group was noninferior to the CS+ group neither in the FAS and PP population: 4.45% 95% confidence interval [CI]: [-0.4% to 9.3%] and 3.0% 95% CI: [-2.7% to 8.6%], respectively. Conclusion:Progression of IF during the first year following kidney transplantation was not inferior among patients without CS compared with patients with CS.

The clinical impact of individual dose adjustment of mycophenolate mofetil is still debated, due to conflicting results from randomized clinical trials. This retrospective study aimed to compare 3-year rejection-free survival and adverse effects between adult kidney transplant recipients (KTRs) with or without mycophenolate mofetil model-informed precision dosing (MIPD). MIPD is defined here as mycophenolic acid area under the curve (AUC0-12h) estimation using a limited sampling strategy, pharmacokinetic models and Bayesian estimators; dose recommendation to reach AUC0-12h = 45 mg.h/L; using a widely used online expert system. The study, nested in two multicenter prospective cohort studies, focused on patients who received a mycophenolate drug and were followed up for 1-3 years. Mycophenolate mofetil MIPD was prescribed as per local practice, on a regular basis, when deemed necessary, or not at all. The MIPD group included 341 KTRs and the control group 392. At 3 years, rejection-free survival was respectively 91.2% and 80.6% (P < 0.001) and the cumulative incidence of rejection 5.08% vs. 12.7% per patient × year (hazard ratio = 0.49 (0.34, 0.71), P < 0.001), corresponding to a 2.5-fold reduction. Significant association with rejection-free survival was confirmed in patients at low or high risk of rejection (P = 0.017 and 0.013) and in patients on tacrolimus, but not on cyclosporine (P < 0.001 and 0.205). The mycophenolate mofetil MIPD group had significantly more adverse effects, but most occurred before the first AUC0-12h, suggesting some may be the reason why MIPD was ordered.

Hematopoietic stem cell transplantation (HSCT) aims to cure multiple hematologic malignancies, non-malignant diseases, metabolic disorders, and immune deficiencies. Along with other transplant-related organ toxicities, both acute and chronic kidney disease (CKD) are common complications of allogeneic HSCT, affecting 10%-73% and 0-60% of patients respectively, depending on the definitions of kidney dysfunction, duration of follow-up and transplant strategies.S1-S4 The proportion of CKD patients develop end-stage renal disease (ESRD) is approximately 4%.

Once-daily extended-release tacrolimus (LCPT) exhibits increased bioavailability versus immediate-release (IR-TAC) and prolonged release (PR-TAC) tacrolimus. Improvements in tremor were previously reported in a limited number of kidney transplant patients who switched to LCPT. We conducted a non-interventional, non-randomized, uncontrolled, longitudinal, prospective, multicenter study to assess the impact of switching to LCPT on tremor and quality of life (QoL) in a larger population of stable kidney transplant patients. The primary endpoint was change in The Essential Tremor Rating Assessment Scale (TETRAS) score; secondary endpoints included 12-item Short Form Survey (SF-12) scores, tacrolimus trough concentrations, neurologic symptoms, and safety assessments. Subgroup analyses were conducted to assess change in TETRAS score and tacrolimus trough concentration/dose (C0/D) ratio by prior tacrolimus formulation and tacrolimus metabolizer status. Among 221 patients, the mean decrease of TETRAS score after switch to LCPT was statistically significant (p < 0.0001 vs. baseline). There was no statistically significant difference in change in TETRAS score after switch to LCPT between patients who had received IR-TAC and those who had received PR-TAC before switch, or between fast and slow metabolizers of tacrolimus. The overall increase of C0/D ratio post-switch to LCPT was statistically significant (p < 0.0001) and from baseline to either M1 or M3 (both p < 0.0001) in the mITT population and in all subgroups. In the fast metabolizers group, the C0/D ratio crossed over the threshold of 1.05 ng/mL/mg after the switch to LCPT. Other neurologic symptoms tended to improve, and the SF-12 mental component summary score improved significantly. No new safety concerns were evident. In this observational study, all patients had a significant improvement of tremor, QoL and C0/D ratio post-switch to LCPT irrespective of the previous tacrolimus formulation administered (IR-TAC or PR-TAC) and irrespective from their metabolism status (fast or slow metabolizers).

Background:Prognostic models are becoming increasingly relevant in clinical trials as potential surrogate end points and for patient management as clinical decision support tools. However, the effect of competing risks on model performance remains poorly investigated. We aimed to carefully assess the performance of competing risk and noncompeting risk models in the context of kidney transplantation, where allograft failure and death with a functioning graft are two competing outcomes. Methods:We included 11,046 kidney transplant recipients enrolled in ten countries. We developed prediction models for long-term kidney graft failure prediction, without accounting (i.e., censoring) and accounting for the competing risk of death with a functioning graft, using Cox, Fine–Gray, and cause-specific Cox regression models. To this aim, we followed a detailed and transparent analytical framework for competing and noncompeting risk modeling and carefully assessed the models' development, stability, discrimination, calibration, overall fit, clinical utility, and generalizability in external validation cohorts and subpopulations. More than 15 metrics were used to provide an exhaustive assessment of model performance. Results:Among 11,046 recipients in the derivation and validation cohorts, 1497 (14%) lost their graft and 1003 (9%) died with a functioning graft after a median follow-up postrisk evaluation of 4.7 years (interquartile range, 2.7–7.0). The cumulative incidence of graft loss was similarly estimated by Kaplan–Meier and Aalen–Johansen methods (17% versus 16% in the derivation cohort). Cox and competing risk models showed similar and stable risk estimates for predicting long-term graft failure (average mean absolute prediction error of 0.0140, 0.0138, and 0.0135 for Cox, Fine–Gray, and cause-specific Cox models, respectively). Discrimination and overall fit were comparable in the validation cohorts, with concordance index ranging from 0.76 to 0.87. Across various subpopulations and clinical scenarios, the models performed well and similarly, although in some high-risk groups (such as donors older than 65 years), the findings suggest a trend toward moderately improved calibration when using a competing risk approach. Conclusions:Competing and noncompeting risk models performed similarly in predicting long-term kidney graft failure.

Background Prognostic models are becoming increasingly relevant in clinical trials as potential surrogate endpoints, and for patient management as clinical decision support tools. However, the impact of competing risks on model performance remains poorly investigated. We aimed to carefully assess the performance of competing risks and non-competing risks models in the context of kidney transplantation, where allograft failure and death with a functioning graft are two competing outcomes. Methods We included 10 546 adult kidney transplant recipients enrolled in 10 countries (3941 patients in the derivation cohort, 6605 patients in international external validation cohorts). We developed prediction models for long-term kidney graft failure prediction, without accounting (i.e., censoring) and accounting for the competing risk of death with a functioning graft, using Cox and Fine-Gray regression models. To this aim, we followed a detailed and transparent analytical framework for competing and non-competing risks modelling, and carefully assessed the models' development, stability, discrimination, calibration, overall fit, and generalizability in external validation cohorts and subpopulations. In total, 15 metrics were used to provide an exhaustive assessment of model performance. Results Among the 3941 recipients included in the derivation cohort, 538 (13.65%) lost their graft and 414 (10.50%) died after a median follow-up post-risk evaluation of 5.77 years (IQR 3.52-7.00). In the external validation cohorts, 896 (13.56%) graft losses and 525 (7.95%) deaths occurred after a median follow-up post-risk evaluation of 4.25 years (IQR 2.35-6.59). At 7 years post-risk evaluation, overestimation of the cumulative incidence was moderate when using Kaplan-Meier, compared to the Aalen-Johansen estimate (16.71% versus 15.67% in the derivation cohort). Cox and Fine-Gray models for predicting the long-term graft failure exhibited similar and stable risk estimates (average MAPE of 0.0140 and 0.0138 for Cox and Fine-Gray models, respectively). At 7 years post-risk evaluation, discrimination and overall fit were good and comparable in the external validation cohorts (concordance index ranging from 0.76 to 0.86, Brier Scores ranging from 0.102 to 0.141). In a large series of subpopulations and clinical scenarios, both models performed well and similarly. Conclusions Competing and non-competing risks models performed similarly in predicting long-term kidney graft failure. These results should be interpreted in light of the low rate of the competing event in our cohort, and do not stand as a general conclusion for competing risks modelling. Depending on the clinical scenario and the population considered, competing risks may be crucial to consider for accurate risk predictions. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement INSERM-Action thematique incitative sur programme Avenir (ATIP-Avenir) provided financial support; OA received a grant from the Fondation Bettencourt Schueller; academic grant support was provided by the non-profit organizations MSD Avenir and OrganX. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The institutional review boards with oversight for patients at each participating center gave ethical approval for this work. Each patient from the Paris Transplant Group cohort provided written informed consent to be included in the Paris Transplant Group database. This database has been approved by the National French Commission for Bioinformatics, Data, and Patient Liberty: CNIL registration number: 363505. The Institutional Review Boards of Necker and Saint-Louis Hospitals approved the Paris Transplant Group's cohort. For the validation sets, data were collected as part of routine clinical practice and entered in centers' databases in compliance with local and national regulatory requirements and sent anonymized to the Paris Transplant Group. These validation cohorts followed the rules applied in each country. As part of research collaborations, the institutional review boards with oversight for patients at each center agreed to send the anonymized data to the Paris Transplant Group. A data audit was then conducted to ensure that the data were sufficient quality for analysis. In each cohort, patients gave written informed consent at the day of transplantation and were over 18 years of age. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

IntroductionHepatitis E virus (HEV) can cause chronic infection (≥3 months) and cirrhosis in immunocompromised patients, especially kidney transplant recipients. Low alanine aminotransferase (ALT) levels and high HEV intrahost diversity have previously been associated with evolution toward chronicity in these patients. We hypothesized that additional clinical and viral factors could be associated with the risk of chronic HEV infection.MethodsWe investigated a series of 27 kidney transplant recipients with HEV infection, including 20 patients with chronic hepatitis E.ResultsHigh tacrolimus trough concentration at diagnosis was the most relevant marker associated with chronic hepatitis E (9.2 vs. 6.4 ng/ml, P = 0.04). Most HEV genetic changes selected during HEV infection were compartmentalized between plasma and feces.ConclusionThis compartmentalization highlights the diversity and complexity of HEV replication compartments. Tacrolimus trough concentration at diagnosis of HEV infection could allow an early identification of patients at high risk of chronic hepatitis E and guide treatment initiation.

Background.In kidney transplant recipients with positive serology (R+) for the cytomegalovirus (CMV), 2 strategies are used to prevent infection, whose respective advantages over the other are still debated. This study aimed to evaluate the cost-effectiveness and cost utility of antiviral prophylaxis against CMV versus preemptive therapy, considering CMV infection-free survival over the first year posttransplantation as the main clinical outcome. Methods.Clinical, laboratory, and economic data were collected from 186 kidney transplant patients CMV (R+) included in the cohort study (85 patients who benefited from CMV prophylaxis and 101 from preemptive therapy). Costs were calculated from the hospital perspective and quality-adjusted life years (QALYs) using the EQ5D form. Using nonparametric bootstrapping, the incremental cost-effectiveness ratio (ICER) and cost utility were estimated (euros) for each case of infection avoided and each QALY gained for 1 y, respectively. Results.Prophylaxis significantly decreased the risk of CMV infection over the first year posttransplantation (hazard ratio 0.22, 95% confidence interval = 0.12-0.37, P < 0.01). Compared with preemptive therapy, prophylaxis saved financial resources (1155 per patient) and was more effective (0.42 infection avoided per patient), resulting in an ICER = 2769 per infection avoided. Prophylaxis resulted in a net gain of 0.046 in QALYs per patient and dominated over preemptive therapy with 1422 cost-saving for 1 QALY gained. Conclusions.This study shows that CMV prophylaxis, although considered as a more expensive strategy, is more cost-effective than preemptive therapy for the prevention of CMV infections in renal transplant patients. Prophylaxis had a positive effect on quality of life at reasonable costs and resulted in net savings for the hospital.

Objective: Arterial hypertension (HTN) is responsible for the largest proportion of preventable mortality in the world. The primary cause of resistant hypertension (rHTN) is poor medication adherence. Blood or urine drug assays enable us to assess chemical adherence more accurately than self-reported questionnaires. We assayed anti-hypertensive drugs in patients with rHTN at our Center of Excellence in Hypertension, in collaboration with the Pharmacology and Toxicology Laboratory. Design and method: Patients with rHTN (office SBP/DBP >140/90 mmHg or out of office daytime >135/85 mmHg despite being prescribed 3 drugs at optimal dosage, including a diuretic, a renin angiotensin system inhibitor (RASI) and a calcium channel blocker (CCB), were informed of the study and agreed to have blood drugs concentrations measured. We describe the results for chemical adherence in the first 54 patients included between January 1, 2021 and September 1, 2023 in our center. Results: Of the 54 patients included, 38 (70%) were men, with a mean age of 65 +/- 11 years. The mean number of antihypertensive treatments prescribed was 5 +/- 1 (min 3, max 8). The proportions of treatments were RASI 87%, CCB (mainly dihydropyridines) 81%, diuretics 81%, beta-blockers 76%, alpha-blockers 57%, mineralocorticoid receptor antagonists (MRA) 37%, and central antihypertensives 26%. The best compliance was observed with alpha-blockers 81%, followed by CCB 50%, RASI 45%, diuretics 37% and beta-blockers 34%. The least compliant were central antihypertensives 0% and MRA 5%. All prescribed drugs were completely absent in the blood in 26% of patients, and 63% of patients had incomplete adherence (1 or more but not all drugs present in the blood), of whom 1/3 were non-compliant to 3 or more medications. Only for 9% of patients chemical adherence was excellent. Conclusions: Chemical adherence when measured at clinical visit was poor in this cohort of patients followed in a center of excellence. Limitations of this study are lack of follow-up for the same patient to assess variation in adherence over time, and small sample size. These results suggest the need to develop therapeutic education to improve patient involvement in the management of HTN and compliance.

Dear Editor, Merkel cell carcinoma (MCC), that is primary cutaneous neuroendocrine carcinoma is a rare skin cancer.1 Main risk factors are UV exposure and immunosuppression.1 In 2008, Feng et al.2 identified genomic integration of the Merkel cell Polyomavirus (MCPyV) as the causative agent of about 80% of MCC cases. MCPyVnegative cases were later identified as UVinduced tumours frequently harbouring TP53 and RB1 mutations and displaying worst outcome.1 A fivefold to 24fold increased risk of MCC is observed in solid organ transplant recipients (OTR).3 Moreover, MCPyVnegative MCC has recently been found to predominate in this setting.4 As we demonstrated that MCPyVnegative MCC can arise from squamous cell carcinoma (SCC),5 a finding independently evidenced by Harms et al.6 and given that SCC are the most frequent neoplasms in OTR,7 we hypothesized that the transformation of SCC towards MCC could constitute the major mechanism of MCC formation in OTR. In this context, the objective of this study was to investigate the predominant aetiology of MCC in kidney transplant recipients. To this purpose, 15 MCC cases with available FFPE material developed in OTR were extracted from the SPIESSER database, a French network of renal transplant recipients (ethical committee EudracCT/ID RCB: 2009A0105651; eight hospital centres, 1995– 2021). Diagnosis of MCC was confirmed as previously described.8 Clinical, microscopic and molecular features of the cases are available in Table 1. Briefly, patients were mostly male (M/F: 10/5), with a median age at MCC diagnosis of 63 years (range 52– 84) and a median delay of 11.5 years (range 1– 24 years) between transplantation and MCC diagnosis. Only 66% of the patients were alive 1 year after the diagnosis and only 20% 4 years later. MCPyV genome was detected by RTPCR9 in five cases (33%; mean MCPyV load = 5.84 copy/cell, range 3– 15), and immunohistochemistry revealed expression of the MCPyV Large T antigen in four of these cases. Accordingly, serum Tantigen antibodies, absent in pretransplant samples, were further detected in all patients after diagnosis of MCPyVpositive MCC (n = 3/3 with available serum) and f luctuated with disease burden, as previously demonstrated in nonimmunosuppressed patients.10 Loss of expression of pRB, a hallmark of UVinduced tumours,9 were detected in all MCPyVnegative cases. No differences were observed in term of sex, age at the diagnosis time, age at the transplantation time, immunosuppressive treatment between MCPyVnegative and MCPyVpositive cases. By contrast, higher frequency of head and neck location was observed among MCPyVnegative tumours than in other (50% vs. 20%) further suggesting a UVrelated pathogenesis of such cases. In line with the hypothesis that MCPyVnegative tumours may derive from SCC, six patients with MCPyVnegative tumours had a prior history of SCC. Such hypothesis was further supported by the microscopic examination of MCC tumours in these cases revealing combined tumours, with the presence of an actinic keratosis or SCC component in association with the MCC in 7/10 samples of MCPyVnegative tumours. To confirm the clonal link between both tumour parts, the SCC and MCC components were microdissected independently in two cases with sufficient material (cases #6 and #8) and analysed by a large custom NGS panel. Such analysis revealed a common copy number variation profile. The nucleotide variation screening also detected a majority of mutations present in both SCC and MCC components in both cases (Figure 1). The occasional divergent mutations in SCC and MCC (one TP53 mutation for case #6 and one CHD8 mutation case #8) do not preclude a filiation between both components. To conclude, our study suggests that SCC to MCC transformation might represent a predominant mechanism of MCC development in kidney transplant recipients.

Introduction Hypertension is a burden for most kidney transplant recipients. Whether respect of hypertension guidelines results in better outcomes is unknown. Methods In this multicenter study, office blood pressure at 12 months following transplantation (i.e., after > 20 outpatient visits), and survival were assessed over 35 years among 2004 consecutive kidney transplant recipients who received a first kidney graft from 1985 to 2019 (follow-up: 26,232 patient-years). Results Antihypertensive medications were used in 1763/2004 (88.0%) patients. Renin-angiotensin-system blockers were used in 35.6% (47.1% when proteinuria was > 0.5 g/day) and calcium-channel blockers were used in 6.0% of patients. Combined treatment including renin-angiotensin-system-blockers, calcium-channel blockers and diuretics was used in 15.4% of patients receiving >= 3 antihypertensive drugs. Blood pressure was controlled in 8.3%, 18.8% and 43.1%, respectively, depending on definition (BP < 120/80, < 130/80, < 140/90 mmHg, respectively) and has not improved since the year 2001. Two-thirds of patients with uncontrolled blood pressure received < 3 antihypertensive classes. Low sodium intake < 2 g/day (vs >= 2) was not associated with better blood pressure control. Uncontrolled blood pressure was associated with lower patient survival (in multivariable analyses) and graft survival (in univariate analyses) vs controlled hypertension or normotension. Low sodium intake and major antihypertensive classes had no influence on patient and graft survival. Conclusions Pharmacological recommendations and sodium intake reduction are poorly respected, but even when respected, do not result in better blood pressure control, or patient or graft survival. Uncontrolled blood pressure, not the use of specific antihypertensive classes, is associated with reduced patient, and to a lesser extent, reduced graft survival, even using the 120/80 mmHg cut-off.

LCP-tacrolimus displays enhanced oral bioavailability compared to immediate-release (IR-) tacrolimus. The ENVARSWITCH study aimed to compare tacrolimus AUC(0-24 h) in stable kidney (KTR) and liver transplant recipients (LTR) on IR-tacrolimus converted to LCP-tacrolimus, in order to re-evaluate the 1:0.7 dose ratio recommended in the context of a switch and the efficiency of the subsequent dose adjustment. Tacrolimus AUC(0-24 h) was obtained by Bayesian estimation based on three concentrations measured in dried blood spots before (V2), after the switch (V3), and after LCP-tacrolimus dose adjustment intended to reach the pre-switch AUC(0-24 h) (V4). AUC(0-24 h) estimates and distributions were compared using the bioequivalence rule for narrow therapeutic range drugs (Westlake 90% CI within 0.90-1.11). Fifty-three KTR and 48 LTR completed the study with no major deviation. AUC(0-24 h) bioequivalence was met in the entire population and in KTR between V2 and V4 and between V2 and V3. In LTR, the Westlake 90% CI was close to the acceptance limits between V2 and V4 (90% CI = [0.96-1.14]) and between V2 and V3 (90% CI = [0.96-1.15]). The 1:0.7 dose ratio is convenient for KTR but may be adjusted individually for LTR. The combination of DBS and Bayesian estimation for tacrolimus dose adjustment may help with reaching appropriate exposure to tacrolimus rapidly after a switch.

Background Thrombotic microangiopathies (TMAs) are rare but can be severe in kidney transplant. recipients (KTR). Methods We analysed the epidemiology of adjudicated TMA in consecutive KTR during the. 2009–2021 period. Results TMA was found in 77/1644 (4.7%) KTR. Early TMA ( n = 24/77 (31.2%); 1.5% of all KTR) occurred during the first two weeks ((median, IQR) 3 [1–8] days). Triggers included acute antibody-mediated rejection (ABMR, n = 4) and bacterial infections ( n = 6). Graft survival (GS) was 100% and recurrence rate (RR) was 8%. Unexpected TMA ( n = 31/77 (40.2%); 1.5/1000 patient-years) occurred anytime during follow-up (3.0 (0.5–6.2) years). Triggers included infections (EBV/CMV: n = 10; bacterial: n = 6) and chronic active ABMR ( n = 5). GS was 81% and RR was 16%. Graft-failure associated TMA ( n = 22/77 (28.6%); 2.2% of graft losses) occurred after 8.8 (4.9–15.5) years). Triggers included acute ( n = 4) or chronic active ( n = 14) ABMR, infections (viral: n = 6; bacterial: n = 5) and cancer ( n = 6). 15 patients underwent transplantectomy. RR was 27%. Atypical ( n = 6) and typical ( n = 2) haemolytic and uremic syndrome, and isolated CNI toxicity ( n = 4) were rare. Two-third of biopsies presented TMA features. Conclusions TMA are mostly due to ABMR and infections; causes of TMA are frequently combined. Management often is heterogenous. Our nosology based on TMA timing identifies situations with distinct incidence, causes and prognosis.

Ischemia-reperfusion injury (IRI) induces several perturbations that alter immediate kidney graft function after transplantation and may affect long-term graft outcomes. Given the IRI-dependent metabolic disturbances previously reported, we hypothesized that proximal transporters handling endo/exogenous substrates may be victims of such lesions. This study aimed to determine the impact of hypoxia/reoxygenation on the human proximal transport system through two semi-targeted omics analyses. Human proximal tubular cells were cultured in hypoxia (6 or 24 h), each followed by 2, 24 or 48-h reoxygenation. We investigated the transcriptomic modulation of transporters. Using semi-targeted LC–MS/MS profiling, we characterized the extra/intracellular metabolome. Statistical modelling was used to identify significant metabolic variations. The expression profile of transporters was impacted during hypoxia (y + LAT1 and OCTN2), reoxygenation (MRP2, PEPT1/2, rBAT, and OATP4C1), or in both conditions (P-gp and GLUT1). The P-gp and GLUT1 transcripts increased (FC (fold change) = 2.93 and 4.11, respectively) after 2-h reoxygenation preceded by 24-h hypoxia. We observed a downregulation (FC = 0.42) of y+LAT1 after 24-h hypoxia, and of PEPT2 after 24-h hypoxia followed by 2-h reoxygenation (FC = 0.40). Metabolomics showed that hypoxia altered the energetic pathways. However, intracellular metabolic homeostasis and cellular exchanges were promptly restored after reoxygenation. This study provides insight into the transcriptomic response of the tubular transporters to hypoxia/reoxygenation. No correlation was found between the expression of transporters and the metabolic variations observed. Given the complexity of studying the global tubular transport systems, we propose that further studies focus on targeted transporters.