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Background: The risk of bleeding after percutaneous biopsy in kidney transplant recipients is usually low but may vary. A pre-procedure bleeding risk score in this population is lacking. Methods: We assessed themajor bleeding rate (transfusion, angiographic intervention, nephrectomy, hemorrhage/hematoma) at 8 days in 28,034 kidney transplant recipients with a kidney biopsy during the 2010–2019 period in France and compared them to 55,026 patients with a native kidney biopsy as controls. Results: The rate of major bleeding was low (angiographic intervention: 0.2%, hemorrhage/hematoma: 0.4%, nephrectomy: 0.02%, blood transfusion: 4.0%). A new bleeding risk score was developed (anemia = 1, female gender = 1, heart failure = 1, acute kidney failure = 2 points). The rate of bleeding varied: 1.6%, 2.9%, 3.7%, 6.0%, 8.0%, and 9.2% for scores 0 to 5, respectively, in kidney transplant recipients. The ROC AUC was 0.649 (0.634–0.664) in kidney transplant recipients and 0.755 (0.746–0.763) in patients who had a native kidney biopsy (rate of bleeding: from 1.2% for score = 0 to 19.2% for score = 5). Conclusions: The risk of major bleeding is low in most patients but indeed variable. A new universal risk score can be helpful to guide the decision concerning kidney biopsy and the choice of inpatient vs. outpatient procedure both in native and allograft kidney recipients.

Rabbit antithymocyte globulins (rATGs) are polyclonal antibodies used to prevent acute cellular rejection in kidney transplantation. Their dosing remains largely empirical and the question of an individualized dose is still unresolved. Data from a prospective study in 17 kidney transplant patients were used to develop a model describing the dose–concentration–response relationship of rATG with T-lymphocyte subpopulation counts over time. The model was validated using an independent cohort of kidney transplant patients treated by rATG in the same center. Pharmacokinetics of rATG was described using a two-compartment model integrating a third compartment and a target-mediated elimination for active rATG. The kinetics of CD3+, CD4+, CD8+, and CD3−CD56+ cell counts over time were described by a pharmacokinetic-pharmacodynamic model with transit compartments, integrating both CD3−CD56+-independent and CD3−CD56+-dependent rATG-mediated lymphocyte depletion, and a positive feedback. Elimination of rATG was influenced by age and body surface area, while its distribution was also influenced by body surface area. CD3+ proliferation rate decreased with age and CD3−CD56+-mediated elimination was influenced by the V158F-FCGR3A polymorphism. Binary efficacy and tolerance endpoints were defined as a CD3+ count 200 mm–3 at 1 year, respectively. Simulations showed that increasing or decreasing the standard 6-mg/kg dose will impact both tolerance and efficacy, while a dose decrease may be beneficial in elderly patients. Our results can be used to design prospective clinical trials testing dose individualization based on patients’ characteristics. Eudract No. 2009-012673-35.

Renal resistive index predicts the risk of death in many populations but the mechanism linking renal resistive index and death remains elusive. Renal resistive index is derived from end-diastolic velocity (EDV) and peak systolic velocity (PSV). However, the predictive value of EDV or PSV considered alone is unknown.We conducted a retrospective analysis of 2362 consecutive patients who received a kidney transplant from 1985 to 2017. EDV and PSV were measured at 3 months after transplantation, renal resistive index was calculated, and the risk of death was assessed [median follow-up: 6.25 years (0.25-29.15); total observation period: 13 201 patient-years].Doppler indices were available in 1721 of 2362 (78.9%) patients (exclusions: 113 who died or returned to dialysis before, 427 with no Doppler studies, 27 with renal artery stenosis, 74 missing values). Among them, 279 (16.4%) had diabetes before transplantation. Mean age was 51.5 ± 14.7, 1097 (63.7%) were male. During follow-up, 217 of 1721 (12.6%) patients died. Renal resistive index and EDV shared many determinants (notably systolic, diastolic and pulse pressure, recipient age and diabetes) unlike renal resistive index and PSV. EDV used as a binary [lowest tertile vs. higher values: (hazard ratio: 2.57 (1.96-3.36), P 0.001)] and as a continuous (the lower EDV, the greater the risk of death) variable was significantly associated with the risk of death. This finding was confirmed in multivariable analyses. Prediction of similar magnitude was found for renal resistive index. No association was found between PSV used as a binary or a continuous variable and the risk of death.Low EDV explains high renal resistive index, and the mechanism-linking renal resistive index to the risk of death is through low EDV.

Background and objectives The risk of major bleeding after percutaneous native kidney biopsy is usually considered low but remains poorly predictable. The aim of the study was to assess the risk of major bleeding and to build a preprocedure bleeding risk score. Design, setting, participants, & measurements Our study was a retrospective cohort study in all 52,138 patients who had a percutaneous native kidney biopsy in France in the 2010–2018 period. Measurements included major bleeding (i.e., blood transfusions, hemorrhage/hematoma, angiographic intervention, or nephrectomy) at day 8 after biopsy and risk of death at day 30. Exposures and outcomes were defined by diagnosis codes. Results Major bleeding occurred in 2765 of 52,138 (5%) patients (blood transfusions: 5%; angiographic intervention: 0.4%; and nephrectomy: 0.1%). Nineteen diagnoses were associated with major bleeding. A bleeding risk score was calculated (Charlson index [2–4: +1; 5 and 6: +2; >6: +3]; frailty index [1.5–4.4: +1; 4.5–9.5: +2; >9.5: +3]; women: +1; dyslipidemia: −1; obesity: −1; anemia: +8; thrombocytopenia: +2; cancer: +2; abnormal kidney function: +4; glomerular disease: −1; vascular kidney disease: −1; diabetic kidney disease: −1; autoimmune disease: +2; vasculitis: +5; hematologic disease: +2; thrombotic microangiopathy: +4; amyloidosis: −2; other kidney diagnosis: −1) + a constant of 5. The risk of bleeding went from 0.4% (lowest score group =0–4 points) to 33% (highest score group ≥35 points). Major bleeding was an independent risk of death (500 of 52,138 deaths: bleeding: 81 of 2765 [3%]; no bleeding: 419 of 49,373 [0.9%]; odds ratio, 1.95; 95% confidence interval, 1.50 to 2.54; P Conclusions The risk of major bleeding after percutaneous native kidney biopsy may be higher than generally thought and is associated with a twofold higher risk of death. It varies widely but can be estimated with a score useful for shared decision making and procedure choice.

Background Autosomal dominant polycystic kidney disease (ADPKD) is associated with an increased risk for developing intracranial aneurysms (IAs). We aimed to evaluate the frequency of diagnosis of IAs in the cross-sectional, population-based, Genkyst cohort, to describe ADPKD-associated IAs and to analyse the risk factors associated with the occurrence of IAs in ADPKD patients. Methods A cross-sectional study was performed in 26 nephrology centres from the western part of France. All patients underwent genetic testing for PKD1/PKD2 and other cystogenes. Results Among the 2449 Genkyst participants, 114 (4.65%) had a previous diagnosis of ruptured or unruptured IAs at inclusion, and ∼47% of them had a positive familial history for IAs. Most aneurysms were small and saccular and located in the anterior circulation; 26.3% of the patients had multiple IAs. The cumulative probabilities of a previous diagnosis of IAs were 3.9%, 6.2% and 8.1% at 50, 60 and 70 years, respectively. While this risk appeared to be similar in male and female individuals 2-fold higher in PKD1 compared with PKD2, with no influence of PKD1 mutation type or location. In multivariate analysis, female sex, hypertension Conclusions This study presents epidemiological data reflecting real-life clinical practice. The increased risk for IAs in postmenopausal women suggests a possible protective role of oestrogen.

Background: Selection of expected phenotypes (ie, expressers/non-expressers) is currently used in CYP3A5*3 genotype-based tacrolimus dosing. The authors assessed whether a dosing regimen based on the 3 CYP3A5 genotypes may reduce the occurrence of inadequate exposure. Methods: Tacrolimus whole blood trough levels ( C 0) were retrieved from a retrospective cohort of 100 kidney transplant recipients treated with a starting dose of 0.15 (non-expressers) or 0.30 (expressers) mg/kg/d. The authors evaluated the occurrence of overexposures (12 < C 0 < 20 ng/mL) or toxic concentrations ( C 0 ≥ 20 ng/mL). These results were used to set up a new strategy based on the 3 distinct CYP3A5 genotypes, which relevance was evaluated in a prospective cohort of 107 patients. Results: In the retrospective cohort, non-expressers exhibited frequent overexposure (63.6%) or toxic C 0 (20.8%). Among expressers, none of the homozygous *1 carriers exhibited overexposure contrary to 25% of the heterozygotes. Based on these results, new tacrolimus starting doses were set at 0.10, 0.20, and 0.30 mg/kg/d for CYP3A5*3/*3, CYP3A5*1/*3, and CYP3A5*1/*1 genotypes, respectively. Tacrolimus overexposure was reduced in the CYP3A5*3/*3 group (63.6% vs 40%, P = .0038). None of the heterozygous patients exhibited toxic tacrolimus C 0. Clinical outcomes were not different between the 2 periods, whatever the genotype. Our results indicate that the best tacrolimus exposure was obtained for doses of 0.10, 0.20, and 0.20 mg/kg/d for CYP3A5*3/3, CYP3A5*1/*3, and CYP3A5*1/*1, respectively. Conclusions: Our results confirm that selecting tacrolimus dosing regimen according to the expected phenotype is appropriate, but that lower than currently recommended doses may be preferable.

The impact of a third dose of COVID-19 vaccine on antibody responses is unclear in immunocompromised patients. The objective of this retrospective study was to characterize antibody responses induced by a third dose of mRNA COVID-19 vaccine in 160 kidney transplant recipients and 20 patients treated for chronic lymphocytic leukemia (CLL). Prevalence of anti-spike IgG ≥ 7.1 and ≥ 30 BAU/mL after the third dose were 47% (75/160) and 39% (63/160) in kidney transplant recipients, and 57% (29/51) and 50% (10/20) in patients treated for CLL. Longitudinal follow-up identified a moderate increase in SARS-CoV-2 anti-spike IgG levels after a third dose of vaccine in kidney transplant recipients (0.19 vs. 5.28 BAU/mL, p = 0.03) and in patients treated for CLL (0.63 vs. 10.7 BAU/mL, p = 0.0002). This increase in IgG levels had a limited impact on prevalence of anti-spike IgG ≥ 30 BAU/mL in kidney transplant recipients (17%, 2/12 vs. 33%, 4/12, p = 0.64) and in patients treated for CLL (5%, 1/20 vs. 45%, 9/20, p = 0.008). These results highlight the need for vaccination of the general population and the importance of non-medical preventive measures to protect immunocompromised patients.

International audience; Background: Renal patients with diabetes mellitus are at very high risk of death before and after chronic dialysis initiation. Risk factors for death in this population are not clearly identified. Methods: We performed a retrospective survival analysis in 861 patients with diabetes mellitus consecutively followed up in the 2000-13 period in a nephrology setting. Results: The mean age was 70 \,±\, 10 years [men 65.2%; diabetes duration 13.7 \,±\, 10.3\,years; mean estimated glomerular filtration rate (eGFR) 42.4 \,±\, 21.0\,mL/min/1.73 m2). During follow-up (median 60\,months; up 15\,years), 263 patients died (184 before and 79 after dialysis initiation) and 183 started chronic dialysis. In multivariate analyses, age, elevated systolic and low diastolic arterial pressures, peripheral artery disease, cancer, loop diuretic use and atrial fibrillation at baseline and acute kidney injury (AKI), heart failure (HF) and amputation during follow-up were identified as risk factors for death. After adjustments on these parameters, eGFRs at the time of the first outpatient visit-eGFR 80 years of age [HR 1.08 (95% CI 0.64-1.81), P\,=\,0.7793]. Conclusions: In patients with diabetes mellitus, high systolic and low diastolic arterial pressure, peripheral artery disease and development of AKI and HF are significant risk factors for death. In addition to these parameters, eGFR

Introduction La mortalite cardiovasculaire est la premiere cause de deces chez les patients transplantes renaux. L’hypertension arterielle (HTA), dont la prevalence, est proche de 80 %, est le premier facteur de risque cardiovasculaire modifiable. Les pratiques concernant la prise en charge de l’HTA chez les patients transplantes renaux sont variees et les donnees scientifiques manquantes. L’objectif de cette etude est de decrire les pratiques, concernant la mesure et la prise en charge pharmacologique de l’HTA, et de confronter les resultats aux donnees recueillies aupres des patients transplantes renaux. Description Un questionnaire a ete diffuse aux medecins assurant le suivi de patients transplantes renaux en France et aux patients transplantes renaux. Methodes Les questions concernaient la mesure de la pression arterielle (PA), sa prise en charge therapeutique et l’observance. Resultats Les reponses obtenues proviennent de 77 nephrologues et 85 patients. Les inhibiteurs calciques suivis des inhibiteurs du systeme renine angiotensine sont les deux classes therapeutiques les plus souvent utilisees en premiere intention (55 % et 38 %), puis les diuretiques non epargneurs de potassium en troisieme intention (47 %) en l’absence de proteinurie. Concernant la mesure de la PA, les reponses des praticiens et des patients sont similaires pour 8 questions mais 5 questions comportent des differences significatives, notamment au sujet des mesures ambulatoires de PA ( Fig. 1 ). Une majorite de patients ressentent une amelioration de leur qualite de vie liee au traitement de l’HTA (88 %) et 79 % declarent etre observant. Conclusion La prise en charge therapeutique de l’HTA est majoritairement faite en adequation avec les recommandations KDIGO. La mesure de la PA ambulatoire est insuffisante et pourtant indispensable dans cette population a haut risque d’HTA resistante, d’HTA masquee et d’HTA nocturne. La mise en place d’etudes interventionnelles sur la mesure ambulatoire de PA chez les patients transplantes renaux semble interessante.

Background Renal resistive index (RI) predicts mortality in renal transplant recipients, but we do not know whether this is true in diabetic patients. The objective of this study was to analyse the long-term predictive value of RI for death with a functioning graft (DWFG) in renal transplant recipients with or without pre-transplant diabetes. Methods We conducted a retrospective study in 1800 renal transplant recipients between 1985 and 2017 who were followed for up to 30 years (total observation period: 14 202 patient years). Donor and recipient characteristics at time of transplantation and at 3 months were reviewed. The long-term predictive value of RI for DWFG and the age–RI and arterial pressure–RI relationships were assessed. Results A total of 284/1800 (15.7%) patients had diabetes mellitus before transplantation. RI was Conclusion Our study indicates that RI is not a predictor of DWFG in diabetic renal transplant recipients, in contrast to non-diabetic recipients. These findings could be due to a different age–RI or pulse pressure–RI relationship.

International audience; High renal resistive index (RI) is observed in diabetes and is associated with poor patient survival, but whether it is primarily due to renal vascular resistance or systemic vascular alterations is unclear. The respective impact of kidney transplant from diabetic donors or to diabetic recipients on RI would shed some light on this issue. The objective of the study was to analyze the impact of donor and recipient diabetes on RI in order to understand the respective impact of the kidney and the vascular environment. The authors conducted a retrospective study in 1827 renal transplant recipients who received a kidney between 1985 and 2017, and had Doppler measurements at 3~months after transplant. Donor and recipient characteristics at the time of transplant and at 3~months were reviewed. Both donor diabetes and recipient diabetes were associated with RI in univariate analysis, but only recipient diabetes remained significantly associated in stepwise multivariate analyses (effect estimate on RI: +0.03~±~0.005, P~

International audience; Depleting induction therapy is recommended in sensitized kidney transplant recipients (KTRs), though the detrimental effect of nondonor-specific anti-HLA antibodies is not undeniable. We compared the efficacy and safety of basiliximab and rabbit anti-thymocyte globulin (rATG) in sensitized KTRs without pre-existing donor-specific antibodies (DSAs). This monocentric retrospective study involved all sensitized KTR adults without pre-existing DSAs (n = 218) who underwent transplantation after June 2007. Patients with basiliximab and rATG therapy were compared for risk of biopsy-proven acute rejection (BPAR) and a composite endpoint (BPAR, graft loss and death) by univariate and multivariate analysis. Patients with basiliximab (n = 60) had lower mean calculated panel reactive antibody than those with rATG (n = 158; 23.7 ± 24.2 vs. 63.8 ± 32.3, P < 0.0001) and more often received a first graft (88% vs. 54%, P < 0.0001) and a transplant from a living donor (13% vs. 2%, P = 0.002). Risks of BPAR and of reaching the composite endpoint were greater with basiliximab than rATG [HR = 3.63 (1.70-7.77), P = 0.0009 and HR = 1.60 (0.99-2.59), P = 0.050, respectively]. Several adjustments did not change those risks [BPAR: 3.36 (1.23-9.16), P = 0.018; composite endpoint: 1.83 (0.99-3.39), P = 0.053]. Infections and malignancies were similar in both groups. rATG remains the first-line treatment in sensitized KTR, even in the absence of pre-existing DSAs.

International audience; The course of autosomal dominant polycystic kidney disease (ADPKD) varies among individuals, with some reaching ESRD before 40 years of age and others never requiring RRT. In this study, we developed a prognostic model to predict renal outcomes in patients with ADPKD on the basis of genetic and clinical data. We conducted a cross-sectional study of 1341 patients from the Genkyst cohort and evaluated the influence of clinical and genetic factors on renal survival. Multivariate survival analysis identified four variables that were significantly associated with age at ESRD onset, and a scoring system from 0 to 9 was developed as follows: being male: 1 point; hypertension before 35 years of age: 2 points; first urologic event before 35 years of age: 2 points; PKD2 mutation: 0 points; nontruncating PKD1 mutation: 2 points; and truncating PKD1 mutation: 4 points. Three risk categories were subsequently defined as low risk (0-3 points), intermediate risk (4-6 points), and high risk (7-9 points) of progression to ESRD, with corresponding median ages for ESRD onset of 70.6, 56.9, and 49 years, respectively. Whereas a score ≤3 eliminates evolution to ESRD before 60 years of age with a negative predictive value of 81.4%, a score \textgreater6 forecasts ESRD onset before 60 years of age with a positive predictive value of 90.9%. This new prognostic score accurately predicts renal outcomes in patients with ADPKD and may enable the personalization of therapeutic management of ADPKD

OBJECTIVE Certain medications have been associated with drug-induced acute interstitial nephritis (AIN), but few prospective studies have been published. This prospective observational study aims to record and assess incidents of drug-induced AIN observed over a period of one year in nephrology units in France. The goal is to determine which medications are involved in AIN and to expound the clinical and biological presentation, management, and evolution of AIN. METHODS Between April 2012 and April 2013, drug-associated cases of AIN were prospectively recorded in 24 patients registered in 11 nephrology units that belong to the Societe de Nephrologie de l'Ouest (SNO). Data sheets, including suspected and concomitant drug(s), kidney function assessment, biological disturbances, clinical signs, histological data, management, and evolution, were collected by the Rennes Regional Pharmacovigilance Center and recorded in the French pharmacovigilance database. RESULTS In order, the most frequently involved medications in the AIN cases were: vitamin K antagonists (33.3% of the cases, almost exclusively fluindione), antibiotics (20.8% of cases) non-steroidal anti-inflammatory drugs (20.8% of cases), and proton pump inhibitors (16.7% of cases). The mean delay of onset to AIN was 8.3 weeks. At the time of diagnosis, mean serum creatinine was 366 μM, higher for vitamin K antagonists (VKAs), except in the case of warfarin. During the course of an AIN event, 70% of patients had complete blood count and/or urine analysis abnormalities, 55% had clinical signs of systemic hypersensitivity, and 13% of patients had hepatic disorders. Renal biopsies were performed in 54% of patients; however, only 37% of patients requiring therapeutic anticoagulation underwent a biopsy. Suspected drugs were discontinued in all patients and the majority was treated with oral corticosteroids. Renal function often continued to be impaired after an AIN event. At baseline, 25% of patients had chronic kidney disease (CKD); after an AIN event, 67% of patients were noted to have CKD. CONCLUSION Physicians need to be aware of the possibility of drug-induced acute interstitial nephritis as a common cause of acute kidney injury (AKI). This study supports increased vigilance when prescribing three therapeutic classes frequently associated with AIN: antibiotics, NSAIDs and PPIs (especially in instances of polypharmacy), which were associated with two thirds of the AIN cases in this study. Fluindione, an oral anticoagulant exclusively marketed in Luxembourg and France where it constitutes the vast majority of VKA prescriptions, was associated with one third of the AIN cases alone, making it a common possible culprit of drug-induced AIN, warranting particular attention.

To describe long-term CD4+ T-cell reconstitution after rabbit antithymocyte globulin (rATG) treatment and identify predictive factors following kidney transplantation. A single-center retrospective study analyzed lymphocyte subsets in rATG-treated kidney transplant recipients (1986–2009). 589 patients were analyzed (maximum follow-up 21 years). A comparator group (n = 298) received an anti-IL-2 receptor monoclonal antibody. CD4+ T-cell lymphopenia (40 years was identified as a cutoff point. CD4+ T-cell reconstitution following rATG treatment remains impaired even after 21 years. Most risk factors for long-term impaired CD4+ T-cell reconstitution may be evaluated pretransplant or are modifiable post-transplant.

International audience; Background - PKD2-related autosomal dominant polycystic kidney disease (ADPKD) is widely acknowledged to be of milder severity than PKD1-related disease, but population-based studies depicting the exact burden of the disease are lacking. We aimed to revisit PKD2 prevalence, clinical presentation, mutation spectrum, and prognosis through the Genkyst cohort. Study design - Case series, January 2010 to March 2016. Settings & participants - Genkyst study participants are individuals older than 18 years from 22 nephrology centers from western France with a diagnosis of ADPKD based on Pei criteria or at least 10 bilateral kidney cysts in the absence of a familial history. Publicly available whole-exome sequencing data from the ExAC database were used to provide an estimate of the genetic prevalence of the disease. Outcomes - Molecular analysis of PKD1 and PKD2 genes. Renal survival, age- and sex-adjusted estimated glomerular filtration rate. Results - The Genkyst cohort included 293 patients with PKD2 mutations (203 pedigrees). PKD2 patients with a nephrology follow-up corresponded to 0.63 (95% CI, 0.54-0.72)/10,000 in Brittany, while PKD2 genetic prevalence was calculated at 1.64 (95% CI, 1.10-3.51)/10,000 inhabitants in the European population. Median age at diagnosis was 42 years. Flank pain was reported in 38.9%; macroscopic hematuria, in 31.1%; and cyst infections, in 15.3% of patients. At age 60 years, the cumulative probability of end-stage renal disease (ESRD) was 9.8% (95% CI, 5.2%-14.4%), whereas the probability of hypertension was 75.2% (95% CI, 68.5%-81.9%). Although there was no sex influence on renal survival, men had lower kidney function than women. Nontruncating mutations (n=36) were associated with higher age-adjusted estimated glomerular filtration rates. Among the 18 patients with more severe outcomes (ESRD before age 60), 44% had associated conditions or nephropathies likely to account for the early progression to ESRD. Limitations - Younger patients and patients presenting with milder forms of PKD2-related disease may not be diagnosed or referred to nephrology centers. Conclusions - Patients with PKD2-related ADPKD typically present with mild disease. In case of accelerated degradation of kidney function, a concomitant nephropathy should be ruled out.

Introduction Le tolvaptan est maintenant disponible depuis plusieurs mois. Nous rapportons l’experience du groupe Genkyst sur 66 patients traites. Patients/Materiels et methodes Les patients polykystiques traites par le tolvaptan sont suivis prospectivement au sein de la cohorte Genkyst. Ils sont tous genotypes et un volume renal calcule avant traitement pour la majorite des patients. Nous avons etudie le profil des patients traites par tolvaptan, les conditions de titration et la tolerance de la molecule. Observation/Resultats Il s’agissait de 66 patients (52 % d’homme) âges de 30 a 71 ans. La majorite des patients etaient actifs. Au moment de l’initiation du traitement 15 % etaient au stade 1 de la MRC, 10 % au stade 2 ; 69 % au stade 3 et 6 % au stade 4. Le volume total renal moyen etait de 1475 mL/m (602 a 4643). Sur le plan genetique, 70 % des patients etaient porteurs d’une mutation tronquante de PKD1, 20 % d’une mutation non tronquante de PKD1 et seulement 8 % d’une mutation de PKD2. Si on applique le score de la Mayo Clinic [1] tous les patients appartenaient aux classes 1 C a 1E (classes a fort risque de progression). Concernant le score PROPKD [2] : 68 % des patients avaient un score > 3. La titration a ete soit hebdomadaire (50 %) soit mensuelle. La totalite des patients a presente a l’initiation un syndrome polyuropolydipsique (volume des boissons de 4 a 8 litres au debut), entrainant des mictions horaires en moyenne et de 2 a 5 levers nocturnes. A distance de la titration : 50 % des patients recevaient la dose maximale 90/30, 15 % 60/30, 10 % 45/45, 20 % avaient stoppe le traitement essentiellement pour les effets secondaires aquaretiques. Dans un sous-groupe de 30 patients, on constate une augmentation de la natremie au debut du traitement (3 mmol/L) et une petite perte de fonction renale et une osmolarite urinaire constamment Discussion/Conclusion Nous rapportons l’experience dans la vraie vie de l’utilisation du tolvaptan. On constate que pour l’instant, les patients traites sont majoritairement au stade 3 de la MRC et qu’ils presentent des criteres de progression rapide. La tolerance semble un peu moins bonne que dans les essais cliniques (20 % d’arret).

Transplant recipients receiving a kidney from an extended-criteria donor (ECD) are exposed to calcineurin inhibitor (CNI) nephrotoxicity, as demonstrated by severe delayed graft function and/or a low GFR. Belatacept is a nonnephrotoxic drug that is indicated as an alternative to CNIs. We reported 25 cases of conversion from a CNI to belatacept due to CNI intolerance within the first 6 mo after transplantation. The mean age of the recipients was 59 years, and 24 of 25 patients received ECD kidneys. At the date of the medication switch, 12 of 25 patients displayed a calculated GFR (cGFR)

Introduction Le lien entre medecin generaliste (MG) et nephrologue est primordial. Au sein d’un CHU, une ligne telephonique directe (sans passer par un secretariat ou un secteur de soin) a ete creee sans financement specifique afin de fluidifier la communication entre ces deux acteurs de sante en septembre 2014. Nous avons voulu evaluer si ce dispositif etait utilise et s’il a permis d’ameliorer la prise en charge des patients. Patients et methodes Il s’agit d’une etude prospective monocentrique portant sur les appels telephoniques par la Hot-line (AT) de MG du departement et souhaitant joindre au telephone un nephrologue. Deux periodes de 3 mois ont ete etudiees : la periode P1 : les 3 mois precedant l’ouverture officielle de la ligne directe (entre juin et septembre 2014) et la periode P2 1 an plus tard (juin a septembre 2015). Tous les AT provenant de MG souhaitant joindre un nephrologue ont ete repertories les jours de semaine entre 8h30 et 18h30. Resultats Le nombre d’AT a augmente de 121 AT pour P1 a 185 AT pour P2 (+ 53,0 %). Par rapport a la periode P1, les motifs d’appels etaient des difficultes diagnostiques pour 46,3 % vs 53,5 %), des difficultes therapeutiques (38,4 % vs 38,8 %), et des motifs mixtes (8,1 % vs 14,9 %). La reponse des nephrologues etait exclusivement telephonique (P1 : 40,0 % vs P2 : 44,6 %), un bilan complementaire propose (en ville) suivi d’une consultation de nephrologie non urgente (24,8 % vs 29,7 %), une consultation urgente (18,2 % vs 16,8 %) ou une hospitalisation immediate (12,4 % vs 13,5 %). Discussion La mise en route de la ligne directe a permis une augmentation des AT de MG souhaitant un avis nephrologique, mais pas une modification qualitative des motifs d’appels. Elle a probablement permis une diminution de passage aux urgences (consultations urgentes ou admission directe dans le service) et une prise en charge plus efficace. Conclusion Une etude medico-economique doit etre realisee.

Introduction Le basiliximab et les anticorps anti-thymocytes polyclonaux de lapins (rATG) sont les traitements d’induction les plus frequemment utilises en transplantation renale. L’utilisation du basiliximab etait habituellement reservee aux patients non immunises. Cependant, la meilleure caracterisation du risque immunologique avec les techniques sensibles d’identification des anticorps anti-HLA a ouvert la voie a son utilisation chez le patient immunise sans DSA, considere a risque immunologique intermediaire. Patients et methodes Etude retrospective monocentrique incluant tous les patients adultes (greffes combinees exclues) entre l’introduction de Luminex (juin 2007) et mai 2016. L’absence de DSA en single antigen a ete validee apres analyse individuelle de chaque dossier. Le risque de rejet aigu (clinique ou infraclinique) et l’apparition de DSA a ete analyse en uni- et multivarie (test de log rank et modele de Cox). Resultats Deux cent dix-huit (21 %) transplantes renaux immunises sans DSA pregreffe ont ete identifies (basiliximab = 60, rATG = 158). Les patients ayant recu du basiliximab avaient un taux de greffons incompatibles (TGI) plus faible (24 ± 26 vs. 66 ± 32 %, p 1000) etait observee chez 13 (21,7 %) et 26 (16,4 %) patients traites respectivement par basiliximab et rATG (p = 0,087). Discussion Le basiliximab semble etre associe a un sur-risque de rejet aigu par rapport au rATG chez les patients transplantes renaux immunises sans DSA avant la transplantation. Conclusion Une etude multicentrique permettra de preciser la strategie d’induction pour la prevention du rejet aigu chez les transplantes renaux immunises sans DSA.

Certain medications have been associated with drug-induced acute interstitial nephritis (AIN), but few prospective studies have been published. This prospective observational study aims to record and assess incidents of drug-induced AIN observed over a period of one year in nephrology units in France. The goal is to determine which medications are involved in AIN and to expound the clinical and biological presentation, management, and evolution of AIN.Between April 2012 and April 2013, drug-associated cases of AIN were prospectively recorded in 24 patients registered in 11 nephrology units that belong to the Société de Néphrologie de l'Ouest (SNO). Data sheets, including suspected and concomitant drug(s), kidney function assessment, biological disturbances, clinical signs, histological data, management, and evolution, were collected by the Rennes Regional Pharmacovigilance Center and recorded in the French pharmacovigilance database.In order, the most frequently involved medications in the AIN cases were: vitamin K antagonists (33.3% of the cases, almost exclusively fluindione), antibiotics (20.8% of cases) non-steroidal anti-inflammatory drugs (20.8% of cases), and proton pump inhibitors (16.7% of cases). The mean delay of onset to AIN was 8.3 weeks. At the time of diagnosis, mean serum creatinine was 366 μM, higher for vitamin K antagonists (VKAs), except in the case of warfarin. During the course of an AIN event, 70% of patients had complete blood count and/or urine analysis abnormalities, 55% had clinical signs of systemic hypersensitivity, and 13% of patients had hepatic disorders. Renal biopsies were performed in 54% of patients; however, only 37% of patients requiring therapeutic anticoagulation underwent a biopsy. Suspected drugs were discontinued in all patients and the majority was treated with oral corticosteroids. Renal function often continued to be impaired after an AIN event. At baseline, 25% of patients had chronic kidney disease (CKD); after an AIN event, 67% of patients were noted to have CKD.Physicians need to be aware of the possibility of drug-induced acute interstitial nephritis as a common cause of acute kidney injury (AKI). This study supports increased vigilance when prescribing three therapeutic classes frequently associated with AIN: antibiotics, NSAIDs and PPIs (especially in instances of polypharmacy), which were associated with two thirds of the AIN cases in this study. Fluindione, an oral anticoagulant exclusively marketed in Luxembourg and France where it constitutes the vast majority of VKA prescriptions, was associated with one third of the AIN cases alone, making it a common possible culprit of drug-induced AIN, warranting particular attention.

Rabbit antithymocyte globulin (rATG; Thymoglobulin(®)) is currently used to prevent acute rejection in kidney transplantation. The dose and regimen of rATG have not been optimized. Moreover, the impact of different treatment regimens on T-cell phenotype reconstitution remains unknown. We conducted a prospective randomized study of 17 renal transplant patients to determine the pharmacokinetics of total and active (bound to human cells) rATG and T-cell phenotype reconstitution after rATG administration. Patients received rATG at a total dose of 6mg/kg, administered either as 1.5mg/kg/day on days 0-3 (Group 1, n=8) or 3mg/kg on days 0 and 3 (Group 2, n=9). All patients received tacrolimus, mycophenolate mofetil and steroids. Blood samples were assayed for total rATG by enzyme linked immunosorbent assay and active rATG by flow cytometry. Maximum concentrations and terminal half-lives were similar between the two groups but at month 3 Group 1 had significantly lower values for total rATG (concentration was 6.2±1.1μg/mL versus 10.2±2.9μg/mL in Group 2, p=0.027) and total rATG dose-normalized AUC (374±83dayg/mL versus 508±149dayg/mL in Group 2, p=0.046). Time to sub-therapeutic levels (1μg/mL) of active rATG was significantly shorter in Group 1 (18.75±6.9days versus 20±7.5days in Group 2, p0.001). rATG induced significant depletion followed by slow reconstitution of CD3(+), CD4(+) and CD8(+) cells, with no marked differences between groups. B-cell count was unaffected, whereas CD3(-)CD56(+) NK-cell depletion was observed in both groups. rATG induced a significant decrease in the proportion of naïve CD4(+) T-cells, which plateaued after month 1 in Group 1 and after month 6 in Group 2. The proportion of central memory CD4(+) T-cells increased to a similar extent in both groups (Group 1: 38±18% at baseline, 74±23% at one year, p=0.009; Group 2: 32±14% at baseline, 65±14% at one year, p=0.001). In conclusion, our results suggest that the dosing regimen for rATG induction influences pharmacokinetic parameters without affecting the quality of immune reconstitution.

Introduction Les facteurs de risque classiques d’insuffisance renale chronique terminale (IRCT) sont connus : eDFG initial, albuminurie, pression arterielle systolique (PAS), retinopathie diabetique (RDIAB). Recemment, l’existence d’un AKI a ete reconnue comme un facteur de risque d’IRCT, mais les consequences renales des evenements cardiaques, independamment de l’AKI qu’ils entrainent, sont mal connues. Patients et methodes Une cohorte de 860 patients diabetiques de type 2 inclus depuis 2000 suivis de 0,1 a 15,5 ans a ete analysee (suivi median : 59 mois ; eDFG initial : 42 mL/mn/1,73 m 2 ). Resultats Durant ce suivi, 194 patients ont atteint le stade d’IRCT (183 dialyses ; 11 greffes en pre-emptif). L’insuffisance cardiaque initiale (HR : 1,47, p = 0,0194) etait un facteur de risque d’IRCT en univarie, mais pas apres ajustements sur l’eDFG, l’albuminurie, la PAS et la RDIAB. En revanche, le developpement d’un AKI restait significatif (HR : 4,51, p p p p = 0,0005) (mais pas d’un AVC) restaient des facteurs de risque d’IRCT meme apres ajustement sur tous ces parametres. Discussion Les evenements cardiaques au cours du suivi ont une influence deletere majeure sur l’evolution renale, independamment du developpement d’un AKI et de l’etat renal et cardiovasculaire initial des patients diabetiques a risque renal. Conclusion La surveillance des parametres renaux devrait etre plus frequente en cas d’apparition d’evenements cardiovasculaires et cet element devrait etre connu des cardiologues.

Introduction Plusieurs etudes suggerent que la rigidite arterielle des gros troncs, evaluee par la VOP elevee est un facteur de risque de deces chez le transplante renal. Cependant, les determinants de la vitesse de l’onde de pouls (VOP) elevee sont mal connus, en particulier ceux lies aux caracteristiques du donneur et aux traitements immunosuppresseurs. Patients et methodes Etude prospective monocentrique incluant des patients transplantes renaux entre octobre 2012 et mars 2015. La vitesse de l’onde de pouls carotido-femorale (VOPcf) est mesuree par tonometrie d’aplanation (SphygmoCor) au decours d’une consultation de suivi. Resultats Au total, 286 patients (âge : 52 ± 18 ans, 57,8 % d’hommes ; 26,1 % de diabetiques, greffes depuis en moyenne 54 ± 73 mois ; 1re greffe chez 88 % d’entre eux) ont ete inclus dans l’etude. L’ischemie tiede etait de 52 ± 17 minutes, l’ischemie froide de 1013 ± 430 minutes ; 15,4 % des greffons ont ete mis sur machine a perfuser. Au total, 49,5 % des patients avaient une VOPcf > 10 m/s et 75 % > 13,2 m/s. En analyse univariee, l’âge du donneur, l’âge du receveur, l’ischemie tiede et la cause cardiovasculaire du deces du donneur etaient associes au risque de VOPcf > 75e percentile (mais pas l’ischemie froide ou la mise sous machine de perfusion). En analyse multivariee, il persistait l’âge du donneur (OR : 3,12 [1,23–7,92]) (OR = 3,12 ; IC95 % [1,23–7,92] ; p = 0,0169) et l’ischemie tiede (OR : 1,92 [1,04–3,55], p = 0,0383). Parmi les traitements immunosuppresseurs, les inhibiteurs de la calcineurine (CNI) etaient associes a une VOPcf elevee plus frequente (OR : 3,21 [1,42–3,25], p = 0,0048) et les inhibiteurs de mTOR (mTORi) a une VOPcf elevee moins frequente (OR : 0,44 [0,21–0,90], p = 0,024), meme en analyse multivariee. Aucune interaction entre CNI et mTORi n’a ete mis en evidence (OR : 0,66 ; [0,05–8,06], p = 0,743). Discussion Des etudes doivent etre organisees pour estimer comment les caracteristiques donneurs et les conditions de prelevement et de greffe peuvent modifier les parametres hemodynamiques des gros troncs. Conclusion L’âge du donneur, l’ischemie tiede, et les traitements immunosuppresseurs influencent la rigidite arterielle du patient transplante renal.

Introduction Les recommandations ne sont pas univoques concernant l’adaptation des doses initiales de tacrolimus au genotype du CYP3A5 du receveur. Materiels et methodes Nous avons analyse retrospectivement les dossiers d’une cohorte de patients ayant recu une greffe de rein dont le genotype CYP3A5 etait connu au moment de la prescription initiale et chez qui la tacrolemie residuelle cible etait entre 8 et 12 ng/mL. Nous avons analyse les concentrations de tacrolimus entre j0 et j10. Une concentration > 12 ng/L a ete consideree comme une surexposition. Tous les patients recevaient du mycophenolate mofetil et un steroide et soit du basiliximab, soit de la thymoglobuline en induction. Resultats Les dossiers de cent patients selectionnes entre aout 2013 et juin 2015 ont ete analyses (77 CYP3A5*3/*3, 20 CYP3A5*3/1* et 3 CYP3A51*/1*). La dose moyenne initiale de tacrolimus etait de 0,07 mg/kg/12 h, 0,06 mg/kg/12 h et 0,1 mg/kg/12 h pour les *3/*3, *3/1* et 1*/1*, respectivement. Les patients *3/*3 etaient significativement plus surexposes en tacrolimus dans les 10 jours post-greffe que les patients *3/1* (45 % vs 86 %, p = 0,0003). Le surdosage survenait plus rapidement dans le groupe *3/*3 (3 ± 2,1 jours vs 5,2 ± 3,3 jours pour les *3/1*) mais de maniere non significative ( p = 0,3). Aucun surdosage n’est survenu chez les patients 1*/1*. Il n’y avait pas difference significative sur l’incidence de reprise retardee de fonction renale entre les *3/*3 et les *3/1* : 22 vs 15 %, p = 0,75. La dose finalement donnee apres 10 jours etait plus basse que la dose initiale pour le groupe *3/*3 (0,06 mg/kg/12 h). Elle etait par contre plus importante pour le groupe *3/1* (0,08 mg/kg/12 h) et pour le groupe 1*/1* (0,15 mg/kg/12 h). Discussion Les doses initiales de tacrolimus administrees etaient plus basses comparees a celles proposees par Thervet et al. Le groupe faible metaboliseur (CYP3A5*3/*3) restait tres expose au risque de surdosage precoce, severe chez 1 malade sur 5. De plus, les doses prescrites etaient plus basses a j10 que celles initialement choisies. Une reduction de la posologie initiale doit etre proposee dans ce groupe. Conclusion Ces resultats nous incitent a modifier nos prescriptions initiales de tacrolimus chez nos patients greffes renaux : *3/*3 : 0,05 mg/kg/12 h, *3/1* : 0,1 mg/kg/12 h et 1*/1* : 0,15 mg/kg/12 h.

Introduction L’hypertension arterielle est un risque de dialyse et de deces en transplantation renale. Les connaissances sont limitees quant a la valeur predictive des traitements antihypertenseurs, independamment du controle de la pression arterielle. Patients et methodes Durant la periode 1985–2014, 1986 patients ont ete transplantes renaux, ils ont ete suivis durant une duree mediane de 7,5 ans. La valeur predictive du controle de la pression arterielle et de son management a 12 mois de la transplantation sur le risque ulterieur de deces et de dialyse chronique a ete estimee. Resultats A 12 mois, 1797 patients (89,0 %) avaient un greffon fonctionnel. Globalement, 52,9 % avaient une pression arterielle > 140 et/ou 90 mmHg. Parmi eux, seulement 33,3 % avaient 3 ou plus molecules antihypertensives. Au cours du suivi, 228 patients sont decedes et 348 sont retournes en dialyse. La pression arterielle systolique etait associee avec une augmentation du risque de deces (HR per 10 mmHg : 1,22 [1,14–1,31], p Discussion La necessite du recours a une multitherapie antihypertensive devrait etre incluse dans les scores de pronostics cardiovasculaires. Conclusion Le besoin d’un recours a une multitherapie antihypertensive est predictrice de deces et de dialyse independamment du controle de la pression arterielle chez les transplantes renaux.

Introduction La pression pulsee (PP) et l’index de resistance intrarenal (IR) sont des marqueurs de risque de deces ; cependant, leur valeur predictive est moins etablie pour le risque de perte de greffon. Il a ete montre recemment que l’IR reflete la rigidite des gros troncs arteriels, tout comme la PP, mais que l’IR est egalement affecte par les anomalies de la microcirculation renale. Finalement, la valeur predictive respective de ces 2 parametres sur le risque de deces et de perte de greffon n’est pas connue. Patients et methodes La PP et l’IR ont ete mesures a 3 mois dans une cohorte de patients consecutifs qui ont ete greffes de 1985 a 2014. Le risque de deces et de perte de greffon a long terme a ete etudie. Resultats Au total, 1237 patients ont ete inclus (âge : 49,3 ± 14,5 ; 61,8 % d’hommes). A 3 mois, l’IR etait de 0,68 ± 0,08 (IR > 0,75 : 17,2 % ; IR > 0,80 : 5,8 %). La pression arterielle etait de 138 ± 16/79 ± 11 mmHg (PP : 59,6 ± 14,5 ; mediane : 60 mmHg). Durant le suivi (mediane : 5,9 ans ; extremes : 0,4–27,5 ans), 130 patients sont decedes et 216 sont retournes en dialyses ou ont ete regreffes (cause la plus frequente : rejet chronique). En analyse univariee, l’IR (tout comme la PP) etait associee au risque de deces (IR > 0,80 : HR : 2,50 ; IR > 0,75 : HR : 3,19, p 0,80 : HR :1,71, p = 0,0068 ; IR > 0,75 : HR : 1,53, p = 0,0035). En analyse multivariee, lorsque ces 2 parametres etaient consideres simultanement dans le meme modele, l’IR etait un facteur de risque de deces (IR > 0,80 : HR : 2,98 ; IR > 0,75 : HR : 3,63, p 60 mmHg (HR : 1,07, p = 0,7088). A l’inverse, la PP > 60 mmHg apres ajustement sur l’IR > 0,80 ou > 0,75 (respectivement : HR : 1,31, p = 0,0457 et 1,30, p = 0,0516) etait associee au risque de perte de greffon (apres ajustement sur âge et IR : HR : 1,32, p = 0,0406 et HR : 1,32, p = 0,0441), mais pas l’IR apres ajustement sur la PP (IR > 0,80 : HR : 1,17, p = 0,5765 ; IR > 0,75 : HR : 1,20, p = 0,2933). Discussion La PP et l’IR sont des parametres associes au risque d’evenements apres greffe renale. Conclusion La PP et l’IR ont un impact different sur le risque a long terme de deces et de perte de greffon en transplantation renale.

Introduction Le pronostic des patients diabetiques suivis en nephrologie est severe ; les recommandations de la HAS preconisent un suivi nephrologique a partir du stade 4 et l’utilite/nocivite de la prise en charge est discutee. Patients et methodes Huit cent soixante et un patients diabetiques de type 2 ont ete inclus consecutivement de 2000 a 2013 (âge : 70,3 ans, 65,2 % d’hommes, DFG : 42,4 mL/min/1,73 m 2 , retinopathie diabetique : 24 %, sous insuline : 45,5 %, antecedents cardiovasculaires : 38,8 %). Resultats Pendant un suivi median de 60 mois, 183 patients ont ete pris en dialyse, 11 greffes en preemptif et 263 patients sont decedes (79 apres dialyse). Apres ajustements, un DFG 2 a la premiere consultation (HR : 1,8 [1,34–2,41], p p p = 0,0626), meme chez les patients de plus de 80 ans (HR : 1,27 [0,64–2,56], p = 0,4957) ne l’etait pas. Discussion Le recours tardif (classe 3b ou plus) au nephrologue est un facteur de risque de deces chez les patients diabetiques de type 2. Conclusion Nos resultats suggerent que les patients diabetiques doivent etre adresses au nephrologue de facon plus precoce que le preconisent les recommandations. La prise en charge en dialyse n’est pas en soi un facteur de risque de deces.

Introduction Dans les suites d’un travail sur les nephropathies immuno-allergiques (NIA) a la fluindione [1] , nous avons souhaite evaluer l’ensemble des medicaments actuellement en cause dans la survenue de cette complication. Il nous semblait important de reactualiser des donnees anciennes menees par la Societe de nephrologie il y a pres de 30 ans [2] . Patients et methodes Etude prospective menee d’avril 2012 a avril 2014 par les nephrologues de l’inter-region ouest qui regroupe les regions Bretagne, Centre, Pays de la Loire et Poitou-Charente. Les donnees collectees ont ete transmises au Centre regional de Pharmacovigilance (CRPV) de Rennes afin de declarer les cas concernes. Resultats Les resultats definitifs de cette enquete seront presentes a la SN/SFD sur plus de 40 cas. Concernant les resultats intermediaires a un an, notre travail a permis de recueillir 24 cas avec realisation d’une biopsie renale chez 13 patients. Les medicaments incrimines sont en relation avec quatre grandes familles : les antivitamines K (AVK) (principalement la fluindione), les antibiotiques (ATB), les anti-inflammatoires non steroidiens (AINS) et les inhibiteurs de la pompe a protons (IPP). La presentation est le plus souvent essentiellement renale avec elevation de la creatininemie et lesions interstitielles a la biopsie renale. Il n’a pas ete observe de syndrome nephrotique en particulier pour les cas associes a la prise d’un AINS. Une majorite des patients ont recu des corticoides. A 3 mois, la recuperation de la fonction renale est le plus souvent incomplete en particulier avec les AVK et les IPP. Discussion et conclusion Ce travail realise conjointement avec le CRPV de Rennes a permis de declarer plus de 40 cas de NIA medicamenteuses recueillies dans 12 centres de nephrologie de l’inter-region ouest. Si les antibiotiques et les AINS restent d’actualite en 2014, il faut egalement evoquer et rechercher la prise recente d’un IPP ou d’un AVK face a un tableau d’insuffisance renale aigue.