Use of a Belatacept-based Immunosuppression for Kidney Transplantation From Donors After Circulatory Death: A Paired Kidney Analysis.

Background: Efficacy and safety of belatacept have not been specifically reported for kidney transplantations from donors after circulatory death. Methods: In this retrospective multicenter paired kidney study, we compared the outcome of kidney transplantations with a belatacept-based to a calcineurin inhibitor (CNI)-based immunosuppression. We included all kidney transplant recipients from donors after uncontrolled or controlled circulatory death performed in our center between February 2015 and October 2020 and treated with belatacept (n = 31). The control group included the recipients of the contralateral kidney that were treated with CNI in 8 other centers (tacrolimus n = 29, cyclosporine n = 2). Results: There was no difference in the rate of delayed graft function. A higher incidence of biopsy-proven rejections was noted in the belatacept group (24 versus 6 episodes). Estimated glomerular filtration rate (eGFR) was significantly higher in the belatacept group at 3-, 12-, and 36-mo posttransplant, but the slope of eGFR was similar in the 2 groups. During a mean follow-up of 4.1 y, 12 patients discontinued belatacept and 2 patients were switched from CNI to belatacept. For patients who remained on belatacept, eGFR mean value and slope were significantly higher during the whole follow-up. At 5 y, eGFR was 80.7 ± 18.5 with belatacept versus 56.3 ± 22.0 mL/min/1.73 m2 with CNI (P = 0.003). No significant difference in graft and patient survival was observed. Conclusions: The use of belatacept for kidney transplants from either uncontrolled or controlled donors after circulatory death resulted in a better medium-term renal function for patients remaining on belatacept despite similar rates of delayed graft function and higher rates of cellular rejection.

Thrombotic microangiopathies after kidney transplantation in modern era: nosology based on chronology.

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.

A Universal Bleeding Risk Score in Native and Allograft Kidney Biopsies: A French Nationwide Cohort Study.

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 the major 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.

Diagnosis and risk factors for intracranial aneurysms in autosomal polycystic kidney disease: a cross-sectional study from the Genkyst cohort.

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 <50 years, after that age, the risk continued to increase more markedly in female patients, reaching 10.8% versus 5.4% at 70 years. The diagnosis rate of IAs was >2-fold higher in PKD1 compared with PKD2, with no influence of PKD1 mutation type or location. In multivariate analysis, female sex, hypertension <35 years, smoking and PKD1 genotype were associated with an increased risk for diagnosis of IAs. 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.

Antibody Responses after a Third Dose of COVID-19 Vaccine in Kidney Transplant Recipients and Patients Treated for Chronic Lymphocytic Leukemia.

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.

Major Bleeding of Transjugular Native Kidney Biopsies. A French Nationwide Cohort Study.

INTRODUCTION: The risk of bleeding associated with transjugular kidney biopsies is unclear, and which patients are the best candidates for this route is unknown. METHODS: This was a retrospective cohort study comparing proportion of bleeding associated with transjugular versus percutaneous native kidney biopsies in all patients in France in the 2010-2019 period. Major bleeding at day 8 (i.e., blood transfusions, hemorrhage/hematoma, angiographic intervention, nephrectomy) and risk of death at day 30 were assessed, and we used a bleeding risk score initially developed for the percutaneous route. RESULTS: Our analysis included 60,331 patients (transjugular route: 5305; percutaneous route: 55,026 patients). The observed proportion of major bleeding varied widely (transjugular vs. percutaneous): 0.4% versus 0.5% for the lowest risk scores (0-4) to 19.1% versus 30.8% for the highest risk scores (≥35). Transjugular was more frequently used than percutaneous route (39% vs. 24%) when the risk score was ≥20 (15,133/60,331; 25% of all patients). Transjugular was associated with a lower risk of major bleeding than percutaneous route in multivariate analyses (odds ratio [OR]: 0.88 [0.78-0.99]), especially for scores ≥20 (OR: 0.83 [0.72-0.96], (i.e., 25% of patients). Major bleeding was associated with an increased risk of death both for transjugular (OR: 1.77 [1.00-3.14]) and percutaneous (OR: 1.80 [1.43-2.28]) routes. CONCLUSIONS: The transjugular route is independently associated with a lower risk of bleeding than the percutaneous route, especially in high-risk patients identified by a preprocedure risk score ≥20 (i.e., 25% of patients). Major bleeding is associated with an increased risk of death for both routes.

Major Bleeding and Risk of Death after Percutaneous Native Kidney Biopsies: A French Nationwide Cohort Study.

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<0.001). 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.

Increased risk of rejection after basiliximab induction in sensitized kidney transplant recipients without pre-existing donor-specific antibodies - a retrospective study.

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.

Renal function at the time of nephrology referral but not dialysis initiation as a risk for death in patients with diabetes mellitus.

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 <45 mL/min/1.73 m2 {hazard ratio [HR] 1.58 [95% confidence interval (CI) 1.15-2.17]}, P = 0.005 and eGFR <30 [HR 1.53 (1.05-2.05)], P = 0.004, but not eGFR <60-were powerful risk factors for death. When initiation of dialysis was entered into the multivariate models, it was not associated with a risk of premature death [HR 1.19 (95% CI 0.91-1.55), P = 0.2069], even in patients >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 <45 mL/min/1.73 m2 at the time of referral is also a powerful risk factor for death.

PKD2-Related Autosomal Dominant Polycystic Kidney Disease: Prevalence, Clinical Presentation, Mutation Spectrum, and Prognosis.

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.

[Prospective study of drug-induced interstitial nephritis in eleven French nephrology units]. / Médicaments à l'origine d'insuffisances rénales aiguës allergiques en France en 2013.

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 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. 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.