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Poor responses to mRNA COVID-19 vaccine have been reported after 2 vaccine injections in kidney transplant recipients (KTRs) treated with belatacept. We analyzed the humoral response in belatacept-treated KTRs without a history of SARS-CoV-2 infection who received three injections of BNT162b2-mRNA COVID-19 vaccine. We also investigated vaccine immunogenicity in belatacept-treated KTRs with prior COVID-19 and characterized symptomatic COVID-19 infections after the vaccine in belatacept-treated KTRs. Among the 62 belatacept-treated KTRs (36 [58%] males), the median age (63.5 years IQR [51-72]), without COVID-19 history, only four patients (6.4%) developed anti-SARS-CoV-2 IgG with low antibody titers (median 209, IQR [20-409] AU/ml). 71% were treated with mycophenolic acid and 100% with steroids in association with belatacept. In contrast, in all the 5 KTRs with prior COVID-19 history, mRNA vaccine induced a strong antibody response with high antibody titers (median 10 769 AU/ml, IQR [6410-20 069]) after two injections. Seroprevalence after three-vaccine doses in 35 non-belatacept-treated KTRs was 37.1%. Twelve KTRs developed symptomatic COVID-19 after vaccination, including severe forms (50% of mortality). Breakthrough COVID-19 occurred in 5% of fully vaccinated patients. Administration of a third dose of BNT162b2 mRNA COVID-19 vaccine did not improve immunogenicity in KTRs treated with belatacept without prior COVID-19. Other strategies aiming to improve patient protection are needed.

Belatacept may increase cytomegalovirus (CMV) disease risk after conversion from CNI-based therapy. We analyzed CMV disease characteristics after belatacept conversion. Propensity score matching was used to compare CMV disease incidence in belatacept- and CNI-treated kidney transplant recipients (KTRs). CMV disease characteristics and risk factors under belatacept were analyzed. In total, 223 KTRs (median age [IQR] 59.2 years [45.4-68.5]) were converted to belatacept (median of 11.5 months [2.5-37.0] post-transplantation); 40/223 (17.9%) developed CMV disease. Independent risk factors included increased age (p = .0164), D+/R- CMV serostatus (p = .0220), and low eGFR at conversion (p = .0355). Among 181 belatacept-treated patients matched to 181 controls, 32/181 (17.7%) experienced CMV disease (vs. 5/181 controls [2.8%]). CMV disease cumulative incidences were 6.33 and 0.91/100 person-years (p-y) in belatacept and control groups, respectively. CMV disease risk was particularly high in elderly patients (converted >70 years) and those with eGFR

International audience; Immunocompromised patients may experience prolonged viral shedding after their initial SARS-CoV-2 infection, however, symptomatic relapses after remission currently remain rare. We herein describe a severe COVID-19 relapse case of a kidney transplant recipient (KTR) following rituximab therapy, 3 months after a moderate COVID-19 infection, despite viral clearance after recovery of the first episode. During the clinical relapse, the diagnosis was established on a broncho-alveolar lavage specimen (BAL) by RT-PCR. The infectivity of the BAL sample was confirmed on a cell culture assay. Whole genome sequencing confirmed the presence of an identical stain (Clade 20A). However, it had an acquired G142D mutation and a larger deletion of 3-amino-acids at position 143-145. These mutations located within the N-terminal domain are suggested to play a role in viral entry. The diagnosis of a COVID-19 relapse should be considered in the setting of unexplained persistent fever and/or respiratory symptoms in KTRs (especially for those after rituximab therapy), even in patients with previous negative naso-pharyngeal SARS-CoV-2 PCR.

The mechanisms underlying the development of glomerular lesions during aging are largely unknown. It has been suggested that senescence might play a role, but the pathophysiological link between senescence and lesion development remains unexplained. Here, we uncovered an unexpected role for glomerular endothelial cells during aging. In fact, we discovered a detrimental cross‐talk between senescent endothelial cells and podocytes, through PAI‐1. In vivo, selective inactivation of PAI‐1 in endothelial cells protected glomeruli from lesion development and podocyte loss in aged mice. In vitro, blocking PAI‐1 in supernatants from senescent endothelial cells prevented podocyte apoptosis. Consistently, depletion of senescent cells prevented podocyte loss in old p16 INK‐ATTAC transgenic mice. Importantly, these experimental findings are relevant to humans. We showed that glomerular PAI‐1 expression was predictive of poor outcomes in transplanted kidneys from elderly donors. In addition, we observed that in elderly patients, urinary PAI‐1 was associated with age‐related chronic kidney disease. Altogether, these results uncover a novel mechanism of kidney disease and identify PAI‐1 as a promising biomarker of kidney dysfunction in allografts from elderly donors., Kidneys develop lesions with age, and in particular glomerulosclerosis, but the molecular mechanisms involved in the deterioration process are unclear. Here, an unexpected role for glomerular endothelial cells during aging was uncovered.

Introduction Belatacept is associated with a higher incidence of cytomegalovirus (CMV) disease and atypical presentations. Ocular manifestations are rare, representing up to 5% of disease manifestations and previous cases consisted in isolated retinitis. Case Description Herein, we report the case of an 81-year-old kidney transplant recipient who developed an anterior and intermediate uveitis under belatacept therapy. The diagnosis was established using quantitative CMV polymerase chain reaction assays in the aqueous humor. Belatacept was interrupted and oral and topical valganciclovir treatments were instituted. Lesions however extended, leading to intensify the treatment by intra-venous and intra-vitreal ganciclovir injections. Visual acuity stabilized and ocular inflammation was finally controlled after 3 months. Conclusion Clinicians should be aware of CMV infection as a cause of anterior uveitis under belatacept-based regimen, even in the absence of symptoms suggestive of systemic CMV replication.

The utility of zero-time kidney biopsies (KB) in deciding to accept expanded criteria donor (ECD) kidneys remains controversial. However, zero-time histology is one of the main causes for discarding kidneys in the United States. In a single-centre study, we examined the utility and impact on outcome of the use of frozen section zero-time KB among ECD. Ninety-two zero-time KB were analysed for accept/discard decision between 2005 and 2015 among ECD. 53% of kidneys were rejected after zero-time KB analysis; there was no difference in individual clinical and biological data between accepted/rejected groups. However, histology of rejected kidneys showed more sclerotic glomeruli (20% vs. 8%; P

IntroductionExpanded-criteria donors (ECDs) are used to reduce the shortage of kidneys for transplantation. However, kidneys from ECDs are associated with an increased risk of delayed graft function (DGF), a risk factor for allograft loss and mortality. HYPOREME will be a multicentre randomised controlled trial (RCT) comparing targeted hypothermia to normothermia in ECDs, in a country where the use of machine perfusion for organ storage is the standard of care. We hypothesise that hypothermia will decrease the incidence of DGF.Methods and analysisHYPOREME is a multicentre RCT comparing the effect on kidney function in recipients of targeted hypothermia (34°C–35°C) and normothermia (36.5°C–37.5°C) in the ECDs. The temperature intervention starts from randomisation and is maintained until aortic clamping in the operating room. We aim to enrol 289 ECDs in order to analyse the kidney function of 516 recipients in the 53 participating centres. The primary outcome is the occurrence of DGF in kidney recipients, defined as a requirement for renal replacement therapy within 7 days after transplantation (not counting a single session for hyperkalemia during the first 24 hours). Secondary outcomes include the proportion of patients with individual organs transplanted in each group; the number of organs transplanted from each ECD and the vital status and kidney function of the recipients 7 days, 28 days, 3 months and 1 year after transplantation. An interim analysis is planned after the enrolment of 258 kidney recipients.Ethics and disseminationThe trial was approved by the ethics committee of the French Intensive Care Society (CE-SRLF-16-07) on 26 April 2016 and by the competent French authorities on 20 April 2016 (Comité de Protection des Personnes-TOURS-Région Centre-Ouest 1, registration #2016-S3). Findings will be published in peer-reviewed journals and presented during national and international scientific meetings.Trial registration numberNCT03098706.

Higher rates of severe COVID-19 have been reported in kidney transplant recipients (KTRs) compared to nontransplant patients. We aimed to determine if poorer outcomes were specifically related to chronic immunosuppression or underlying comorbidities. We used a 1:1 propensity score-matching method to compare survival and severe disease-free survival (defined as death and/or need for intensive care unit [ICU]) incidence in hospitalized KTRs and nontransplant control patients between February 26 and May 22, 2020. Patients were matched for risk factors of severe COVID-19: age, sex, body mass index, diabetes mellitus, preexisting cardiopathy, chronic lung disease, and basal renal function. We included 100 KTRs (median age [interquartile range (IQR)]) 64.7 years (55.3-73.1) in three French transplant centers. After a median follow-up of 13 days (7-30), transfer to ICU was required for 34 patients (34%) and death occurred in 26 patients (26%). Overall, 43 patients (43%) developed a severe disease during a median follow-up of 8.5 days (2-14). Propensity score matching to a large French cohort of 2017 patients hospitalized in 24 centers, revealed that survival was similar between KTRs and matched nontransplant patients with respective 30-day survival of 62.9% and 71% (p = .38) and severe disease-free 30-day survival of 50.6% and 47.5% (p = .91). These findings suggest that severity of COVID-19 in KTRs is related to their associated comorbidities and not to chronic immunosuppression.

Background and Aims In age-related chronic kidney disease (CKD), the most frequent histological lesion observed is glomerulosclerosis. The molecular mechanisms involved in this deterioration process are unclear, but cellular senescence might play a role. Method By combining several murine models of physiological and accelerated aging with transgenic animals and in vitro models, we discovered the role of endothelial senescence in the development of glomerular lesions. Results These senescent glomerular endothelial cells secreted several molecules, grouped under the senescence associated secretory phenotype (SASP) including the plasminogen activator inhibitor 1 (PAI-1). Specific deletion of PAI-1 in endothelial cells prevented the development of glomerulosclerosis during physiological and accelerated aging, by decreasing podocyte loss. In addition, we showed that PAI-1 mediates a detrimental endothelial-podocyte crosstalk, as incubation of podocytes by supernatant of senescent glomerular endothelial cells led to their detachment. Consistently, preincubation of the senescent supernatant with tiplaxtinin, a PAI-1 inhibitor, preserved podocytes. More importantly, we demonstrated that these data are relevant to humans. In fact, PAI-1 staining the day of the transplantation was predictive of kidney allograft dysfunction 12 months after transplantation from elderly donors. Conclusion In conclusion, our study uncovers the critical role played by endothelial senescence in the development of glomerulosclerosis during aging and identified PAI-1 as a novel promising biomarker for predicting kidney dysfunction in patients receiving a kidney from elderly donors.

Background Oral anticoagulation therapy is frequently prescribed to kidney transplant recipients (KTRs) for prevention and treatment of thrombotic events. Over the past 10 y, direct oral anticoagulants (DOACs) have shown similar efficacy with a safety profile equal or superior to that of vitamin K antagonist anticoagulants (VKAs) in the general population. However, little data are available on kidney transplantation. Methods We investigated the efficacy (thrombotic events) and safety (hemorrhagic and other adverse events and graft outcomes) of DOACs in a cohort of KTRs with a renal function >30 mL/min. We then compared these patients to a control group treated by VKA. Results Fifty-two KTRs treated by DOACs between 2013 and 2018 at Necker Hospital were included. Patients were with a mean age of 62 ± 13 y old and a mean glomerular filtration rate of 59 ± 20 mL/min/1.73m. The major indication was atrial fibrillation (n = 31 [60%]). Apixaban was the most commonly used agent (n = 36 [69%]). No thrombotic complications were reported under DOAC until last follow-up (14.1 ± 13 mo). In comparison to 50 controls under VKA during the same period, the bleeding rate under DOAC was significantly lower (11.5 versus 22.9 per 100 patient-y, P = 0.037) with a hazard ratio of 0.39 (95% confidence interval, 0.19-0.85, P = 0.041). No significant changes in kidney function, rejection rate, or hemoglobin level were reported. Conclusions DOACs appear to be effective and safe anticoagulants in KTRs with stable renal function.

The urinary chemokines CXCL9 and CXCL10 are promising noninvasive diagnostic markers of acute rejection (AR) in kidney recipients, but their levels might be confounded by urinary tract infection (UTI) and BK virus (BKV) reactivation. Multiparametric model development and validation addressed these confounding factors in a training set of 391 samples, optimizing the diagnostic performance of urinary chemokines. CXCL9/creatinine increased in UTI and BKV viremia with or without nephropathy (BKVN) (no UTI/leukocyturia/UTI: -0.10/1.61/2.09, P = .0001 and no BKV/viremia/BKVN: -0.10/1.90/2.29, P

Atypical hemolytic uremic syndrome (aHUS) is an orphan disease with a high rate of recurrence after kidney transplantation. However, reports of successful prevention of posttransplant aHUS recurrence with eculizumab emerged a few years ago. To further delineate its optimal use, we describe the largest series of kidney transplant recipients treated with prophylactic eculizumab.Twelve renal transplant recipients with aHUS-related end-stage renal disease received eculizumab: 10 from day 0 and 2 at the time of recurrence (days 6 and 25). Clinical and histological features, complement assessment, and free eculizumab measurements were analyzed. The median follow-up was 24.6 months.Five patients had failed at least 1 previous renal transplant from aHUS. A genetic mutation was identified in 9 patients, anti-H antibodies were found in 2. No patient demonstrated biological recurrence of thrombotic microangiopathy under treatment. Three antibody-mediated rejections (AMRs) occurred without detectable C5 residual activity. AMR was associated with subclinical thrombotic microangiopathy in 2 patients. One patient lost his graft after several complications, including AMR. One patient experienced posttransplant C3 glomerulonephritis. The last median serum creatinine was 128.2 ± 40.8 μmol/L.These data confirm that eculizumab is highly effective in preventing posttransplantation aHUS recurrence, yet may not fully block AMR pathogenesis.

MicroRNAs (miRNAs) play an important role in the kidneys under physiological and pathological conditions, but their role in immune glomerulonephritis is unclear. miR-146a has been identified as a key player in innate immunity and inflammatory responses, and in the kidney, this miRNA is involved in the response of injured tubular cells. We studied the renal and immune phenotypes of miR-146a +/+ and miR-146a −/− mice at 12 months of age, and the results showed that miR-146a −/− mice developed autoimmunity during aging, as demonstrated by circulating antibodies targeting double-stranded DNA and an immune complex-mediated glomerulonephritis associated with a mild renal immune infiltrate. In addition, miR-146a −/− mice showed reduced expression of the transmembrane protein Kim1/Tim1, a key regulator of regulatory B cell (Breg) homeostasis, in the kidney and the immune cells. The numbers of memory B cells and plasmablasts were increased in miR-146a −/− mice compared with the numbers in wild-type mice, whereas Bregs were decreased in number and displayed an altered capacity to produce IL-10. Finally, we showed that miR-146a −/− mice develop an autoimmune syndrome with increasing age, and this syndrome includes immune complex glomerulonephritis, which might be due to altered B cell responses associated with Kim1/Tim1 deficiency. This study unravels a link between miR-146a and Kim1 and identifies miR-146a as a significant player in immune-mediated glomerulonephritis pathogenesis.

Background During routine post-kidney transplant care, most European transplant physicians screen patients for asymptomatic bacteriuria. The usefulness of this strategy is debated. To make screening cost-effective, asymptomatic bacteriuria should be prevalent enough to justify the expense, and antibiotics should improve patient outcomes significantly if asymptomatic bacteriuria is detected. Regrettably, the prevalence of asymptomatic bacteriuria among kidney transplant recipients is not well defined. Methods To determine the prevalence of asymptomatic bacteriuria among kidney transplant recipients, we did a cross-sectional study among kidney transplant recipients undergoing routine surveillance in three outpatient transplant clinics in Belgium and France. We excluded patients who were in the first two months post-transplantation and/or had a urinary catheter. Asymptomatic participants who had a urine culture with one organism isolated at .105 CFU/mL were asked to provide a confirmatory urine specimen. Asymptomatic bacteriuria was defined per Infectious Diseases Society of America guidelines. Results We screened 500 consecutive kidney transplant recipients. Overall, the prevalence of asymptomatic bacteriuria was 3.4% (17/500 patients). It was similarly low among kidney transplant recipients who were between 2 and 12 months after transplantation (1.3%, 1/76 patients) and those who were farther after transplantation (3.8%, 16/424 patients: P = 0.49). Asymptomatic bacteriuria was significantly associated with female gender (risk ratio 3.7, 95% CI 1.3-10.3, p = 0.007) and older age (mean age: 61 ± 12 years [bacteriuric participants], versus 53 ± 15 years [non-bacteriuric participants], p = 0.03). One participant's colistin-resistant Escherichia coli isolate carried the globally disseminated mcr-1 gene. Conclusions Among kidney transplant recipients who are beyond the second month post-transplant, the prevalence of asymptomatic bacteriuria is low. Further studies are needed to ascertain the cost-effectiveness of a screen-and-treat strategy for asymptomatic bacteriuria in this population., SCOPUS: ar.j, info:eu-repo/semantics/published

Immunosuppressive drug tapering is currently the recommended treatment of BK virus (BKV) viremia after kidney transplantation; however, its exact modalities remain unclear. We retrospectively compared two consecutive strategies in 111 patients with sustained viremia: a gradual monitoring/tapering group (GT, n = 57) before 2012 and a rapid monitoring/tapering group (RT, n = 54) after 2012. At viremia diagnosis, the dose of mycophenolic acid (MPA) and tacrolimus levels (T0 ) were similar among patient groups. However, following onset, the dose of MPA at 1 month (P = 0.002) and 3 months (P = 0.005) and Tac T0 at 1 month (P = 0.030) and 3 months (P = 0.006) were lower in the RT group. This rapid minimization shortened BKV viremia (P < 0.001) and resulted in a better protection of graft function in patients with confirmed BKV-associated nephropathy (P = 0.033) without impacting 5-year graft survival. Survival without rejection was similar (P = 0.571), but the RT group had increased the development of de novo donor-specific antibodies (dnDSAs; P < 0.001). Multivariate Cox analysis identified basiliximab versus Thymoglobulin® induction [hazard ratio (HR), 3.090; P = 0.001] and the RT strategy (HR, 6.021; P = 0.002) as independently associated with dnDSAs. Compared to a gradual tapering, rapid immunosuppression tapering to treat sustained BKV viremia does not improve medium-term clinical outcome but increases the risk of developing dnDSAs.

Background Diarrhoea is one of the most frequent complications after kidney transplantation (KT). Non-infectious diarrhoea has been associated with reduced graft survival in kidney transplant recipients. However, the risk factors for renal allograft loss following diarrhoea remain largely unknown. Methods Between January 2010 and August 2011, 195 consecutive KT recipients who underwent standardized microbiological workups for diarrhoea at a single centre were enrolled in this retrospective study. Results An enteric pathogen was readily identified in 91 patients (47%), while extensive microbiological investigations failed to find any pathogen in the other 104. Norovirus was the leading cause of diarrhoea in these patients, accounting for 30% of the total diarrhoea episodes. The baseline characteristics were remarkably similar between non-infectious and infectious diarrhoea patients, with the exception that the non-infectious group had significantly lower graft function before diarrhoea (P = 0.039). Infectious diarrhoea was associated with a longer duration of symptoms (P = 0.001) and higher rates of acute kidney injury (P = 0.029) and hospitalization (P Conclusion Our study shows that pre-existing conditions (re-transplantation, chronic graft dysfunction and late occurrence) determine the primary functional long-term consequences of post-transplant diarrhoea.

AKI leads to tubular injury and interstitial inflammation that must be controlled to avoid the development of fibrosis. We hypothesized that microRNAs are involved in the regulation of the balance between lesion formation and adaptive repair. We found that, under proinflammatory conditions, microRNA-146a (miR-146a) is transcriptionally upregulated by ligands of IL-1 receptor/Toll–like receptor family members via the activation of NF-κB in cultured renal proximal tubular cells. In vivo, more severe renal ischemia-reperfusion injury (IRI) associated with increased expression of miR-146a in both allografts and urine of human kidney transplant recipients, and unilateral IRI in mice induced miR-146a expression in injured kidneys. After unilateral IRI, miR-146a−/− mice exhibited more extensive tubular injury, inflammatory infiltrates, and fibrosis than wild-type mice. In vitro, overexpression or downregulation of miR-146a diminished or enhanced, respectively, IL-1 receptor–associated kinase 1 expression and induced similar effects on C-X-C motif ligand 8 (CXCL8)/CXCL1 expression by injured tubular cells. Moreover, inhibition of CXCL8/CXCL1 signaling prevented the development of inflammation and fibrosis after IRI in miR-146a−/− mice. In conclusion, these results indicate that miR-146a is a key mediator of the renal tubular response to IRI that limits the consequences of inflammation, a key process in the development of AKI and CKD.

Acute clinical antibody-mediated rejection is currently defined by (1), an acute renal failure occurring during the first months following transplantation, (2), at least a microcirculation inflammation (glomerulitis and peritubular capillaritis) on kidney biopsy and (3), the presence in peripheral blood of donor specific antibodies, mostly anti-human leukocyte antigen (HLA) antibodies. The prognosis of this rejection is scored using the severity of vascular lesions and the positivity of C4d on peritubular capillaries. Recently, a subclinical variety of antibody-mediated rejection was recognized as an entity because, as the clinical rejection, it leads to chronic antibody-mediated rejection, currently the most frequent cause of graft loss. The description of these various aspects of antibody-mediated rejection allowed a better understanding of its pathophyiology that may lead in a near future to a more specific treatment.

Background Donor (D)+/recipient (R)- serostatus is closely associated with a higher risk of cytomegalovirus (CMV) infection and disease. Antiviral prophylaxis is conventionally used in such patients, but late onset CMV infection/disease still occurs after the discontinuation of prophylaxis. Methods We retrospectively analyzed the data of 215 low immunological risk patients who received kidney transplantation in our center between 2011 and 2016. Results Ninety-seven patients received a combination of everolimus (EVL)/reduced doses of calcineurin inhibitors (CNI) (EVL group) de novo, and 118 received a combination of mycophenolic acid (MPA)/standard doses of CNI (MPA group) de novo. All patients received induction by basiliximab, steroids, and standardized antiviral prophylaxis depending on their CMV D/R serostatus. D+/R- recipients comprised 17% (n = 16) of the EVL group and 19% (n = 22) of the MPA group (P = .722). In the D+/R- subgroup, the 1-year incidence of late onset CMV primary disease after the withdrawal of prophylaxis was lower in the EVL group than in the MPA group (6% vs 41%, P = .025) while the rate of CMV disease in the D+/R+ group (8% vs 6%, P = 1) and the D-/R+ group (12% vs 9%, P = 1) were similar. Kaplan-Meier analysis of 1-year CMV primary disease-free survival in seronegative patients was significantly better in the EVL group (P = .029, log-rank test). Conclusions Our data suggest that de novo use of EVL may reduce late onset CMV primary disease after the withdrawal of antiviral prophylaxis in kidney transplantation patients.

There is an increasing number of anti-HLA sensitized and highly sensitized renal transplant candidates on waiting lists, and the presence of donor-specific alloantibodies (DSAs) at the time of transplantation leads to acute and chronic antibody-mediated rejection (AMR). Acceptable short-term outcomes have been described, notably because of desensitization protocols, but mid- and long-term data are still required.Our high immunologic risk program included 95 patients with high peak or day 0 DSA levels (mean fluorescence intensity [MFI]3000) with a complement-dependent cytotoxicity-negative crossmatch, who received a posttransplant desensitization protocol starting at day 0 with high-dose intravenous immunoglobulin, plasma exchanges, and eventually rituximab. Their characteristics were compared with a control group including 39 patients with a lower immunologic risk (MFI between 500 and 3000 at day 0) who received the same posttransplant desensitization.The median MFI of the immunodominant class I or II DSA in the peak or day 0 serum was 9421 (interquartile range, 4959-12 610). An AMR occurred during the first posttransplant year in 31 patients (32.6%), and at one year, the rate of chronic AMR was 39.5%. The 1-, 3-, 5- and 7-year death-censored allograft survival rates were 98%, 91%, 86%, and 78%, respectively, with concomitant recipient survival rates of 97%, 93%, 85%, and 79%, respectively.These results suggest that DSA-sensitized patients with high MFI levels can receive transplantation across the HLA-barrier, with the use of an intensified posttransplant immunosuppressive therapy starting at day 0 combined with close clinical, immunologic, and histologic monitoring.

Dramatic improvements in short-term graft outcomes after solid organ transplantation over the past decade have not translated into major improvements in long-term allograft acceptance and patient survival. Innovative approaches to develop individualized therapy for the graft recipient are critically needed and have stimulated active research in the field of biomarker discovery. MicroRNAs (miRNAs) are small non-coding RNAs that function as important regulators of gene and protein expression by RNA interference. They are implicated in many biological processes and diseases. Their characteristics prompted their evaluation as candidate molecular markers to evaluate the transplant patient: their expression profile is specifically altered in pathological conditions, they can be easily detected and quantified in tissues, and they are highly stable in almost all body fluids, allowing the development of non-invasive approaches. We aimed to review the existing knowledge about miRNA biogenesis and function and summarize the recent findings demonstrating their potential use as biomarkers in solid organ transplantation. Although they still need to be validated in larger patient cohorts, miRNAs are not far from being used in transplant clinical practice as usefulness biomarkers. Ongoing multi-center trials should help to further define the clinical utility of miRNA profiles as biomarkers of allograft status and outcome.

International audience; Urinary messenger RNA (mRNA) quantification is a promising method for noninvasive diagnosis of renal allograft rejection (AR), but the quantification of mRNAs in urine remains challenging due to degradation. RNA normalization may be warranted to overcome these issues, but the strategies of gene normalization have been poorly evaluated. Herein, we address this issue in a case-control study of 108 urine samples collected at time of allograft biopsy in kidney recipients with (n = 52) or without (n = 56) AR by comparing the diagnostic value of IP-10 and CD3ε mRNAs—two biomarkers of AR—after normalization by the total amount of RNA, normalization by one of the three widely used reference RNAs—18S, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Hypoxanthine-guanine phosphoribosyltransferase (HPRT)—or normalization using uroplakin 1A (UPK) mRNA as a possible urine-specific reference mRNA. Our results show that normalization based on the total quantity of RNA is not substantially improved by additional normalization and may even be worsened with some classical reference genes that are overexpressed during rejection. However, considering that normalization by a reference gene is necessary to ensure polymerase chain reaction (PCR) quality and reproducibility and to suppress the effect of RNA degradation, we suggest that GAPDH and UPK1A are preferable to 18S or HPRT RNA.

Les microARN (miARN) constituent une classe abondante de petits ARN naturels non codants. Ils jouent un role fondamental dans la regulation post-transcriptionnelle des genes. Des donnees recentes suggerent leur implication dans le developpement de l’appareil urinaire et des cellules renales et dans des processus impliques dans la physiopathologie des maladies renales comme la fibrogenese, l’immunite innee et adaptative et les maladies dysimmunitaires ou le rejet du greffon renal. Nous proposons une revue de la litterature sur l’implication des miARN en physiopathologie renale.

Introduction La maladie de Fabry est une maladie hereditaire du metabolisme due a un deficit en alphagalactosidase A, enzyme lysosomale qui, lorsqu’elle fonctionne normalement clive les sphingolipides permettant leur degradation et leur elimination. En cas d’anomalie quantitative ou qualitative de cette enzyme, la globotriaosylceramide (Gb3) se depose a l’interieur des cellules. Les principales atteintes sont cardiaque, renale et neurologique mais l’atteinte digestive est probablement sous-estimee [1] . Patients/Materiels et methodes/Observation Nous rapportons le cas d’un patient de 45 ans atteint d’une maladie de FABRY diagnostiquee en mars 2014 avec atteinte renale, cardiaque et neurologique peripherique. La biopsie renale mettait en evidence des depots glomerulaires de sphingolipides. Le diagnostic etait confirme par une diminution de l’alpha galactosidase et une elevation de la Gb3 urinaire. L’analyse genetique retrouvait une mutation AGAL : c.1277_1278del/chrY. Malgre une enzymotherapie substitutive–agalsidase beta, Fabrazyme®–, l’evolution renale est defavorable et le patient est transplante pour la premiere fois le 20/06/2017 avec le rein de son epouse. L’evolution est favorable avec une reprise de fonction immediate et un nadir de creatinine a 100 μmol/L. Un an plus tard, il est adresse pour une douleur epigastrique evoluant depuis 48 h partiellement soulagee par la morphine. La biologie (creatinine, cycle de troponine, lipase, LDH, Lactates, CRP) est normale. Le traitement par IPP est inefficace. Enfin, la TDM abdominopelvienne injectee elimine l’ischemie mesenterique mais retrouve une colectasie transverse importante. Une colo-exsufflation est alors pratiquee et soulage le patient. Le diagnostic de colectasie transverse en lien avec la maladie de Fabry est retenu. Resultats/Discussion Le pronostic des patients transplantes renaux dans le cadre d’une maladie de Fabry est bon mais ne prevaut pas de l’apparition d’autres atteintes. La frequence des atteintes digestives varie de 19 a 69 % [1] , parfois au premier plan, parfois plus difficiles a diagnostiquer comme dans le cas present. La physiopathologie est liee a une dysfonction du systeme nerveux autonome a l’origine de troubles de la motilite intestinale. On retrouve ainsi des glycosphingolipides au sein des cellules nerveuses du plexus mesenterique. L’apparition sous enzymotherapie conduit par ailleurs a rechercher des anticorps anti-Fabrazyme®. Conclusion Meme apres transplantation renale et sous enzymotherapie substitutive, de nouvelles atteintes de la maladie de Fabry peuvent survenir, notamment au niveau digestif.

We monitored the urinary C-X-C motif chemokine (CXCL)9 and CXCL10 levels in 1722 urine samples from 300 consecutive kidney recipients collected during the first posttransplantation year and assessed their predictive value for subsequent acute rejection (AR). The trajectories of urinary CXCL10 showed an early increase at 1 month (p = 0.0005) and 3 months (p = 0.0009) in patients who subsequently developed AR. At 1 year, the AR-free allograft survival rates were 90% and 54% in patients with CXCL10:creatinine (CXCL10:Cr) levels2.79 ng/mmoL and2.79 ng/mmoL at 1 month, respectively (p 0.0001), and 88% and 56% in patients with CXCL10:Cr levels5.32 ng/mmoL and5.32 ng/mmoL at 3 months (p 0.0001), respectively. CXCL9:Cr levels also associate, albeit less robustly, with AR-free allograft survival. Early CXCL10:Cr levels predicted clinical and subclinical rejection and both T cell- and antibody-mediated rejection. In 222 stable patients, CXCL10:Cr at 3 months predicted AR independent of concomitant protocol biopsy results (p = 0.009). Although its positive predictive value was low, a high negative predictive value suggests that early CXCL10:Cr might predict immunological quiescence on a triple-drug calcineurin inhibitor-based immunosuppressive regimen in the first posttransplantation year, even in clinically and histologically stable patients. The clinical utility of this test will need to be addressed by dedicated prospective clinical trials.

Urinary levels of C-X-C motif chemokine 9 (CXCL9) and CXCL10 can noninvasively diagnose T cell-mediated rejection (TCMR) of renal allografts. However, performance of these molecules as diagnostic/prognostic markers of antibody-mediated rejection (ABMR) is unknown. We investigated urinary CXCL9 and CXCL10 levels in a highly sensitized cohort of 244 renal allograft recipients (67 with preformed donor-specific antibodies [DSAs]) with 281 indication biopsy samples. We assessed the benefit of adding these biomarkers to conventional models for diagnosing/prognosing ABMR. Urinary CXCL9 and CXCL10 levels, normalized to urine creatinine (Cr) levels (CXCL9:Cr and CXCL10:Cr) or not, correlated with the extent of tubulointerstitial (i+t score; all P

Acute clinical antibody-mediated rejection is currently defined by (1), an acute renal failure occurring during the first months following transplantation, (2), at least a microcirculation inflammation (glomerulitis and peritubular capillaritis) on kidney biopsy and (3), the presence in peripheral blood of donor specific antibodies, mostly anti-human leukocyte antigen (HLA) antibodies. The prognosis of this rejection is scored using the severity of vascular lesions and the positivity of C4d on peritubular capillaries. Recently, a subclinical variety of antibody-mediated rejection was recognized as an entity because, as the clinical rejection, it leads to chronic antibody-mediated rejection, currently the most frequent cause of graft loss. The description of these various aspects of antibody-mediated rejection allowed a better understanding of its pathophyiology that may lead in a near future to a more specific treatment.

Introduction L’agression renale conduit au developpement de lesions tubulaires et a une inflammation aboutissant au developpement d’une fibrose renale. Nous avons emis l’hypothese que les micro-ARNs sont impliques dans la reponse tubulaire renale a l’inflammation. Materiels et methodes Nous avons etudie in vitro, dans des cellules tubulaires proximales de la lignee HK-2, la reponse epitheliale a differentes cytokines pro-inflammatoires ainsi que la regulation de miR-146a. L’etude des cibles de miR-146a a ete realisee apres stimulation par l’IL-1β. In vivo nous avons etudie l’effet une ischemie-reperfusion renale unilaterale (IR) sur des souris wild-type (WT) et invalidees de facon systemique pour miR-146a (miR-146a–/–). Le parenchyme renal de ces souris a ete etudie 14 jours apres IR renale. Resultats En conditions pro-inflammatoires, nous avons identifie l’induction d’expression de miR-146a par les ligands des recepteurs a l’IL-1β et des Toll-like recepteurs. L’induction de miR-146a par l’IL-1β est secondaire a l’activation de la voie NF-κB, et nous avons montre que miR-146a constitue un retrocontrole negatif de la voie NF-κB en ciblant la proteine IRAK1, induisant en aval la diminution d’expression de la chimiokine CXCL8/CXCL1. In vivo, miR-146a est induit chez la souris 7 jours apres une IR renale unilaterale ; chez l’homme miR-146a est induit dans les biopsies de greffons renaux presentant une necrose tubulaire aigue precocement apres la greffe par rapport a des biopsies normales (p Discussion miR-146a est impliquee dans la reponse renale a l’IR, chez l’homme et la souris. Conclusion Ces resultats suggerent le role de miR-146a comme mediateur cle de la reponse renale a l’agression tubulaire en permettant de limiter les consequences de l’inflammation renale, un processus majeur dans le developpement des maladies renales chroniques.

Resume L’aggravation paradoxale d’une tuberculose lors de la restauration immunitaire sous traitement antiviral chez les patients co-infectes par le VIH est connue sous le nom d’IRIS. Nous decrivons ici un cas d’aggravation paradoxale d’une tuberculose lors de l’arret des anti-TNFα contemporaine de la restauration d’une immunite specifique anti-infectieuse. Cette observation permet d’attirer l’attention sur la possible aggravation des complications, ici tuberculose, apres l’arret des anti-TNFα et pouvant necessiter paradoxalement parfois la reprise de l’immunosuppression.

The detection of preformed donor-specific alloantibodies (DSA) with multiplex-bead arrays has led to the common observation that individuals without a history of pregnancy, transfusion or transplantation can have circulating anti-HLA antibodies of unknown etiology. We retrospectively analyzed the risk of antibody-mediated rejection (AMR) and graft outcome in 41 kidney transplant recipients with DSA of unknown etiology (DSA cause-unk) at the time of transplantation. Twenty-one patients received a posttransplantation desensitization protocol, and 20 received standard immunosuppressive therapy. The mean number of DSA was 1.4 ± 0.8, ranging from 1 to 5. Complement-dependent cytotoxicity crossmatches were negative for all the patients. Flow cytometry crossmatches were positive in 47.6% of cases. The incidence of acute AMR was 14.6% at 1 year, regardless of the immunosuppressive regimen. No patients experienced graft loss following AMR. At month 12, across the entire population of patients with DSA cause-unk, the outcomes were favorable: the measured glomerular filtration rate was 63.8 ± 16.4 mL/min/1.73 m(2), the screening biopsies showed low frequencies of microvascular inflammation and no transplant glomerulopathy, and graft and patient survival were 100%. In conclusion, patients with DSA cause-unk are able to mount AMR but have favorable 1-year outcomes.

Introduction Notre objectif est de rapporter notre experience de l’association de l’everolimus (EVL) a des doses reduites d’inhibiteurs de la calcineurine (CNI) apres transplantation renale. Patients et methodes Il s’agit d’une etude monocentrique de 251 patients a faible risque immunologique transplantes de 05/2011 a 02/2016, traites par basiliximab, CNI [ciclosporine, n = 19 ; tacrolimus (Tac), n = 232], corticoides, et EVL (n = 118) ou acide mycophenolique (MPA, n = 133). La comparaison des groupes EVL et MPA est presentee en intention de traiter. Resultats Les caracteristiques etaient similaires dans les 2 groupes en dehors du delai de suivi, superieur dans le groupe MPA, historique (706 ± 493 jours vs 268 ± 224 jours, p ≤ 0,01). Dans le groupe EVL, les concentrations (T0) d’EVL etaient de 5,9 ± 2,0 μg/L a M3 et 5,6 ± 1,4 μg/L a M12. Dans le groupe MPA, les doses de MPA etaient de 1645 ± 503 mg/j a M3 et 1147 ± 573 mg/j a M12. Les T0 de Tac etaient respectivement dans les groupes Tac/EVL et Tac/MPA de 5,6 ± 1,7 μg/l vs 8,2 ± 2,5 μg/L a M3, 4,1 ± 1,2 μg/L vs 6,5 ± 1,9 μg/L a A1. L’incidence de rejet aigu (cliniques et infracliniques) etait similaire dans les groupes EVL et MPA a A1 (15 % vs 17 %, p = 0,86) ainsi que le delai d’apparition du rejet aigu (107 ± 90 vs 102 ± 76 jours, p = 1), l’incidence de DSA de novo a A1 (14 % vs 8 %, p = 0,22). Le delai d’apparition de DSA de novo etait plus precoce dans le groupe EVL (118 ± 70 jours vs 367 ± 374 jours, p = 0,07). Les creatininemies a j14 (211 ± 176 μmol/L vs 189 ± 135 μmol/L, p = 0,96), M3 (138 ± 48 μmol/L vs 140 ± 54 μmol/L, p = 0,84) et A1 (136 ± 40 μmol/L vs 141 ± 61 μmol/L p = 0,97) etaient similaires dans les 2 groupes. La proteinurie etait plus elevee a j14 (0,38 ± 0,40 g/L vs 0,30 ± 0,51 g/L, p Discussion Chez les patients a faible risque, un traitement initial par EVL/CNI est caracterisee par une efficacite similaire a l’association CNI/MPA en termes de rejet, de survie et de pronostic renal. Conclusion Ces resultats confirment l’efficacite de cette association chez les patients a risque faible.

Introduction Nous rapportons la tolerance de l’association d’everolimus (EVL) et d’une exposition reduite d’anticalcineurine (CNI) dans notre centre et la comparons a une population historique. Patients et methodes Il s’agit d’une etude retrospective de 251 patients transplantes de 05/2011 a 02/2016, traites par basiliximab, CNI (CsA, n = 19 ou tacro, n = 232), corticoides, et EVL ( n = 118) ou acide mycophenolique (MPA, n = 133). La comparaison est presentee en intention de traiter. Resultats Les caracteristiques etaient similaires dans les 2 groupes en dehors du delai de suivi, superieur dans le groupe MPA historique (706 ± 493 jours vs 268 ± 224 jours, p p = 0,02) et plus precoce (92 ± 105 jours vs 216 ± 212, p p = 1), de lymphocele (8 % vs 4 %, p = 0,18), de retard de cicatrisation (8 % vs 3 %, p = 0,15), d’anemie apres 3 mois (64 % vs 55 %, p = 0,20), de diarrhee (10 % vs 17 %, p = 0,14), d’aphtes (3 % vs 1 %, p = 0,42), de folliculite (4 % vs 4 %, p = 1) et de diabete (27 % vs 26 %, p = 0,88) etait similaire dans les 2 groupes. L’incidence de lymphœdeme (17 % vs 4 %, p p p = 0,02) et de leucopenie (8 % vs 35 %, p p = 0,01). Nous n’avons pas trouve de difference entre les groupes en termes d’infections bacteriennes, d’infection a BK virus et de viremie a CMV. En revanche, parmi les receveurs CMV negatifs, le taux de primo-infection a CMV etait moins eleve dans le groupe EVL (5 % vs 32 %, p Discussion La crainte de son inefficacite est souvent responsable d’une modification du protocole CNI/EVL. Le lymphœdeme constitue le principal effet secondaire de l’EVL. L’association CNI/EVL est associee a une forte reduction des primo-infections a CMV. Conclusion L’interet de cette association sur le risque viral necessite de mieux apprehender le profil d’efficacite et de tolerance de l’association CNI/EVL.

Introduction L’analyse histologique extemporanee pre-implantatoire peut etre un outil d’aide a la decision d’acceptation d’un greffon renal. Sa superiorite par rapport aux seules donnees cliniques et biologiques n’est pas encore clairement demontree. Patients et methodes Il s’agit d’une etude monocentrique portant sur les examens extemporanes realises entre novembre 2005 et decembre 2014. Nous avons compare les donnees clinico-biologiques et histologiques des donneurs a criteres elargis (ECD) entre les greffons acceptes ou refuses. Resultats Au cours de cette periode, 85 examens extemporanes pre-implantatoires ont ete realises sur 1222 transplantations a partir d’un donneur decede (7,0 %). Sur les 614 greffes renales a partir d’ECD, 68 examens extemporanes ont ete realises pour evaluer la qualite du greffon (11 %). Les donneurs ECD avec examen extemporane etaient âges de 73 ± 10 ans, decedes de cause vasculaire pour 79 % avec un antecedent d’hypertension arterielle dans 79 %, de diabete dans 16 % et une creatininemie moyenne au prelevement de 111 ± 59 μmol/L. Apres analyse extemporanee, 46 % ( n = 31) des reins ont ete acceptes, 47 % ( n = 32) ont ete refuses sur les criteres histologiques et 7 % ( n = 5) pour d’autres raisons (cross-match positif ou contre-indication du receveur). L’âge des donneurs (73 ± 11 vs 74 ±9 ans), la creatininemie (111 ± 67 vs 118 ± 52 umol/L), l’existence d’une hypertension arterielle (71 % vs 81 %) ou d’un diabete (7 % vs 25 %) et la cause de deces vasculaire (74 % vs 88 %) ne differaient pas significativement entre les donneurs dont le rein a ete accepte ou recuse, respectivement. En revanche, l’histologie des reins de donneurs recuses retrouvait plus de glomerules sclereux (25 % ± 14 vs 12 % ± 15 ; p p p p = 0,006). Discussion Pour un petit contingent de donneurs de type ECD, l’analyse extemporanee de la biopsie pre-implantatoire a ete un element decisif d’acceptation ou non du greffon. Des elements histologiques pejoratifs etaient determinants pour le refus dans 47 % des cas, alors que les donneurs recuses ou acceptes ne differaient pas par les criteres biocliniques usuels. Conclusion La place definitive du role de l’analyse extemporanee de certains donneurs a criteres elargis reste cependant a etablir.

MicroRNAs (miRNAs) are an abundant class of small noncoding RNAs, evolutionarily conserved, that post-transcriptionnaly regulate gene expression by promoting degradation or repressing translation of the targetted messenger RNA. Recent data suggest the implication of miRNAs in renal development, and in renal diseases pathophysiology including fibrogenesis, regulation of innate and adaptive immunity, autoimmune diseases and acute rejection of the renal allograft. Herein, we review the implication of miRNAs in renal pathophysiology.

Paradoxical worsening of tuberculosis associated with immune reconstitution during antiretroviral therapy in patients with HIV infection is known as the immune reconstitution inflammatory syndrome (IRIS). Here, we report a case of paradoxical worsening of IFN-alpha induced tuberculosis in a patient experiencing reconstitution of pathogen-specific immune responses after discontinuing TNFα antagonist therapy. This case serves to alert clinicians that complications such as tuberculosis may worsen after TNFα antagonist discontinuation. This situation may paradoxically require readministration of the immunosuppressive drug in some patients.