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.
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.
SYNOPSIS
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.
Senescent glomerular endothelial cells increased with age, whereas the number of podocytes decreased.
The existence of a detrimental crosstalk between senescent glomerular endothelial cells and podocyte was demonstrated in vivo and in vitro.
Depletion of senescent cells prevented podocyte loss with age.
PAI‐1 was a critical mediator of this cross‐stalk, and its selective inactivation in endothelial cell preserved kidneys from glomerulosclerosis during aging.
PAI‐1 immunostaining predicted kidney allograft dysfunction after transplantation from elderly donors. PAI‐1 excretion was increased in the urine of elderly patients with recognized aging nephropathy.
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.
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.
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.
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.
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.
Belatacept, a CTLA4-Ig, was designed to prevent rejection and graft loss in kidney transplant recipients. This immunotherapy showed a long-term clinical benefit mainly on renal function and better ...glycemic control but was also associated with a higher number of severe infectious diseases, particularly CMV disease, and lymphoproliferative disease. Therapeutic drug monitoring usually guides the benefit–risk assessment of long-term immunosuppression. In this study, an analytical method by LC-MS/MS was developed in 20 microL of plasma for the belatacept quantification. Intra- and inter-assay precision and accuracy were lower than 20% for the limit of quantification, and 15% for higher concentrations. The method was implemented in our lab and provided data about the inter-variability (N = 108) and intra-variability (N = 33) of belatacept concentrations in kidney transplant recipients with a stable renal function, after conversion from a CNI- to a belatacept-based regimen.
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‐treated kidney transplant recipients without history of COVID‐19 present a weak humoral response after 3 injections of BNT162b2 mRNA COVID‐19 vaccine, contrasting with belatacept‐treated patients with prior COVID‐19 infection for whom mRNA vaccine elicits strong antibody response with high antibody titers after 2 injections.
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.
Kidney transplant recipients matched to nontransplant patients for severe COVID‐19 risk factors present similar survival and incidence of severe COVID‐19, suggesting that chronic immunosuppression is not associated with the severity of COVID‐19.
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.
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.
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.
DOACs appear to be effective and safe anticoagulants in KTRs with stable renal function.
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 <30 ml/min; cumulative incidences were 18.4 and 5.2/100 p‐y, respectively. CMV diseases under belatacept were atypical, with late‐onset disease (24/40 patients 60%), high CMV seropositivity (27/40, 67%), increased severe and tissue‐invasive disease rates (gastrointestinal involvement in 32/40 80%) and life‐threatening diseases (4/40 10%). These findings should stimulate further research to secure the use of belatacept as a valuable rescue therapy in KTRs.
Compared to matched controls treated with calcineurin inhibitors, kidney transplant recipients converted to belatacept have a seven‐ fold increased risk of CMV disease with atypical phenotype, including severe and tissue‐invasive clinical presentations, high recurrence rates, and occurrence in patients without classical risk factors for CMV disease.
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