Immune checkpoint inhibitor therapy associated with IgA nephropathy: a case report and literature review.

Immune checkpoint inhibitors (ICIs) dramatically improve the prognosis of many malignancies but at the cost of numerous side effects, which may limit their benefits. Acute kidney injury associated with immune checkpoint inhibitors most frequently are acute tubulointerstitial nephritis (ATIN), but various cases of glomerulonephritis have also been reported. Herein, we report a case of severe IgA nephropathy (IgAN) associated with ICIs and carry out a literature review. IgAN was diagnosed in a median time of 5 months (range 1-12 months) after the initiation of ICIs, with heterogeneous severity, and usually treated by corticosteroid and discontinuation of ICIs. In contrast to our case, renal outcomes in literature were often favorable, with recovery of renal function and a reduction in proteinuria on treatment. Although IgAN related to ICIs is a much rarer complication than ATIN, it may still be underdiagnosed. Careful questioning and screening for asymptomatic hematuria should be performed before using ICIs.

Optimization of Rituximab Therapy in Adult Patients With PLA2R1-Associated Membranous Nephropathy With Artificial Intelligence.

Introduction: Rituximab is a first-line treatment for membranous nephropathy. Nephrotic syndrome limits rituximab exposure due to urinary drug loss. Rituximab underdosing (serum level <2 µg/ml at month-3) is a risk factor for treatment failure. We developed a machine learning algorithm to predict the risk of underdosing based on patients' characteristics at rituximab infusion. We investigated the relationship between the predicted risk of underdosing and the cumulative dose of rituximab required to achieve remission. Methods: Rituximab concentrations were measured at month-3 in 92 sera from adult patients with primary membranous nephropathy, split into a training (75%) and a testing set (25%). A forward-backward machine-learning procedure determined the best combination of variables to predict rituximab underdosing in the training data set, which was tested in the test set. The performances were evaluated for accuracy, sensitivity, and specificity in 10-fold cross-validation training and test sets. Results: The best variables combination to predict rituximab underdosing included age, gender, body surface area (BSA), anti-phospholipase A2 receptor type 1 (anti-PLA2R1) antibody titer on day-0, serum albumin on day-0 and day-15, and serum creatinine on day-0 and day-15. The accuracy, sensitivity, and specificity were respectively 79.4%, 78.7%, and 81.0% (training data set), and 79.2%, 84.6% and 72.7% (testing data set). In both sets, the algorithm performed significantly better than chance (P < 0.05). Patients with an initial high probability of underdosing experienced a longer time to remission with higher rituximab cumulative doses required to achieved remission. Conclusion: This algorithm could allow for early intensification of rituximab regimen in patients at high estimated risk of underdosing to increase the likelihood of remission.

The effects of switching from ceftriaxone to cefotaxime on the occurrence of third-generation cephalosporin-resistant Enterobacterales: A stepped-wedge cluster randomized trial.

OBJECTIVES: To evaluate the effects of the replacement of ceftriaxone by cefotaxime on the incidence of third-generation cephalosporin-resistant Enterobacterales (3GC-RE). PATIENTS AND METHODS: We conducted a 24-month monocentric prospective, stepped-wedge cluster randomized controlled trial. During the control phase of the study, clinicians prescribed either ceftriaxone or cefotaxime. During the intervention phase, they systematically prescribed cefotaxime. RESULTS: The cefotaxime/ceftriaxone ratio was inversely correlated with the incidence of 3GC-RE. All in all, 3GC-RE incidence was 1.05 (27/25,692) acquired cases/1000 hospitalization days during the control phase and 0.54 (11/20,419) acquired cases/1000 hospitalization days during the intervention phase (incidence rate ratio [IRR] = 0.51 [0.22-1.07], p = 0.06). In multivariable analysis, intervention phase (versus control phase) (p = 0.007), cefotaxime/ceftriaxone ratio (p = 0.003) and imported 3GC-RE (p = 0.005) were associated with the incidence of acquired cases of 3GC-RE. CONCLUSIONS: We found that replacing ceftriaxone with cefotaxime reduced the occurrence of 3GC-RE isolates. More studies are needed to confirm these results.

Immune modulation with extracorporeal photopheresis in renal transplantation: proof of concept clinical outcomes and perspective / Immunomodulation par photo-chimiothérapie extracorporelle en transplantation rénale : preuves de concept, données cliniques et perspectives

For 30 years, photopheresis is used to treat graft versus host disease and heart or lung allograft rejection. In this review, we discuss the place of photopheresis in kidney transplantation both in prevention or treatment of rejection. Mechanisms of action in kidney transplantation are mainly based on results observed in graft versus host disease and in heart or lung transplantation. Photopheresis may induce innate and adaptive immunity changes with restauration of a favourable Th1/Th2 immune balance, an expansion of LT /LB reg subsets, and a local enrichment in IL-10. French national clinical and mechanistic studies are underway to define the place of photopheresis therapy in immunomodulation strategies in kidney transplantation.

Depuis presque 30 ans, l'utilisation de la photo-chimiothérapie (PEC) a montré son efficacité dans le contrôle de la maladie du greffon contre l'hôte et dans le traitement du rejet d'allogreffe cardiaque et pulmonaire. L'utilisation de la PEC en transplantation rénale pourrait apporter un bénéfice thérapeutique sans majoration du risque infectieux ou oncologique, tant en prévention que dans le traitement du rejet. Il existe peu de données sur les mécanismes d'action de la PEC, les principales hypothèses reposant sur les résultats observés dans la maladie du greffon contre l'hôte ou en transplantation cardiaque et pulmonaire. La PEC induirait des modifications de l'immunité innée et adaptative dont la restauration d'un équilibre de la balance Th1/Th2 et une expansion des sous-populations LT/B régulatrices ainsi qu'une modification de l'environnement cytokinique avec enrichissement en IL-10. En France, des études cliniques et mécanistiques sont en cours pour affiner la place de la PEC dans les stratégies d'immunomodulation en transplantation rénale.

Triglyceride-Glucose Index and Cardiovascular Events in Kidney Transplant Recipients.

Introduction: Kidney transplant recipients (KTRs) have an increased risk of cardiovascular (CV) events (CVEs) compared with the general population. The impact of insulin resistance on CV risk after transplantation is not well defined. Methods: We tested whether triglyceride-glucose (TyG) index, a surrogate marker of insulin resistance, may predict posttransplant CVEs in a cohort of 715 consecutive KTRs all included 1 year after transplant. Results: Follow-up was 9.1 ± 4.6 years. Mean TyG at inclusion was 4.75 ± 0.29 (median, 4.73 [4.14-5.84]). In multiple regression analysis, having a TyG above the median value was associated with higher body mass index (BMI), low high-density lipoprotein (HDL) cholesterol level, and greater urinary protein excretion. A total of 127 CVEs (17.7%) occurred during the study period. In univariate analysis, TyG was strongly associated with CVE occurrence (hazard ratio [HR] 2.06, 95% CI 1.42-3.50, for each increase of 0.1 in TyG, P < 0.001). The best predictive value was 4.87 (HR 6.32, 95% CI 3.30-12.11, P < 0.001). The risk of CVE gradually increased with higher TyG index (quartile 2, HR 1.71, 95% CI 0.84-5.20, P = 0.139; quartile 3, HR 3.12, 95% CI 1.61-6.02, P < 0.001; quartile 4, HR 7.46, 95% CI 4.03-13.80, P < 0.001, vs. quartile 1). TyG remained associated with CVE in multivariate analysis (HR 2.11, 95% CI 1.22-3.68, for each increase of 0.1 in TyG, P < 0.001). Conclusion: Insulin resistance, as measured by the TyG index is strongly associated with CVE in KTRs. Improving insulin sensitivity seems to be a major issue to prevent CV morbidity and mortality in this high-risk population.

Automated evaluation with deep learning of total interstitial inflammation and peritubular capillaritis on kidney biopsies.

BACKGROUND: Interstitial inflammation and peritubular capillaritis are observed in many diseases on native and transplant kidney biopsies. A precise and automated evaluation of these histological criteria could help stratify patients' kidney prognoses and facilitate therapeutic management. METHODS: We used a convolutional neural network to evaluate those criteria on kidney biopsies. A total of 423 kidney samples from various diseases were included; 83 kidney samples were used for the neural network training, 106 for comparing manual annotations on limited areas to automated predictions, and 234 to compare automated and visual gradings. RESULTS: The precision, recall and F-score for leukocyte detection were, respectively, 81%, 71% and 76%. Regarding peritubular capillaries detection the precision, recall and F-score were, respectively, 82%, 83% and 82%. There was a strong correlation between the predicted and observed grading of total inflammation, as for the grading of capillaritis (r = 0.89 and r = 0.82, respectively, all P < .0001). The areas under the receiver operating characteristics curves for the prediction of pathologists' Banff total inflammation (ti) and peritubular capillaritis (ptc) scores were respectively all above 0.94 and 0.86. The kappa coefficients between the visual and the neural networks' scores were respectively 0.74, 0.78 and 0.68 for ti ≥1, ti ≥2 and ti ≥3, and 0.62, 0.64 and 0.79 for ptc ≥1, ptc ≥2 and ptc ≥3. In a subgroup of patients with immunoglobulin A nephropathy, the inflammation severity was highly correlated to kidney function at biopsy on univariate and multivariate analyses. CONCLUSION: We developed a tool using deep learning that scores the total inflammation and capillaritis, demonstrating the potential of artificial intelligence in kidney pathology.

C3 Glomerulopathy With Concurrent Thrombotic Microangiopathy: Clinical and Immunological Features.

RATIONALE & OBJECTIVE: C3 glomerulopathy (C3GN) and atypical hemolytic uremic syndrome (aHUS) are 2 distinct rare kidney diseases caused by dysregulation of the alternative complement pathway. Patients with C3GN and concurrent kidney lesions of thrombotic microangiopathy (TMA) have been rarely reported. We characterized the clinical features and underlying immunological abnormalities in these patients. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Patients with C3GN and concomitant TMA lesions on biopsy registered from 2009 to 2019 in the French National Registry of C3GN. FINDINGS: Among 278 registered patients with C3GN, 16 (6%) had biopsy-proven glomerular and/or vascular TMA lesions. Their median age at diagnosis was 39 years (range, 7-76), and 59% were female. Fourteen of the 16 patients (88%) had an estimated glomerular filtration rate of<30mL/min/1.73m2 and 3 of 16 (19%) required dialysis. Twelve of the 14 evaluated patients (86%) showed evidence of mechanical hemolysis. Fifty percent of the patients had low C3 levels. Six of the 14 evaluated patients had a rare variant in complement genes, and 4 of the 16 patients (25%) had monoclonal gammopathy. Among the 16 patients, 10 (63%) received eculizumab, 5 (31%) received immunosuppressive therapy, and 4 (25%) received clone-targeted chemotherapy. Median kidney survival was 49 months. LIMITATIONS: Small retrospective case series with a limited number of biopsies including electron microscopy. CONCLUSIONS: Concomitant C3GN and TMA is extremely rare and is associated with poor kidney outcomes. Genetic or acquired abnormalities of the alternative complement pathway are common as is the presence of monoclonal gammopathy, which may inform the selection of treatment approaches.

Deep learning automation of MEST-C classification in IgA nephropathy.

BACKGROUND: Although the MEST-C classification is among the best prognostic tools in immunoglobulin A nephropathy (IgAN), it has a wide interobserver variability between specialized pathologists and others. Therefore we trained and evaluated a tool using a neural network to automate the MEST-C grading. METHODS: Biopsies of patients with IgAN were divided into three independent groups: the Training cohort (n = 42) to train the network, the Test cohort (n = 66) to compare its pixel segmentation to that made by pathologists and the Application cohort (n = 88) to compare the MEST-C scores computed by the network or by pathologists. RESULTS: In the Test cohort, >73% of pixels were correctly identified by the network as M, E, S or C. In the Application cohort, the neural network area under the receiver operating characteristics curves were 0.88, 0.91, 0.88, 0.94, 0.96, 0.96 and 0.92 to predict M1, E1, S1, T1, T2, C1 and C2, respectively. The kappa coefficients between pathologists and the network assessments were substantial for E, S, T and C scores (kappa scores of 0.68, 0.79, 0.73 and 0.70, respectively) and moderate for M score (kappa score of 0.52). Network S and T scores were associated with the occurrence of the composite survival endpoint (death, dialysis, transplantation or doubling of serum creatinine) [hazard ratios 9.67 (P = .006) and 7.67 (P < .001), respectively]. CONCLUSIONS: This work highlights the possibility of automated recognition and quantification of each element of the MEST-C classification using deep learning methods.

Nivolumab-induced capillary leak syndrome associated with chylothorax in a melanoma patient: A case report and review of the literature.

Introduction: Adverse events (AEs) of immune checkpoint inhibitors (ICIs) are frequent and mainly due to an overactivity of the immune system leading to excessive inflammatory responses (immune-related AE) that can affect any organ of the body. Beside the most frequent AEs, there are rare AEs whose diagnosis and treatment can be challenging. We report here a singular case of capillary leak syndrome (CLS) associated with chylothorax occurring in a patient who has been treated with adjuvant nivolumab (anti-PD1) for resected AJCC stage IIB primary melanoma. Case presentation: A 43-year-old woman was diagnosed with a nodular stage IIB melanoma of her left thigh, according to the AJCC 8th edition (T3bN0M0). The woman was treated with adjuvant nivolumab. She stopped the treatment after 4 infusions due to thrombopenia. Three months later, she developed facial and leg edema and ascites due to capillary leak syndrome. The CLS was associated with chylothorax and elevated vascular endothelial growth factor. The patient was initially treated with several pleural puncturing and steroids. CLS and chylothorax progressively decreased with intravenous immunoglobulins and fat-free diet without recurrence of melanoma at one-year follow-up. Conclusion: CLS is a rare and potentially life-threatening AE of ICIs such as anti-PD1. This AE may be associated with chylothorax probably related to lymphatic permeability induced by anti-PD1.

Cryptococcal Meningitis in Kidney Transplant Recipients: A Two-Decade Cohort Study in France.

Cryptococcosis is the third most common cause of invasive fungal infection in solid organ transplant recipients and cryptococcal meningitis (CM) its main clinical presentation. CM outcomes, as well as its clinical features and radiological characteristics, have not yet been considered on a large scale in the context of kidney transplantation (KT). We performed a nationwide retrospective study of adult patients diagnosed with cryptococcosis after KT between 2002 and 2020 across 30 clinical centers in France. We sought to describe overall and graft survival based on whether KT patients with cryptococcosis developed CM or not. Clinical indicators of CNS involvement and brain radiological characteristics were assessed. Eighty-eight cases of cryptococcosis were diagnosed during the study period, with 61 (69.3%) cases of CM. Mortality was high (32.8%) at 12 months (M12) but not significantly different whether or not patients presented with CM. Baseline hyponatremia and at least one neurological symptom were independently associated with CM (p < 0.001). Positive serum cryptococcal antigen at diagnosis was also significantly associated with CM (p < 0.001). On magnetic resonance imaging (MRI), three patterns of brain injury were identified: parenchymal, meningeal, and vascular lesions. Although CM does not affect graft function directly, it entails a grim prognosis.

Automatic Evaluation of Histological Prognostic Factors Using Two Consecutive Convolutional Neural Networks on Kidney Samples.

BACKGROUND AND OBJECTIVES: The prognosis of patients undergoing kidney tumor resection or kidney donation is linked to many histologic criteria. These criteria notably include glomerular density, glomerular volume, vascular luminal stenosis, and severity of interstitial fibrosis/tubular atrophy. Automated measurements through a deep-learning approach could save time and provide more precise data. This work aimed to develop a free tool to automatically obtain kidney histologic prognostic features. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In total, 241 samples of healthy kidney tissue were split into three independent cohorts. The "Training" cohort (n=65) was used to train two convolutional neural networks: one to detect the cortex and a second to segment the kidney structures. The "Test" cohort (n=50) assessed their performance by comparing manually outlined regions of interest to predicted ones. The "Application" cohort (n=126) compared prognostic histologic data obtained manually or through the algorithm on the basis of the combination of the two convolutional neural networks. RESULTS: In the Test cohort, the networks isolated the cortex and segmented the elements of interest with good performances (>90% of the cortex, healthy tubules, glomeruli, and even globally sclerotic glomeruli were detected). In the Application cohort, the expected and predicted prognostic data were significantly correlated. The correlation coefficients r were 0.85 for glomerular volume, 0.51 for glomerular density, 0.75 for interstitial fibrosis, 0.71 for tubular atrophy, and 0.73 for vascular intimal thickness, respectively. The algorithm had a good ability to predict significant (>25%) tubular atrophy and interstitial fibrosis level (receiver operator characteristic curve with an area under the curve, 0.92 and 0.91, respectively) or a significant vascular luminal stenosis (>50%) (area under the curve, 0.85). CONCLUSION: This freely available tool enables the automated segmentation of kidney tissue to obtain prognostic histologic data in a fast, objective, reliable, and reproducible way.

Rituximab Immunomonitoring Predicts Remission in Membranous Nephropathy.

Primary membranous nephropathy (pMN) is an autoimmune kidney disease and a common cause of nephrotic syndrome in adults. Rituximab is becoming a first line therapy for patients with persistent nephrotic syndrome with proven safety and efficacy, achieving remission in 60%-80% of cases. For the remaining 20%-40% of patients there is an urgent need to identify early biomarkers of resistance to rituximab to adapt therapeutic management. In nephrotic patients, rituximab is found in the blood more transiently than in other autoimmune diseases without proteinuria, due to rituximab wasting in the urine. However, rituximab immunomonitoring is not routinely performed. We evaluated the predictive value of serum rituximab levels in patients with pMN three months after rituximab injection (month-3) on clinical remission rates six months (month-6) and 12 months (month-12) after injection and investigated predictive factors for serum rituximab levels at month-3. Sixty-eight patients treated with rituximab between July 2015 and January 2020 from two French nephrology centers were included. We identified residual rituximab levels at month-3 as a novel early predictor of remission at month-6 (p <0.0001) and month-12 (p = 0.001). Reduced likelihood of remission in patients with undetectable rituximab at month-3 was associated with lower serum albumin and higher anti-PLA2R1 titers at baseline and with lower serum albumin, higher proteinuria, higher CD19+ counts and higher anti-PLA2R1 titers during follow-up. In multivariate analysis, high baseline proteinuria and undetectable rituximab levels at month-3 were independent risk factors for treatment failure at month-6 and high baseline weight and undetectable rituximab levels at month-3 were independent risk factors for treatment failure at month-12. We identified serum albumin at baseline as a predictive factor for serum rituximab levels at month-3. Patients with serum albumin below 22.5 g/L at baseline had an 8.66-fold higher risk of having undetectable rituximab levels at month-3. Therefore, rituximab immunomonitoring in pMN patients treated with rituximab would allow the detection of patients at risk of treatment failure as early as month-3. Studies are needed to assess whether patients with low residual rituximab levels at month-3 may benefit from an early additional course of rituximab.

End-Stage Renal Disease-Related Accelerated Immune Senescence: Is Rejuvenation of the Immune System a Therapeutic Goal?

End-stage renal disease (ESRD) patients exhibit clinical features of premature ageing, including frailty, cardiovascular disease, and muscle wasting. Accelerated ageing also concerns the immune system. Patients with ESRD have both immune senescence and chronic inflammation that are resumed in the so-called inflammaging syndrome. Immune senescence is particularly characterised by premature loss of thymic function that is associated with hyporesponsiveness to vaccines, susceptibility to infections, and death. ESRD-related chronic inflammation has multiple causes and participates to accelerated cardiovascular disease. Although, both characterisation of immune senescence and its consequences are relatively well-known, mechanisms are more uncertain. However, prevention of immune senescence/inflammation or/and rejuvenation of the immune system are major goal to ameliorate clinical outcomes of ESRD patients.

Pre-transplant Thymic Function Predicts Is Associated With Patient Death After Kidney Transplantation.

Accelerated thymic involution is a main feature of end-stage renal disease (ESRD)-associated immune senescence. Recent evidences suggest that ESRD-associated immune senescence is associated with adverse outcomes in dialysis patients. However, no study focused on the association between pre-transplant thymic function and patient survival after transplantation. We conducted a prospective, multicenter study to assess whether pre-transplant thymic function measured by recent thymic emigrants (RTE) may predict death after first kidney transplantation. Results were tested in a validation cohort. Nine hundred and sixty-seven incident kidney transplant recipients were included in the prospective study. Mean follow up was 5.1 + 2.9 years. Eighty two patients (8.5%) died during follow up. Lower RTE levels were associated with a higher risk of death (2.53; 95%CI, 1.54-4.39 for each decrease of 1 log in RTE; p < 0.001). Cancer-related death was particularly increased in patients with low RTE levels (4.23; 95%CI, 1.43-12.13; p = 0.007). One hundred and thirty-six patients having received a first kidney transplantation were included in the validation cohort. Lower TREC levels were associated with higher risk of death (1.90; 95%CI, 1.11-3.51 for each decrease of 1 log in RTE; p = 0.025). RTE were not associated with death-censored graft loss. Pre-transplant thymic function is strongly associated with death after transplantation. Attempt to reverse ESRD-related thymic loss may prevent premature death.

A simple score to predict early death after kidney transplantation.

BACKGROUND: Few studies have focused on risk stratification for premature death after transplantation. However, stratification of individual risk is an essential step in personalized care. MATERIAL AND METHODS: We have developed a risk score of early post-transplant death (ORLY score) in a prospective multicentre cohort including 942 patients and validated our model in a retrospective independent replication cohort including 874 patients. RESULTS: 60 patients (6.4%) from the prospective cohort died during the first three-year post-transplant. Age, male gender, diabetes, dialysis duration and chronic respiratory failure were associated with early post-transplant death. The multivariable model exhibited good discrimination ability (C-index = 0.78, 95%CI [0.75-0.81]). ORLY score highly predicted early death after transplantation (1.34; 95%CI, 1.22 to 1.48 for each increase of 1 point in score; P < .001). The predictive value of the score in the validation cohort was close to that observed in the experimental cohort (1.41; 95%CI, 1.27 to 1.56 for each increase of 1 point in score; P < .001). Merging the two cohorts, four categories of risk could be individualized: low, 0-5 (n = 522, mean risk, 1%); intermediate, 6-7 (n = 739, mean risk 4.7%); moderate, 8-10 (n = 429, mean risk 10%); and high risk 11-15 (n = 132, mean risk 19%). CONCLUSIONS: The ORLY score discriminates patients with high risk of early death.

Clinicopathologic features of infection-related glomerulonephritis with IgA deposits: a French Nationwide study.

BACKGROUND: Infection-related glomerulonephritis with IgA deposits (IRGN-IgA) is a rare disease but it is increasingly reported in the literature. Data regarding epidemiology and outcome are lacking, especially in Europe. We aimed to assess the clinical, pathologic and outcome data of IRGN-IgA. METHODS: Clinical and outcome data from patients from 11 French centers over the 2007-2017 period were collected retrospectively. We reviewed pathologic patterns and immunofluorescence of renal biopsies and evaluated C4d expression in IRGN-IgA. We analyzed the correlation between histological presentation and outcome. RESULTS: Twenty-seven patients (23 men, mean age: 62 ± 15 years) were included. Twenty-one (78%) had Staphylococcus aureus infection and twelve (44%) were diabetic. At the time of biopsy, 95.2% had haematuria, 48.1% had a serum creatinine level of > 4 mg/dL, and 16% had hypocomplementemia. The most common pathologic presentation included mesangial (88.9%) and endocapillary proliferative glomerulonephritis (88.9%) with interstitial fibrosis and tubular atrophy (IF/TA) (85.1%). Diffuse and global glomerular C4d expression was found in 17.8%, mostly in biopsies with acute or subacute patterns, and was associated with a short delay between infection and renal biopsy compared to segmental and focal staining. After median follow-up of 13.2 months, 23.1% died, 46.2% had persistent renal dysfunction and 15.4% reached end-stage renal disease. Renal outcome was correlated to IF/TA severity. CONCLUSIONS: Infection-related glomerulonephritis with IgA deposits is usually associated with Staphylococcus infections and mainly affects adult men. This entity has a poor prognosis which is correlated to interstitial fibrosis and tubular atrophy severity.

Uraemia-induced immune senescence and clinical outcomes in chronic kidney disease patients.

BACKGROUND: Patients with chronic kidney disease (CKD) are more prone to develop premature age-related diseases. Data on immune senescence are scarce in CKD populations, except in end-stage renal disease and dialysis. We designed a longitudinal prospective study to evaluate immune senescence at different CKD stages and its influence on CKD patient outcomes. METHODS: Clinical and biological data collections were performed on 222 patients at different CKD stages [1-2 (n = 85), 4 (n = 53) and 5 (n = 84)]. Immune senescence biomarkers were measured by cytometry on T cells (CD28, CD57, CD45RA, CD31, γH2A.X) or by quantitative polymerase chain reaction [relative telomere length (RTL)] on peripheral blood mononuclear cells and analysed according to CKD stages and outcomes. RESULTS: CKD was associated with an increase in immune senescence and inflammation biomarkers, as follows: low thymic output (197 ± 25 versus 88 ± 13 versus 73 ± 21 CD4+CD45RA+CD31+ T cells/mm3), an increased proportion of terminally differentiated T cells (CD8+CD28-CD57+) (24 ± 18 versus 32 ± 17 versus 35 ± 19%) restricted to cytomegalovirus-positive patients, telomere shortening (1.11 ± 0.36 versus 0.78 ± 0.24 versus 0.97 ± 0.21 telomere:single copy ratio) and an increase in C-reactive protein levels [median 2.9 (range 1.8-4.9) versus 5.1 (27-9.6) versus 6.2 (3.4-10.5) mg/L]. In multivariate analysis, shorter RTL was associated with death {hazard ratio [HR] 4.12 [95% confidence interval (CI) 1.44-11.75]}. Low thymic output was associated with infections [HR 1.79 (95% CI (1.34-9.58)] and terminally differentiated CD8+ T-cell expansion with a risk of cardiovascular events [CEs; HR 4.86 (95% CI 1.72-13.72)]. CONCLUSION: CKD was associated with premature immune ageing. Each of these alterations increased the risk of specific age-related diseases, such as RTL and death, thymic function and infections and terminally differentiated CD8+ T-cell expansion and CEs.

[Premature immune senescence and chronic kidney disease: Update and perspectives]. / Maladie rénale chronique et immunosénescence prématurée : données et perspectives.

Immune senescence is associated with age-related diseases (i.e. infectious disease, cardiovascular diseases and cancers). Chronic kidney disease patients die prematurely when compared with general population, because of a higher occurrence of infections, cardiovascular events and cancer. These diseases are commonly observed in the elderly population and frequently associated with immune senescence. Indeed, chronic kidney disease causes a premature aging of the T lymphocyte compartment, widely related to a decrease in thymic function, a phenomenon that plays a key role in the onset of age-related diseases in chronic kidney disease patients. The degree of immune senescence also influences patients' outcome after renal transplantation, particularly the risk of acute rejection and infections. Partial reversion of pre-transplant immune senescence is observed for some renal transplant patients. In conclusion, to reduce the increasing incidence of morbidity and mortality of chronic kidney disease patients, a better knowledge of uremia-induced immune senescence would help to pave the way to build clinical studies and promote innovative therapeutic approaches. We believe that therapeutic reversion and immune senescence prevention approaches will be part of the management of chronic kidney disease patients in the future.