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BACKGROUND AND AIMS The complement system plays a key role in the pathophysiology of renal thrombotic microangiopathies (TMA), as illustrated by atypical hemolytic uremic syndrome (HUS) characterized by a high rate of mutations in complement proteins. However, complement abnormalities are not fully sufficient to drive to TMA lesions. Among other suspected pathophysiological actors, we hypothesize that the alteration of heparan sulfate (HS) of endothelial glycocalyx—a cell membrane glycoaminoglycans and glycoproteins matrix able of regulating complement by binding factor H—may play a significant role. METHOD We recorded clinical and histological features in native kidney biopsies from a monocentric retrospective cohort of 72 TMA-patients. Glomerular HS integrity and local complement activation markers (C3 and C5b9 staining) were analyzed by immunofluorescence (IF) and immunohistochemistry. Using an in vitro endothelial cells model (human umbilical vein endothelial cells, HUVECs), we studied the impact of heme exposure (30’, 37°C)—a major product of hemolysis—on endothelial HS integrity by IF and flow cytometry (FCM). Heme-induced HS disruption was studied by slot blot of HS core-protein Syndecan (SDC) 1 and 4 in cells supernatant. Artificial enzymatic degradation of HS was achieved after exposure of HUVECs to a combination of heparinases I, II and III (30', 37°C), and we studied its effect on the ability of the HS-free cell membrane to locally activate complement by analyzing C3b deposition by IF and FCM, and the release of complement anaphylatoxins C3a and soluble attack complex membrane s-C5b9 in the cell supernatants by ELISA. The HS remodeling process induced by heme exposure (16 h, 37°C) were indirectly analyzed via a transcriptional profiling of the expression of the key enzymes involved in HS synthesis by RT–qPCR. RESULTS Glomerular HS staining decreased in 57 TMA-patients (79%), moderately (2+) or strongly (0–1+) in 20 (28%) and 37 (51%) cases, respectively. Reduced HS density was significantly associated with hemolysis at the time of biopsy (P = 0.008) and local complement activation (C3d and/or C5b-9 deposits, P CONCLUSION This study highlights the impact of hemolysis on the integrity of endothelial glycocalyx HS, both in kidney biopsy of TMA-patients and in an in vitro endothelial cell model, and suggests that acute alteration of HS is a mechanism of heme-induced complement activation. The endothelial glycocalyx appears then to be an important key in the understanding of TMA and could lead to the development of therapeutics targeting its preservation and/or reconstitution, in order to better control the disease.

The association between blood transfusion and the occurrence of de novo HLA donor specific antibodies (DSA) after kidney transplantation remains controversial. In this single-center observational study, we examined the association between early blood transfusion, i.e. before 1-month post-transplantation, and the risk of DSA occurrence, using Luminex based-methods. In total, 1,424 patients with a minimum of 1-month follow-up were evaluated between January 2007 and December 2018. During a median time of follow-up of 4.52 years, we observed 258 recipients who had at least one blood transfusion during the first month post-transplantation. At baseline, recipients in the transfused group were significant older, more sensitized against HLA class I and class II antibodies and had a higher 1-month serum creatinine. Cox proportional hazards regression analyses did not show any significant association between blood transfusion and the risk of de novo DSA occurrence (1.35 [0.86–2.11], p = 0.19), the risk of rejection (HR = 1.33 [0.94–1.89], p = 0.11), or the risk of graft loss (HR = 1.04 [0.73–1.50], p = 0.82). These data suggest then that blood transfusion may not be limited when required in the early phase of transplantation, and may not impact long-term outcomes.

International audience; Background Atypical hemolytic uremic syndrome (HUS) is associated with high recurrence rates after kidney transplant, with devastating outcomes. In late 2011, experts in France recommended the use of highly individualized complement blockade-based prophylaxis with eculizumab to prevent post-transplant atypical HUS recurrence throughout the country.Methods To evaluate this strategy's effect on kidney transplant prognosis, we conducted a retrospective multicenter study from a large French nationwide registry, enrolling all adult patients with atypical HUS who had undergone complement analysis and a kidney transplant since January 1, 2007. To assess how atypical HUS epidemiology in France in the eculizumab era evolved, we undertook a population-based cohort study that included all adult patients with atypical HUS (n=397) between 2007 and 2016.Results The first study included 126 kidney transplants performed in 116 patients, 58.7% and 34.1% of which were considered to be at a high and moderate risk of atypical HUS recurrence, respectively. Eculizumab prophylaxis was used in 52 kidney transplants, including 39 at high risk of recurrence. Atypical HUS recurred after 43 (34.1%) of the transplants; in four cases, patients had received eculizumab prophylaxis and in 39 cases they did not. Use of prophylactic eculizumab was independently associated with a significantly reduced risk of recurrence and with significantly longer graft survival. In the second, population-based cohort study, the proportion of transplant recipients among patients with ESKD and atypical HUS sharply increased between 2012 and 2016, from 46.2% to 72.3%, and showed a close correlation with increasing eculizumab use among the transplant recipients.Conclusions Results from this observational study are consistent with benefit from eculizumab prophylaxis based on pretransplant risk stratification and support the need for a rigorous randomized trial.

BACKGROUND Further study is needed on the prognostic impact of cirrhosis on haemodialysis patients. AIM To evaluate cirrhosis' impact according to severity on survival and to provide therapeutic guidelines for haemodialysis cirrhotic patients. METHODS Patients with end-stage renal failure treated with haemodialysis were included retrospectively from 01/01/2000 to 31/12/2004 and prospectively from 01/01/2005 to 31/12/2014 in our French Region. Clinical data, presence of cirrhosis and its severity were recorded at the beginning of haemodialysis. The primary endpoint was 2-year survival. RESULTS Seven thousand three hundred and fifty-four patients (96%) without cirrhosis and 304 patients (4%) with cirrhosis were included. Two-year survival in noncirrhotic patients was higher than in cirrhotic patients (71.7% vs 54.4%, P

Despite improvements in organ preservation techniques and efforts to minimize the duration of cold ischemia, ischemia–reperfusion (IR) injury remains associated with poor graft function and long-term survival in kidney transplantation. We recently demonstrated a clinically significant day-time variation in myocardial tolerance to IR, transcriptionally orchestrated by the circadian clock. Patient and graft post-transplant survival were studied in a cohort of 10,291 patients first transplanted between 2006 and 2017 to test whether kidney graft tolerance to IR depends on the time-of-the-day of clamping/declamping, and thus impacts graft and patient survival. Post-transplant 1- and 3-year survival decreased with increasing ischemia duration. Time-of-the-day of clamping did not influence outcomes. However, night-time (vs. day-time) declamping was associated with a significantly worse post-transplant survival. After adjustment for other predictors, night-time (vs. day-time) declamping remained associated with a worse 1-year (HR= 1.26 (1.08–1.47), p = 0.0028 by Cox multivariable analysis) and 3-year (HR= 1.14 (1.02–1.27), p = 0.021) outcome. Interestingly, the deleterious impact of prolonged ischemia time (&gt, 15 h) was partially compensated by day-time (vs. night-time) declamping. Compared to night-time declamping, day-time declamping was associated with a better prognosis of kidney transplantation despite a longer duration of cold ischemia.

International audience; The incidence of kidney disease is rising, constituting a significant burden on the healthcare system and making identification of new therapeutic targets increasingly urgent. The heme oxygenase (HO) system performs an important function in the regulation of oxidative stress and inflammation and, via these mechanisms, is thought to play a role in the prevention of non-specific injuries following acute renal failure or resulting from chronic kidney disease. The expression of HO-1 is strongly inducible by a wide range of stimuli in the kidney, consequent to the kidney's filtration role which means HO-1 is exposed to a wide range of endogenous and exogenous molecules, and it has been shown to be protective in a variety of nephropathological animal models. Interestingly, the positive effect of HO-1 occurs in both hemolysis- and rhabdomyolysis-dominated diseases, where the kidney is extensively exposed to heme (a major HO-1 inducer), as well as in non-heme-dependent diseases such as hypertension, diabetic nephropathy or progression to end-stage renal disease. This highlights the complexity of HO-1's functions, which is also illustrated by the fact that, despite the abundance of preclinical data, no drug targeting HO-1 has so far been translated into clinical use. The objective of this review is to assess current knowledge relating HO-1's role in the kidney and its potential interest as a nephroprotection agent. The potential therapeutic openings will be presented, in particular through the identification of clinical trials targeting this enzyme or its products.

Heme's interaction with Toll-like receptor 4 (TLR4) does not fully explain the proinflammatory properties of this hemoglobin-derived molecule during intravascular hemolysis. The receptor for advanced glycation end products (RAGE) shares many features with TLR4 such as common ligands and proinflammatory, prothrombotic, and pro-oxidative signaling pathways, prompting us to study its involvement as a heme sensor. Stable RAGE-heme complexes with micromolar affinity were detected as heme-mediated RAGE oligomerization. The heme-binding site was located in the V domain of RAGE. This interaction was Fe3+ -dependent and competitive with carboxymethyllysine, another RAGE ligand. We confirmed a strong basal gene expression of RAGE in mouse lungs. After intraperitoneal heme injection, pulmonary TNF-α, IL1β, and tissue factor gene expression levels increased in WT mice but were significantly lower in their RAGE-/- littermates. This may be related to the lower activation of ERK1/2 and Akt observed in the lungs of heme-treated, RAGE-/- mice. Overall, heme binds to RAGE with micromolar affinity and could promote proinflammatory and prothrombotic signaling in vivo, suggesting that this interaction could be implicated in heme-overload conditions.

We report a case of a 43 years old man who was intoxicated by a 25g vancomycin overload. An anuric acute renal failure rapidly occured. The vancomycinemia was measured as high as 360mg/L (normal range: 15-35mg/L). We started an intermittent hemodialysis program to clear out the vancomycin. The vancomycinemia decreased below the treshold of our laboratory after the eighth session. Three supplementary sessions were needed because of a persistant oliguria. The kidney function slowly improved and was back to normal (seric creatinin: 80micromol/L) 3 weeks after the patient had gone home. To our knowledge, it is the first success of this technic concerning vancomycin poisoning in adults with anuric kidney failure.

In renal transplant medicine, several scores have been recently developed in order to help decision-making in clinical practice. The aim of this update is to focus on these new scores that allow to better estimate the quality of the renal transplant, to refine the allocation policy, to help registration of old recipients on the waiting list, or to evaluate the risk to develop end-stage renal failure after living donation.

Introduction Le Syndrome Hemolytique et Uremique (SHU) atypique est associe dans 50–60 % des cas a des anomalies de la voie alterne du complement (VAC). De penetrance variable, les mutations identifiees ne sont cependant que des facteurs de susceptibilite, sous-entendant d’autres acteurs. Parmi eux, le glycocalyx endothelial, dont les heparanes sulfates (HS) servent de ligand au facteur H, principal regulateur de la VAC reste peu etudie. Description Caracterisation du glycocalyx endothelial sur des biopsies renales : 1- de patients admis pour un SHU ; 2- avec microangiopathie thrombotique (MAT) d’autre etiologie ; 3- de reins sains peri-tumoraux (RSPT, controle positif). Methodes Etude monocentrique incluant les biopsies de 8 patients-SHU, 4 patients-MAT non SHU et 4 RSPT. Le glycocalyx etait caracterise en immunofuorescence via un marquage par WGA (W849, Thermo Fisher), marqueur global du glycocalyx et par JM403 (370730, Amsbio), anticorps specifique des heparanes sulfates. Une double lecture semi-quantitative (0 a 3 + ), en aveugle, etait realisee. Resultats Lors de la biopsie (delais admission SHU-biopsie : 18 (5-90) jours), 8/8 patients restaient hemolytiques, et 5/8 dialyse dependants. Une anomalie de la VAC etait identifiee chez 4 d’entre eux (anomalie C3 : 3 ; anti-FH : 1). Parmi les patients-MAT, aucun n’etait hemolytique, 1 avait une insuffisance renale aigue et 2 chroniques. Le marquage endothelial glomerulaire et arteriolaire des HS etait quantifie a 3+ chez 4/4 RSPT. Il etait conserve chez les patients-MAT-non-SHU (3+ chez 3/4 patients), tandis qu’il diminuait majoritairement chez les patients-SHU, quantifie a 0-1+, 2+ ou 3+ chez 5,2 et 1 patient-SHU respectivement. Conclusion Nos resultats, en cours de validation sur une cohorte de 55 patients avec MAT, sont en faveur d’une baisse de la densite des heparanes sulfates du glycocalyx endothelial renal dans le SHU, en parallele de quoi de quoi nous etudions sur un modele cellulaire les tenants moleculaires de cette association.

International audience; The renal resistive index has been demonstrated to predict the progression of renal disease and recurrence of major cardiac events in high-risk cardiovascular patients, in addition to other comorbidities. We aimed to assess the prognostic significance of the renal resistive index in type 2 diabetic patients for primary prevention. From 2008 to 2011, patients with type 2 diabetes underwent cardiovascular evaluation, including renal resistive index assessment by renal Doppler ultrasound. The incidence of all-cause death, cardiovascular events, dialysis requirement or a twofold increase in creatinine was recorded. Survival curves were estimated by the Kaplan-Meier method. Two hundred sixty-six patients were included; 50% of the patients were men, an HbA1C level of 8.1 ± 1.7% (65 ± 13.6 mmol/mol) and a serum creatinine level of 8 [7-9] mg/L. The mean 24-hour systolic blood pressure, 24-hour diastolic blood pressure, and 24-hour pulse pressure were 133.4 ± 16.7, 76.5 ± 9.4, and 56.9 ± 12.4 mm Hg, respectively. The median renal resistive index was 0.7 [0.6-0.7] with a threshold of 0.7 predictive of monitored events. After adjustment of the 24-hour pulse pressure, age and 24-hour heart rate, a renal resistive index ≥0.70 remained associated with all-cause death (hazard ratio: 3.23 (1.16-8.98); P = .025) and the composite endpoint of major clinical events (hazard ratio: 2.37 (1.34-4.18); P = .003). An elevated renal resistive index with a threshold of 0.7 is an independent predictor of a first cardiovascular or renal event in type 2 diabetic patients. This simple index should be implemented in the multiparametric staging of diabetes.

International audience; Rhabdomyolysis is a life-threatening condition caused by skeletal muscle damage with acute kidney injury being the main complication dramatically worsening the prognosis. Specific treatment for rhabdomyolysis-induced acute kidney injury is lacking and the mechanisms of the injury are unclear. To clarify this, we studied intra-kidney complement activation (C3d and C5b-9 deposits) in tubules and vessels of patients and mice with rhabdomyolysis-induced acute kidney injury. The lectin complement pathway was found to be activated in the kidney; likely via an abnormal pattern of Fut2-dependent cell fucosylation, recognized by the pattern recognition molecule collectin-11 and this proceeded in a C4-independent, bypass manner. Concomitantly, myoglobin-derived heme activated the alternative pathway. Complement deposition and acute kidney injury were attenuated by pre-treatment with the heme scavenger hemopexin. This indicates that complement was activated in a unique double-trigger mechanism, via the alternative and lectin pathways. The direct pathological role of complement was demonstrated by the preservation of kidney function in C3 knockout mice after the induction of rhabdomyolysis. The transcriptomic signature for rhabdomyolysis-induced acute kidney injury included a strong inflammatory and apoptotic component, which were C3/complement-dependent, as they were normalized in C3 knockout mice. The intra-kidney macrophage population expressed a complement-sensitive phenotype, overexpressing CD11b and C5aR1. Thus, our results demonstrate a direct pathological role of heme and complement in rhabdomyolysis-induced acute kidney injury. Hence, heme scavenging and complement inhibition represent promising therapeutic strategies.

The names of the working groups that collaborated in the study reported in this article were inadvertently omitted from the byline. The corrected byline should … 2019;42

In our aging population, kidney disease management needs to take into account the frailty of the elderly. Standardized geriatric assessments can be proposed to help clinicians apprehend this dimension in their daily practice. These tools allow to better identify frail patients and offer them more personalized and harmless treatments. This article aims to focus on the kidney diseases commonly observed in elderly patients and analyze their specific nephrogeriatric care modalities. It should be noticed that all known kidney diseases can be also observed in the elderly, most often with a quite similar clinical presentation. This review is thus focused on the diseases most frequently and most specifically observed in elderly patients (except for monoclonal gammopathy associated nephropathies, out of the scope of this work), as well as the peculiarities of old age nephrological care.

In our aging population, kidney disease management needs to take into account the frailty of the elderly. Standardized geriatric assessments can be proposed to help clinicians apprehend this dimension in their daily practice. These tools allow to better identify frail patients and offer them more personalized and harmless treatments. This article aims to focus on the kidney diseases commonly observed in elderly patients and analyze their specific nephrogeriatric care modalities. It should be noticed that all known kidney diseases can be also observed in the elderly, most often with a quite similar clinical presentation. This review is thus focused on the diseases most frequently and most specifically observed in elderly patients (except for monoclonal gammopathy associated nephropathies, out of the scope of this work), as well as the peculiarities of old age nephrological care.

To evaluate medical treatments, in terms of adverse events (AEs) and therapeutic goals, in a large series of patients with cystinuria.Data from 442 patients with cystinuria were recorded retrospectively. Crystalluria was studied in 89 patients. A mixed-effects logistic regression model was used to estimate how urine pH, specific gravity and cysteine-binding thiols (CBT) correlate with risk of cystine crystalluria.Alkalizing agents and CBT agents were given to 88.8% (n = 381) and 55.3% (n = 238) of patients, respectively. Gastrointestinal AEs were reported in 12.3%, 10.4% and 2.6% of patients treated with potassium bicarbonate, potassium citrate and sodium bicarbonate, respectively (P = 0.008). The percentages of patients who experienced at least one AE with tiopronin (24.6%) and with D-penicillamine (29.5%) were similar (P = 0.45). Increasing urine pH and decreasing urine specific gravity significantly reduced the risk of cystine crystalluria, whereas D-penicillamine and tiopronin treatments did not reduce this risk (odds ratio [OR] 1 for pH ≤6.5; OR 0.52 [95% confidence interval {95% CI} 0.28-0.95] for 7.0pH ≤7.5, P = 0.03; OR 0.26 [95% CI 0.13-0.53] for 7.5pH ≤8.0, P0.001; OR 1 for specific gravity ≤1.005 OR 5.76 [95% CI 1.45-22.85] for 1.006 ≤ specific gravity ≤1.010, P = 0.01; and OR 11.06 [95% CI 2.76-44.26] for 1.011 ≤ specific gravity ≤ 1.014, P0.001). Increased urine pH significantly increased the risk of calcium phosphate crystalluria (OR 1 for pH≤ 6.5; OR 6.09 [95% CI 2.15-17.25] for pH8.0, P0.001).Adverse events were frequent with D-penicillamine and tiopronin. Alkaline hyperdiuresis was well tolerated and reduced cystine crystalluria. Urine specific gravity ≤1.005 and urine pH7.5, while warning about calcium-phosphate crystallization, should be the goals of medical therapy.

International audience; Vascular diseases are multifactorial, often requiring multiple challenges, or 'hits', for their initiation. Intra-vascular hemolysis illustrates well the multiple-hit theory where a first event lyses red blood cells, releasing hemolysis-derived products, in particular cell-free heme which is highly toxic for the endothelium. Physiologically, hemolysis derived-products are rapidly neutralized by numerous defense systems, including haptoglobin and hemopexin which scavenge hemoglobin and heme, respectively. Likewise, cellular defense mechanisms are involved, including heme-oxygenase 1 upregulation which metabolizes heme. However, in cases of intra-vascular hemolysis, those systems are overwhelmed. Heme exerts toxic effects by acting as a damage-associated molecular pattern and promoting, together with hemoglobin, nitric oxide scavenging and ROS production. In addition, it activates the complement and the coagulation systems. Together, these processes lead to endothelial cell injury which triggers pro-thrombotic and pro-inflammatory phenotypes. Moreover, among endothelial cells, glomerular ones display a particular susceptibility explained by a weaker capacity to counteract hemolysis injury. In this review, we illustrate the 'multiple-hit' theory through the example of intra-vascular hemolysis, with a particular focus on cell-free heme, and we advance hypotheses explaining the glomerular susceptibility observed in hemolytic diseases. Finally, we describe therapeutic options for reducing endothelial injury in hemolytic diseases.

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

The aims of this study were to determine whether tubulointerstitial damage in the form of interstitial fibrosis/tubular atrophy and total interstitial inflammation predicted progression to end stage renal disease (ESRD) and/or renal relapse (RR) in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). One hundred thirteen patients with AAV from six French centers with an index biopsy performed between 2003 and 2013 were included. Histological assessments using the AAV glomerular classification and the kidney allograft Banff classification were performed on pathological review. Biopsy tissues were also investigated by CD3, CD20, CD68, CD163, FOXP3 and RORγt immunohistochemical staining. Competing risks models were calculated. Of the 113 patients, 26 (23.0%) died during follow-up and 29 (25.6%) developed ESRD. Among the 94 patients who achieved remission by the end of induction therapy without developing ESRD, 26 (27.6%) experienced RR. The two independent prognostic factors for ESRD were the estimated glomerular filtration rate at presentation (HR 0.35; 95% CI 0.23-0.51; P 0.0001) and IF/TA 25% (HR 2.27; 95% CI 1.18-4.37; P = 0.014). When the distribution of interstitial immune cell phenotypes was included in a second multivariable model, the organization of lymphocytic infiltrates was also an independent predictor of ESRD (HR 2.86; 95% CI 1.35-6.1, P = 0.006). The independent risk factors for RR were a higher CD3/CD20 ratio (HR 1.39; 95% CI 1.05-1.85; P = 0.02) and the presence of RORγt positive cells (HR 2.70; 95% CI 1.11-6.54; P = 0.02). Our results highlight the prognostic value of initial histological evaluations in AAV. Measurements of tubulointerstitial damage and interstitial immune cell phenotype distributions should be considered to improve risk assessments for ESRD and RR.

A few cases of hypercalcemia related to Pneumocystis jirovecii pneumonia (PJP) have previously been described, supposedly associated with an 1α-hydroxylase enzyme-dependent mechanism. The prevalence and significance of hypercalcemia in PJP remain unclear, especially in kidney transplant recipients (KTR) who frequently display hypercalcemia via persisting hyperparathyroidism. We here retrospectively identified all microbiologically-proven PJP in adult KTR from 2005 to 2017 in the Lille University Hospital, and studied the mineral and bone metabolism parameters during the peri-infectious period. Clinical features of PJP-patients were analyzed according to their serum calcium level. Hypercalcemia (12.6 ± 1.6 mg/dl) was observed in 37% (18/49) of PJP-patients and regressed concomitantly to specific anti-infectious treatment in all cases. No other cause of hypercalcemia was identified. In hypercalcemic patients, serum levels of 1,25-dihydroxyvitamin D were high at the time of PJP-diagnosis and decreased after anti-infectious treatment (124 ± 62 versus 28 ± 23 pg/mL, p = 0.006) while PTH serum levels followed an inverse curve (35 ± 34 versus 137 ± 99 pg/mL, p = 0.009), suggesting together a granuloma-mediated mechanism. Febrile dyspnea was less frequent in hypercalcemic PJP-patients compared to non-hypercalcemic (29 versus 67%). In summary, hypercalcemia seems common during PJP in KTR. Unexplained hypercalcemia could thus lead to specific investigations in this particular population, even in the absence of infectious or respiratory symptoms.

Caveolin-1 is a protein (encoded by the CAV1 gene) supposedly harboring a protective effect against fibrosis. CAV1 rs4730751 single nucleotide polymorphism (SNP) AA genotype was initially associated with lower graft survival compared to non-AA. However, subsequent studies could not find the same effect. CAV1 rs4730751 SNP was investigated on 918 kidney donors. Multivariate Cox-model analyses were performed to evaluate risk factors for graft loss. Longitudinal changes on long-term estimated glomerular filtration rate (eGFRs) were evaluated with a linear mixed model. Histopathological findings from protocolled biopsies after 3 months post transplantation were also analyzed. Donor CAV1 rs4730751 genotyping proportions were 7.1% for AA, 41.6% for AC and 51.3% for CC. The AA genotype, compared to non-AA, was not associated with lower graft survival censored or not for death (multivariate analysis: HR = 1.23 [0.74–2.05] and HR = 1.27 [0.84–1.92]). Linear mixed model on long-term eGFRs revealed also no significant difference according to the genotype, yet we observed a trend. AA genotype was also not associated with a higher degree of fibrosis index on protocolled kidney biopsies at 3 months. To conclude, donor CAV1 rs4730751 SNP may impact on kidney transplantation outcomes, but this study could not confirm this hypothesis.

OBJECTIVE The long-term outcome of allogenic islet transplantation is unknown. The aim of this study was to evaluate the 10-year outcome of islet transplantation in patients with type 1 diabetes and hypoglycemia unawareness and/or a functioning kidney graft. RESEARCH DESIGN AND METHODS We enrolled in this prospective parallel-arm cohort study 28 subjects with type 1 diabetes who received islet transplantation either alone (ITA) or after a kidney graft (IAK). Islet transplantation consisted of two or three intraportal infusions of allogenic islets administered within (median [interquartile range]) 68 days (43–92). Immunosuppression was induced with interleukin-2 receptor antibodies and maintained with sirolimus and tacrolimus. The primary outcome was insulin independence with A1C ≤6.5% (48 mmol/mol). Secondary outcomes were patient and graft survival, severe hypoglycemic events (SHEs), metabolic control, and renal function. RESULTS The primary outcome was met by (Kaplan-Meier estimates [95% CI]) 39% (22–57) and 28% (13–45) of patients 5 and 10 years after islet transplantation, respectively. Graft function persisted in 82% (62–92) and 78% (57–89) of case subjects after 5 and 10 years, respectively, and was associated with improved glucose control, reduced need for exogenous insulin, and a marked decrease of SHEs. ITA and IAK had similar outcomes. Primary graft function, evaluated 1 month after the last islet infusion, was significantly associated with the duration of graft function and insulin independence. CONCLUSIONS Islet transplantation with the Edmonton protocol can provide 10-year markedly improved metabolic control without SHEs in three-quarters of patients with type 1 diabetes, kidney transplanted or not.

International audience; The kidney harbours different types of endothelia, each with specific structural and functional characteristics. The glomerular endothelium, which is highly fenestrated and covered by a rich glycocalyx, participates in the sieving properties of the glomerular filtration barrier and in the maintenance of podocyte structure. The microvascular endothelium in peritubular capillaries, which is also fenestrated, transports reabsorbed components and participates in epithelial cell function. The endothelium of large and small vessels supports the renal vasculature. These renal endothelia are protected by regulators of thrombosis, inflammation and complement, but endothelial injury (for example, induced by toxins, antibodies, immune cells or inflammatory cytokines) or defects in factors that provide endothelial protection (for example, regulators of complement or angiogenesis) can lead to acute or chronic renal injury. Moreover, renal endothelial cells can transition towards a mesenchymal phenotype, favouring renal fibrosis and the development of chronic kidney disease. Thus, the renal endothelium is both a target and a driver of kidney and systemic cardiovascular complications. Emerging therapeutic strategies that target the renal endothelium may lead to improved outcomes for both rare and common renal diseases.

International audience; In C3 glomerulopathy (C3G), the alternative pathway of complement is frequently overactivated by autoantibodies that stabilize the C3 convertase C3bBb. Anti-C3b and anti-factor B (anti-FB) IgG have been reported in three patients with C3G. We screened a cohort of 141 patients with C3G and Ig-associated membranoproliferative GN (Ig-MPGN) for anti-FB and anti-C3b autoantibodies using ELISA. We identified seven patients with anti-FB IgG, three patients with anti-C3b IgG, and five patients with anti-FB and anti-C3b IgG. Of these 15 patients, ten were diagnosed with Ig-MPGN. Among those patients with available data, 92% had a nephrotic syndrome, 64% had AKI, and 67% had a documented infection. Patients negative for anti-C3b and anti-FB IgG had much lower rates of infection (17 [25%] patients with C3G and one [10%] patient with Ig-MPGN). After 48 months, four of 15 (26%) positive patients had developed ESRD or died. All 15 patients had high plasma Bb levels, six (40%) patients had low levels of C3, and nine (60%) patients had high levels of soluble C5b9. In vitro, IgG purified from patients with anti-FB Abs selectively enhanced C3 convertase activity; IgG from patients with anti-C3b/anti-FB Abs enhanced C3 and C5 cleavage. IgG from patients with anti-C3b Abs stabilized C3bBb and perturbed C3b binding to complement receptor 1 but did not perturb binding to factor H. In conclusion, the prevalence of anti-C3b/anti-FB Abs and alternative pathway activation is similar in Ig-MPGN and C3G, suggesting similar pathogenic mechanisms. Identification of the underlying defect in Ig-MPGN could lead to improved treatment.

Introduction Le syndrome hemolytique et uremique atypique (SHUa) est une microangiopathie thrombotique renale caracterisee par une hemolyse mecanique et une suractivation du complement. Il est demontre que l’heme, derive de l’hemolyse, lie C3a, amplifiant ainsi l’activation du complement. Les mecanismes d’action du complexe heme-C3a sont inconnus. Une interaction du C3a avec le Recepteur aux produits de glycation avancee (RAGE) est rapportee. RAGE, recepteur multi-ligands ubiquitaire, est implique dans differentes pathologies a tropisme renal (nephropathie diabetique, lupique, polykystose) mais aucun role dans le SHUa n’est decrit a ce jour. Notre objectif etait ainsi d’analyser l’interaction C3a-RAGE en conditions hemolytiques. Patients/Materiels et methodes Les interactions entre RAGE, l’heme et C3a etaient etudiees en resonance plasmonique de surface (SPR), spectrophotometrie et chromatographie d’exclusion serique. Pour analyser in vivo l’impact de RAGE en conditions hemolytiques, des souris C57Bl/6 RAGE−/− et leurs controles +/ + littermates recevaient ± une injection intraperitoneale d’heme (50, 100, 200 μmol/kg) avant sacrifice a 16 h. L’expression renale des genes de RAGE et de marqueurs inflammatoires (IL1β, IL6, TNFα) etait etudiee par RTqPCR. Observation/Resultats En SPR, le RAGE recombinant liait la carboxymethyllysine, son principal ligand connu, mais l’interaction RAGE-C3a restait indetectable. A contrario, C3a expose a l’heme liait le RAGE avec une haute affinite. Cette interaction etait donc mediee par l’heme, qui liait RAGE de facon dose-dependante. L’immobilisation des differents domaines de RAGE permettait d’identifier le site de liaison de l’heme sur le domaine V. L’interaction domaine V-heme etait tres affine et specifique, alors que l’heme ne se liait pas aux domaines C1 et C2. Cette liaison etait confirmee en spectroscopie et chromatographie d’exclusion. In vivo, l’injection d’heme a des souris induisait une augmentation dose-dependante de l’expression de RAGE ainsi que l’activation du complement au niveau renal, menant au clivage du C3 et la generation de fragments d’activation du C3 sur l’endothelium glomerulaire. Nous observions egalement une augmentation dose-dependante de l’expression renale des marqueurs de l’inflammation, quantifiee a la condition heme 200 μM/kg autour de × 4, × 200 et × 3,5 pour IL1β, IL6 et TNFα respectivement par rapport au controle (PBS). Les analyses preliminaires montraient une elevation moindre de l’expression de ces genes chez les souris RAGE−/−, dans les memes conditions : × 1,5, × 50 et × 2 respectivement. Discussion/Conclusion Ce travail revele RAGE comme un nouveau recepteur de l’heme. En conditions hemolytiques, les souris RAGE−/− semblent en partie protegees de l’inflammation au niveau renal, ouvrant des perspectives therapeutiques dans les maladies hemolytiques via les molecules anti-RAGE.

While either pancreas or pancreatic islet transplantation can restore endogenous insulin secretion in patients with diabetes, no beta-cell replacement strategies are recommended in the literature. For this reason, the aim of this national expert panel statement is to provide information on the different kinds of beta-cell replacement, their benefit-risk ratios and indications for each type of transplantation, according to type of diabetes, its control and association with end-stage renal disease. Allotransplantation requires immunosuppression, a risk that should be weighed against the risks of poor glycaemic control, diabetic lability and severe hypoglycaemia, especially in cases of unawareness. Pancreas transplantation is associated with improvement in diabetic micro- and macro-angiopathy, but has the associated morbidity of major surgery. Islet transplantation is a minimally invasive radiological or mini-surgical procedure involving infusion of purified islets via the hepatic portal vein, but needs to be repeated two or three times to achieve insulin independence and long-term functionality. Simultaneous pancreas-kidney and pancreas after kidney transplantations should be proposed for kidney recipients with type 1 diabetes with no surgical, especially cardiovascular, contraindications. In cases of high surgical risk, islet after or simultaneously with kidney transplantation may be proposed. Pancreas, or more often islet, transplantation alone is appropriate for non-uraemic patients with labile diabetes. Various factors influencing the therapeutic strategy are also detailed in this report.

Introduction L’insuffisance renale aigue (IRA) est la principale complication de la rhabdomyolyse. La myoglobine joue un role important dans sa physiopathologie par vasoconstriction intra-renale (favorisant l’ischemie-reperfusion), obstruction intra-tubulaire, et liberation d’heme. L’heme libre est capable d’activer le systeme du complement en cas d’hemolyse intravasculaire, mais l’existence d’un tel mecanisme au cours de la rhabdomyolyse reste par contre inconnu. L’objectif de cette etude est d’analyser le role et les mecanismes d’activation du complement dans l’IRA de la rhabdomyolyse. Methodes Nous avons utilise un modele murin de rhabdomyolyse par injection intramusculaire de glycerol induisant une destruction musculaire associee a une insuffisance renale aigue. Les depots de C3 clive (C3b/iC3b) etaient evalues en immunofluorescence. Des souris C3−/−, C1q−/−, C4−/− et TLR4−/− ont ete utilisees pour dissequer les mecanismes d’activation du complement. L’analyse de l’expression des genes a ete realisee par RNAseq et validee par RTqPCR. L’infiltration des macrophages a ete etudiee par cytometrie en flux. Dix biopsies humaines sont en cours d’analyse. Resultats obtenus ou attendus Les souris WT, apres injection de glycerol, presentaient des depots profus de C3 tubulaire, diminues chez les souris TLR4−/− au contraire des souris C1q−/−, en faveur d’une activation du complement mediee par l’heme (A). Comme attendue, la rhabdomyolyse etait associee chez les souris WT a une sur-expression des genes d’agression tubulaire (NGAL). De maniere plus etonnante, on retrouvait des signes d’activation endotheliale (sur-expression de P-selectin, E-selectin, ICAM1, sous-expression de VEGFR2) ainsi qu’une sur-expression renale des transcrits de C3 et C5aR1. Remarquablement, les souris C3−/− etaient protegees de l’atteinte tubulaire et de l’agression vasculaire tout comme les souris TLR4−/−, et leurs fonctions renales restaient normales (B–D). Conclusion Ces resultats suggerent un lien entre la voie heme/TLR4, l’activation du complement et l’IRA de la rhabdomyolyse. A l’avenir, des strategies bloquant l’activation du complement pourraient etre envisagees a la phase aigue de la rhabdomyolyse.

International audience; After detection of small cell lung cancer in a 67-year-old patient who had donated a kidney 7 months earlier, the graft recipient underwent FDG-PET/CT to determine the presence/absence of tumor cell transmission. It showed abnormal increased uptake of the renal graft, associated with hypermetabolic lymph nodes and hepatic, pulmonary and bone lesions. Emergency graft resection was performed 5 days after PET/CT, permitting immunosuppressive therapy withdrawal. Pathologic examination of the kidney showed parenchymal infiltration by tumor cells compatible with small cell lung cancer. Thereafter, pathologists proved that the recipient's and donor's tumor cells matched using microsatellite markers. FDG-PET/CT was performed in the follow-up and showed progression in the donor despite chemotherapy and radiotherapy. He died a few months later. However, FDG-PET/CT showed a complete metabolic response after only 3 courses of chemotherapy in the recipient.

Atypical hemolytic uremic syndrome (aHUS) is classically described to result from a dysregulation of the complement alternative pathway, leading to glomerular endothelial cell (EC) damage and thrombosis. However, recent findings in families with aHUS of mutations in the DGKE gene, which is not an integral component of the complement cascade, led us to consider other pathophysiologic mechanisms for this disease. Here, we demonstrate that loss of DGKε expression/activity in EC induces an increase in ICAM-1 and tissue factor expression through the upregulation of p38-MAPK-mediated signals, thus highlighting a proinflammatory and prothrombotic phenotype of DGKε-deficient ECs. More interestingly, DGKE silencing also increases EC apoptosis and impairs EC migration and angiogenesis in vitro, suggesting that DGKE loss-of-function mutations impair EC repair and angiogenesis in vivo. Conversely, DGKE knockdown moderately decreases the expression of the complement inhibitory protein MCP on quiescent EC, but does not induce complement deposition on their surface in vitro. Collectively, our data strongly suggest that in DGKE-associated aHUS patients, thrombotic microangiopathy results from impaired EC proliferation and angiogenesis rather than complement-mediated EC lesions. Our study expands the current knowledge of aHUS mechanisms and has implications for the treatment of patients with isolated DGKE mutations.

In hemolytic diseases, such as sickle cell disease (SCD), intravascular hemolysis results in the release of hemoglobin, heme, and heme-loaded membrane microvesicles in the bloodstream. Intravascular hemolysis is thus associated with inflammation and organ injury. Complement system can be activated by heme in vitro. We investigated the mechanisms by which hemolysis and red blood cell (RBC) degradation products trigger complement activation in vivo. In kidney biopsies of SCD nephropathy patients and a mouse model with SCD, we detected tissue deposits of complement C3 and C5b-9. Moreover, drug-induced intravascular hemolysis or injection of heme or hemoglobin in mice triggered C3 deposition, primarily in kidneys. Renal injury markers (Kim-1, NGAL) were attenuated in C3-/- hemolytic mice. RBC degradation products, such as heme-loaded microvesicles and heme, induced alternative and terminal complement pathway activation in sera and on endothelial surfaces, in contrast to hemoglobin. Heme triggered rapid P selectin, C3aR, and C5aR expression and downregulated CD46 on endothelial cells. Importantly, complement deposition was attenuated in vivo and in vitro by heme scavenger hemopexin. In conclusion, we demonstrate that intravascular hemolysis triggers complement activation in vivo, encouraging further studies on its role in SCD nephropathy. Conversely, heme inhibition using hemopexin may provide a novel therapeutic opportunity to limit complement activation in hemolytic diseases.

We report a case of a 43 years old man who was intoxicated by a 25g vancomycin overload. An anuric acute renal failure rapidly occured. The vancomycinemia was measured as high as 360mg/L (normal range: 15-35mg/L). We started an intermittent hemodialysis program to clear out the vancomycin. The vancomycinemia decreased below the treshold of our laboratory after the eighth session. Three supplementary sessions were needed because of a persistant oliguria. The kidney function slowly improved and was back to normal (seric creatinin: 80micromol/L) 3 weeks after the patient had gone home. To our knowledge, it is the first success of this technic concerning vancomycin poisoning in adults with anuric kidney failure.

Aim: The contribution of epithelial–mesenchymal transition (EMT) has been suggested in renal transplant recipients receiving calcineurin inhibitors and developing nephrotoxicity. Materials & methods: We assessed whether interindividual variability in tacrolimus pharmacokinetics is associated with the occurrence in tubular cells of two EMT markers (vimentin, β-catenin) detected at 3‐month in 140 allograft biopsies. We investigated whether genetic polymorphisms affecting CYP3A5 and ABCB1 influence EMT and kidney fibrosis. Results: In univariate analysis, the donor CYP3A5*1 allele was significantly associated with a lower vimentin expression. In multivariate analysis, grafts carrying ABCB1 3435T allele(s) developed significantly less EMT and less interstitial fibrosis. Conclusion: Donor SNPs significantly influence the epithelial program in the context of kidney transplantation, and the epithelial metabolism of tacrolimus is one key to understand graft fibrogenesis.

Pro‐aging effects of endogenous advanced glycation end‐products (AGEs) have been reported, and there is increasing interest in the pro‐inflammatory and ‐fibrotic effects of their binding to RAGE (the main AGE receptor). The role of dietary AGEs in aging remains ill‐defined, but the predominantly renal accumulation of dietary carboxymethyllysine (CML) suggests the kidneys may be particularly affected. We studied the impact of RAGE invalidation and a CML‐enriched diet on renal aging. Two‐month‐old male, wild‐type (WT) and RAGE−/− C57Bl/6 mice were fed a control or a CML‐enriched diet (200 μg CML/gfood) for 18 months. Compared to controls, we observed higher CML levels in the kidneys of both CML WT and CML RAGE−/− mice, with a predominantly tubular localization. The CML‐rich diet had no significant impact on the studied renal parameters, whereby only a trend to worsening glomerular sclerosis was detected. Irrespective of diet, RAGE−/− mice were significantly protected against nephrosclerosis lesions (hyalinosis, tubular atrophy, fibrosis and glomerular sclerosis) and renal senile apolipoprotein A‐II (ApoA‐II) amyloidosis (p

In renal transplant medicine, several scores have been recently developed in order to help decision-making in clinical practice. The aim of this update is to focus on these new scores that allow to better estimate the quality of the renal transplant, to refine the allocation policy, to help registration of old recipients on the waiting list, or to evaluate the risk to develop end-stage renal failure after living donation.

Advanced glycation end-product (AGE) is the generic term for a heterogeneous group of derivatives arising from a non-enzymatic reaction between reducing sugars and proteins. In recent years, evidence has accumulated that incriminates AGEs in pathogenic processes associated with both chronic hyperglycaemia and age-related diseases. Regardless of their exogenous or endogenous origin, the accumulation of AGEs and their derivatives could promote accelerated ageing by leading to protein modifications and activating several inflammatory signalling pathways via AGE-specific receptors. However, it remains to be demonstrated whether preventing the accumulation of AGEs and their effects is an important therapeutic option for successful ageing. The present review gives an overview of the current knowledge on the pathogenic role of AGEs by focusing on three AGE target organs: kidney, heart and brain. For each of these organs we concentrate on an age-related disease, each of which is a major public health issue: chronic kidney disease, heart dysfunction and neurodegenerative diseases. Even though strong connections have been highlighted between glycation and age-related pathogenesis, causal links still need to be validated. In each case, we report evidence and uncertainties suggested by animal or epidemiological studies on the possible link between pathogenesis and glycation in a chronic hyperglycaemic state, in the absence of diabetes, and with exogenous AGEs alone. Finally, we present some promising anti-AGE strategies that are currently being studied.