Relevance of Tacrolimus Trough Concentration and Hepatitis E virus Genetic Changes in Kidney Transplant Recipients With Chronic Hepatitis E.

Introduction: Hepatitis E virus (HEV) can cause chronic infection (≥3 months) and cirrhosis in immunocompromised patients, especially kidney transplant recipients. Low alanine aminotransferase (ALT) levels and high HEV intrahost diversity have previously been associated with evolution toward chronicity in these patients. We hypothesized that additional clinical and viral factors could be associated with the risk of chronic HEV infection. Methods: We investigated a series of 27 kidney transplant recipients with HEV infection, including 20 patients with chronic hepatitis E. Results: High tacrolimus trough concentration at diagnosis was the most relevant marker associated with chronic hepatitis E (9.2 vs. 6.4 ng/ml, P = 0.04). Most HEV genetic changes selected during HEV infection were compartmentalized between plasma and feces. Conclusion: This compartmentalization highlights the diversity and complexity of HEV replication compartments. Tacrolimus trough concentration at diagnosis of HEV infection could allow an early identification of patients at high risk of chronic hepatitis E and guide treatment initiation.

Assessment of epidemiology and outcomes of adult patients with kidney-limited thrombotic microangiopathies.

Thrombotic microangiopathies (TMA) are usually associated with hematological features (RH-TMA). The epidemiology of TMA limited to kidneys (RL-TMA) is unclear Therefore, patients with TMA and native kidney biopsies were identified during 2009-2022 in 20 French hospitals and results evaluated. RL-TMA was present in 341/757 (45%) patients and associated with lower creatinine levels (median 184 vs 346 µmol/L) than RH-TMA. RL-TMA resulted from virtually all identified causes, more frequently from anti-VEGF treatment and hematological malignancies but less frequently from shigatoxin-associated hemolytic uremic syndrome (HUS), systemic sclerosis, gemcitabine and bacterial infection, and even less frequently when three or more causes/triggers were combined (RL-TMA: 5%; RH-TMA: 12%). RL-TMA was associated with significantly lower major cardiovascular events (10% vs 20%), kidney replacement therapy (23% vs 43%) and death (12% vs 20%) than RH-TMA during follow-up (median 28 months). Atypical HUS (aHUS) was found in 326 patients (RL-TMA: 43%, RH-TMA: 44%). Among the 69 patients with proven complement-mediated aHUS, eculizumab (anti-C5 therapy) was used in 43 (62%) (RL-TMA: 35%; RH-TMA: 71%). Among the 257 other patients with aHUS, including 51% with RL-TMA, eculizumab was used in 29 but with unclear effects of this treatment. Thus, RL-TMA represents a very high proportion of patients with TMA and results from virtually all known causes of TMA and includes 25% of patients with complement-mediated aHUS. Adverse outcomes of RL-TMA are lower compared to RH-TMA but remain significant. Anti-C5 therapy was rarely used in RL-TMA, even in proven complement-mediated aHUS, and its effects remain to be assessed.

Eculizumab dose tapering should take into account the nonlinearity of its pharmacokinetics.

AIMS: Eculizumab is a monoclonal antibody targeting complement protein C5 used in renal diseases. As recommended dosing regimen leads to unnecessarily high concentrations in some patients, tailored dosing therapeutic drug monitoring was proposed to reduce treatment cost. The objectives of the present work were (i) to investigate the target-mediated elimination of eculizumab and (ii) whether a pharmacokinetic model integrating a nonlinear elimination allows a better prediction of eculizumab concentrations than a linear model. METHODS: We analysed 377 eculizumab serum concentrations from 44 patients treated for atypical haemolytic uraemic syndrome and C3 glomerulopathy with a population pharmacokinetic approach. Critical concentrations (below which a non-log-linear decline of concentration over time is evidenced) were computed to estimate the relevance of the target-mediated elimination. Simulations of dosing regimens were then performed to predict probabilities of target attainment (i.e. trough >100 mg/L). RESULTS: Pharmacokinetics of eculizumab was nonlinear and followed a mixture of first-order (CL = 1.318 mL/day/kg) and Michaelis-Menten elimination (Vmax = 26.07 mg/day, Km = 24.06 mg/L). Volume of distribution (72.39 mL/kg) and clearance were weight-dependent. Critical concentrations (Vmax/CL) ranged from 144.7 to 759.7 mg/L and were inversely related to body weight (P = .013). Nonlinearity was thus noticeable at therapeutic concentrations. Simulations predicted that 1200 mg of eculizumab every 21 days would allow 85% and 76% of patients to maintain a therapeutic exposure, for 50 or 90 kg body weight, respectively. CONCLUSIONS: Our study investigates the nonlinear elimination of eculizumab and discusses the importance of accounting for eculizumab target-mediated elimination in therapeutic drug monitoring.

Albumin influences leucocyte FcRn expression in the early days of kidney transplantation.

FcRn, a receptor originally known for its involvement in IgG and albumin transcytosis and recycling, is also important in the establishment of the innate and adaptive immune response. Dysregulation of the immune response has been associated with variations in FcRn expression, as observed in cancer. Recently, a link between autophagy and FcRn expression has been demonstrated. Knowing that autophagy is strongly involved in the development of reperfusion injury in kidney transplantation and that albuminemia is transiently decreased in the first two weeks after transplantation, we investigated variations in FcRn expression after kidney transplantation. We monitored FcRn levels by flow cytometry in leukocytes from 25 renal transplant patients and considered parameters such as albumin concentrations, estimated glomerular filtration rate, serum creatinine, serum IgG levels and ischaemia/reperfusion time. Two groups of patients could be distinguished according to their increased or non-increased FcRn expression levels between day 2 and day 6 (d2-d6) post-transplantation. Leukocyte FcRn expression at d2-d6 was correlated with albumin concentrations at d0-d2. These results suggest that albumin concentrations at d0-d2 influence FcRn expression at d2-d6, raising new questions about the mechanisms underlying these original observations.

Adding 6-month parameters for the prediction of kidney prognosis in ANCA-associated glomerulonephritis.

Background: Antineutrophil-cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with kidney involvement (AAV-GN) frequently evolves to end-stage kidney disease (ESKD) despite aggressive immunosuppressive treatment. Several risk scores have been used to assess renal prognosis. We aimed to determine whether kidney function and markers of AAV-GN activity after 6 months could improve the prediction of ESKD. Methods: This retrospective and observational study included adult patients with AAV-GN recruited from six French nephrology centers (including from the Maine-Anjou AAV registry). The primary outcome was kidney survival. Analyses were conducted in the whole population and in a sub-population that did not develop ESKD early in the course of the disease. Results: When considering the 102 patients with all data available at diagnosis, Berden classification and Renal Risk Score (RRS) were not found to be better than kidney function [estimated glomerular filtration rate (eGFR)] alone at predicting ESKD (C-index = 0.70, 0.79, 0.82, respectively). Multivariables models did not indicate an improved prognostic value when compared with eGFR alone.When considering the 93 patients with all data available at 6 months, eGFR outperformed Berden classification and RRS (C-index = 0.88, 0.62, 0.69, respectively) to predict ESKD. RRS performed better when it was updated with the eGFR at 6 months instead of the baseline eGFR. While 6-month proteinuria was associated with ESKD and improved ESKD prediction, hematuria and serological remission did not. Conclusion: This work suggests the benefit of the reassessment of the kidney prognosis 6 months after AAV-GN diagnosis. Kidney function at this time remains the most reliable for predicting kidney outcome. Of the markers tested, persistent proteinuria at 6 months was the only one to slightly improve the prediction of ESKD.

A pig model of chronic hepatitis E displaying persistent viremia and a downregulation of innate immune responses in the liver.

BACKGROUND: Hepatitis E virus (HEV) is a zoonotic virus transmitted by pig meat and responsible for chronic hepatitis E in immunocompromised patients. It has proved challenging to reproduce this disease in its natural reservoir. We therefore aimed to develop a pig model of chronic hepatitis E to improve the characterization of this disease. METHODS: Ten pigs were treated with a tacrolimus-based regimen and intravenously inoculated with HEV. Tacrolimus trough concentration, HEV viremia, viral diversity, innate immune responses, liver histology, clinical disease and biochemical markers were monitored for 11 weeks post-infection (p.i.). RESULTS: HEV viremia persisted for 11 weeks p.i. HEV RNA was detected in the liver, small intestine, and colon at necropsy. Histological analysis revealed liver inflammation and fibrosis. Several mutations selected in the HEV genome were associated with compartmentalization in the feces and intestinal tissues, consistent with the hypothesis of extrahepatic replication in the digestive tract. Antiviral responses were characterized by a downregulation of IFN pathways in the liver, despite an upregulation of RIG-I and ISGs in the blood and liver. CONCLUSIONS: We developed a pig model of chronic hepatitis E that reproduced the major hallmarks of this disease. This model revealed a compartmentalization of HEV genomes in the digestive tract and a downregulation of innate immune responses in the liver. These original features highlight the relevance of our model for studies of the pathogenesis of chronic hepatitis E and for validating future treatments.

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

BACKGROUND: Thrombotic microangiopathies (TMAs) are rare but can be severe in kidney transplant. recipients (KTR). METHODS: We analysed the epidemiology of adjudicated TMA in consecutive KTR during the. 2009-2021 period. RESULTS: TMA was found in 77/1644 (4.7%) KTR. Early TMA (n = 24/77 (31.2%); 1.5% of all KTR) occurred during the first two weeks ((median, IQR) 3 [1-8] days). Triggers included acute antibody-mediated rejection (ABMR, n = 4) and bacterial infections (n = 6). Graft survival (GS) was 100% and recurrence rate (RR) was 8%. Unexpected TMA (n = 31/77 (40.2%); 1.5/1000 patient-years) occurred anytime during follow-up (3.0 (0.5-6.2) years). Triggers included infections (EBV/CMV: n = 10; bacterial: n = 6) and chronic active ABMR (n = 5). GS was 81% and RR was 16%. Graft-failure associated TMA (n = 22/77 (28.6%); 2.2% of graft losses) occurred after 8.8 (4.9-15.5) years). Triggers included acute (n = 4) or chronic active (n = 14) ABMR, infections (viral: n = 6; bacterial: n = 5) and cancer (n = 6). 15 patients underwent transplantectomy. RR was 27%. Atypical (n = 6) and typical (n = 2) haemolytic and uremic syndrome, and isolated CNI toxicity (n = 4) were rare. Two-third of biopsies presented TMA features. CONCLUSIONS: TMA are mostly due to ABMR and infections; causes of TMA are frequently combined. Management often is heterogenous. Our nosology based on TMA timing identifies situations with distinct incidence, causes and prognosis.

Impact of hypoxia and reoxygenation on the extra/intracellular metabolome and on transporter expression in a human kidney proximal tubular cell line.

INTRODUCTION: Ischemia-reperfusion injury (IRI) induces several perturbations that alter immediate kidney graft function after transplantation and may affect long-term graft outcomes. Given the IRI-dependent metabolic disturbances previously reported, we hypothesized that proximal transporters handling endo/exogenous substrates may be victims of such lesions. OBJECTIVES: This study aimed to determine the impact of hypoxia/reoxygenation on the human proximal transport system through two semi-targeted omics analyses. METHODS: Human proximal tubular cells were cultured in hypoxia (6 or 24 h), each followed by 2, 24 or 48-h reoxygenation. We investigated the transcriptomic modulation of transporters. Using semi-targeted LC-MS/MS profiling, we characterized the extra/intracellular metabolome. Statistical modelling was used to identify significant metabolic variations. RESULTS: The expression profile of transporters was impacted during hypoxia (y + LAT1 and OCTN2), reoxygenation (MRP2, PEPT1/2, rBAT, and OATP4C1), or in both conditions (P-gp and GLUT1). The P-gp and GLUT1 transcripts increased (FC (fold change) = 2.93 and 4.11, respectively) after 2-h reoxygenation preceded by 24-h hypoxia. We observed a downregulation (FC = 0.42) of y+LAT1 after 24-h hypoxia, and of PEPT2 after 24-h hypoxia followed by 2-h reoxygenation (FC = 0.40). Metabolomics showed that hypoxia altered the energetic pathways. However, intracellular metabolic homeostasis and cellular exchanges were promptly restored after reoxygenation. CONCLUSION: This study provides insight into the transcriptomic response of the tubular transporters to hypoxia/reoxygenation. No correlation was found between the expression of transporters and the metabolic variations observed. Given the complexity of studying the global tubular transport systems, we propose that further studies focus on targeted transporters.

Blood pressure management and long-term outcomes in kidney transplantation: a holistic view over a 35-year period.

INTRODUCTION: Hypertension is a burden for most kidney transplant recipients. Whether respect of hypertension guidelines results in better outcomes is unknown. METHODS: In this multicenter study, office blood pressure at 12 months following transplantation (i.e., after > 20 outpatient visits), and survival were assessed over 35 years among 2004 consecutive kidney transplant recipients who received a first kidney graft from 1985 to 2019 (follow-up: 26,232 patient-years). RESULTS: Antihypertensive medications were used in 1763/2004 (88.0%) patients. Renin-angiotensin-system blockers were used in 35.6% (47.1% when proteinuria was > 0.5 g/day) and calcium-channel blockers were used in 6.0% of patients. Combined treatment including renin-angiotensin-system-blockers, calcium-channel blockers and diuretics was used in 15.4% of patients receiving ≥ 3 antihypertensive drugs. Blood pressure was controlled in 8.3%, 18.8% and 43.1%, respectively, depending on definition (BP < 120/80, < 130/80, < 140/90 mmHg, respectively) and has not improved since the year 2001. Two-thirds of patients with uncontrolled blood pressure received < 3 antihypertensive classes. Low sodium intake < 2 g/day (vs ≥ 2) was not associated with better blood pressure control. Uncontrolled blood pressure was associated with lower patient survival (in multivariable analyses) and graft survival (in univariate analyses) vs controlled hypertension or normotension. Low sodium intake and major antihypertensive classes had no influence on patient and graft survival. CONCLUSIONS: Pharmacological recommendations and sodium intake reduction are poorly respected, but even when respected, do not result in better blood pressure control, or patient or graft survival. Uncontrolled blood pressure, not the use of specific antihypertensive classes, is associated with reduced patient, and to a lesser extent, reduced graft survival, even using the 120/80 mmHg cut-off.

Characteristics and Prognosis of Patients With Hypertensive Encephalopathy: A French Nationwide Cohort Study.

BACKGROUND: Hypertensive encephalopathy (HE) constitutes a serious condition, usually observed in patients with long-lasting hypertension. Hypertension-associated HE is sometimes differentiated from the stroke-associated hypertensive emergency. Whether prognosis of hypertension-associated and stroke-associated HE is different is unclear. METHODS: Characteristics and prognosis of HE were assessed in this nationwide retrospective cohort study in all patients with an administrative code of HE compared with age-, sex- and year of inclusion-matched controls admitted to French hospitals during the 2014 to 2022 period. RESULTS: HE was identified in 7769 patients. Chronic kidney disease (19.3%), coronary artery disease (13.8%), diabetes (22.1%), and ischemic stroke (5.2%) were frequent but thrombotic microangiopathy, hemolytic-uremic syndrome, systemic sclerosis or renal infarction were <1%. HE prognosis was poor (death: 10.4%/y, heart failure: 8.6%/y, end-stage kidney disease: 9.0%/y, ischemic stroke: 3.6%/y, hemorrhagic stroke: 1.6%/y, dementia: 4.1%/y). The risk of death was increased to a similar extent in patients with HE, regardless of the presence of known hypertension or concomitant stroke (versus patients without HE). Among patients with HE, known hypertension was significantly associated with increased risks of ischemic stroke, hemorrhagic stroke, heart failure, vascular dementia, and all-cause dementia and to a lesser extent with chronic dialysis in multivariable analyses including adjustment on concomitant stroke. CONCLUSIONS: HE remains a considerable health burden and is associated with a poor prognosis. The distinction between hypertension- versus stroke-associated HE is relevant as these 2 situations convey different risks of stroke, heart failure, vascular dementia, and end-stage kidney disease.

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

BACKGROUND: The risk of bleeding after percutaneous biopsy in kidney transplant recipients is usually low but may vary. A pre-procedure bleeding risk score in this population is lacking. METHODS: We assessed the major bleeding rate (transfusion, angiographic intervention, nephrectomy, hemorrhage/hematoma) at 8 days in 28,034 kidney transplant recipients with a kidney biopsy during the 2010-2019 period in France and compared them to 55,026 patients with a native kidney biopsy as controls. RESULTS: The rate of major bleeding was low (angiographic intervention: 0.2%, hemorrhage/hematoma: 0.4%, nephrectomy: 0.02%, blood transfusion: 4.0%). A new bleeding risk score was developed (anemia = 1, female gender = 1, heart failure = 1, acute kidney failure = 2 points). The rate of bleeding varied: 1.6%, 2.9%, 3.7%, 6.0%, 8.0%, and 9.2% for scores 0 to 5, respectively, in kidney transplant recipients. The ROC AUC was 0.649 (0.634-0.664) in kidney transplant recipients and 0.755 (0.746-0.763) in patients who had a native kidney biopsy (rate of bleeding: from 1.2% for score = 0 to 19.2% for score = 5). CONCLUSIONS: The risk of major bleeding is low in most patients but indeed variable. A new universal risk score can be helpful to guide the decision concerning kidney biopsy and the choice of inpatient vs. outpatient procedure both in native and allograft kidney recipients.

The 2022-2026 Transplantation Plan: objectives and priorities for a new development of kidney transplantation / Le Plan greffe 2022-2026 : objectifs et priorités pour un nouvel essor de la transplantation rénale

The 2022-2026 Transplantation Plan has been launched by the French government to stimulate the activities of organ harvesting and transplantation, after the failure of the previous one. It has been designed by the Biomedicine Agency in collaboration with learning societies, including the SFNDT, and patient associations. The plan is original in its objectives, its regional organization with its driving by the Regional Health Agencies, the involvement of advanced practice nurses and its funding. The ambition is to transplant every transplantable patient. The increase in the number of kidney transplantations, more of all from a living donor, requires the active participation of all the nephrologists, who are the first in delivering information to the patients and their family on advanced chronic kidney disease treatment and living donation.

Le Plan greffe 2022-2026 a été lancé par le Gouvernement pour stimuler le prélèvement et la transplantation rénale, après l'échec du plan précédent. Il a été élaboré par l'Agence de biomédecine en concertation avec les sociétés savantes, dont la Société française de néphrologie, dialyse et transplantation (SFNDT), et les associations de patients. Il est original, du fait de ses objectifs concernant l'activité de prélèvement et de transplantation ­ exprimés non pas en données chiffrées mais en couloirs de croissance ­, de son organisation régionale pilotée par les agences régionales de santé, tendant à aligner les niveaux d'activité entre les régions, de l'implication des infirmières de pratique avancée et de son financement. L'ambition est de donner un accès à la greffe à tous les patients transplantables. L'augmentation du nombre de transplantations rénales, en premier lieu à partir d'un donneur vivant, nécessite l'implication de tous les néphrologues, premiers intervenants dans l'information aux patients sur le traitement de l'insuffisance rénale chronique avancée et le don du vivant.

Type 2 diabetes and cardiorenal syndromes. A nationwide French hospital cohort study.

AIM: Type 2 diabetes mellitus (T2DM) is a risk factor for cardiac and renal complications; its effect on cardiorenal syndromes is unknown. METHODS: In a French nationwide cohort of 5,123,193 patients hospitalized in 2012 with ≥5 years of follow-up, we assessed the effect of T2DM on cardiorenal syndrome (CRS) (using cardiorenal, renocardiac, and simultaneous subtypes) incidence and outcomes using 1:1 propensity matching. RESULTS: Among 4,605,236 adults without cardiorenal syndrome, 380,581 (8.5%) with T2DM were matched to 380,581 adults without T2DM. During follow-up, CRS occurred in 104,788 patients: simultaneous n = 25,225 (24.0%); cardiorenal n = 51,745 (49.4%); renocardiac n = 27,818 (26.5%). T2DM doubled the risk of incident CRS (1.30% versus 0.65%/year; adjusted hazard ratio (HR) for any cardiorenal syndrome: 2.14 [95% confidence interval 2.10;2.19]; renocardiac: 2.43 [2.34;2.53]; cardiorenal: 2.09 [2.03;2.15]; simultaneous: 1.94 [1.86;2.03]. Among the 26,396 adults with CRS in 2012, 11,355 (43.0%) had T2DM and were younger than non-diabetic adults (77.4 ± 9.5 versus 82.3 ± 10.0); 8,314 patients with T2DM were matched to 8,314 patients without. T2DM increased risk of: end-stage kidney disease, adjusted HR 1.50 [1.39;1.62]; myocardial infarction 1.35 [1.19;1.53]; cardiovascular death 1.20 [1.13;1.27]; heart failure 1.17 [1.12;1.21]; and all-cause death 1.09 [1.06;1.13], but not ischemic stroke. CONCLUSION: Patients with T2DM represent almost half of patients with CRS and are younger than their non-diabetic counterparts. T2DM doubles the risk of CRS and increases the risk of death, cardiovascular outcome, and end-stage kidney disease but not ischemic stroke after CRS.

High extracellular sodium chloride concentrations induce resistance to LPS signal in human dendritic cells.

Recent evidence showed that in response to elevated sodium dietary intakes, many body tissues retain Na+ ions for long periods of time and can reach concentrations up to 200 mM. This could modulate the immune system and be responsible for several diseases. However, studies brought contrasted results and the effects of external sodium on human dendritic cell (DC) responses to danger signals remain largely unknown. Considering their central role in triggering T cell response, we tested how NaCl-enriched medium influences human DCs properties. We found that DCs submitted to high extracellular Na+ concentrations up to 200 mM remain viable and maintain the expression of specific DC markers, however, their maturation, chemotaxis toward CCL19, production of pro-inflammatory cytokines and ROS in response to LPS were also partially inhibited. In line with these results, the T-cell allostimulatory capacity of DCs was also inhibited. Finally, our data indicate that high NaCl concentrations triggered the phosphorylation of SGK1 and ERK1/2 kinases. These results raised the possibility that the previously reported pro-inflammatory effects of high NaCl concentrations on T cells might be counterbalanced by a downregulation of DC activation.

End-diastolic velocity mediates the relationship between renal resistive index and the risk of death.

OBJECTIVE: Renal resistive index predicts the risk of death in many populations but the mechanism linking renal resistive index and death remains elusive. Renal resistive index is derived from end-diastolic velocity (EDV) and peak systolic velocity (PSV). However, the predictive value of EDV or PSV considered alone is unknown. METHODS: We conducted a retrospective analysis of 2362 consecutive patients who received a kidney transplant from 1985 to 2017. EDV and PSV were measured at 3 months after transplantation, renal resistive index was calculated, and the risk of death was assessed [median follow-up: 6.25 years (0.25-29.15); total observation period: 13 201 patient-years]. RESULTS: Doppler indices were available in 1721 of 2362 (78.9%) patients (exclusions: 113 who died or returned to dialysis before, 427 with no Doppler studies, 27 with renal artery stenosis, 74 missing values). Among them, 279 (16.4%) had diabetes before transplantation. Mean age was 51.5 ±â€Š14.7, 1097 (63.7%) were male. During follow-up, 217 of 1721 (12.6%) patients died. Renal resistive index and EDV shared many determinants (notably systolic, diastolic and pulse pressure, recipient age and diabetes) unlike renal resistive index and PSV. EDV used as a binary [lowest tertile vs. higher values: (hazard ratio: 2.57 (1.96-3.36), P  < 0.001)] and as a continuous (the lower EDV, the greater the risk of death) variable was significantly associated with the risk of death. This finding was confirmed in multivariable analyses. Prediction of similar magnitude was found for renal resistive index. No association was found between PSV used as a binary or a continuous variable and the risk of death. CONCLUSION: Low EDV explains high renal resistive index, and the mechanism-linking renal resistive index to the risk of death is through low EDV.

Association between kinetic of anti-neutrophil cytoplasmic antibody (ANCA), renal survival and relapse risk in ANCA glomerulonephritis.

BACKGROUND: Anti-neutrophil cytoplasmic antibody (ANCA) kinetic in ANCA-associated vasculitis with glomerulonephritis (AAV-GN) has been suggested to be associated with AAV relapse. Few studies have focused on its association with renal prognosis. Thus we aimed to investigate the relationship between ANCA specificity and the evolutive profile and renal outcomes. METHODS: This multicentric retrospective study included patients diagnosed with ANCA-GN since 1 January 2000. Patients without ANCA at diagnosis and with fewer than three ANCA determinations during follow-up were excluded. We analysed estimated glomerular filtration rate (eGFR) variation, renal-free survival and relapse-free survival according to three ANCA profiles (negative, recurrent and persistent) and to ANCA specificity [myeloperoxidase (MPO) or proteinase 3 (PR3)]. RESULTS: Over a follow-up of 56 months [interquartile range (IQR) 34-101], a median of 19 (IQR 13-25) ANCA determinations were performed for the 134 included patients. Patients with a recurrent/persistent ANCA profile had a lower relapse-free survival (P = .019) and tended to have a lower renal survival (P = .053) compared with those with a negative ANCA profile. Patients with a recurrent/persistent MPO-ANCA profile had the shortest renal survival (P = .015) and those with a recurrent/persistent PR3-ANCA profile had the worst relapse-free survival (P = .013) compared with other profiles. The negative ANCA profile was associated with a greater eGFR recovery. In multivariate regression analysis, it was an independent predictor of a 2-fold increase in eGFR at 2 years [odds ratio 6.79 (95% confidence interval 1.78-31.4), P = .008]). CONCLUSION: ANCA kinetic after an ANCA-GN diagnosis is associated with outcomes. MPO-ANCA recurrence/persistence identifies patients with a lower potential of renal recovery and a higher risk of kidney failure, while PR3-ANCA recurrence/persistence identifies patients with a greater relapse risk. Thus ANCA kinetics may help identify patients with a smouldering disease.

Unraveling complexity of antibody-mediated rejections, the mandatory way towards an accurate diagnosis and a personalized treatment.

Antibody-mediated rejection (ABMR) remains one of the most challenging issues after organ transplantation and particularly after kidney transplantation. Despite many progresses during the last decade, ABMR is still the main cause of kidney graft loss and this all over the post- transplant period. In this review, we describe the recent knowledge about molecular and cellular mechanisms involved in ABMR. We focused our report on the role of the complement pathway in the process of ABMR and we give some insights into the role of inflammatory cells, NK lymphocytes and the role of endothelial cells. We further describe the potential role of non-HLA antibodies, of which the importance has been increasingly emphasized in recent years. Overall, this report could be of interest for all physicians who are working in the field of organ transplantation or who are working in the field of immunology. It gives essential information to understand new diagnosis advances and further therapeutic approaches. Antibody-mediated rejection (ABMR) is the leading cause of graft failure ([1,2]). In contrast to T-cell mediated rejection usually sensitive to steroids, active ABMR remains a therapeutic challenge. ABMR diagnosis relies on the presence of renal injuries and donor-specific antibodies (DSA) (HLA and non HLA antibodies) with sometimes the evidence of interaction between DSA and graft endothelium. Regularly revised during expert conferences, ABMR definition is currently categorized as active or chronic active. [3] The emergence of validated molecular assays targeting a better phenotyping of ABMR and the recent advances regarding the detrimental effect of DSA directed against minor antigens open the way to a better assessment of the heterogeneity of ABMR. In this review, we will address new aspects of ABMR regarding its mechanisms, diagnosis and treatments.

Absence of Mortality Differences Between the First and Second COVID-19 Waves in Kidney Transplant Recipients.

Introduction: SARS-CoV-2 pandemic evolved in 2 consecutive waves during 2020. Improvements in the management of COVID-19 led to a reduction in mortality rates among hospitalized patients during the second wave. Whether this progress benefited kidney transplant recipients (KTRs), a population particularly vulnerable to severe COVID-19, remained unclear. Methods: In France, 957 KTRs were hospitalized for COVID-19 in 2020 and their data were prospectively collected into the French Solid Organ Transplant (SOT) COVID registry. The presentation, management, and outcomes of the 359 KTRs diagnosed during the first wave were compared to those of the 598 of the second wave. Results: Baseline comorbidities were similar between KTRs of the 2 waves. Maintenance immunosuppression was reduced in most patients but withdrawal of antimetabolite (73.7% vs. 58.4%, P < 0.001) or calcineurin inhibitor (32.1% vs. 16.6%, P < 0.001) was less frequent during the second wave. Hydroxychloroquine and azithromycin that were commonly used during the first wave (21.7% and 30.9%, respectively) but were almost abandoned during the second wave. In contrast, the use of high dose corticosteroids doubled (19.5% vs. 41.6%, P < 0.001). Despite these changing trends in COVID-19 management, 60-day mortality was not statistically different between the 2 waves (25.3% vs. 23.9%; Log Rank, P = 0.48) and COVID-19 hospitalization period was not associated with death due to COVID-19 in multivariate analysis (Hazard ratio 0.89, 95% confidence interval 0.67-1.17, P = 0.4). Conclusion: We conclude that changing of therapeutic trends during 2020 did not reduce COVID-19 related mortality among KTRs. Our data indirectly support the importance of vaccination and neutralizing monoclonal anti-SARS-CoV-2 antibodies to protect KTRS from severe COVID-19.