Introduction:Recurrent focal segmental glomerulosclerosis (FSGS, rFSGS) is a severe complication after kidney transplantation, often resistant to standard therapies and requiring prolonged apheresis. Combined depletion of plasma cells (anti-CD38) and B cells (anti-CD20) has emerged as a potential strategy; however, multicenter real-world data integrating clinical, biological, and histological characterization remain limited. Methods:We retrospectively studied 17 kidney transplant recipients with rFSGS treated with daratumumab (anti-CD38) administered after and/or in combination with anti-CD20 therapy across 12 French centers. Patients were clinically and histologically characterized at treatment initiation. Clinical response, safety, and longitudinal antinephrin antibody trajectories were assessed. Results:Median time from recurrence to daratumumab initiation was 5 months. All patients had previously received B-cell-depleting therapy. After the first daratumumab course (1-8 injections), 7 patients (41%) achieved complete remission (CR) and 4 (24%) achieved partial remission (PR), allowing discontinuation of apheresis in all responders. Median response time was 24 days. During a median follow-up of 8 months, 3 responders relapsed but regained remission after retreatment. Median proteinuria decreased from 3.9 g/g to 1.4 g/g at 1 month (P = 0.029). Among 11 patients tested, 3 had positive antinephrin antibodies. Two patients showed marked posttreatment declines paralleling clinical response, whereas 1 did not. Treatment was well-tolerated. Conclusion:In this multicenter real-world cohort, combined plasma cell and B-cell depletion was associated with meaningful remission rates in refractory rFSGS and was accompanied by dynamic changes in antinephrin antibodies in selected cases. Prospective trials are warranted to define optimal patient selection and dosing, and to clarify its place in therapy.

Introduction Antiglomerular basement membrane (anti-GBM) disease is a rare, small-vessel vasculitis because of antibodies targeting the glomerular and alveolar capillaries, leading to rapidly progressive glomerulonephritis and/or pulmonary hemorrhage. Data on children with anti-GBM are scarce. Methods We collected clinical and biochemical data from European pediatric and adult patients diagnosed with anti-GBM disease between 2020 and 2024. Results A total of 72 patients (35% children) with anti-GBM disease and with a median follow-up of 18 months were analyzed. Pediatric cases were more often female and had higher estimated glomerular filtration rate (eGFR) at the time of diagnosis (each P < 0.01), whereas the percentage of patients requiring dialysis, presence of pulmonary hemorrhage, and immunological findings did not statistically differ between groups. Treatment consisted mainly of daily plasma exchanges (PEXs)and corticosteroids at higher weight-based doses in children (P < 0.0001), in combination with cyclophosphamide (CYC) or, preferably in children (P < 0.05), with rituximab (RTX) and mycophenolate mofetil (MMF). Final eGFR was higher in children than in adults (P < 0.0001), although the frequency of kidney failure did not significantly differ between children (24%) and adults (38%). Adult patients and patients who required dialysis at the time of diagnosis had a 16-fold and 11-fold increased risk of chronic kidney disease (CKD) stage 3 or higher, respectively. Conclusion Our study indicates that girls predominate among children with anti-GBM disease and that children have a better outcome in terms of eGFR than adults, which is at least partly because of better eGFR values at diagnosis. The need for dialysis is a strong predictor of outcome, regardless of age.

Background: Decline in renal function is common in patients (pts) with transthyretin amyloidosis (ATTR) and is a marker of disease progression associated with mortality in ATTR with cardiomyopathy (ATTR-CM). The TTR-silencing RNAi therapeutic vutrisiran reduced risk of all-cause mortality (ACM) and cardiovascular (CV) events vs placebo (PBO) in pts with ATTR-CM in the Phase 3 HELIOS-B study (NCT04153149). Aims: To assess the potential impact of vutrisiran on renal function and efficacy/safety of vutrisiran in pts who advanced to CKD Stage 4 during the HELIOS-B double-blind (DB) period. Methods: HELIOS-B eligibility criteria included eGFR ≥30 mL/min/1.73m 2 . Pts were randomized 1:1 to vutrisiran 25 mg or PBO Q3M. In this post hoc analysis of the DB period (up to 33–36 months), the proportion of pts with eGFR decline ≥40% from baseline was assessed. The primary composite endpoint of ACM and CV events, as well as ACM, CV events, and safety, were also assessed in pts who progressed to CKD Stage 4 (eGFR <30 mL/min/1.73m 2 ) during the DB period. Outcomes were assessed overall and by baseline tafamidis use (monotherapy and baseline tafamidis subgroups). Results: Median (IQR) eGFR at baseline in pts receiving vutrisiran and PBO was 64 (50–81) and 65 (53–81) mL/min/1.73m 2 , respectively. In the overall population, fewer pts in the vutrisiran group experienced a ≥40% decline in eGFR from baseline vs PBO (12.7% vs 21.2%, respectively); results were consistent in monotherapy and baseline tafamidis subgroups ( Figure 1 ). Among pts who advanced to CKD Stage 4, in the overall population, vutrisiran reduced the risk of composite ACM and CV events vs PBO (HR [95% CI] 0.47 [0.26, 0.85]); similar results were seen in ACM and CV events, separately, and in the monotherapy and baseline tafamidis subgroups ( Figure 2 ; CV-related death: 34.3% with PBO; 9.7% with vutrisiran in the overall population). The safety profile of vutrisiran in pts who advanced to CKD Stage 4 was comparable with PBO. No new safety signals were reported. Conclusion: Vutrisiran appeared to preserve renal function in pts with ATTR-CM. Consistent with results from the overall population, vutrisiran reduced the risk of ACM and CV events vs PBO in pts with ATTR-CM and advanced CKD in HELIOS-B; results require corroboration in a larger pt population.

OBJECTIVE:Systemic sclerosis (SSc) is an autoimmune disease characterized by autoantibody production, fibrosis, and vasculopathy. The coexistence of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) in SSc is rare and poorly characterized, with limited data on the impact of treatments, particularly high-dose glucocorticoids (GCs), on both conditions. This study aimed to describe the clinical phenotype, management, and outcomes of patients with overlapping SSc and AAV. METHODS:We conducted a multicenter retrospective study in 18 French centers, including patients who met the 2013 American College of Rheumatology (ACR)/EULAR criteria for SSc and the 2022 ACR/EULAR criteria for AAV. Clinical, biologic, and radiologic data were collected. RESULTS:We included 30 patients (median age 51.5 years, 83% female). SSc preceded AAV in all cases; 27% had diffuse cutaneous SSc, whereas 73% had limited cutaneous SSc. Anti-Scl70 antibodies were detected in 50%, and interstitial lung disease (ILD) was present in 80%, predominantly with a fibrosing nonspecific interstitial pneumonia pattern (54%). AAV was microscopic polyangiitis in 90%, with myeloperoxidase (MPO)-ANCA positivity in 93%. Renal involvement was common (76%), with a median serum creatinine level of 170 μmol/L (interquartile range [IQR] 120-361 μmol/L) and proteinuria (urine protein to creatinine ratio of 2 g/g creatinine [IQR 0.9-2.3 g/g creatinine]). All patients received GCs in combination with cyclophosphamide (50%) or rituximab (47%). No cases of scleroderma renal crisis were observed. SSc manifestations, including ILD and skin involvement, remained stable during follow-up. CONCLUSION:AAV, predominantly microscopic polyangiitis with MPO-ANCA, can occur in SSc, particularly in patients with fibrosing ILD and anti-Scl70. Standard vasculitis treatments appear to be effective and do not worsen outcomes in SSc.

BACKGROUND:In HELIOS-B (HELIOS-B: A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy), vutrisiran reduced the risk of all-cause mortality and cardiovascular events associated with ATTR-CM. We assessed the effects of vutrisiran on renal function and on outcomes by renal function. METHODS:Patients were randomized to double-blind treatment with vutrisiran 25 mg or placebo every 3 months for ≤36 months. We evaluated the proportion of patients with a ≥40% decline in the estimated glomerular filtration rate (eGFR) from baseline and the primary composite end point (all-cause mortality or recurrent cardiovascular events) in subgroups based on baseline eGFR levels, and development of chronic kidney disease (CKD) stage ≥4 (eGFR <30 mL/min/1.73 m2) during treatment. RESULTS:In HELIOS-B, 654 patients were randomized and treated with vutrisiran (n = 326) or placebo (n = 328). A ≥40% decline in the eGFR was seen in significantly fewer patients receiving vutrisiran vs placebo in the overall (12.7% vs 21.2%, P = .0041) and monotherapy (12.0% vs 21.9%, P = .0102) populations. The effect of vutrisiran on the primary composite end point in subgroups based on renal function was directionally consistent with the effect in the overall population. Among patients receiving vutrisiran vs placebo, 9.5% vs 9.8%, respectively, developed CKD stage ≥4. The risk of a primary composite end point event was significantly lower with vutrisiran vs placebo in patients who developed CKD stage ≥4 (hazard ratio 0.467, 95% confidence interval 0.258-0.845). No new safety concerns were identified. CONCLUSIONS:Vutrisiran may slow eGFR decline and is effective and well-tolerated in patients with ATTR-CM with declining renal function, including those developing CKD stage ≥4.

Introduction:The identification of autoantibodies against nephrin, a key signaling protein of the podocyte slit diaphragm, and their pathogenic role in patients with minimal change disease (MCD) has substantially changed our understanding of primary podocytopathies. However, details on underlying immune pathophysiological mechanisms such as the relation of anti-nephrin autoantibodies with immune cell subsets and therapy response remain to be determined. Methods:In this prospective study, we evaluated blood samples from adults with newly diagnosed, biopsy-proven MCD for circulating anti-nephrin antibodies using immunoprecipitation (IP) and B-cell subpopulations by fluorescence-activated cell sorting. Samples were collected at diagnosis (t0) and after 8 weeks of steroid therapy (t1). Results:We detected anti-nephrin antibodies in 12 of 17 (70.6%) therapy-naïve patients with MCD at t0. All 12 patients (100%) positive for anti-nephrin antibodies achieved complete remission with no anti-nephrin antibodies detectable after 8 weeks of steroid treatment (t1). Two of 5 anti-nephrin negative patients (40%) did not reach clinical remission at t1. Anti-nephrin positive patients exhibited a larger fraction of plasmablasts than anti-nephrin negative patients at t0, albeit not statistically significant. Plasmablasts, naïve B cells, and transitional B cells significantly decreased, whereas marginal zone-like B cells increased within 8 weeks of steroid treatment in anti-nephrin positive patients (t1). Conclusion:Our study shows, for the first time, a therapeutically relevant short-term effect of steroids on the B-cell compartment and anti-nephrin antibody levels, explaining the high clinical response rate in patients with anti-nephrin-associated MCD.

BACKGROUNDAfter identifying 2 immunomarkers of acute injury, KIM-1 and LCN2, in all kidney biopsies from 31 patients with COVID-19 pneumonia and de novo kidney dysfunction, we investigated whether circulating markers of kidney epithelial injury are common in patients with laboratory-confirmed COVID-19 who require oxygen support but do not have critical illness.METHODSWe studied 196 patients admitted to 15 hospitals with moderate to severe pneumonia who were enrolled in 2 independent randomized clinical trials. We measured 41 immune mediators and markers of kidney and endothelial injury in peripheral blood in these patients within 24 hours of randomization.RESULTSWe constructed a generalized linear CORIMUNO model combining serum levels of KIM-1, LCN2, IL-10, and age at hospital admission that showed high discrimination for mortality (derivation cohort: AUC = 0.82, 95% CI: 0.73-0.92; validation cohort: AUC = 0.83, 95% CI: 0.74-0.92). An early rise in circulating kidney injury markers, in the absence of acute kidney injury criteria, was markedly associated with the risk of developing a severe form of COVID-19 and death within 3 months.CONCLUSIONThe CORIMUNO score may be a helpful tool for risk stratification, and for the first time to our knowledge, it identifies the overlooked impact of subclinical kidney injury on pneumonia outcomes.TRIAL REGISTRATIONClinicalTrials.gov NCT04324047, NCT04324073, and NCT04331808.FUNDINGThis research was funded by the French Ministry of Health, Programme Hospitalier de Recherche Clinique (PHRC COVID-19-20-0151, PHRC COVID-19-20-0029), Fondation de l'Assistance Publique Hôpitaux de Paris (Alliance Tous Unis Contre le Virus), Assistance Publique Hôpitaux de Paris, and grants from the Fondation pour la Recherche Médicale (FRM) (REA202010012514) and Agence Nationale de Recherches sur le Sida and emerging infectious diseases (ANRS) (ANRS0147) from the VINTED sponsorship.

In membranous lupus nephritis (LN), positivity for the target antigen exostosin 1/2 (EXT) is associated with a lower chronicity index (CI) at first biopsy and a lower risk of progression to end-stage kidney disease (ESKD) compared to EXT-negative patients. Repeat kidney biopsies (RKB) in LN may reveal increasing CI and class transition with prognostic significance. In a cohort of membranous LN with RKB, we assessed the variation in EXT and neural cell adhesion molecule 1 (NCAM1) expression and their association with class III/IV + V transition and renal outcomes. Thirty patients with 78 biopsies were enrolled. Index biopsies included 60

Introduction:The optimal management of thromboembolism (TE) in patients with nephrotic syndrome (NS) remains challenging. Until now, anticoagulation therapy for NS consisted of vitamin K antagonists (VKAs) or heparin. Data on direct oral anticoagulant (DOAC) use in NS are limited, and their safety and convenience have been well-demonstrated in other indications. Methods:We conducted a multicenter retrospective study of adult patients with NS treated with therapeutic-dose anticoagulation between 2014 and 2022. We compared the incidences of bleeding and TE events between patients receiving DOAC and those receiving VKAs or heparin (standard-of-care [SOC]). Patients with end-stage kidney disease were excluded. Results:The overall population consisted of 144 patients (median [interquartile range] age of 54 [38-67] years, 34.7% women) with a median albumin level at 1.5 (1.2-1.8) g/dl and a median urinary protein-to-creatinine ratio of 8.8 (5.5-12.3)g/g. Membranous nephropathy was the main NS etiology (45.8%). No significant differences were observed between the DOAC (n = 72) and the SOC (n = 72) groups. The anticoagulant strategy was primary prophylaxis in 79.2% of patients taking DOAC and 83.3% of patients with SOC (P = 0.67). DOAC use was not associated with an increased rate of TE (4.2% vs. 0%, P = 0.25) or bleeding events (6.9% vs. 13.9%, P = 0.28) compared with the SOC group. Univariate analysis identified female sex, age > 75 years, and anticoagulant exposure > 90 days as risk factors for bleeding. Conclusion:This study suggests that DOAC are safer and more effective than conventional anticoagulant strategies for both primary and secondary prophylaxis in patients with NS.

Introduction: Although rituximab has significantly improved outcomes for patients with membranous nephropathy, response to treatment is not universal and drug resistance can occur. One mechanism of resistance is the occurrence of antidrug antibodies. Obinutuzumab and ofatumumab are humanized and human monoclonal antibodies, respectively, that target B cells. These treatments have been shown to be effective in membranous nephropathy. However, obinutuzumab and ofatumumab have never been compared with rituximab in the treatment of patients with membranous nephropathy with anti-rituximab antibodies. We aimed to compare the efficacy and safety of obinutuzumab and ofatumumab with rituximab in patients with membranous nephropathy with anti-rituximab antibodies. Methods: This international retrospective multicenter study enrolled 34 patients with membranous nephropathy from 5 nephrology departments in France, India, and Italy. All the patients had previously developed anti-rituximab antibodies. Nineteen patients received rituximab, 12 received obinutuzumab, and 3 received ofatumumab. Results: Patients treated with obinutuzumab or ofatumumab were more likely to achieve clinical remission than those treated with rituximab at month 6 (87% vs. 37%, P = 0.005) and month 12 (87% vs. 42%, P = 0.01). Patients treated with obinutuzumab or ofatumumab were more likely to achieve immunological remission and B-cell depletion at month 6 than the patients treated with rituximab (92% vs. 56%, P = 0.04 and 93% vs. 35%, P = 0.002, respectively). No serious adverse events were reported in the obinutuzumab or ofatumumab group. Conclusion: Obinutuzumab and ofatumumab are more effective than rituximab in treating patients with membranous nephropathy with anti-rituximab antibodies. Anti-rituximab antibodies should be systematically monitored, to determine appropriate treatment.

Chronic kidney disease (CKD) is common and a major contributor to increased morbidity and early mortality in people with sickle cell anemia (SCA). Urine albumin-to-creatinine ratio (uACR) is recommended to identify patients with SCA-related CKD but its utility in predicting long-term kidney dysfunction remains unclear in this patient population. In two independent, longitudinal cohorts of patients with hemoglobin SS or Sβ0-thalassemia (USA: n = 268, median follow-up 6 years; France: n = 310, median follow-up 8.2 years) we investigated the utility of uACR, as well as other clinical and modifiable risk factors, for predicting a decline in kidney function as determined by the rate of estimated glomerular filtration rate (eGFR) decline. Using linear mixed-effects models, a higher baseline uACR independently predicted a faster rate of eGFR decline as well as a more rapid annual eGFR decline, defined as ≥ 3 mL/min/1.73m2 (p ≤ 0.009). Furthermore, baseline uACR of ≥ 100 mg/g creatinine was independently associated with the rate of eGFR decline and rapid annual eGFR decline in both cohorts. Tobacco smoking was also associated with a faster rate of eGFR decline and was congruous between the two cohorts. In conclusion, we demonstrate that uACR is an important clinical tool that predicts a more rapid decline in kidney function and should be routinely monitored in people with SCA. Our data also support preventative care to reduce tobacco smoking for mitigating the risk of CKD progression in this high-risk population.

Introduction:The identification of prognostic factors for renal failure in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) remains a challenge. The benefit of plasma exchange (PLEX) has been questioned, and the target population remains to be defined. We investigated the outcome of patients requiring renal replacement therapy (RRT) at baseline and factors associated with their prognosis at 1 year. Methods:This retrospective multicenter study evaluated the 1-year composite end point of death or end-stage kidney disease (ESKD) in patients with biopsy-proven renal AAV involvement. Results:Of the 394 patients included, 105 (26.6%) were on dialysis at baseline. Of these, 60 (57.1%) reached the composite end point compared with 29 patients (10.0%) who were not on RRT at baseline (P < 0.001). On multivariate analysis, age and sex were not associated with the composite outcome (P = 0.945 and P = 0.154, respectively); however, myeloperoxidase (MPO)-ANCA was (odds ratio [OR]: 3.60; 95% confidence interval [CI]: 1.79-7.60), as was a high baseline histologic renal risk score (OR: 1.29; 95% CI 1.17-1.44). The most strongly associated factor remained the need for dialysis at baseline (OR: 10.91; 95% CI: 5.52-22.70). Of the 91 patients surviving after requiring dialysis at baseline, 45 were weaned from RRT (49.5%) at 1 year, and PLEX was independently associated with a reduced risk of the composite outcome (OR: 0.23, 95% CI: 0.05-0.80). Conclusion:MPO-ANCA, need for dialysis, and high histological renal risk score at baseline were associated with the 1-year composite end point of death or ESKD. Almost half of the patients on dialysis at baseline were off dialysis at 1 year, with a better prognosis in those who had received PLEX.

Abstract Background The optimal therapeutic strategies for adult sickle cell disease (SCD) patients with nephropathy remains to be determined. Observational studies suggested that Hydroxyurea (HU), the main disease-modifying therapy, by increasing fetal hemoglobin (HbF), reducing hemolysis and inflammation, may have reno-protective effects. However, robust randomized trial evidence is lacking. Aims To determine the effect of HU on albuminuria after 6 and 12 months compared with placebo in adults SCD patients. Methods SIKAMIC is a phase IIb, multicenter, randomized, double-blind, placebo-controlled trial conducted in 34 sites across France, Senegal, Mali, and Ivory Coast. Among the enrolled patients, 34.3% were recruited in France and 65.7% in Africa. Adults ≥18 years with confirmed HbSS or HbSβ0 genotypes and persistent albuminuria (urine albumin-to-creatinine ratio [UACR] >3 mg/mmol and <100 mg/mmol on three first-morning samples) were eligible. Key exclusion criteria included prior HU administration within 6 months, chronic transfusion, Angiotensin-converting enzyme (ACE) inhibitors or Angiotensin receptors blockers (ARBs) use, and etimated glomerula filtration rate (eGFR) < 60 or ≥ 140 ml/min/1,73m². Patients were randomized for receiving HU 15 mg/kg/day or placebo for 6 months. The primary endpoint was the proportion of patients achieving at least a 30% UACR reduction at M6. Those reaching this threshold could continue blinded treatment up to 12 months, while patients not meeting the criterion were considered non-responders. Secondary endpoints included absolute and relative UACR changes, eGFR changes, and safety. Results Ninety-nine patients were randomized (HU n=51; placebo n=48); 46 (90.2%) and 40 (83.3%) received at least one dose and had post-baseline UACR data. Baseline characteristics were similar between groups (mean age 30.2±9.3 years, 69% female). Due to high intra-patient UACR variability (CV >50% at baseline), median values were analyzed. Median baseline UACR was 7.9 mg/mmol (IQR: 4.9–18.7) (HU) and 10.5 mg/mmol (IQR: 5.3-16.8) (placebo). At Month 6, compared to baseline, the median ACR decreased by 1.2 mg/mmol in the HU group (a 21.0% reduction) and by 1.1 mg/mmol in the placebo group (a 14.4% reduction). The primary endpoint —a ≥30% reduction in UACR at 6 months—was achieved by 39.1% of patients in the HU group and 37.5% in the placebo group (not statistically significant). However, a ≥20% reduction in UACR was significantly more frequent with HU than with placebo (46% vs 25%, p=0.03). At 12 months, the median UACR decreased in both groups, 2.5 mg/mmol (IQR 0.7-4.5) in the HU group and 3.1 mg/mmol (IQR 3.0-8.6) in the placebo group. Additionally, 26% of HU-treated patients achieved a ≥30% reduction in UACR (vs 10% with placebo, p=0.07), and 34.7% achieved a ≥20% reduction (vs 15% with placebo, p=0.04). Median eGFR increased by 4.3 mL/min/1.73m² in the HU group (from 115.7 to 123.5) at M6 and remained stable in the placebo group (124.4 to 125.1). Among responders at M12, eGFR was 116.5 mL/min/1.73m² (HU) versus 123.6 (placebo). Hematologic parameters improved as expected in the HU group : median HbF increased by 9.8% at M6 (vs +0.1% in placebo) and by 11.0% at M12 (vs +1.6% in placebo). Median hemoglobin increased by 11 g/L at M6 (HU) and by 14 g/L at M12 (HU), vs decreases or minimal change in placebo (-2 at M6 and +0.5 g/L at M12). Markers of hemolysis declined accordingly. All serious treatment emergent adverse events (TEAEs) were related to the underlying disease. Five HU and seven placebo patients experienced serious TEAEs. No unexpected safety signals were reported. Conclusion This first randomized, placebo-controlled trial targeting albuminuria in SCD showed that HU led to a ≥30% reduction in nearly 40% of patients at 6 months, consistent with prior data. The high placebo response at 6 months likely reflects regression to the mean and was not sustained at 12 months, where HU's benefit persisted. Notably, imputing patients as non-responders if they did not respond by 6 months—even if they might have between 6 and 12 months—introduces a bias that likely underestimates HU's true effect. These results highlight the potential of HU to improve renal outcomes in SCD.

Background:Membranous nephropathy is a renal autoimmune disease associated with autoantibodies against phospholipase A2 receptor (PLA2R1) in 50-80% of cases. Patients develop immunity towards a single or multiple PLA2R1 domains, defining a cascade immunization or epitope spreading associated with worse prognosis and low rate of spontaneous remission. We aimed to compare the efficacy of standard versus personalized treatment (based on biomarker: epitope spreading) with the immunosuppressor rituximab on remission rate at month-12. Methods:A randomized, prospective clinical trial (NCT03804359) was conducted in 12 French hospitals. Enrollment between November 2019 and October 2022. Follow-up lasted two years after inclusion and ended in October 2024. Sixty-four patients with PLA2R1-associated membranous nephropathy were randomly assigned (1:1) to the GEMRITUX protocol (symptomatic treatment for six months followed by two 375 mg/m2 rituximab infusions at month-6 in case of persistent nephrotic syndrome) or to the personalized protocol (patients without epitope spreading at month-0/month-6 followed the GEMRITUX protocol, while patients with epitope spreading at month-0/month-6 were treated immediately with two 1 g rituximab infusions). The primary outcome was the combined endpoint of partial or complete clinical remission at month-12. Findings:Thirty-one patients (48%) were randomized to the GEMRITUX arm and 33 (52%) to the personalized arm. In the GEMRITUX arm, four patients were treated with NIAT only since they entered into spontaneous remission at month-6, while 24 patients received low dose rituximab at month-6. In the personalized arm stratified according to their epitope spreading status, non-spreaders (n = 16) received NIAT for six months, while spreaders (n = 17) were immediately treated with high-dose rituximab. At month-12, the clinical remission rate was higher in the personalized group (67% versus 35%, p = 0.01), associated with improved kidney function (p = 0.0498 for estimated glomerular filtration rate). There was no difference in the rate of spontaneous remission nor in the number of adverse events between both groups suggesting that patients in the personalized arm were not over-treated. Interpretation:Personalized treatment protocol based on PLA2R1 epitope spreading status is superior to the standard GEMRITUX protocol in achieving clinical remission at month-12 by stratifying the patients according to the immunological severity of the disease and by immediately treating the patients at risk of treatment failure with rituximab. Funding:DGOS, PHRC National 2017.

Introduction: The diagnosis of thrombotic microangiopathy (TMA) relies on common biological parameters, the diagnostic value of which are unknown. Methods: The presence of common biological parameters was assessed in 967 patients with TMA from 2009 to 2023 (ClinicalTrials.gov: NCT05991245). Results: The median age was 49 (36–64) years and 53.2% were male. All TMA causes were represented (atypical hemolytic uremic syndrome [aHUS]: 41.6%, drugs: 24.9%, malignancy: 21.4%, autoimmune disease: 18.8%, infection: 7.6%, complement-mediated HUS: 6.8%, organ transplantation: 5.8%, pregnancy: 3.8%, bone marrow transplantation [BMT]: 2.9%, Shiga toxin Escherichia coli hemolytic uremic syndrome [STEC-HUS]: 0.6%, and thrombotic thrombocytopenic purpura [TTP]: 0.6%). The presence of TMA-related parameters concerned virtually all patients with TTP but varied widely for the other patients as follows: anemia: 81.7%, high lactate dehydrogenase (LDH) (75.4%), low haptoglobin (53.7%), and thrombocytopenia (40.3%). Their diagnostic performance was accurate only for TTP. Eleven distinct ways were used for schistocyte metrics and reporting. Relying on schistocyte presence as the single diagnostic criterion would lead to missed diagnosis in 23.8% (STEC-HUS) to 86.4% (BMT) of patients (for anemia: 8.2%–22.3%; thrombocytopenia: 31.8%–67.9%; high LDH: 10.0%–40.7%, low haptoglobin: 0%–70.4%, according to the causes of TMA). The overall risk of missed diagnosis using these parameters was ≥ 50% in all TMA, except in TTP. The best diagnostic performances were obtained when fibrinogen levels were < 5 g/l, creatinine ≥ 300 μmol/l, prothrombin time (PT) < 90%; and when TMA causes were TTP, STEC-HUS, infection, or complement-mediated HUS. Conclusion: Common biological parameters miss the diagnosis in more than 50% of TMA except when fibrinogen is < 5 g/l, creatinine ≥ 300 μmol/l, and PT < 90%. Schistocyte reporting is heterogenous, and its results are usually deceptive in TMA.

Background Despite recent progress, the prognosis of patients with transthyretin (TTR) cardiac amyloidosis remains poor; this is primarily due to late diagnosis, when irreversible damage has already occurred. Today’s diagnostic work-up still relies on peripheral tissue or a cardiac biopsy, while circulating levels of TTR or other plasma markers have little diagnostic value. Although extracellular vesicles (EVs, as key mediators of intercellular communication) may reflect disease-specific molecular changes, their protein cargo has not yet been explored in the context of TTR amyloidosis (ATTR) cardiomyopathy. Objectives To characterize the plasma EV proteome in ATTR cardiomyopathy and identify potential biomarkers for pathophysiological pathways, diagnosis, or prognosis. Methods We performed mass-spectrometry-based, label-free, proteomic profiling of plasma EVs from 65 patients with hypertrophic cardiomyopathy due to TTR amyloidosis (the ATTR+ group, n=41) or non-amyloid cardiac disease (the ATTR- group, n=24). The groups were matched by age and sex. Results A distinct protein signature comprising 117 deregulated proteins was identified in EVs from ATTR+ patients. The ATTR+ EVs were enriched in proteins associated with vascular homeostasis, coagulation, and inflammation. At least 18 of these proteins formed an interconnected network centered on plasmin/plasminogen. Notably, EV levels of TTR and plasminogen levels were elevated, while the level of alpha2-antiplasmin (plasmin’s primary inhibitor) was low. This imbalance is particularly relevant because plasmin is known to promote amyloidogenesis via TTR cleavage. Conclusions Our findings provide new insights into the molecular mechanisms underlying ATTR cardiomyopathy and suggest that plasma EV proteins are potential diagnostic or prognostic biomarkers and/or therapeutic targets. CONDENSED ABSTRACT TTR amyloidosis (ATTR) causes severe cardiac damage, which is often diagnosed late. Through a comparative proteomic analysis of plasma extracellular vesicles (EVs) in patients with ATTR cardiomyopathy vs. patients with other cardiomyopathies, we identified several proteins of relevance to the pathophysiology of ATTR. Our analysis is the first to have highlighted an enrichment of plasmin/plasminogen (known to initiate the amyloidogenic process) and TTR in circulating EVs. Our results might foster the development of (i) diagnostic and prognostic markers for ATTR cardiomyopathy that do not require invasive procedures, and (ii) new therapeutic strategies. ![Figure][1] ETHICAL APPROVAL The present analysis was based on blood samples collected as part of a research project entitled "Study of the myocardial microenvironment and toxicity of amyloid proteins in patients with cardiac amyloidosis", which was approved by an institutional review board (CPP Sud- Méditerranée II, Marseille, France; approval references: 2021T2-12/2021-A00950-41 and 2022-A02416-37). ### Competing Interest Statement The authors have declared no competing interest. [1]: pending:yes

Introduction:Kidney involvement is underestimated in patients with hereditary transthyretin amyloidosis (ATTRv), and few data are available about the renal outcomes of patients treated with targeted therapies. Methods:Patients with ATTRv nephropathy (ATTRv-N) from 6 French referral centers were retrospectively included. The evolution of estimated glomerular filtration rate (eGFR) and proteinuria, and the specific treatments of ATTRv were collected. Renal survival was assessed by using a renal composite end point, including an eGFR decline > 50% from baseline and/or dialysis requirement. Results:Twenty-three patients (70% female) with a median age at ATTRv-N diagnosis of 50 (interquartile range [IQR]: 37-63) years were included. Baseline eGFR was 60 (39-83) ml/min per 1.73 m2. Median urine protein-to-creatinine ratio (UPCR) was 100 (IQR: 20-240) mg/mmol. ATTRv-N was documented by kidney biopsy in 20 of 23 patients (87%). Eleven patients were treated with the transthyretin (TTR) stabilizer, tafamidis; 6 patients with a small interfering RNA (siRNA); 4 with exclusive orthotopic liver transplantation (OLT); whereas 2 received no specific treatment. After a median follow-up of 5.8 (IQR: 3.3-18.6) years, all patients with OLT or no treatment had a progressive eGFR decline, requiring dialysis in 3 of 6 patients. Among patients treated with tafamidis, 8 of 11 (73%) had a progressive eGFR decline, requiring dialysis in 1 patient; and proteinuria was either stable or increasing over time in all patients. All patients who received siRNA therapy had stable or improving eGFR. Renal survival was 44%, 44%, and 100% at 60 months for the patients with exclusive OLT or no treatment, TTR stabilizers, and siRNA, respectively (P = 0.12). Four patients with baseline nephrotic syndrome or high-grade proteinuria, including 3 patients resistant to tafamidis, responded dramatically to siRNA therapy, with a fast, complete, and sustained remission of proteinuria within 1 year. Conclusion:Our study highlights the underrecognized risk of chronic kidney disease (CKD) and end-stage kidney disease in ATTRv and suggests that siRNA could be a promising therapeutic option for the stabilization of kidney function.