ABSTRACT:Congenital thrombotic thrombocytopenic purpura (cTTP) is caused by a severe inherited ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) deficiency. Although acute episodes are life-threatening, long-term burden of ischemic complications, and effectiveness of prophylactic strategies remain underexplored. We conducted a 25-year national, multicenter study of 88 patients with cTTP enrolled in the French Thrombotic Microangiopathy registry. Patients were stratified by age and clinical context at disease onset: pediatric (n = 42), pregnancy (n = 33), and adult onset (n = 13). Clinical features, genotypes, treatment regimens, and long-term ischemic outcomes were analyzed. Pediatric patients exhibited early-onset disease (median age at diagnosis, 2 years [interquartile range, 0-13]) with recurrent episodes and a high burden of neurological complications. In patients with pregnancy-onset disease, no relapses were observed outside pregnancy. Adult-onset patients, typically diagnosed aged >50 years, showed prevalent cardiovascular disease, stroke, and kidney injury. Mental health disorders were common across all groups. Despite long-term plasma prophylaxis, organ dysfunction persisted, particularly in pediatric- and adult-onset groups. In pregnancy-onset cTTP, tailored midterm prophylaxis during pregnancy reduced maternal and fetal complications. Thirty-nine patients received recombinant human ADAMTS13 (rhADAMTS13) prophylaxis (median follow-up, 5 months [interquartile range, 6-17]). Prophylactic treatment significantly improved relapse-free survival, with a comparable outcome using intensive plasma-derived products and rhADAMTS13 in pediatric-onset cases, although adverse events were more prevalent using plasma therapy. Our findings highlight the clinical and genetic heterogeneity of cTTP and the burden of organ dysfunction. Intensive prophylaxis improves relapse-free survival. rhADAMTS13 represents a safe and promising first-line option that should help reduce long-term organ damage and improve quality of life.

Chronic kidney disease (CKD) is a complex and progressive condition ultimately leading to premature death. Diabetes is the leading cause of end-stage kidney disease worldwide. Up till 2024, international clinical guidelines have established three therapeutic pillars to delay CKD progression in people with type 2 diabetes (T2D): renin-angiotensin system inhibitors, sodium-glucose cotransporter 2 inhibitors, and the non-steroidal mineralocorticoid receptor antagonist finerenone. With the recent results from the Evaluate Renal Function with Semaglutide Once Weekly study, the glucagon-like peptide-l receptor agonist (GLP-1 RA) class is now considered a new therapeutic pillar in reducing CKD complications in this patient population. In this expert opinion, we identify patient populations at risk of developing new onset or worsening pre-existing CKD to explore optimal therapeutic strategies, introducing GLP-1 RAs. We highlight the important challenges that remain in optimising, sequencing, and combining these four therapeutic pillars. Even though the conventional approach of combining the pillars has been based on the historical emergence of evidence, we discuss the factors that would influence physicians' decision for preferring one pillar over another, and for selecting a certain combination, whether performed simultaneously or sequentially. These factors include the grade of CKD and the level of albuminuria; diabetic control (glycaemia); comorbidities: atherosclerotic cardiovascular disease, heart failure, obesity; concomitant medications; biological variables: potassium serum levels. The efficacy and safety profiles of each pillar, as demonstrated in landmark trials that have clearly shown the nephroprotective effects, along with real-world data, should also be carefully considered when selecting the most appropriate therapeutic option.

BACKGROUND:Emerging evidence suggests that uremic toxins (UTs) may exacerbate organ dysfunction in septic-shock-associated AKI. However, the dynamic changes in serum concentrations of these solutes and their specific prognostic implications remain largely unexplored. METHODS:This prospective study enrolled 114 patients with septic shock and AKI, alongside 15 non-AKI septic shock controls. We measured serum levels of seven UTs (indoxyl sulfate, indole-3-acetic acid, para-cresyl sulfate, para-cresyl glucuronide, hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), and trimethylamine N-oxide ) daily from Day 0 to Day 6. We analysed toxin kinetics and their relationship with 28-day mortality and the time to successful liberation from vasopressor and invasive mechanical ventilation, using joint modelling for longitudinal and survival data. RESULTS:Upon inclusion, 30% of patients had Stage 1, 30% Stage 2, and 40% Stage 3 AKI. Except for CMPF, all toxins accumulated significantly compared to controls and remained significantly higher in severe AKI throughout the observation period (p<0.001). Indoxyl sulfate showed the strongest longitudinal correlations with serum creatinine (r=0.67, p<0.001). Daily kidney replacement therapy (KRT) status was associated with lower levels of most UTs, with the notable exceptions of indoxyl sulfate (unaffected) and hippuric acid (positively associated). Forty-four patients (39%) died within 28 days. After adjusting for baseline SAPS II and nonrenal SOFA scores, UT trajectories were not significantly associated with 28-day mortality or the time to successful liberation from organ support. CONCLUSIONS:Changes in serum UT concentrations correlated with the severity and trajectory of AKI during septic shock, and exhibited variable clearance during KRT, but were not independently associated with 28-day mortality or organ support dependence.

BACKGROUND AND HYPOTHESIS:The standard approach to anaemia in non-dialysis chronic kidney disease (CKD) does not account for potential age- or sex-specific related risks. We assessed differences in the association between haemoglobin and major cardiovascular events (MACE+) in men and women with CKD, by age groups. METHODS:Using 5-year longitudinal data from the Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort, we studied patients with CKD stage 2-5 not treated with erythropoiesis-stimulating agents (ESA). The main outcome was MACE+, defined as cardiovascular death, myocardial infarction, stroke or hospitalization for acute heart failure. Competing events were initiation of kidney replacement therapy and non-cardiovascular death. In each of the four predefined subgroups by sex and age (≤70 versus >70 years at baseline), we estimated hazard ratios (HR) of current values of haemoglobin using a cause-specific Cox model adjusted for current values of glomerular filtration rate and transferrin saturation. All current values of biomarkers were first estimated in a multivariate-shared random effect joint model. RESULTS:Analyses considered 29 042 haemoglobin measurements from 2791 patients, and 364 MACE+. The association between current haemoglobin and log hazard of MACE+ was linear in men and J-shaped in women. For a haemoglobin of 10.5 g/dL, as compared with 11.5 g/dL, the hazard of MACE+ at any time was increased by 60% in younger women [HR = 1.6, 95% confidence interval (CI) 1.1-2.4], 70% in older women (HR = 1.7, 95% CI 1.3-2.4), 30% in younger men (HR = 1.3 95% CI 1.1-1.5) and 20% in older men (HR = 1.2 95% CI 1.1-1.4). Results were similar in the sensitivity analysis not censoring at the first ESA treatment. CONCLUSION:Our longitudinal analysis in patients with CKD not on ESA therapy highlights a stronger association between anaemia and increased hazard of MACE+ in women than in men. This sex difference should inform the design of trials addressing anaemia correction in CKD.

Background: Emerging evidence suggests that uremic toxins (UTs) may exacerbate organ dysfunction in septic-shock-associated AKI. However, the dynamic changes in serum concentrations of these solutes and their specific prognostic implications remain largely unexplored. Methods: This prospective study enrolled 114 patients with septic shock and AKI, alongside 15 non-AKI septic shock controls. We measured serum levels of seven UTs (indoxyl sulfate, indole-3-acetic acid, para-cresyl sulfate, para-cresyl glucuronide, hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), and trimethylamine N-oxide ) daily from Day 0 to Day 6. We analysed toxin kinetics and their relationship with 28-day mortality and the time to successful liberation from vasopressor and invasive mechanical ventilation, using joint modelling for longitudinal and survival data. Results: Upon inclusion, 30% of patients had Stage 1, 30% Stage 2, and 40% Stage 3 AKI. Except for CMPF, all toxins accumulated significantly compared to controls and remained significantly higher in severe AKI throughout the observation period (p<0.001). Indoxyl sulfate showed the strongest longitudinal correlations with serum creatinine ( r =0.67, p<0.001). Daily kidney replacement therapy (KRT) status was associated with lower levels of most UTs, with the notable exceptions of indoxyl sulfate (unaffected) and hippuric acid (positively associated). Forty-four patients (39%) died within 28 days. After adjusting for baseline SAPS II and nonrenal SOFA scores, UT trajectories were not significantly associated with 28-day mortality or the time to successful liberation from organ support. Conclusions: Changes in serum UT concentrations correlated with the severity and trajectory of AKI during septic shock, and exhibited variable clearance during KRT, but were not independently associated with 28-day mortality or organ support dependence.

Background:Real-world practices for managing anemia and iron deficiency in chronic kidney disease appear heterogeneous and sometimes controversial. This study aimed to describe the prescribing preferences and habits of French nephrologists in this area. Methods:All nephrologists seeing patients at one of the 40 centers participating in the Chronic Kidney Disease – Renal Epidemiology and Information Network (CKD-REIN) cohort were invited to participate in two waves (2015–2016 and 2019–2020) of a practice survey. The self-administered questionnaires collected information on nephrologists’ characteristics and their management strategies for anemia and iron deficiency in patients with stage 4–5 CKD. Results:A total of 137 nephrologists participated in the first wave and 60 in the second wave. Most reported initiating treatment with erythropoiesis-stimulating agents (ESAs) when hemoglobin levels were between 9.5 and 10.5 g/dL (85% in the first wave and 96% in the second). In patients with anemia and iron deficiency, the thresholds for initiating iron therapy varied widely: for oral iron, transferrin saturation (TSAT) ranged from 10% to more than 35% and ferritin from 50 to 500 μg/L; for intravenous iron, TSAT ranged from 10 to 30% and ferritin from 50 to 500 μg/L. Conclusion:Between 2015–2016 and 2019–2020, French nephrologists’ practices for ESA management were relatively homogeneous and in line with current recommendations. In contrast, approaches to iron deficiency varied greatly among practitioners.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is caused by a severe, antibody-mediated deficiency of ADAMTS13 activity. The B-cell depleting agent rituximab is effective in restoring ADAMTS13 activity and therefore preventing relapses. However, the risk of relapse appears heterogeneous among patients, although the underlying causes are elusive. Preliminary reports suggested that African ancestry could be associated with decreased relapse-free survival (RFS). Data from the registry of the French National Thrombotic Microangiopathy Reference Center were used to further address the role of ethnicity on response and RFS after rituximab administration in the acute as well as in the preemptive setting. A total of 790 patients (134 patients of African ancestry and 656 patients of European ancestry) were included in the study. Time from rituximab administration to ADAMTS13 recovery was comparable between the two cohorts. Patients of African ancestry had inferior 3-year RFS after the first rituximab-treated episode compared to patients of European ancestry (P<0.05). In multivariate analyses, African ancestry was identified as an independent risk factor for relapse (hazard ratio [HR]=1.36; P<0.05), as well as male sex (HR=1.21; P<0.05) and type of index episode treated by rituximab (relapsed disease vs. initial episode, HR=1.62; P<0.05). Moreover, time to relapse shortened progressively after consecutive courses of rituximab, regardless of ethnicity (P<0.05). These results indicate that ethnicity affects RFS with patients of African ancestry relapsing earlier, suggesting that a closer ADAMTS13 monitoring might be necessary in high-risk patients.

Anemia and iron deficiency (ID) are common and significant complications in kidney transplant recipients (KTRs) that can affect their health-related quality of life (HRQoL) and outcomes. Current anemia guidelines equate the post-transplant situation with the anemia associated with chronic kidney disease (CKD) in non-transplanted persons, not acknowledging relevant differences ranging from pathophysiology to clinical manifestation. Nephrologists caring for these patients tend to pay less attention to post-transplant anemia (PTA) and ID than in non-transplanted persons with CKD. In this narrative review we summarize the available evidence about PTA and ID and their specifics in KTRs, including associations with patient and graft survival and poorer HRQoL. The prevalence of anemia is higher in KTRs than in non-transplanted patients with CKD for a given level of glomerular filtration rate (GFR) due to kidney transplant (KT)-specific pathophysiological factors. ID should be detected and corrected in KTRs using oral or intravenous (IV) iron. Some IV iron formulations are associated with an increased risk of hypophosphatemia a typical complication in KTRs. Current guidelines suggest the same hemoglobin targets for erythropoiesis stimulating agent therapy in transplanted and non-transplanted patients, despite the fact that a higher hemoglobin target has been associated with a slower estimated GFR decline in KT. There are insufficient data to recommend the widespread use of hypoxia-inducible factor-prolyl-hydroxylase inhibitors in PTA. Red blood cell transfusions should be avoided to minimize alosensitization. We call for increased awareness and targeted trials on anemia and ID in KTRs, accounting for the diverse and specific profiles of these patients.

Kidney function was independently associated with free drug concentration; the latter concentration was higher in patients with a lower eGFR. The conformational changes in albumin induced by carbamylation may alter its binding capacity to vitamin K antagonists. The results on the accumulation of free fraction of drugs in patients with low eGFR may be applicable to other drugs that are bound to plasma proteins. The metabolic disturbances associated with CKD might alter drug distribution, decrease albumin drug binding, and thus increase the free (unbound) drug concentrations. Uremic toxins (UTs) can affect the pharmacokinetic or pharmacodynamic activity of certain drugs. Vitamin K antagonists (VKAs) are interesting candidates for the evaluation of potential interactions between UTs and drugs. The primary objective of this study was to investigate the association between free VKA concentrations and the eGFR. Furthermore, we sought to determine whether this relationship was mediated by protein carbamylation (measured by homocitrulline levels) and/or the accumulation of protein-bound UTs (PBUTs). In this prospective cross-sectional study, 389 adult patients treated with VKA were included between May 2021 and June 2023. Levels of free VKAs, total VKAs, homocitrulline, and PBUTs were assayed using liquid chromatography-tandem mass spectrometry. We used a linear regression model to explore the association between kidney function and free VKA levels and mediation analyses to determine whether the association between kidney function and free VKA levels was mediated (at least partly) by PBUTs and/or protein carbamylation. Patients with an eGFR <40 ml/min per 1.73 m 2 or those on chronic hemodialysis had lower total VKA levels, higher free VKA levels, and thus a higher of free/total VKA ratio than those with an eGFR ≥40 ml/min per 1.73 m 2 . Kidney function was independently associated with free VKA levels ( β 1 =0.31 [0.19 to 0.42], P < 0.001). Twenty-one percent (95% confidence interval, 1% to 35%) of the association between kidney function and free VKA levels was mediated by homocitrulline, but not by PBUTs. Our results showed that a low kidney function was associated with an elevation in the VKA free drug fraction. This association was independent of blood albumin levels and appeared to be partly mediated by protein carbamylation.

BACKGROUND:Vacuolar myopathy is a muscle disease characterized by inefficient autophagy and the accumulation of intracytoplasmic degradation products in autophagic vacuoles. Acquired vacuolar myopathy associated with monoclonal gammopathy is a novel clinical entity first described in 2019. The objective of the present article is to describe the first case of an acquired vacuolar myopathy associated with lambda light chain myeloma. CASE PRESENTATION:A 52-year-old man was admitted to our nephrology department for acute kidney injury and was diagnosed with lambda light chain multiple myeloma. The patient presented with supraventricular arrythmia and developed rapidly progressing muscle weakness of the face and all four limbs, with a myogenic electromyographic pattern. A muscle biopsy highlighted muscle fibre vacuoles and lambda light chain deposits. Cardiac magnetic resonance imaging revealed concentric hypertrophy and subepicardial areas of fibrosis that were suggestive of an infiltrative disease. There were no signs of amyloidosis. Treatment with a combination of bortezomib, lenalidomide and dexamethasone gave a good hematologic response, and the patient recovered near-normal levels of muscle strength in the following six months. The number of episodes of arrythmia decreased. CONCLUSION:Clinicians should be aware that lambda light chain myeloma may cause lambda light-chain deposits within muscle fibres and vacuolar myopathy. A corticosteroid-sparing strategy for vacuolar myopathy does not appear to be necessary when the course of the myeloma is favourable. Myopathy associated with monoclonal gammopathy is an emerging entity. Given that monoclonal gammopathy is very common in older adults, the appearance of muscle impairments in this context could prompt the physician to consider the initiation of corticosteroids, immunosuppressive agents, or intravenous immunoglobulins. Electromyography and muscle biopsy results can guide the diagnosis.

Chronic kidney disease (CKD) is associated with cardiovascular (CV) disorders, including CV calcifications that contribute to the development of cardiac dysfunction. This study aimed to assess functional cardiovascular impairments due to CKD-related CV calcifications over time using cardiac echography. CKD associated with cardiovascular calcifications was induced in a rat model using a diet enriched with adenine and phosphate. Twelve male Sprague-Dawley rats (8 weeks old) were divided into two groups: the control group (CT) and the adenine-phosphate (AP) group, which received a diet enriched with 0.3% adenine and 1.2% phosphate for 9 weeks. Cardiac echography was performed at baseline, week 5, and week 9 before euthanasia, followed by histological analysis of the heart and aorta. AP rats exhibited progressive kidney function impairment, elevated serum phosphorus levels, and CV calcifications. Echographic imaging revealed a progressive decline in cardiac output in AP rats compared to CT rats (Week 0: 87.3 [81.3–95.2] vs. 68.0 [63.8–84.3] mL/min, P = 0.43; Week 5: 38.8 [31.2–40.4] vs. 79.2 [57.5–94.4] mL/min, P = 0.01; Week 9: 33.9 [30.1–35.9] vs. 78.2 [62.4–94.8] mL/min, P = 0.029). No differences were observed in contractility parameters. However, by week 5, isovolumetric relaxation time was significantly prolonged in AP rats (31.5 [27.1–32.7] vs. 24.9 [24.6–25.1] ms, P = 0.009) compared to CT rats, suggesting diastolic dysfunction. This dysfunction occurred without left ventricular hypertrophy. Linear regression analysis revealed a relationship between systolic aortic expansion and kidney function (P = 0.002) as well as the phosphocalcic product (P < 0.001), suggesting aortic stiffness resulting from kidney function impairment and CV calcifications. Our CKD rat model was associated with cardiovascular calcifications, aortic stiffness and exhibited diastolic dysfunction over time. Further studies are needed to confirm these findings and elucidate the underlying mechanisms.

Background The serum calcification propensity test (or T50 test) might become a standard tool for the assessment of vascular calcification risk and T50 might be a valuable biomarker in clinical trials of treatments intended to slow the progression of vascular calcification. Literature data suggest that non-calcium-containing phosphate binders can influence T50 in chronic dialysed patients. However, it is not clear whether similar interventions are effective in patients at earlier stages of chronic kidney disease (CKD).Methods The FGF23 Reduction: Efficacy of a New phosphate binder in CHronic kidney disease (FRENCH) trial was a multicentre, double-blind, placebo-controlled, randomized trial of sevelamer carbonate in participants with stage 3b/4 CKD. In this subanalysis of the FRENCH data, T50 and other laboratory variables (including fetuin-A and ionized and total magnesium) were measured centrally at baseline and after 12 weeks of treatment.Results A total of 96 patients were screened and 78 (55 men and 23 women) met the inclusion criteria and were randomized to receive placebo (n = 39) or sevelamer carbonate (n = 39). The median patient age was 66 years [interquartile range (IQR) 56-72], the median eGFR was 25 ml/min/1.73 m2 (IQR 21-30) and the mean T50 was 335 minutes (standard deviation 82). In a linear regression model, T50 was independently associated with serum ionized magnesium, fetuin-A and bicarbonate levels and inversely associated with phosphate concentration. The within-group changes in the mean T50 between week 0 and week 12 were not significant in the sevelamer group or the placebo group {4.6 minutes [95% confidence interval (CI) -13.6-22.8; P = .61] and 7.8 minutes [95% CI -16.4-32.1; P = .51], respectively}. Furthermore, we did not observe significant changes in fetuin-A and magnesium levels.Conclusion A 12-week course of the non-calcium-containing phosphate binder sevelamer carbonate was not associated with a significant change in T50 in patients with stage 3b/4 CKD. Phosphate binders might not be an effective strategy for modifying serum calcification propensity in non-dialysis-dependent patients with CKD.

Background/Objectives: Inflammation may contribute to hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) and is often present in patients with chronic kidney disease (CKD). Roxadustat is approved in multiple countries for the treatment of anemia of CKD. This pooled analysis evaluated the efficacy and safety of roxadustat in patients with dialysis-dependent (DD) or non-dialysis-dependent (NDD) CKD by inflammation status. Methods: Data from five studies comparing roxadustat versus ESAs were pooled by patient populations in this analysis (NDD: DOLOMITES; DD: ROCKIES, SIERRAS, HIMALAYAS, PYRENEES). The mean change from baseline in hemoglobin levels to Weeks 28-52 and mean weekly dose of roxadustat or ESA at Week 24 were assessed by baseline inflammation levels (determined by high-sensitivity C-reactive protein [hsCRP] levels, divided into quintiles). Safety data were summarized descriptively. Results: In total, 613 patients with NDD CKD (roxadustat n = 320; ESA n = 293) and 4072 patients with DD CKD (roxadustat n = 2022; ESA n = 2050) were evaluated. Roxadustat increased hemoglobin levels in a manner similar to ESAs, independent of baseline inflammation status. In both the NDD and DD populations, roxadustat doses did not increase at Week 24 in patients with higher hsCRP levels at baseline. Patients with high baseline hsCRP levels required greater ESA doses at Week 24 compared with patients who had lower baseline hsCRP levels in both patient populations. The incidence rates of treatment-emergent adverse events were generally comparable with those of roxadustat and ESA across hsCRP quintiles in both the NDD and DD populations. Conclusions: Roxadustat addresses the multiple causes of anemia of CKD, regardless of inflammatory status, without requiring dose increases.

Chronic kidney disease represents an immunocompromising condition and a cause of a lower vaccine efficacy, even in patients undergoing maintenance dialysis. Recent SARS-CoV-2 outbreaks have prompted clinicians to better understand the underlying mechanisms and establish more suitable vaccination schedules. In a single-center, retrospective, observational study of patients undergoing maintenance dialysis in France, we studied the factors associated with the intensity of the humoral response to a SARS-CoV-2 vaccine in this population, including specific dialysis-related variables. After having received three doses of SARS-CoV-2 mRNA vaccine, a cohort of 80 patients was divided into low-responders (28 patients with an anti-SARS-CoV-2 antibody level of 50-1830 AU/mL) and responders (52 patients with an antibody level > 1830 AU/mL). We found that chronic heart failure (p < 0.00001), higher performance status (p = 0.004), hypoalbuminemia (p < 0.001), lymphopenia (p = 0.003), Rhesus status positivity (p = 0.02), and absence of response to a hepatitis B virus vaccine (p = 0.02) were associated with a poor response to a third dose of SARS-CoV-2 vaccine. In contrast, none of the dialysis-related variables were associated with the vaccine response. In multivariate logistic regression, chronic heart failure (p < 0.0001) and hypoalbuminemia (p = 0.0004) remained associated with a lower humoral response to SARS-CoV-2 vaccine. Our results showed that chronic heart failure and hypoalbuminemia were factors associated with a poor humoral response after three doses of SARS-CoV-2 vaccine. However, we found no association between specific dialysis-related variables and the anti-SARS-CoV-2 antibody titer.