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Background and Hypothesis: Unlike X-linked or autosomal recessive Alport Syndrome, no clear genotype/phenotype correlation has yet been demonstrated in patients carrying a single variant of COL4A3 or COL4A4., Methods: We carried out a multicenter retrospective study to assess the risk factors involved in renal survival in patients presenting a single pathogenic variant on COL4A3 or COL4A4., Results: 97 patients presenting a single pathogenic variant of COL4A3 or COL4A4 were included. The prevalence of end-stage kidney disease (ESKD) during follow-up was 28.7% (median age 47.5 years [IQR, 39.1-55.8]). 23 patients carried a 'severe' mutation (frameshift, stop gain, extensive deletion, impacting splicing), and 60 patients presented a glycine substitution in a collagenous domain. In patients with glycine missense variants, the location of the mutation in the distal exons was associated with worse renal survival with a more pronounced decline in eGFR compared to variants in proximal exons. Conversely, the presence of a severe mutation did not impact renal survival., Conclusion: Our results confirm that ADAS can lead to ESKD. We demonstrated that a glycine substitution involving the distal exons had a negative impact on renal survival in ADAS patients, probably due to a trimerization defect. This could help improve personalized follow-up in ADAS patients with glycine substitution and could be integrated to a future prognostic score to accurately predict renal outcomes., (© The Author(s) 2025. Published by Oxford University Press on behalf of the ERA.)

Background: Alport Syndromes (AS) are the second leading genetic cause of Kidney Failure (KF). Whether multiple kidney cysts (MKC) phenotype belongs to the AS spectrum remains debated., Methods: This multicenter retrospective study focused on patients genotyped with pathogenic COL4A3, COL4A4, or COL4A5 variants (classified as ACMG-AMP 4 or 5) between January 2011 and January 2023 across four French university hospitals. The study aimed to compare characteristics between two groups based on the presence or absence of MKC, defined by three or more cysts per kidney. The MKC group was compared to a control group with negative exome sequencing results for undetermined kidney disease (ES-UKD) to assess the association between MKC and AS., Results: Among the 257 AS patients included, 38 (14.8%) presented MKC without variation from hereditary cystic kidney panel. MKC showed a significant association with male gender (p=0.004), cardiovascular risk factors, and loss of function variants (p=0.012). KF onset appeared significantly later, by 6 years, in MKC patients (p=0.035). Comparison with ES-UKD (n=990) control group showed no significant association between AS and MKC by univariate and multivariate analysis. Multivariate analysis identified patient age and male gender (p<0.001) as factors linked to MKC., Conclusions: A 14.8% prevalence of MKC was found in our cohort of 257 patients with AS. MKC-AS patients exhibited clinical and histological characteristic akin to nephroangiosclerosis. Our comprehensive analysis, incorporating a sizable ES-UKD cohort, revealed no significant association between MKC and AS, thus questioning the inclusion of MKC within the spectrum of AS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Given the risk of rejection, the presence of preformed donor specific antibodies (DSA) contraindicates transplantation in most allocation systems. However, HLA-Cw and -DP DSA escape this censorship. We performed a multicentric observational study, in which the objective was to determinate risk factors of acute antibody-mediated rejection (aABMR) in recipients transplanted with preformed isolated Cw- or DP-DSA. Between 2010 and 2019, 183 patients were transplanted with a preformed isolated Cw- or DP-DSA (92 Cw-DSA; 91 DP-DSA). At 2 years, the incidence of aABMR was 12% in the Cw-DSA group, versus 28% in the DP-DSA group. Using multivariable Cox regression model, the presence of a preformed DP-DSA was associated with an increased risk of aABMR (HR = 2.32 [1.21-4.45 ( p = 0.001)]) compared with Cw-DSA. We also observed a significant association between the DSA's MFI on the day of transplant and the risk of aABMR (HR = 1.09 [1.08-1.18], p = 0.032), whatever the DSA was. Interaction term analysis found an increased risk of aABMR in the DP-DSA group compared with Cw-DSA, but only for MFI below 3,000. These results may plead for taking these antibodies into account in the allocation algorithms, in the same way as other DSA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Laboux, Lenain, Visentin, Flahaut, Chamley, Provôt, Top, Kerleau, Labalette, Choukroun, Couzi, Blancho, Hazzan and Maanaoui.)

Introduction: Patients with immune-mediated glomerular diseases are considered at high risk for severe COVID-19 outcomes. However, conclusive evidence for this patient population is scarce., Methods: We created a global registry and retrospectively collected clinical data of patients with COVID-19 and a previously diagnosed immune-mediated glomerular disease to characterize specific risk factors for severe COVID-19 outcomes., Results: Fifty-nine patients with a history of immune-mediated glomerular diseases were diagnosed with COVID-19 between 01.03.2020 and 31.08.2021. Over a mean follow-up period of 24.79 ± 18.89 days, ten patients (16.9%) developed acute kidney injury. Overall, 44.1% of patients were managed in an outpatient setting and therefore considered as having "non-severe" COVID-19, while 55.9% of patients had severe COVID-19 requiring hospitalization including worse outcomes. Comparing both groups, patients with severe COVID-19 were significantly older (53.55 ± 17.91 versus 39.77 ± 14.95 years, p = .003), had lower serum albumin levels at presentation (3.00 ± 0.80 g/dL versus 3.99 ± 0.68 g/dL, p = .016) and had a higher risk of developing acute kidney injury (27% versus 4%, p = .018). Male sex (p <.001) and ongoing intake of corticosteroids at presentation (p = .047) were also significantly associated with severe COVID-19 outcomes, while the overall use of ongoing immunosuppressive agents and glomerular disease remission status showed no significant association with the severity of COVID-19 (p = .430 and p = .326, respectively)., Conclusion: Older age, male sex, ongoing intake of corticosteroids and lower serum albumin levels at presentation were identified as risk factors for severe COVID-19 outcomes in patients with a history of various immune-mediated glomerular diseases., Competing Interests: PG received consulting fees from CLS Vifor and lecture fees from Otsuka Pharma GmbH. AK received grants from CSL Vifor and Otsuka, consulting fees from CSL Vifor, Otsuka, Walden Biosciences and Catalyst Biosciences, honoraria for lectures from CSL Vifor and Otsuka and support for attending meetings from CSL Vifor and Otsuka. DG received consulting fees from ChemoCentryx, Amgen, Otsuka, Aurinia Inc and GSK. BO reports receiving fees or research grants from CSL Vifor, Otsuka and Delta4. FA received consulting fees and honoraria for lectures from AstraZeneca. AB received consulting fees and honoraria for lectures from AstraZeneca, Bayer, ChemoCentryx, Fresenius, Merck/MSD, and Vifor and received payment for expert testimony from The Swedish National Board of Health and Welfare and chaired the Immunonephrology Working Group of ERA unpaid. VA received supporting attending meetings from Sanofi Genzyme, and reports board participations for Alnylam, Addmedica, AstraZeneca, Bayer and ViforPharma. KJ received consulting fees from GlaxoSmithKline, George Clinical, PMV Pharmaceuticals and Caliditas and honoraria for lectures from ASN and uptodate.com. MW received honoraria for lectures from Otsuka and participated on advisory boards for Otsuka, Delta4 and CSL Vifor. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gauckler, Kesenheimer, Geetha, Odler, Eller, Laboux, Alberici, Zappa, Chebotareva, Moiseev, Bonilla, Jhaveri, Oniszczuk, Audard, Costa, Mastroianni-Kirsztajn, Bruchfeld, Muto, Windpessl, Mayer and Kronbichler.)

The complement system plays a key role in the pathophysiology of kidney thrombotic microangiopathies (TMA), as illustrated by atypical hemolytic uremic syndrome. But complement abnormalities are not the only drivers of TMA lesions. Among other potential pathophysiological actors, we hypothesized that alteration of heparan sulfate (HS) in the endothelial glycocalyx could be important. To evaluate this, we analyzed clinical and histological features of kidney biopsies from a monocentric, retrospective cohort of 72 patients with TMA, particularly for HS integrity and markers of local complement activation. The role of heme (a major product of hemolysis) as an HS-degrading agent in vitro, and the impact of altering endothelial cell (ECs) HS on their ability to locally activate complement were studied. Compared with a positive control, glomerular HS staining was lower in 57 (79%) patients with TMA, moderately reduced in 20 (28%), and strongly reduced in 37 (51%) of these 57 cases. Strongly reduced HS density was significantly associated with both hemolysis at the time of biopsy and local complement activation (C3 and/or C5b-9 deposits). Using primary endothelial cells (HUVECs, Glomerular ECs), we observed decreased HS expression after short-term exposure to heme, and that artificial HS degradation by exposure to heparinase was associated with local complement activation. Further, prolonged exposure to heme modulated expression of several key genes of glycocalyx metabolism involved in coagulation regulation (C5-EPI, HS6ST1, HS3ST1). Thus, our study highlights the impact of hemolysis on the integrity of endothelial HS, both in patients and in endothelial cell models. Hence, acute alteration of HS may be a mechanism of heme-induced complement activation., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Metabolic acidosis is a frequent complication of chronic kidney disease. Although it is known to appear at advanced stages, many studies suggest a state of "global protonic retention" starting at early stages of the disease, responsible of tissue damage, particularly musculoskeletal, alteration of protidic metabolism and endocrine disorders, promoting malnutrition and chronic inflammation, and finally increasing mortality. The majority of international recommandations suggest of supplementation by alkali, most of the time by sodium bicarbonate, to struggle against this complication. An interesting alternative to correct acidosis would consist on the modulation of the endogenous production of acid by playing with the alimentary incomes. In fact, it has been demonstrated that some different types of food produce or consume protons during their metabolism. Low protein diet and rich fresh fruits and vegetables diet would manage to correct at least as well as the supplementation by sodium bicarbonate the metabolic acidosis, and to struggle against its complications, noteworthy by slowing the decline of glomerular filtration rate by limiting the toxic adaptative fibrotic mechanisms, demonstrated by the decrease of urinary tubulo-interstitial suffering markers. Of the condition of being well led, those diets do not seem to expose patients to an over-risk of malnutrition or hyperkaliemia. They therefore appear to be an attractive alternative, efficiency and safe, to fight against chronic kidney disease metabolic acidosis and its complications., (Copyright © 2019. Published by Elsevier Masson SAS.)