ArticleJournal of hepatology2024
Inhibition of the renal apical sodium dependent bile acid transporter prevents cholemic nephropathy in mice with obstructive cholestasis.
Article in Journal of hepatology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 47 citations in OpenAlex.
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- Altered Bile Acid Transport in Liver Disease.Biomedicines · 2026Review
- Impact of Early Allograft Dysfunction on Renal Function Outcomes Following Liver Transplantation.Medicina (Kaunas, Lithuania) · 2026Article
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- Multimodal single-cell profiling reveals crosstalk between macrophages and stromal cells in poor prognostic cholangiocarcinoma patients.NPJ precision oncology · 2026Article
- Targeting gut-liver-kidney axis: microbiota-derived metabolites and therapeutic implications.Cell communication and signaling : CCS · 2026Review
- Multiorgan repair by MSC-derived extracellular vesicles in hepatorenal syndrome through necroptosis alleviation, immune reprogramming and fibrosis resolution.Extracellular vesicles and circulating nucleic acids · 2026Article
- Stage-dependent effects of systemic ASBT inhibition in a cholestasis-induced cholemic nephropathy mouse model.JHEP reports : innovation in hepatology · 2025Article
- Impact of gut microbiota in chronic kidney disease: natural polyphenols as beneficial regulators.Renal failure · 2025Review
- Kidney-organ interactions: recent advances and clinical implications.Current opinion in critical care · 2025Review
- Enteronephrohepatic circulation of bile acids and therapeutic potential of systemic bile acid transporter inhibitors.Journal of hepatology · 2025Review
- Benefits and challenges to therapeutic targeting of bile acid circulation in cholestatic liver disease.Hepatology (Baltimore, Md.) · 2025Review
- Linear ubiquitination prevents lipodystrophy and obesity-associated metabolic syndrome.Science advances · 2025Article
- Odevixibat treatment reverses severe phenotype of PFIC in a young adult: A real-life experience beyond the genetic diagnosis.JHEP reports : innovation in hepatology · 2025Article
- Fluorescent 4-Nitrobenzo-2-oxa-1,3-diazole-Coupled Bile Acids as Probe Substrates of Hepatic and Intestinal Bile Acid Transporters of the Solute Carrier Families SLC10 and SLCO.Journal of medicinal chemistry · 2025Article
- Cell-based approaches for the mechanistic understanding of drug-induced cholestatic liver injury.Archives of toxicology · 2025Review
- Kidney and vascular involvement in Alagille syndrome.Pediatric nephrology (Berlin, Germany) · 2025Review
- Exceptional Uptake, Limited Protein Expression: Liver Macrophages Lost in Translation of Synthetic mRNA.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
Corrections and comments
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Authors and funding
54 authors at 15 institutions in 7 countries.
Funding
Abstract
BACKGROUND &
aimsCholemic nephropathy (CN) is a severe complication of cholestatic liver diseases for which there is no specific treatment. We revisited its pathophysiology with the aim of identifying novel therapeutic strategies.
methodsCholestasis was induced by bile duct ligation (BDL) in mice. Bile flux in kidneys and livers was visualized by intravital imaging, supported by MALDI mass spectrometry imaging and liquid chromatography-tandem mass spectrometry. The effect of AS0369, a systemically bioavailable apical sodium-dependent bile acid transporter (ASBT) inhibitor, was evaluated by intravital imaging, RNA-sequencing, histological, blood, and urine analyses. Translational relevance was assessed in kidney biopsies from patients with CN, mice with a humanized bile acid (BA) spectrum, and via analysis of serum BAs and KIM-1 (kidney injury molecule 1) in patients with liver disease and hyperbilirubinemia.
resultsProximal tubular epithelial cells (TECs) reabsorbed and enriched BAs, leading to oxidative stress and death of proximal TECs, casts in distal tubules and collecting ducts, peritubular capillary leakiness, and glomerular cysts. Renal ASBT inhibition by AS0369 blocked BA uptake into TECs and prevented kidney injury up to 6 weeks after BDL. Similar results were obtained in mice with humanized BA composition. In patients with advanced liver disease, serum BAs were the main determinant of KIM-1 levels. ASBT expression in TECs was preserved in biopsies from patients with CN, further highlighting the translational potential of targeting ASBT to treat CN.
conclusionsBA enrichment in proximal TECs followed by oxidative stress and cell death is a key early event in CN. Inhibiting renal ASBT and consequently BA enrichment in TECs prevents CN and systemically decreases BA concentrations. IMPACT AND IMPLICATIONS: Cholemic nephropathy (CN) is a severe complication of cholestasis and an unmet clinical need. We demonstrate that CN is triggered by the renal accumulation of bile acids (BAs) that are considerably increased in the systemic blood. Specifically, the proximal tubular epithelial cells of the kidney take up BAs via the apical sodium-dependent bile acid transporter (ASBT). We developed a therapeutic compound that blocks ASBT in the kidneys, prevents BA overload in tubular epithelial cells, and almost completely abolished all disease hallmarks in a CN mouse model. Renal ASBT inhibition represents a potential therapeutic strategy for patients with CN.
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