Inhibition of the renal apical sodium dependent bile acid transporter prevents cholemic nephropathy in mice with obstructive cholestasis.

BACKGROUND & AIMS: Cholemic 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. METHODS: Cholestasis 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. RESULTS: Proximal 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. CONCLUSIONS: BA 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.

Compromised blood-bile barrier after acetaminophen overdose.

N-acetylcysteine (NAC) is the only approved drug for the treatment of acetaminophen (APAP) intoxication. A limitation of NAC is the short therapeutic time-window as it is only effective within approximately eight hours after APAP ingestion, which is critical since patients seek medical attention often after the onset of symptoms approximately 24 h after overdose. Recently, a so far unknown mechanism was identified by which APAP causes an increase of intracellular bile acid concentrations in hepatocytes to concentrations that exceed cytotoxic thresholds. APAP compromises the tight junctions of bile canaliculi that leads to the leakage of highly concentrated bile acids into the sinusoids. From the sinusoidal blood, a high fraction of the released bile acids is transported back into hepatocytes by basolateral uptake carriers and secreted into bile canaliculi. Repeated leakage from the canaliculi followed by hepatocellular reuptake and canalicular secretion causes an increase of intracellular bile acid concentrations and finally hepatocyte death. Importantly, inhibition of bile acid uptake carriers reduced intracellular bile acid concentrations and strongly ameliorated APAP hepatotoxicity, a finding that could result in a new therapeutic option for APAP-intoxicated patients.