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.

Depression in patients treated with haemodialysis: a cross-sectional study.

BACKGROUND: The increasing incidence of end-stage renal disease in the Palestinian population and the effect of the disease on the psychological status of the patient underlie the importance of increasing knowledge about the mental health status of patients with end-stage renal disease. The aim of this study was to estimate the prevalence of depression in Palestinian patients treated with haemodialysis and its correlation with patients' clinical characteristics, health-related quality of life (HRQoL), and adherence to medications. METHODS: In this cross-sectional study, we collected a convenience sample from ten haemodialysis centres in the West Bank, occupied Palestinian territory, over 3 months in 2015. The Beck Depression Inventory-II scale (BDI-II) was used to assess depression, the EuroQol-5 Dimension scale was used to assess HRQoL, and the Morisky Medication Adherance-8 scale was used to assess compliance. We used SPSS version 16.0 for all statistical analyses. The study was approved by the Institutional Review Board at the An-Najah National University. Informed verbal consent was obtained from the participants before the start of the study. FINDINGS: We interviewed 286 patients who were treated with haemodialysis. The mean age was 52·0 years (SD 14·3), and 172 (60%) patients were men. The median number of years of dialysis was 2 years (IQR 1-4). 209 (73%) patients had depression. Most participants were non-compliant with their drug regimens and had low HRQoL. High depression scores were associated with old age (p<0·0001), female sex (p=0·036), low income (p=0·041), living in rural areas or in a camp (p=0·032), not doing regular exercise (p<0·0001), unemployment (p<0·0001), having multiple comorbidities (p<0·0001), and low adherence to medications (p=0·0075). We found an inverse correlation between depression and HRQoL (p<0·0001). INTERPRETATION: This study is to our knowledge the first of its kind in the West Bank. The incidence of depression is higher than reported in other communities. Most patients treated with haemodialysis were moderately to severely depressed and had low HRQol. There is a need to provide for a patient's needs in term of psychologist interviews and pharmacological and non-pharmacological interventions. FUNDING: None.