New therapeutic approach for the treatment of cholemic nephropathy discovered

Cholaemic nephropathy is a serious kidney disease that occurs as a result of liver disease. There are no treatment options for the disease, as the mechanisms by which cholemic nephropathy is caused were previously unknown. The project groups of Prof. Ghallab and Prof. Hengstler at the Leibniz Institute for Occupational Research in Dortmund (IfADo) have now discovered the molecular cause of the disease and found a way to prevent the harmful effects that lead to kidney disease. These research findings could lead to new therapies to better help patients suffering from the disease.

Microscope image of epithel cells of the kidney
Bile acid destroys the epithelial cells of the kidney. The inhibition of the transport protein responsible for this is intended to prevent cell death.

Cholemic nephropathy occurs as a result of liver diseases such as obstructive cholestasis, cirrhosis, acute or chronic liver failure and alcohol-associated hepatitis. What these liver diseases have in common is that so-called cholephiles, such as bilirubin, cytokines and bile acids, rise sharply in the blood. These are normally found in the bile of the liver. Using imaging technologies developed at IfADo, the research teams of Prof. Ghallab and Prof. Hengstler were able to show that bile acids accumulate in a certain cell type in the kidneys, which then leads to the death of these cells. This cell death triggers a series of harmful processes in the kidney, such as the formation of blockages in the renal tubules, the dilation of parts of the kidney, the invasion of immune cells and the formation of scar tissue. These processes ultimately lead to kidney failure.

Bile acids enter the kidney through a transport protein

The teams of Ghallab and Hengstler used a preclinical mouse model in which all known cholephiles increase in the blood, leading to cholemic nephropathy similar to that in humans. They discovered that the accumulation of bile acids occurs via a transport protein called SLC10A2 (also known as ASBT). By developing an inhibitor for this protein, they were able to successfully prevent the symptoms of cholemic nephropathy in a mouse model. An inhibitor is a substance that inhibits the activity of a specific protein or enzyme. As certain kidney cells in humans also produce the transport protein SLC10A2, the inhibitors used in mice have been optimized for use in humans and a clinical phase I study has already been completed. Blood tests on patients with cholemic nephropathy also showed similar disease-causing mechanisms as in the mouse model in which the original drug development took place. Together with their cooperation partners, the teams at IfADo are now planning a Phase II clinical trial to investigate the efficacy of this approach in patients.

The results and treatment options with SLC10A2 inhibitors were recently published in the Journal of Hepatology.

Original publication:
Ahmed Ghallab, Daniela González, Ellen Strängberg, Ute Hofmann, Maiju Myllys, Reham Hassan, Zaynab Hobloss, Lisa Brackhagen, Brigitte Begher-Tibbe, Julia C. Duda, Carolin Drenda, Franziska Kappenberg, Joerg Reinders, Adrian Friebel, Mihael Vucur, Monika Turajski et al.: Inhibition of the Renal Apical Sodium Dependent Bile Acid Transporter Prevents Cholemic Nephropathy in Mice with Obstructive Cholestasis, Journal of Hepatology, November 2023
Scientific contact:
Prof. Dr. Ahmed Ghallab
Scientific staff
Ardeystrasse 67 Dortmund Nordrhein-Westfalen DE 44139
Prof. Dr. Jan G. Hengstler
Head of department Toxicology
Ardeystrasse 67 Dortmund Nordrhein-Westfalen DE 44139
Press contact:
Anne Gregory
Press officer
Ardeystrasse 67 Dortmund Nordrhein-Westfalen DE 44139