Intestinal excretion of oxalate in chronic kidney disease

• Applicant: Professor Dr. Felix Knauf
• Subject Area: Nephrology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421415650

Oxalate is a compound found in the diet we ingest, and it is also produced as a waste product by the human body. The kidney is critical to remove oxalate from the body through the urine. Too much oxalate in the urine may cause kidney stones. When oxalate levels increase in blood, oxalate crystals can also deposit in the heart, bone and skin. This leads to organ dysfunction and eventually death.Several investigators have demonstrated that the intestine can similar to the kidney contribute to oxalate elimination from the body. Upregulation of intestinal oxalate secretion in animal models of chronic kidney disease (CKD) has been described over 20 years ago prior to the molecular identification of oxalate transporters. Our research group has verified these findings by using a mouse model with CKD. Subsequently, we have been able to demonstrate that oxalate transporter SLC26A6 is strongly upregulated in the colon of mice with CKD as compared to mice with healthy kidney function. Oxalate concentrations were increased in the stool of mice with CKD and reduced in mice lacking SLC26A6. Vice versa, plasma oxalate levels were increased in mice deficient for SLC26A6 as compared to mice without the gene defect. Together, our findings suggest that intestinal SLC26A6 is important to clear oxalate from the body and thereby reduce the body burden of oxalate.The general goal of the current research proposal is to define the mechanisms by which intestinal SLC26A6 is regulated. We plan to translate the findings made in mice to humans suffering from CKD and unexplained high plasma oxalate levels. To accomplish these goals, the following specific aims will be pursued: 1. We will measure oxalate transport in intestine of mice with CKD in the presence and absence of SLC26A6. In addition, we will pursue the novel concept that SLC26A1 may be responsible for the basolateral uptake of oxalate in the colon and function in series with SLC26A6. 2. We will examine whether changes in the bacterial composition (microbiota) of the colon regulate SLC26A6 expression using mouse models and a newly developed cell culture model. 3. We will examine patients identified with severely elevated oxalate levels for mutations of SLC26A6, additional oxalate transporters and genes involved in oxalate homeostasis. Identification of the mechanisms and genes that contribute to oxalate homeostasis in the intestine will allow the development of targeted therapeutic interventions to lower blood and urine oxalate and thereby prevent oxalate-related diseases.

• DFG Programme: Research Grants