Kidney Organoid Unlocks Genetic Cause of Chronic Kidney Disease

Chronic kidney disease (CKD) affects more than 700 million people worldwide and is caused by genetic and environmental factors, as well as existing medical conditions. Known genetic risk factors for CKD include mutations in a gene called APOL1.  These are rare in most populations, but two risk variants are present in as much as 13 percent of people with West African origin and another 38% possess one copy (carriers). The causes for APOL1-mediated kidney disease (AMKD) are currently not well understood, and treatments are lacking.

To gain better understanding of AMKD, Siebe Spijker and his team from the University of Leiden, Netherlands generated stem cells from skin biopsies of AMKD patients and turned them into microscopic structures known as kidney organoids, which can model aspects of human kidney function. In some of these organoids, the APOL1 mutations were corrected by genetic engineering. The research was published today in Stem Cell Reports. Through a panel of lab-based tests, the researchers found that APOL1 mutations impair the proper function of mitochondria, which are required for respiration and energy production, in the kidney. A cell type called the podocyte, which is essential for the kidney’s filtering function, was particularly affected by APOL1 mutations since these podocytes are the cells which make the most APOL1 protein in the kidneys. These negative effects mainly present when cells were stressed by inflammatory proteins. This finding could explain why inflammation in the body, e.g., from viral infections or autoimmune disease, often triggers the onset of AMKD in patients.

"We anticipate that this human kidney organoid model will advance our understanding of AMKD and accelerate drug discovery, particularly given that APOL1 is not endogenously expressed in rodents, Spijker added.

This research shows that mutant APOL1 affects mitochondrial function in podocytes and may open up avenues for designing targeted treatments for patients with AMKD.

Image: Immunofluorescence staining of kidney organoid, podocytes in red, APOL1 in green

Credit: Heein Song

Paper: APOL1 Risk Variants Induce Metabolic Reprogramming of Podocytes in Patient-Derived Kidney Organoids, Stem Cell Reports