Kidney organoids unlock genetic cause of chronic kidney disease

Researchers from the lab of reNEW PI Ton Rabelink and AI Siebe Spijker successfully used stem cell-based models of the kidney to study chronic kidney disease. Doing so, they obtained valuable insight into APOL1-mediated kidney disease. The findings, published October 2nd in Stem Cell Reports, open avenues for further research into this understudied 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). Despite this, the causes for APOL1-mediated kidney disease (AMKD) are currently not well understood, and treatments are lacking.

From skin biopsy to kidney in a dish
To gain better understanding of AMKD, Siebe Spijker and his team from Leiden University Medical Center with collaborator Barry Freedman from Wake Forest University School of Medcine generated stem cells from skin biopsies of AMKD patients. They subsequently 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.

A defect in the cell’s power plant
The researchers then performed a panel of lab-based tests on these organoids to learn morn about AMKD and the mechanisms driving this disease. Heein Song, first author of the paper, explains: “We 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.”

Stress as a trigger
The team discovered that these negative effects mainly present when kidney 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.

A valuable tool
This research shows that mutant APOL1 affects mitochondrial function in podocytes and may open up avenues for designing targeted treatments for patients with AMKD. Spijker concludes: “We anticipate that this human kidney organoid model will advance our understanding of AMKD and accelerate drug discovery. Particularly since animal models cannot be used to this end given that APOL1 is not expressed in rodents.”