Human Kidney Organoids Offer New Insights into APOL1-Mediated Kidney Disease

Chronic kidney disease (CKD) impacts over 700 million individuals globally and occurs from a combination of genetic and environmental influences, along with pre-existing health conditions.

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Mutations in a gene known as APOL1 are known genetic contributors to CKD. These mutations are uncommon in the majority of populations; however, in individuals of West African descent, two risk variants can be found in approximately 13 %, while an additional 38 % are carriers of one copy. The mechanisms behind APOL1-mediated kidney disease (AMKD) remain poorly understood, and there is a notable absence of effective treatments.

Siebe Spijker and team at the University of Leiden in the Netherlands created stem cells from skin biopsies of AMKD patients. They transformed them into microscopic structures referred to as kidney organoids, which can simulate certain aspects of human kidney function.

The APOL1 mutations in several of these organoids were emended through genetic engineering. The study was published in Stem Cell Reports. Through a series of laboratory tests, the researchers discovered that APOL1 mutations disrupt the proper functioning of mitochondria, which are essential for respiration and energy production within the kidney.

A specific cell type known as the podocyte, crucial for the kidney’s filtering capabilities, was notably impacted by APOL1 mutations, as these podocytes produce the highest levels of APOL1 protein in the kidneys. These adverse effects are most apparent when cells are subjected to stress from inflammatory proteins. This discovery may reveal why inflammation in the body, such as that caused by viral infections or autoimmune diseases, frequently triggers the onset of AMKD in affected individuals.

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.

Siebe Spijker, University of Leiden

This study demonstrates that the mutant form of APOL1 influences mitochondrial function in podocytes, potentially facilitating the development of targeted therapies for individuals suffering from AMKD.