Investigating the impact of APOL1 mutations

Chronic kidney disease (CKD) affects more than 700 million people worldwide and can arise from genetic and environmental factors as well as pre-existing medical conditions. One known risk factor involves mutations in the APOL1 gene. While rare in most populations, two APOL1 variants are carried by up to 13% of individuals of West African ancestry, and about 38% carry one copy. Despite this link, the mechanisms behind APOL1-mediated kidney disease (AMKD) remain poorly understood and no targeted treatments are currently available.

Researchers at Leiden University in the Netherlands developed kidney organoids derived from patient stem cells to examine the effect of APOL1 variants. These three-dimensional structures mimic some aspects of kidney tissue and allow scientists to investigate disease mechanisms in a human-relevant system.

Effects on mitochondria and podocytes

Some organoids underwent genetic correction to remove APOL1 risk variants. Laboratory tests showed that mutations in APOL1 impaired mitochondrial function. Mitochondria are responsible for respiration and energy production in cells, and disruption in this process compromises overall cell health.

A specific kidney cell type known as the podocyte was most affected. Podocytes are essential for maintaining the kidney’s filtering function and are also the main producers of APOL1 protein in the kidney. The damaging effects of APOL1 mutations became more pronounced under conditions of cellular stress caused by inflammatory proteins. This observation may explain why inflammatory triggers such as viral infection or autoimmune disease often coincide with the onset of AMKD symptoms in patients.

Using organoids to explore genetic kidney disease

Rodent models are limited in this area of research since APOL1 is not expressed in these animals. The organoid approach therefore provides a unique opportunity to study AMKD in a human context.

The study concluded that APOL1 mutations alter mitochondrial function in podocytes, providing a potential explanation for disease development. The organoid model offers a way to further investigate this process and could guide future research into therapeutic strategies for patients with AMKD.

Reference: Song H, Dumas SJ, Wang G, et al. APOL1 risk variants induce metabolic reprogramming of podocytes in patient-derived kidney organoids. Stem Cell Rep. 2025. doi: 10.1016/j.stemcr.2025.102650 

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