A kidney organoid platform may reduce the need for laboratory animal models and provide a more reliable, relevant system for drug development, ultimately helping to reduce disease burden and improve quality of life for patients with kidney disease.

In a study published in Stem Cell Reports, investigators used induced pluripotent stem cells (iPSCs) derived from two patients homozygous for the APOL1 risk variants G1 and G2 to model APOL1-mediated kidney disease (AMKD) in kidney organoids.

Individuals carrying two APOL1 gene risk variants (G1 or G2) are at a higher risk for chronic kidney disease (CKD). Kidney organoids, three-dimensional tissue structures grown from iPSCs, are generated by exposing stem cells to a defined mix of factors that guide differentiation and self-organization into structures resembling fetal kidneys.

“By using iPSCs obtained from patients with a genetic kidney disorder, such as AMKD, we can create disease-specific kidney models. These organoid-based models allow us to study the disease mechanism at a molecular level in a reproducible and patient-specific manner, without causing any additional burden to the patient,” said study investigator H. Siebe Spijker, MD, clinical nephrologist at Leiden University Medical Center in Leiden, Netherlands.

Spijker’s team generated stem cells from skin biopsies of patients with AMKD and turned them into kidney organoids to model aspects of human kidney function. In a subset of organoids, the APOL1 mutations were corrected by genetic engineering to create isogenic controls.

A Better Understanding of CKD Development

Using a panel of lab-based tests, the researchers found that APOL1 mutations impaired mitochondrial function, which is critical for respiration and energy production in the kidney. Podocytes, a cell type essential for filtration and the main source of APOL1 in the kidney, were particularly affected.

“The organoids reflect the underlying biology driving disease progression. While this study focused on AMKD, the approach is broadly applicable. iPSCs can be generated from any patient with a genetic kidney disease, enabling the development of tailored organoid models for a wide range of kidney diseases,” Spijker told Medscape Medical News.

Although the current work centers on disease mechanisms, the team intends to apply the model for drug discovery.

“This could involve targeted strategies based on the specific disease mechanism or a large-scale compound screening to uncover novel therapeutic targets,” Spijker said.

Clinical Implications for Treating CKD

Mattia F.M. Gerli, MSc, PhD, associate professor of stem cell science and biomaterials at UCL Royal Free Hospital in London, England, said these findings have significant clinical implications and point toward completely new types of treatment.

“Organoids modelling is currently becoming a clinical reality for modelling human disease and testing therapeutics in a personalized manner. This piece is very timely, as it fits perfectly with the recent advancement in complex renal modelling using iPSC-derived organoids. Through this work, [the authors] help bring clarity on the underlying mechanisms of APOL1-mediated AMKD,” Gerli told Medscape Medical News.

Multiomics analysis demonstrated metabolic reprogramming in APOL1 risk variant podocytes, which also displayed functional and structural mitochondrial impairment.

“This advances our understanding on the effect of APOL1 in metabolic-mediated cell death, proposing mitochondria dysfunction as its core,” said Gerli, who was not involved in the study. “This work provides an innovative platform to study the condition and paves the way for future studies to conduct personalized modelling and to test genetic correction and therapeutic targets for this condition.”

Wake Forest University Health Sciences and study Co-author Barry I. Freedman have rights to a US patent related to APOL1 gene testing. Freedman is a consultant for and reported receiving research support from AstraZeneca. Spijker and Gerli reported having no financial disclosures.

John Schieszer, MA, is an award-winning national journalist and podcast broadcaster of The Medical Minute. He can be reached at medicalminutes@gmail.com.