by Michaela Martinez,Duke University

Mesenchymal phenotype observed in vascular cells differentiated from SMAD2 mutant iPS cells. Credit:Nature Biomedical Engineering(2025). DOI: 10.1038/s41551-025-01543-0

Biomedical engineers at Duke University have shown that a genetic mutation that causes congenital heart disease also contributes to kidney damage and developmental defects. Identifying this early cause of kidney damage could enable clinicians to diagnose and address kidney problems much sooner than current practices allow. The research waspublishedon November 3 in the journalNature Biomedical Engineering.

Congenital heart disease (CHD) is a common cause of death in childhood and affects 1 out of every 1,000 births. The disease occurs when the heart doesn't form correctly before birth, causing leaky valves, defective vessels, or holes in the heart. While some cases of CHD can be remedied, children with life-threatening complications often require surgery or even a heart transplant. More than 25% of patients also end up developing problems with other organs, which severely compromise life expectancy.

"Research has shown that children diagnosed with CHD almost always have kidney problems by age 4," said Samira Musah, the Alfred M. Hunt Faculty Scholar Assistant Professor of Biomedical Engineering and Assistant Professor of Medicine at Duke University, and the senior author of the study. "Given the shared developmental origin of the heart and kidney, I wondered if a genetic mutation tied to CHD also causes thekidney damageobserved in affected patients."

Musah is well-equipped to answer this question. Her laboratory was among the first to successfully grow functional kidney tissue fromstem cellsand develop an "organ-on-a-chip" kidney model to investigate these types of issues. This technique is critical, as current diagnostic tools aren't sensitive enough to catch the small changes in humans during development that could indicate kidney damage.

To pursue her hunch, Musah reached out to Tarsha Ward, a research fellow in the labs of Drs. Christine Seidman and Jonathan Seidman at Harvard Medical School, who works on thegenetic mutationsthat cause CHD. They decided to narrow their focus to CHD cases caused by a mutation to the SMAD2 gene, which the Seidmans' lab had previously correlated with pediatric and adult heart disease.

"There is an urgent need for continued development of human stem cell models that allow us to investigate the causes of congenital disorders in an integrated way and pave the path toward innovative personalized therapies," said Ward. "If we can detect heart and kidney defects earlier, we have the chance to change the trajectory of care for children born withcongenital heart diseaseand greatly improve their quality of life."

In the research, the team generated human inducedpluripotent stem cellscarrying the SMAD2 mutation, which can be used to study development of any cell type, tissue, and organ in the body. Musah's laboratory then coaxed them into becoming functional kidney cells and integrated them into an organ-on-a-chip complete with multiple cell types, simulated blood flow and an integrated circuit that recreates the kidney's blood filtration capabilities.

The research showed that the gene mutation caused the cells to organize themselves poorly as they grew into complex tissues. They also saw significant changes in the genes and proteins expressed in the cells, which subsequently influence cellular development, tissue patterning and organ function. These changes were happening so early in tissue development that they conceivably influenced nearly all kidney cell types.

Beyond these initial changes, the team specifically saw problems with podocytes, important cells that help regulate blood filtration in the kidneys. Many of the podocytes failed to effectively branch off and connect with other cells, negatively affecting cell communication and tissue development.

"This is the first and direct human-relevant experimental evidence that kidney damage occurs so early in development," said Musah.

"Our findings not only enhance understanding of the connection between CHD and kidney problems but also emphasize the urgent need for routine kidney function screening in children with CHD. Reduced kidney filtration is closely associated with a higher risk of death in CHD patients, underscoring the importance of early detection and preventive care," added Rohan Bhattacharya, the first author of the study and a recent graduate from the Musah Lab.

Moving forward, Musah and her team are using these approaches to discover more early biomarkers of kidney disease. In parallel, they aim to study how kidney cells injured from diseases can be stimulated to help repair damage. One avenue of exploration is to alter stem cells to transform into key kidney cells to help replenish damaged cell populations. They also hope to target gene regulatory networks and work with geneticists to explore SMAD2 mutations as a potential target for future gene therapies.

But for the moment, the researchers say, prevention and early intervention are key.

"There are several ways to address cardiac problems from CHD, but kidney damage is currently not repairable," said Musah. "If we can develop reliable methods to identify those susceptible to these kidney complications early, we can intervene sooner. Preserving kidney function or halting disease progression is much easier than trying to recover a damaged organ."

More information: Rohan Bhattacharya et al, Engineered human induced pluripotent stem cell models reveal altered podocytogenesis in congenital heart disease-associated SMAD2 mutations, Nature Biomedical Engineering (2025). DOI: 10.1038/s41551-025-01543-0 Journal information: Nature Biomedical Engineering

Provided by Duke University