Approximately 13% of the world’s population is affected by chronic kidney disease (CKD). CKD is a serious condition that in some cases can be reversible. When kidney damage reaches a certain point, however, it is beyond repair. What determines that tipping point between fixable and permanent damage has been unclear. 

In a study published in the journal Science Translational Medicine, scientists used human kidney organoids (miniature models grown from human stem cells) in an attempt to solve the mystery. Learn what Dr. Navin Gupta, a physician-scientist at Massachusetts General Hospital and Harvard Medical School with a specialty in genetic kidney disease, says about the research. 

What Did the Researchers Set Out to Do?

According to Gupta, kidney injuries become irreversible when there is scarring and fibrosis present. Using organoids as a model of human kidney tissue, researchers studied the mechanisms that would decide whether a patient would develop kidney scarring or a reversible injury in which normal kidney structure would be preserved. 

What Was Their Process?

When an injury is either very severe or repeated, it is more likely to lead to chronic disease. Therefore, researchers repeatedly injured the kidney organoid by applying multiple pulses of cisplatin, a chemotherapy drug, resulting in very low-level acute kidney injury (AKI). During this process, they monitored the organoids for transitions from healthy tissue to scarring and fibrosis, which would indicate irreversible damage. 

What did they find?

Researchers discovered two important observations from the organoids: 

• The transition from reversible to irreversible disease was linked to the loss of homology-directed repair, one of two methods used by cells to repair DNA lesions.
• The addition of small molecule inhibitors (drugs that block certain protein enzymes) to the organoid’s damaged tubular cells preserved kidney structures and reduced fibrosis.

What needs to happen next?

For researchers, these findings are only the beginning. More studies need to be done with kidney organoids to better understand the mechanisms of AKI and CKD progression, but the team is encouraged that its research will help to better identify effective compounds and reduce the high drug failure rate in clinical trials.

“We imagine ourselves sort of on the cusp of the bench to bedside translation,” Gupta concludes. “Our studies are trying to go as close to supporting preclinical studies that the next thing after it would be clinical trials in humans.”

*Cooney, E. (2022, March 2). Organoids reveal the tipping point when kidney damage turns irreversible. STAT News. https://www.statnews.com/2022/03/02/organoids-tipping-point-kidney-damage-irreversible/