Unravelling the Mystery Behind a Rare, Fatal Kidney Disorder

A recently published study in Nature Communications has illuminated the potential cause of autosomal recessive renal tubular dysgenesis (AR-RTD), a rare and fatal kidney disorder. The research, spearheaded by Naomi Pode-Shakked, MD, PhD, and Raphael (Rafi) Kopan, PhD of Cincinnati Children’s, has unveiled a developmental delay in kidney vascularization that may be a contributing factor to the disease.

AR-RTD is an inherited disorder that leads to the absence or severe malformation of proximal tubules in the kidney, ultimately resulting in the demise of affected individuals before or shortly after birth. The study has presented evidence suggesting that a delay in kidney vascularization leads to a deficiency of nutrients for the maturing tubules, potentially driving the disease.

Previous research has identified mutations in four genes underlying AR-RTD. The current study has focused on mutations in two of these genes: angiotensin converting enzyme (ACE) and the AngII receptor type 1 (AGTR1). Through a series of experiments using lab-grown kidney organoids, the research team observed the impact of these mutations on the development of the organoids. They found that organoids incapable of “hearing” the AngII signal due to the AGTR1 mutation failed to thrive when transplanted into mice.

Further investigations have revealed that the delayed production of vascular endothelial growth factor A (VEGF-A), a protein crucial for healthy microvascular growth, is responsible for the poor transplantation success of the organoids lacking AGTR1. Reintroducing VEGF-A to mutant cells was sufficient to rescue proximal tubule production, indicating the potential to reverse the effects of the mutation.

The study has raised an intriguing question: Could administering AngII during human pregnancy prevent the development of this deadly kidney malformation? The researchers caution against this approach, citing potential life-threatening side effects. Instead, they propose identifying critical nutrients that support proximal tubule growth and providing them as a supplement as a more promising preventive strategy.

The findings of this study not only provide insight into the potential cause of AR-RTD but also pave the way for exploring new approaches to preventing this devastating disease. With further research and development, there is hope that a more effective strategy for addressing AR-RTD can be established, offering a brighter future for individuals at risk of this rare, fatal kidney disorder.