Early Inflammation Could Drive Both ADTKD and Alport Syndrome Kidney Disease, Study Suggests

Early inflammation probably contributes to the tissue scarring and kidney damage seen in autosomal dominant tubulointerstitial kidney disease, according to an Italian study noting that the same thing occurs in Alport syndrome.

Researchers reported that the inflammation they found in animal models of ADTKD has also been seen in mouse models of Alport.

The study, published in Scientific Reports, was titled “Early involvement of cellular stress and inflammatory signals in the pathogenesis of tubulointerstitial kidney disease due to UMOD mutations.”

Identifying the processes that trigger the inflammation could lead to treatments for the earliest stages of kidney disease, according to the team at the IRCCS San Raffaele Scientific Institute in Milan.

Mutations in a number of genes can cause ADTKD, but an UMOD gene mutation is one of the most common. That mutation produces a faulty version of uromodulin protein. Healthy uromodulin plays a key role in the kidneys’ functioning, but a faulty version can lead to kidney disease.

To understand the role that faulty uromodulin plays in the disease’s development, the researchers genetically engineered a mouse to generate abnormal uromodulin.

When they looked at gene activity in one-month-old mice that had yet to develop kidney disease, they noticed molecular events signaling that inflammation was occurring. They also detected inflammation-regulating factors in the mutant mice’s kidneys.

In addition, they noticed that tissue-scarring-related molecular pathways were activated in the mice and that genes governing fat metabolism were less active than in healthy mice.

As the team followed the mice, they discovered a connection between inflammatory activity and progression of the disease. As the disease worsened, more genes became involved in inflammatory activity, suggesting that inflammation was worsening, they said.

The researchers categorized the inflammatory response they saw as an early innate immune response — the same kind that other studies have reported in Alport syndrome.

A previous study identified inflammatory cells as the major sign of disease in an animal model of Alport syndrome-related kidney disease, supporting the Italian researchers’ view that inflammation helps drive kidney disease progression.

While the study suggests that targeting inflammation could be a way to prevent the progression of the disease, the researchers said they now face the arduous task of assessing the contribution that each of the gene mutations and mediating factors makes to the disease.