Biopsies reveal breadth of drug’s kidney protection

New research has uncovered clues about how a medication appears to help protect the kidneys of teenagers and young adults with type 1 diabetes. Diabetic kidney disease is a leading cause of kidney failure worldwide. No new kidney-protective therapies have been approved for type 1 diabetes in decades.

A randomized, placebo-controlled clinical trial of 98 youth ages 12 to 21 with type 1 diabetes evaluated the effect of treatment with the SGLT2 inhibitor dapagliflozin, in combination with adjustable insulin, over a 16-week period. 

SGLT2 inhibitors are a type of medication currently used to treat type 2 diabetes. They help to correct overly high blood sugar levels by increasing the amount of glucose removed by urination. 

Researchers examined biopsies of the participants’ kidney tissue before and after treatment. 

The study found that the medication appeared to reset many of the abnormal biological processes linked to early kidney damage. The treated kidney cells showed healthier energy use, less inflammation and oxidative stress, improved oxygen balance and fewer signs of injury. More than 55% of the genes that changed with treatment shifted toward the patterns seen in healthy kidneys.

The findings were published July 22 in the journal Science Translational Medicine.

“This was a look ‘under the hood’ at what an SGLT2 inhibitor does inside the kidneys,” said corresponding author Dr. Petter Bjornstad, professor of pediatrics and medicine at the University of Washington School of Medicine. “Most of what we know about these drugs comes from blood and urine tests, which tell you that the kidney is doing better but not why.”

The researchers examined the individual molecular signatures of more than 214,000 kidney cells. This mapping may aid future drug development.

By parsing exactly which pathways the medication engaged, Bjornstad said future therapies could aim directly at those same pathways, potentially complementing SGLT2 inhibitors or helping people who cannot take them due to contraindications.

He said the research team was surprised by the breadth of biological changes observed. “We expected changes mostly in the sugar-handling cells where the drug directly acts, but we saw a coordinated, whole-kidney response reaching the blood vessel lining and the filter cells, too.” 

The researchers found the treated kidneys were less oxygen-rich, a result that initially worried them. 

“But diabetic kidneys are abnormally over-oxygenated in a way that reflects inefficient, overworked plumbing, and the drug appears to bring that back toward the healthy pattern,” Bjornstad said. “It turned out to be a sign of the kidney working more efficiently.”

The study provides some of the strongest biological evidence to date for how SGLT2 inhibitors may protect kidneys. 

“We deliberately studied young people early in their disease with no overt kidney damage and saw that the kidney is remarkably ‘plastic,’ responding to this drug at a molecular level well before any test would flag a problem,” said Bjornstad, who is also executive director of the UW Medicine Diabetes Institute.

“That raises the real possibility of shifting from repairing kidney damage to preventing it. It still has to be proven in long-term studies, but the biology points toward ‘the earlier, the better,’” he said.

Roughly 1 in 3 people with type 1 diabetes eventually develops chronic kidney disease, but the kidney damage is typically undetected for a long time. 

“By the time standard tests turn abnormal, real damage has often already happened,” Bjornstad said. “The window where you can prevent rather than repair is early — often in adolescence and young adulthood, long before anyone feels sick. Our participants had a subtle early warning sign called hyperfiltration, where the kidney is essentially straining and overworking. Catching and calming that early is exactly where we'd most want a protective drug to help.”

Broader and larger trials are underway to measure the effect of SGLT2 inhibitors on kidney function in adults with type 1 diabetes over years.

The research was supported by funding from Breakthrough T1D (2-SRA-2019-845-S-B, 3-SRA-2022-1097-M-B and 3-SRA-2025-1641-M-B).