Diabetic kidney disease (DKD) remains one of the most pressing unmet medical needs in diabetes. Everyone with diabetes, regardless of type, is at increased risk for DKD.
“We don’t know who is more likely to develop serious morbidity and mortality with diabetic kidney disease,” said Jose C. Florez, MD, PhD, Chief of the Endocrine Division at Massachusetts General Hospital/Broad Institute. “The second issue is that we don’t have many agents to prevent, ameliorate, or reverse the pathophysiology that happens with DKD. We are not good at preventing or treating DKD, so a lot of people end up requiring transplantation or dialysis, with the additional morbidity and mortality.”
Kidney disease explains nearly all of the excess mortality associated with diabetes, added Katalin Susztak, MD, PhD, University of Pennsylvania. Genomic analysis, single-cell sequencing, and epigenomic approaches are uncovering new mechanisms in DKD development and progression. Changes in proteinuria, for example, are associated with changes in podocytes, while changes in glomerular filtration rate are linked to alterations in proximal tubules.
“We have identified new genes and new pathways that are likely causing DKD that may be targets for new drug development,” Dr. Susztak said. “If you can target a genetically driven pathway, you have a much greater chance of developing a successful new drug.”
Drs. Florez and Susztak are two of the researchers who will share the latest human genetic and genomic findings in DKD during the symposium Novel Mechanisms of Diabetic Kidney Disease on Tuesday, June 7. The two-hour session begins at 7:30 a.m. CT in Room 356 at the convention center.
“The ways we have been doing things for the past 50 years obviously have not helped in terms of preventing this terrible complication from happening,” Dr. Florez said. “We have the techniques and the analytical methods to be able to leverage omics to give us a better understanding of DKD. There’s no question that omics technologies will influence how we practice medicine a decade from now.”
Dr. Florez and his team are using the latest tools to query the entire genome in people with and without DKD. The combination of enough people and the right technologies has already uncovered novel genes and pathways that were not previously known to play roles in the pathogenesis of DKD.
“We are part of a large international consortium that has already identified the collagen pathway as one potential contributor to DKD,” Dr. Florez said. “There are additional efforts afoot with larger sample sizes that include participants with both type 1 and type 2. The goal is to use genome-wide association studies, expression data, and experimental systems to inform how genetic variants affect cellular function to help us understand new mechanisms of disease and potentially identify new therapeutic targets.”
Also during the session, Benjamin D. Humphreys, MD, PhD, Washington University School of Medicine, St. Louis, will explore future directions in DKD therapy based on initial findings from a preclinical study using single-cell sequencing to compare standard therapies and two combination therapy groups—an angiotensin-converting enzyme (ACE) inhibitor plus rosiglitazone and an ACE inhibitor plus sodium-glucose cotransporter 2 (SGLT2) inhibition.
Dr. Humphreys found diverse cellular responses to each therapeutic regimen, which suggests there is good biologic rationale for combination therapy because therapies are hitting different cell types. Combining therapies targeting non-overlapping cell types should at least be additive, he said.
The trial has also found unexpected results from the SGLT2-inhibition arm. The single-cell approach helped differentiate between the systemic effects of diabetes treatment and the cell-specific effects of SGLT2 inhibition in the kidney, leading to new insights about the mechanism of action of this drug class, Dr. Humphreys said.
“The caveat is the same as every mouse study—mice are not small humans,” he said. “We are endeavoring to design studies to verify our findings in human samples. This symposium can change the ways we think about therapies for DKD in general, and SGLT2 inhibition in particular.”