Featuring Dr. Matthias Kretzler; Warner-Lambert/Parke-Davis Professor of Medicine, Professor of Internal Medicine and Research Professor, Computation Medicine and Bioinformatics

Chronic kidney disease (CKD), the progressive decline in kidney function, affects nearly 30 million Americans, with millions of others at increased risk [1]. Diabetes is currently the leading cause of kidney disease, with more than 29 million people in the United States living with diabetes (an estimated 8.1 million undiagnosed) [2]. Current treatments for CKD are lacking, something Dr. Matthias Kretzler seeks to change.

“We have not seen new therapeutic strategies successfully implemented in close to two decades,” Kretzler explained. “We have to change that and we are very much underway.”

Dr. Kretzler’s research focuses on identifying the mechanisms which cause kidneys to fail across a variety of scenarios. Using kidney biopsy tissues, kidney tissue gene expression networks can be performed to link molecular functional status to disease manifestation overtime. Using Kretzler’s studies, Eli Lilly has launched a successful clinical trial repurposing baricitinib, an inhibitor of the Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway. This drug has shown efficacy in treatment of chronic inflammatory diseases such as rheumatoid arthritis by selectively inhibiting JAK1 and JAK2, blocking activation of an inflammatory cascade. Individuals with early and late-stage diabetic kidney disease (DKD) have increased activation and expression of JAK-STAT, which furthers DKD progression, making baricitinib an excellent candidate for experimental trial. The results of the clinical trial were recently published in Nephrology Dialysis Transplantation; investigators found that treatment with baricitinib significantly reduced albuminuria—a clinical biomarker of DKD progression. Although future research is required, these results show clear progress.

Dr. Kretzler said he and his team are also pursuing a variety of additional novel therapeutic targets, together with the Life Sciences Institute and AstraZeneca, as well as a precision medicine clinical trial to observe the natural progression of kidney disease.

Dr. Kretzler first established cohort studies on kidney disease out of Munich, Germany. Since coming to Michigan 12 years ago, he notes that the opportunity for multidisciplinary research is particularly fascinating.

“One of the strengths in Michigan is that we have so many different people who have deep knowledge in these specific areas, but are also very interested to work in a comprehensive research network,” he said.

Kretzler credited critical partnerships within the Medical School with Rheumatology, Cardiology, Pathology and Nephropathology, Ophthalmology, and Neurology. He has also worked closely with the Biomedical Research Core Facilities’ DNA Sequencing Core and Bioinformatics Core.

“Bob Lyons has been instrumental for us to generate the molecular information and genetic information from our cohorts,” Kretzler stated. This data is now widely available across the globe with his research network, thanks to assistance from the Bioinformatics Core in creation of several data-sharing platforms. The most prominent platform, Nephroseq, allows the renal research community to access datasets in a way that all scientists can understand, not just bioinformaticians. Kretzler’s team has also been working with the Transgenic Animal Model Core to research causality in mouse models.

Dr. Kretzler is very thankful for his patients here at Michigan Medicine. He states that an estimated 75 percent of his patients are engaged in their research studies, working with his team closely to “really push the boundaries for how to impact their disease more effectively.” With Dr. Kretzler and so many other researchers, at the University and abroad, studying this widespread disease, we will hopefully see the arrival of new treatments in the near future.

[1] About Chronic Kidney Disease. National Kidney Foundation website. https://www.kidney.org/atoz/content/about-chronic-kidney-disease. February 15, 2017. Accessed October 11, 2018.
[2] Diabetes and Chronic Kidney Disease. National Kidney Foundation website. https://www.kidney.org/news/newsroom/factsheets/Diabetes-And-CKD. Janurary 2016. Accessed October 11, 2018.
[3] Tuttle KR, Brosius III FC, Adler SG, Kretzler M, et al. JAK1/JAK2 inhibition by baricitinib in diabetic kidney disease: results from a Phase 2 randomized controlled clinical trial. Nephrol Dial Transplant. 2018; 1-10. https://doi.org/10.1093/ndt/gfx377.