Precision Health member Matthias Kretzler, MD, PhD, is the Warner-Lambert/Parke-Davis Professor of internal medicine/nephrology and a professor of computational medicine and bioinformatics. He is the principal investigator for the Nephrotic Syndrome Research Network (NEPTUNE), part of the NIH’s Rare Disease Clinical Research Network, and director of the Applied Systems Biology Core at U-M’s George M. O’Brien Kidney Translational Core Center.

Dr. Kretzler has 25 years of experience integrating bioinformatics, molecular, and clinical approaches in more than 300 collaborative studies on gene expression analysis of renal disease. Kretzler and his research team—the Michigan Kidney Translational Med. Core (MIKTMC)—focus on the analysis of molecular mechanism of glomerular failure, with a special focus on integrating responses in progressive organ dysfunction across species, tissues, and diseases. MIKTMC recently received three National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) competing renewal awards to lead the Kidney Precision Medicine Project, totaling a funding volume of $32M to lead the central hub, the kidney mapping center, and the single-cell tissue interrogation core facility.

Fill us in on the details of your NIDDK renewal awards. What is the Kidney Precision Medicine Project, and what are the aims of the project?
The goal of the Kidney Precision Medicine Project (KPMP) is to better understand the mechanisms of acute kidney injury (AKI) and chronic kidney disease (CKD), which will enable implementation of a precision medicine approach in the treatment of patients with kidney diseases.

In collaboration with 180+ scientists across the United States, the KPMP is obtaining kidney tissue for research from KPMP participants, analyzing it using state-of-the-art technologies, and developing next-generation software tools to visualize and share the resulting data.

What is unique about this project, and the funding your team received?
KPMP is the most ambitious multi-year project funded by the NIDDK, with the purpose of understanding and finding new ways to treat kidney diseases. Unique features are the generation of research kidney biopsies to enable comprehensive multi-scalar data generation and the patient-/participant-driven design of the study. KPMP involves collaboration across a spectrum of stakeholders, including patient representatives, researchers, clinicians, NIH program officers, and software developers to meet the needs of the various communities involved in or affected by kidney diseases. The project involves 19 academic institutions in the United States, with oversight from a study monitoring board comprising representatives from NIH, NIDDK, patient advocacy groups, FDA, and other external researchers.

Within this umbrella project, the University of Michigan is involved in 3 main components:

1. Co-leading the central hub that coordinates and manages the various activities
2. Leading the Kidney Mapping Atlas Project (KMAP) to create the KPMP Kidney Tissue Atlas (KTA) from kidney biopsies of participants with AKI and CKD, define disease subgroups, and identify critical cells, interstitial components, pathways, and targets for novel therapies
3. The KPMP Precision Medicine through Interrogation of RNA in the Kidney (PREMIERE) Tissue Interrogation Site (TIS), tasked with implementing single-cell RNA sequencing and an analysis pipeline to generate high-quality data that capture the molecular and cellular landscape across the entire spectrum of kidney diseases represented in KPMP participants.

What is the anticipated outcome of this research?
The KPMP research will help answer important questions for people with kidney disease, such as: What type of kidney disease do I have? What will happen to me? and What can I do about it? Ultimately, KPMP research hopes to find new markers and treatment targets that make personalized, effective, and safe treatments possible for kidney diseases. The KMAP project involves developing the KTA, which is a set of interactive tools built to promote retrieval, exploration, discovery, and analysis of KPMP data by the greater research community. For maximal impact to the kidney community, it deploys a user-centric design to reach all stakeholders, from patient participants, to clinican scientists, to expert bioinformaticians.

What are your research interests, broadly?
The overarching goal of my research is to define kidney diseases based on their underlying disease mechanisms to enable the development of targeted therapeutic interventions—the cornerstone of precision medicine. To achieve this goal, my interdisciplinary research team has developed a translational research pipeline centered on an integrated systems biology approach to understanding kidney diseases. We have published 400 peer-reviewed papers from research projects spanning more than 25 years, using large-scale datasets from international multi-disciplinary research networks in the US, Europe, China, and Sub-Saharan Africa.

These research projects have enabled precision medicine across the genotype-phenotype continuum using carefully monitored environmental exposures, genetic predispositions, transcriptional networks, proteomic profiles, metabolic fingerprints, digital histological biopsy archives, and prospective clinical disease characterization. Most important, these findings have led to new disease predictors and successful clinical trials, bringing urgently needed novel treatments to our patients.

Highlights from KPMP:
A recent paper in Science Advances describes KPMP’s efforts toward building a spatially specified human tissue atlas at the single-cell resolution with molecular details of the kidney in health and disease: https://www.science.org/doi/10.1126/sciadv.abn4965.

Learn more about the study from different perspectives in a video here: https://www.kpmp.org/for-participants

The website also hosts letters from participants: https://www.kpmp.org/participant-letters