Defining Molecular Mechanisms and Biomarkers for Progressive Renal End Organ Damage in Vasculitis

Matthias Kretzler, MD

Warner-Lambert/Parke-Davis Professor of Medicine
Professor of Internal Medicine
Research Professor, Computational Medicine and Bioinformatics
University of Michigan Medical School
kretzler@umich.edu
Funded JI Projects
Towards Molecular Prognosis of Chronic Kidney Disease (CKD) in UMMS and PUHSC
Defining Molecular Mechanisms and Biomarkers for Progressive Renal End Organ Damage in Vasculitis
Single Cell RNA Sequencing to identify transcriptional signatures of failure to repair after Acute Kidney Injury in patients with and without Covid‐19 disease

JI Program: Renal

Status: Active/ Ongoing

Outcome

  • 450 subjects have been enrolled in the study, with urine and plasma samples collected.
  • JAK-STAT pathway activation was identified as a mechanism shared between nephrotic syndrome and potential impact on health ANCA-associated vasculitis. Non-invasive biomarkers that represent the activation of this pathway were identified and we currently are validating the assays. A draft manuscript hasbeen deposited in bioarchives in advance of submission to Kidney International.
  • The bioinformatic result has been deposited in bioarchives in advance of submission to Kidney International: "Inflammatory and JAK-STAT Pathways as Shared Molecular Targets for ANCA-Associated Vasculitis and Nephrotic Syndrome".

Summary

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is one of the common autoimmune diseases in adults. Left untreated, the prognosis is usually fatal, with a 1-year mortality rate of about 80%. Introduction of aggressive immunosuppressive therapy has improved outcomes.  However, disease progression, treatment resistance and frequent relapse remain major challenges for clinicians. This is particularly challenging for renal disease in AAV, with the need to differentiate between ongoing immunological damage versus chronic progression of CKD. We will integrate data from the AAV patients across continents, using a data driven approach to identify pathways and networks that are AAV specific and those shared with other CKDs, identify non-invasive biomarker candidates that can monitor disease progression and propose disease targets that can serve as the basis for the creation of novel small molecules or that can be targeted through drug repurposing of FDA approved drugs/small molecules in a precision medicine manner to improve treatment options for patients with AAV.

Extramural Funding

Awarded $1 million dollars from NIH funding generated from the JI project.

Publications

1. Li X-Q, Goyal T, Eddy S, Kretzler M, Ju WJ, Chen M, Zhao MH. Urinary epidermal growth factor predicts renal prognosis in antineutrophil cytoplasmic antibody associated vasculitis. Ann Rheum Dis. 2018 Sep;77(9):1339-1344. doi: 10.1136/annrheumdis-2017-212578. Epub 2018 May 3. PMID: 29724728 DOI: 10.1136/annrheumdis-2017-212578