Although patients with Nephrotic Syndrome (NS) present with shared clinical signs and symptoms (proteinuria, hypoalbuminemia, hyperlipidemia and edema), there is dramatic variability in prognosis and response to therapy, frustrating patients, families and their clinicians. Even within the histopathologic categories used in the current diagnostic approach (e.g. minimal change disease, focal segmental glomerulosclerosis), there is dramatic variability in disease progression and response to therapy, highlighting the underlying biological heterogeneity within the groups. Small studies with broad, clinical patient inclusion criteria have demonstrated that a subset of patients respond well to anti-TNF therapy, but accurate pre-treatment response of those individuals is not possible based on routine clinical parameters. This project will leverage the Nephrotic Syndrome Study Network (NEPTUNE) cohort study, a multi-center prospective study of 600 patients with FSGS, MCD and MN with rich clinical data, kidney biopsy tissue and gene expression profiles. This study will leverage the kidney tissue gene expression data to identify a subgroup of patients with TNF-alpha pathway activation, assess associated clinical outcomes and identify non- molecular predictors of the subgroup.
The aims are:
Aim 1 : To identify a subgroup of Nephrotic Syndrome patients with homogeneous activation of the TNF-alpha transcriptional pathway.
Aim 2 : To compare molecular subgroups with conventional clinical-pathologic classification in clinical outcome prediction.
Aim 3 : To identify non-invasive markers (e.g. demographics, blood and urine markers), standard pathology features and novel pathologic biopsy descriptors associated with the TNF-alpha subgroup. To accomplish this project, the applicant will pursue formal training in systems biology, genetic epidemiology and bioinformatics. She will be mentored by a multi-disciplinary team with expertise in systems biology, epidemiology and bioinformatics. The long term objective is to improve the clinical care of patients with Nephrotic Syndrome by improved understanding of the underlying biology, identifying novel biomarkers and potential therapeutic targets for future validation in animal models and mechanistic-based interventional clinical trials.

Public Health Relevance

Nephrotic Syndrome, caused by several rare kidney diseases, is characterized by an abnormal amount of protein in the urine, swelling and kidney failure. Patients affected by the syndrome suffer complications of the disease as well as the toxicity of the immunosuppressive therapy used to treat it, but their individual presentations, response to treatment and prognosis can vary markedly. This project aims to use gene expression levels from kidney biopsy tissue to identify the subgroup patients most likely to respond to TNF- alpha blocking medications, an approach which, if validated, may help to inform targeted therapy selections for these patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08DK115891-01
Application #
9431752
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2018-07-01
Project End
2022-04-30
Budget Start
2018-07-01
Budget End
2019-04-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109