Chronic kidney failure, also known as end-stage renal disease (ESRD), results in the build-up of waste toxins that affect organs and tissues throughout the body, and causes significant mortality. The most common cause of death in chronic kidney failure is cardiovascular disease that results from chronic inflammation. Infections are the second most common cause of death in patients with ESRD, suggesting that ESRD results in alterations to the immune system. Previous attempts to understand these changes in immune function have focused on the characterization of circulating immune cells from relatively small numbers of patients with ESRD. As such, these studies are limited by multiple different causes for the kidney failure, and it is often not possible to distinguish the effect of kidney failure frm the effects of the dialysis used to replace kidney function. In order to gain a better understanding of the primary effect of kidney failure on immune function it may be valuable to use an experimentally reproducible model system. For this proposal, the well-established and reproducible mouse model of ESRD represented by 5/6 nephrectomy (SNx) will be used. In this proposal's first specific aim, macrophages, a key cell in the innate immune system, will be isolated from SNx and control mice. These macrophages will be examined in tissue culture to understand how chronic kidney failure primes the innate immune system to generate excess pro-inflammation. In the second specific aim, T- lymphocytes, the cell type responsible for directing immune responses, will be isolated from SNx and control mice, and examined in tissue culture to understand how chronic kidney failure alters adaptive immune responses. In the third specific aim, the immune systems of SNx and control mice will be challenged in vivo with the fungus Aspergillus fumigatus, which will serve as a model organism to probe pro-inflammatory immune responses that depend upon the coordinated activity of both innate and adaptive immunity. In all three aims, experiments will be conducted to isolate nuclear DNA from immune system cells to determine if the difference in their responses will be reflected in acquired modifications to their DNA (i.e. epigenetic alterations). The information gained from these studies is a first step in order to better understand how chronic kidney failure alters immune function, and how these alterations contribute to the high mortality in ESRD. Ultimately, it is hoped that these studies will lead to the development of new methods to reset immune responses in ESRD, and help to prevent both cardiovascular disease and lethal infections.

Public Health Relevance

Cardiovascular disease and infections are the two leading causes of death in patients with chronic kidney failure, which affects at least 500,000 children and adults in the US. This proposal aims to improve the public health by using an animal model to gain insight into how chronic kidney failure alters the immune system in order to cause so much mortality. The ultimate goal of these basic science studies is to translate the findings to the bedside for new methods to prevent and treat lethal infections and reverse the chronic inflammation that causes cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK093785-03
Application #
8661180
Study Section
Special Emphasis Panel (ZDK1-GRB-G (M2))
Program Officer
Rankin, Tracy L
Project Start
2012-07-15
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
$153,360
Indirect Cost
$11,360
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Blatt, Neal B; Srinivasan, Sushant; Mottes, Theresa et al. (2014) Biology of sepsis: its relevance to pediatric nephrology. Pediatr Nephrol 29:2273-87