Chronic kidney disease (CKD) has both a clinical description (reduced kidney function and protein in the urine) and a pathological description (nephrosclerosis as characterized by glomerulosclerosis, tubular atrophy, interstitial fibrosis, and arteriosclerosis). Both occur with age, but little is known about their relationship to each other. The goal of this study is to characterize age-related changes in the kidney in a large sample of living kidney donors at two sites (Mayo Clinic and Cleveland Clinic), to identify biomarkers that predict these changes, and to eventually relate renal pathology and biomarkers that detect renal pathology to clinical outcomes in future studies. Combining computed tomography (CT) scan findings (total renal cortex volume) and renal biopsy findings (glomeruli per renal cortex unit volume) allows estimation of nephron endowment (total number of nephrons a person is born with). Our central hypothesis is that with aging, progressive nephrosclerosis leads to atrophy of nephrons with cortical volume loss and scarring. This volume loss is initially compensated by hypertrophy of viable nephrons, which leads to further nephrosclerosis. Eventually, however, volume loss from nephrosclerosis overwhelms the compensatory hypertrophy of remaining nephrons and the kidneys decrease in size.
Aim 1. To test the hypothesis that age, GFR, urine albumin, and CKD risk factors associate with A) macro- anatomy findings of decreased renal cortical volume and focal scarring on CT scan among adults undergoing a standardized evaluation for potential kidney donation (n=4300), and B) micro-anatomy findings of nephrosclerosis and nephron size on renal biopsy among adults who actually donate a kidney (n=2500), and furthermore, to determine if increased nephron endowment is protective against age-related nephrosclerosis and the increased size of viable nephrons.
Aim 2. To test the hypothesis that 10 novel serum and urine biomarkers for CKD (e.g., kidney injury molecule 1) associate with age-related changes A) in decreased renal cortical volume and focal scarring by CT scan (1500 potential donors) and B) in nephrosclerosis and nephron size by renal biopsy (1000 actual donors).

Public Health Relevance

As adults age, some of the healthy tissue in the kidney is gradually replaced by scar tissue. We plan to determine whether clinical tests can detect these age-related changes in the kidney. This will improve our understanding of how chronic kidney disease develops in people as they age and eventually lead to better ways to diagnose, prevent, and treat chronic kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK090358-04
Application #
8602520
Study Section
Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Flessner, Michael Francis
Project Start
2011-02-10
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
4
Fiscal Year
2014
Total Cost
$596,261
Indirect Cost
$197,040
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Rule, Andrew D; Kremers, Walter K (2016) What Is the Correct Approach for Comparing GFR by Different Methods across Levels of GFR? Clin J Am Soc Nephrol 11:1518-21
Denic, Aleksandar; Glassock, Richard J; Rule, Andrew D (2016) Structural and Functional Changes With the Aging Kidney. Adv Chronic Kidney Dis 23:19-28
Denic, Aleksandar; Alexander, Mariam P; Kaushik, Vidhu et al. (2016) Detection and Clinical Patterns of Nephron Hypertrophy and Nephrosclerosis Among Apparently Healthy Adults. Am J Kidney Dis 68:58-67
Keddis, Mira T; Amer, Hatem; Voskoboev, Nikolay et al. (2016) Creatinine-Based and Cystatin C-Based GFR Estimating Equations and Their Non-GFR Determinants in Kidney Transplant Recipients. Clin J Am Soc Nephrol 11:1640-9
Hommos, Musab S; Rule, Andrew D (2016) Should We Always Defer Treatment of Kidney Disease When There Is Extensive Interstitial Fibrosis on Biopsy? Am J Nephrol 44:286-288
Delanaye, Pierre; Glassock, Richard J; Pottel, Hans et al. (2016) An Age-Calibrated Definition of Chronic Kidney Disease: Rationale and Benefits. Clin Biochem Rev 37:17-26
Wang, Xiangling; Lieske, John C; Alexander, Mariam P et al. (2016) Tubulointerstitial Fibrosis of Living Donor Kidneys Associates with Urinary Monocyte Chemoattractant Protein 1. Am J Nephrol 43:454-9
Turco, Anne E; Lam, Wing; Rule, Andrew D et al. (2016) Specific renal parenchymal-derived urinary extracellular vesicles identify age-associated structural changes in living donor kidneys. J Extracell Vesicles 5:29642
Denic, Aleksandar; Lieske, John C; Chakkera, Harini A et al. (2016) The Substantial Loss of Nephrons in Healthy Human Kidneys with Aging. J Am Soc Nephrol :
Chakkera, Harini A; Chang, Yu-Hui H; Thomas, Leslie F et al. (2015) Obesity Correlates With Glomerulomegaly But Is Not Associated With Kidney Dysfunction Early After Donation. Transplant Direct 1:1-6

Showing the most recent 10 out of 30 publications