Only patients thought to have a severe nephropathy undergo a kidney biopsy to assess structural pathology. Much effort has been expended to identify new biomarkers for kidney pathology, but the extent to which kidney pathology predicts adverse outcomes in patients without a severe nephropathy is unknown. This renewal proposal will fill this key knowledge gap by detailing the age-related and subclinical disease-related structural pathology on renal biopsy and CT scan of patients without a severe nephropathy. Structural pathology and morphology based on biopsy (nephrosclerosis and nephron hypertrophy) and computed tomography (CT) scans (cortical volume, surface roughness, cysts); and nephron number (estimated from biopsy and CT) will be analyzed to determine how they relate to adverse kidney outcomes. Three complementary populations not defined by a severe nephropathy will be studied: living kidney donors, kidney transplant recipients paired to these living donors, and tumor nephrectomy patients. These specific populations will also benefit most from the findings. Kidney donor selection and post-donation monitoring will be improved by identifying donors at highest risk for chronic kidney disease (CKD). Kidney transplant recipients usually take any donated kidney they can due to limited options, but a major determinant of allograft failure is the age of the living donor. Determining the structural findings in older allografts that predict kidney failure risk is a needed step to improved management of kidney recipients. In patients with a renal tumor, decisions regarding a complete (radical) versus partial nephrectomy versus monitoring would be informed by the risk for kidney failure as predicted by non-tumor kidney pathology. The study hypotheses are that 1) nephrosclerosis, nephron hypertrophy, and reduced nephron number are predictive of adverse kidney outcomes independent of age, kidney function, and (CKD) risk factors, and 2) CT scans of the kidneys detect this underlying renal pathology and can be used to predict adverse kidney outcomes.
Three Specific Aims test these hypotheses: 1. In 3,000 living kidney donors, nephrosclerosis, larger nephron size, and decreased nephron number (as determined by implantation renal biopsy and pre-donation CT scan) are predictive of lower glomerular filtration rate (GFR), lower residual GFR (rGFR), proteinuria, and hypertension at 3-6 months after donation and at 5-20 years after donation. 2. In the 3,000 kidney transplant recipients matched to these donors, the same baseline structural findings in the donor kidney are predictive of death-censored graft loss (kidney failure), all-cause graft loss (kidney failure or death), GFR decline, proteinuria, and increased interstitial fibrosis on ensuing protocol biopsies. 3. In 1,000 tumor nephrectomy patients, these same kidney structural findings are predictive of kidney failure, non-cancer mortality, and lower rGFR (follow-up GFR/pre-nephrectomy GFR).

Public Health Relevance

Very little is known about the underlying health status of the kidneys in most patients. Unfortunately, blood and urine tests do not adequately solve this problem. However, due to the unique situation of kidney donation and kidney removal for cancer, CT scans and biopsies are available to detect unhealthy kidney tissue. This research project will determine which patients have unhealthy kidney tissue that can lead to chronic kidney disease in order to improve the medical care of these patients.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Kidney, Nutrition, Obesity and Diabetes Study Section (KNOD)
Program Officer
Hoshizaki, Deborah K
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Mayo Clinic, Rochester
United States
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Chakkera, Harini A; Denic, Aleksandar; Kremers, Walter K et al. (2018) Comparison of high glomerular filtration rate thresholds for identifying hyperfiltration. Nephrol Dial Transplant :
Piras, Doloretta; Masala, Marco; Delitala, Alessandro et al. (2018) Kidney size in relation to ageing, gender, renal function, birthweight and chronic kidney disease risk factors in a general population. Nephrol Dial Transplant :
Denic, Aleksandar; Mathew, Jerry; Nagineni, Venkata V et al. (2018) Clinical and Pathology Findings Associate Consistently with Larger Glomerular Volume. J Am Soc Nephrol 29:1960-1969
Hommos, Musab S; Zeng, Caihong; Liu, Zhihong et al. (2018) Global glomerulosclerosis with nephrotic syndrome; the clinical importance of age adjustment. Kidney Int 93:1175-1182
Denic, Aleksandar; Lieske, John C; Chakkera, Harini A et al. (2017) The Substantial Loss of Nephrons in Healthy Human Kidneys with Aging. J Am Soc Nephrol 28:313-320
Denic, Aleksandar; Mathew, Jerry; Lerman, Lilach O et al. (2017) Single-Nephron Glomerular Filtration Rate in Healthy Adults. N Engl J Med 376:2349-2357
Hommos, Musab S; Glassock, Richard J; Rule, Andrew D (2017) Structural and Functional Changes in Human Kidneys with Healthy Aging. J Am Soc Nephrol 28:2838-2844
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
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
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

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