End-stage liver disease (ESLD) resulting from various causes of chronic liver disease is one of the leading causes of premature mortality in the United States. For these patients, liver transplantation (LTx) can improve survival and restore health. One of the most common and serious complications in patients with ESLD undergoing LTx is acute and chronic kidney disease. We have recently demonstrated that many (50%) of LTx recipients have evidence of serious kidney damage known as acute tubular necrosis (ATN) and nephrosclerosis (NSc). In particular, essentially all of the patients who had ATN at the time of LTx developed chronic kidney disease (CKD) within 4 months of LTx. In this application, we ask the following clinically relevant questions: (1) Is the high prevalence of ATN and NSc shown in our study generalizable to LTx recipients at large;(2) can these histologic changes be diagnosed by non-invasive markers;and (3) does incorporating the renal histology information into patient management improve patient outcome following LTx? In order to address these questions, we propose to undertake the following studies.
In AIM1, we will evaluate renal histology as a predictor of post-LTx renal function. In a well-established multicenter prospective cohort of LTx recipients, we will perform intraoperative renal biopsies at the time of LTx and (1) determine the prevalence of ATN and NSc in LTx recipients and (2) measure the impact of ATN and NSc on kidney function 1 year after LTx.
In AIM2, we will examine urinary biomarkers as a correlate of ATN in ESLD patients, based on our preliminary data that urinary biomarkers such as 1- microglobulin, neutrophil gelatinase-associated lipocalin, kidney injury molecule-1 and microalbumin correlate with renal histology, specifically ATN. Individual studies of AIM2 will (1) develop and validate a mathematical model to diagnose ATN in LTx recipients based on a panel of urinary biomarkers and (2) determine the clinical significance of these biomarkers by correlating them with future kidney function.
In AIM3, we will conduct a pilot trial for individualized medical management ('renal sparing protocol') in LTx recipients utilizing information obtained from the renal biopsy. Taken together, these studies will advance knowledge about the renal abnormalities in ESLD and LTx patients and help optimize patient outcomes by providing valid, accurate and practical clinical tools with which to identify patients at risk of serious morbidity and mortality and provide effective, individualized intervention.

Public Health Relevance

The goal of this research is to understand the nature of kidney disease that occurs in patients with cirrhosis undergoing liver transplantation. We will accomplish this goal by obtaining and analyzing biopsies of the kidney and urine samples in patients undergoing liver transplantation and correlating their results with kidney function after transplantation. We will also conduct a pilot trial to evaluate whether individualized care of live transplant recipients can help improve their kidney function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK034238-28
Application #
8724473
Study Section
Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Sherker, Averell H
Project Start
1986-01-15
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
28
Fiscal Year
2014
Total Cost
$544,027
Indirect Cost
$87,918
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Allen, Alina M; Kim, W Ray; Heimbach, Julie K et al. (2015) Reply to: "Chronic kidney disease (CKD) and NAFLD: time for awareness and screening". J Hepatol 62:984-5
Allen, Alina M; Kim, W Ray; Therneau, Terry M et al. (2014) Chronic kidney disease and associated mortality after liver transplantation--a time-dependent analysis using measured glomerular filtration rate. J Hepatol 61:286-92
Kim, Bo Hyun; Park, Joong-Won; Nam, Byung-Ho et al. (2014) Validation of a model to estimate survival in ambulatory patients with hepatocellular carcinoma: a single-centre cohort study. Liver Int 34:e317-23
Allen, A M; Kim, W R; Xiong, H et al. (2014) Survival of recipients of livers from donation after circulatory death who are relisted and undergo retransplant for graft failure. Am J Transplant 14:1120-8

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