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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Kidney, Nutrition, Obesity and Diabetes (KNOD)
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Sherker, Averell H
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Stanford University
Internal Medicine/Medicine
Schools of Medicine
United States
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Heo, Nae-Yun; Mannalithara, Ajitha; Kim, Donghee et al. (2018) Long-term Patient and Graft Survival of Kidney Transplant Recipients With Hepatitis C Virus Infection in the United States. Transplantation 102:454-460
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Yang, Ju Dong; Mannalithara, Ajitha; Piscitello, Andrew J et al. (2018) Impact of surveillance for hepatocellular carcinoma on survival in patients with compensated cirrhosis. Hepatology 68:78-88
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Kwong, Allison; Kim, W Ray; Mannalithara, Ajitha et al. (2018) Decreasing mortality and disease severity in hepatitis C patients awaiting liver transplantation in the United States. Liver Transpl 24:735-743
Flemming, Jennifer A; Kim, W Ray; Brosgart, Carol L et al. (2017) Reduction in liver transplant wait-listing in the era of direct-acting antiviral therapy. Hepatology 65:804-812
Kim, Sang Gyune; Larson, Joseph J; Lee, Ji Sung et al. (2017) Beneficial and harmful effects of nonselective beta blockade on acute kidney injury in liver transplant candidates. Liver Transpl 23:733-740
Allen, Alina M; Kim, W Ray; Larson, Joseph J et al. (2016) The Epidemiology of Liver Diseases Unique to Pregnancy in a US Community: A Population-Based Study. Clin Gastroenterol Hepatol 14:287-94.e1-2
Yang, Ju Dong; Mohamed, Hager Amed; Cvinar, Jessica L et al. (2016) Diabetes Mellitus Heightens the Risk of Hepatocellular Carcinoma Except in Patients With Hepatitis C Cirrhosis. Am J Gastroenterol 111:1573-1580

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