The purpose of this multi-disciplinary project is to provide this outstanding candidate with mentored training in patient-oriented research focused on complications of cirrhosis and liver transplantation (LT) outcomes and to prepare her for a career as an independent clinician-scientist. The candidate's research and training activities will be closely supervised and guided by a primary mentor, co-mentors, an Advisory Committee and consultants, each with unique expertise germane to different aspects of the proposed project. The candidate's preliminary data showed that women with serum creatinine (Cr) e 1.0 mg/dl had lower survival rates on the LT waiting list compared to men;this was likely caused by underestimating renal dysfunction in women when using Cr rather than glomerular filtration rate (GFR) to calculate Model for End-Stage Liver Disease (MELD) scores. Moreover, serum Cr is not an accurate biomarker to detect kidney dysfunction in cirrhosis regardless of gender. The PI will test the hypotheses that (1) gender disparity is caused by underestimating severity of kidney disease in women when using serum Cr rather than GFR to calculate MELD scores, (2) that cystatin C and symmetric dimethylarginine (SDMA) are more accurate biomarkers of renal function in cirrhosis than Cr, and (3) that an equation that includes serum cystatin C, SDMA or both and patient characteristics will be more accurate and precise for determining renal dysfunction in subjects with cirrhosis than existing Cr- and cystatin C-based GFR-estimating equations that were derived in populations without cirrhosis. To test these hypotheses, the PI proposes three Specific Aims: 1) Test the hypothesis that gender disparity on the LT waiting list is caused by underestimating renal dysfunction in women when using serum Cr rather than GFR to calculate MELD scores. The PI will elucidate factors underlying gender disparity on the LT waiting list by analyzing United Network for Organ Sharing data of subjects with cirrhosis listed between 2002 and 2009. 2) Establish an accurate biomarker of kidney function in cirrhosis. The PI will enroll 100 subjects with cirrhosis, directly measure GFR using the validated method of non-radiolabeled iothalamate plasma clearance and simultaneously measure serum cystatin C, SDMA, Cr and 24-hour urinary Cr clearance and compare the accuracy of each biomarker for estimating true GFR. 3) Develop an accurate and precise equation to estimate GFR in cirrhosis. The PI will derive and assess the performance of a novel GFR-estimating equation in cirrhosis, based on serum cystatin C, SDMA or both and patient characteristics. The results of this study are anticipated to spur modifications of the MELD score that will reduce gender disparity in liver allocation and establish an inexpensive, readily available, accurate, non-invasive measure of kidney function in cirrhosis. The mentored research training and courses supported by this K23 award will provide the PI with excellent grounding for a successful academic career in health services and patient-oriented research.

Public Health Relevance

Cirrhosis (advanced scarring of the liver) is a leading cause of death and the most common indication for liver transplantation. Patients with cirrhosis are at high risk to develop kidney disease. If kidney disease is not timely and accurately detected in patients with cirrhosis, it may progress to kidney failure and lead to higher mortality rates in women on the liver transplant waiting list causing gender disparity. Currently, existing blood and urine tests are not sensitive enough to detect kidney injury in patients with cirrhosis. This proposed project will examine the gender disparity on the liver transplant waiting list, how well the kidneys work (kidney function) and determine which blood tests are the most accurate for detecting kidney disease in cirrhosis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZDK1-GRB-8 (M2))
Program Officer
Podskalny, Judith M,
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University of Maryland Baltimore
Internal Medicine/Medicine
Schools of Medicine
United States
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Mindikoglu, Ayse L; Opekun, Antone R; Mitch, William E et al. (2018) Cystatin C Is a Gender-Neutral Glomerular Filtration Rate Biomarker in Patients with Cirrhosis. Dig Dis Sci 63:665-675
Mindikoglu, Ayse L; Opekun, Antone R; Putluri, Nagireddy et al. (2018) Unique metabolomic signature associated with hepatorenal dysfunction and mortality in cirrhosis. Transl Res 195:25-47
Urrunaga, Nathalie H; Magder, Laurence S; Weir, Matthew R et al. (2016) Prevalence, Severity, and Impact of Renal Dysfunction in Acute Liver Failure on the US Liver Transplant Waiting List. Dig Dis Sci 61:309-16
Mindikoglu, Ayse L; Dowling, Thomas C; Magder, Laurence S et al. (2016) Estimation of Glomerular Filtration Rate in Patients With Cirrhosis by Using New and Conventional Filtration Markers and Dimethylarginines. Clin Gastroenterol Hepatol 14:624-632.e2
Mindikoglu, Ayse L; Dowling, Thomas C; Schaub, David J et al. (2015) Pharmacokinetics and Tolerability of Intravenous Sildenafil in Two Subjects with Child-Turcotte-Pugh Class C Cirrhosis and Renal Dysfunction. Dig Dis Sci 60:3491-4
Urrunaga, Nathalie H; Mindikoglu, Ayse L; Rockey, Don C (2015) Renal dysfunction in cirrhosis. Curr Opin Gastroenterol 31:215-23
Mindikoglu, Ayse L; Dowling, Thomas C; Weir, Matthew R et al. (2014) Performance of chronic kidney disease epidemiology collaboration creatinine-cystatin C equation for estimating kidney function in cirrhosis. Hepatology 59:1532-42
Reddy, Srinevas K; Reilly, Colleen; Zhan, Min et al. (2014) Long-term influence of chemotherapy on steatosis-associated advanced hepatic fibrosis. Med Oncol 31:971
Mindikoglu, Ayse L; Dowling, Thomas C; Wong-You-Cheong, Jade J et al. (2014) A pilot study to evaluate renal hemodynamics in cirrhosis by simultaneous glomerular filtration rate, renal plasma flow, renal resistive indices and biomarkers measurements. Am J Nephrol 39:543-52
Urrunaga, N H; Rachakonda, V P; Magder, L S et al. (2014) Outcomes of living versus deceased donor liver transplantation for acute liver failure in the United States. Transplant Proc 46:219-24

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