This is a resubmission of a K23 application for Dr. Vasantha Jotwani, a nephrologist at the University of California, San Francisco. Dr. Jotwani is establishing herself as a young investigator in patient-oriented clinical research of biomarkers and drug-induced kidney injury in HIV-infected and uninfected individuals. Her goal is to become a leading clinical investigator in the utilization of novel kidney biomarkers for the detection of nephrotoxicity. This K23 award will provide Dr. Jotwani with the support necessary to accomplish the following goals: 1) to become an expert at patient-oriented clinical research on novel biomarkers and drug-induced kidney injury; 2) to gain expertise in advanced statistical methods for cohort analyses; 3) to become proficient in the evaluation of biomarker performance; 4) to implement biomarker measures in a prospective clinical study; and 5) to develop an independent clinical research career. To achieve these goals, Dr. Jotwani has assembled a multidisciplinary mentorship team comprised of a primary mentor, Dr. Michael Shlipak, a renowned expert on biomarkers for kidney disease diagnosis and prognostication, and the following additional mentors and advisors: Dr. Phyllis Tien, an authority on the long-term consequences of HIV infection; Dr. Chirag Parikh, an international leader in biomarkers of acute kidney injury; Dr. Eric Vittinghoff, an applied statistician in epidemiologic and clinical research studies; and Dr. Albert Liu, who has expertise in the implementation of HIV prevention strategies. Tenofovir disoproxil fumarate (TDF), a widely prescribed antiretroviral medication for HIV treatment and pre-exposure prophylaxis (PrEP), has been associated with the development of acute kidney injury and chronic kidney disease. However, current clinical measures lack sensitivity and specificity for the detection of TDF-associated nephrotoxicity. Dr. Jotwani proposes to utilize novel urine biomarkers of tubular and mitochondrial damage to identify and monitor kidney injury in HIV-infected and uninfected persons who are receiving TDF.
In Aim 1, she will measure the novel urine biomarkers longitudinally following TDF initiation to characterize the onset and progression of kidney damage in HIV-infected participants of the Women's Interagency HIV Study (WIHS) and the Multicenter AIDS Cohort Study (MACS); then, she will compare these markers with existing clinical measures of tubular health.
In Aim 2, she will evaluate whether the integration of biomarkers with clinical factors can improve long-term prognostication of kidney disease risk among HIV- infected TDF users in WIHS and MACS. Finally, Aim 3 will apply the most promising biomarkers from Aims 1 and 2 to investigate the impact of PrEP on kidney injury in the PrEP-T Demonstration Project, a prospective clinical study of HIV-uninfected transgender persons who will initiate PrEP with TDF/emtricitabine through the San Francisco Department of Public Health. This research will lay the groundwork for the implementation of a biomarker-based algorithm for the detection and monitoring of nephrotoxicity in HIV-infected and uninfected persons, to be proposed in an R01 grant application towards the end of this K award.

Public Health Relevance

Tenofovir disoproxil fumarate is commonly prescribed for HIV treatment and prevention, but it can cause severe kidney damage. The findings from these studies will help clinicians to diagnose kidney damage from tenofovir and other medicines at the earliest stages, which may reduce the burden of kidney disease among millions of individuals worldwide.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23DK109868-05
Application #
9951037
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2016-09-15
Project End
2021-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Jotwani, Vasantha; Scherzer, Rebecca; Glidden, David V et al. (2018) Pre-exposure Prophylaxis With Tenofovir Disoproxil Fumarate/Emtricitabine and Kidney Tubular Dysfunction in HIV-Uninfected Individuals. J Acquir Immune Defic Syndr 78:169-174
Jotwani, Vasantha; Katz, Ronit; Ix, Joachim H et al. (2018) Urinary Biomarkers of Kidney Tubular Damage and Risk of Cardiovascular Disease and Mortality in Elders. Am J Kidney Dis 72:205-213
Baxi, Sanjiv M; Scherzer, Rebecca; Jotwani, Vasantha et al. (2017) Changes in Urinary Biomarkers Over 10 Years Is Associated With Viral Suppression in a Prospective Cohort of Women Living With HIV. J Acquir Immune Defic Syndr 74:e138-e145
Park, M; Katz, R; Shlipak, M G et al. (2017) Urinary Markers of Fibrosis and Risk of Cardiovascular Events and Death in Kidney Transplant Recipients: The FAVORIT Trial. Am J Transplant 17:2640-2649
Chen, Ruijun; Scherzer, Rebecca; Hsue, Priscilla Y et al. (2017) Association of Tenofovir Use With Risk of Incident Heart Failure in HIV-Infected Patients. J Am Heart Assoc 6:
Jotwani, Vasantha; Scherzer, Rebecca; Estrella, Michelle M et al. (2017) Association of HIV infection with biomarkers of kidney injury and fibrosis in the Multicenter AIDS Cohort Study. Antivir Ther 22:421-429
Jotwani, Vasantha; Scherzer, Rebecca; Estrella, Michelle M et al. (2016) Brief Report: Cumulative Tenofovir Disoproxil Fumarate Exposure is Associated With Biomarkers of Tubular Injury and Fibrosis in HIV-Infected Men. J Acquir Immune Defic Syndr 73:177-81
Jotwani, Vasantha; Scherzer, Rebecca; Estrella, Michelle M et al. (2016) HIV Infection, Tenofovir, and Urine ?1-Microglobulin: A Cross-sectional Analysis in the Multicenter AIDS Cohort Study. Am J Kidney Dis 68:571-581