This proposal describes a five year intensive mentored training program with the goal of developing the Principal Investigator (PI) into an independent and high impact, patient-oriented researcher. The PI is a fully trained adult cardiologist, has obtained formal research training in the Masters in Translational Research program, and is currently completing an advanced heart failure (HF) and cardiac transplantation clinical fellowship at the University of Pennsylvania. His clinical research mentorship to date has been lead by Dr. Stephen Kimmel (Primary Mentor of this proposal) and as evidenced by the PI's 11 first author publications under Dr. Kimmel's supervision, this is a highly effective mentoring relationship. However, successful transition of the PI to research independence will require substantial additional training and intense mentored career development. A comprehensive training proposal is thus proposed to facilitate the above, which will include: 1) Intensive mentoring from a team lead by Dr. Kimmel 2) Advanced didactic coursework 3) Hands on experience in prospective patient-oriented research 4) Scientific advisory by eminent cardio-renal scholars such as Drs. John Burnett and Robert Schrier 5) Structured career development and establishment of a body of scientific work with which the transition to independence will be based. The overall objective of the scientific aspect of this proposal is to better define cardio-renal phenotypes and their prognostic importance in HF. Renal dysfunction (RD) is a common complication of HF and one of the strongest risk factors for death in these patients. Severe HF and its treatment (i.e., loop diuretics) are known to result in progressive neurohormonal activation and peripheral organ dysfunction (i.e., RD). The risk attributable to RD appears to be isolated to patients with an elevated blood urea nitrogen to creatinine ratio (BUN/Cr), which is a surrogate for renal neurohormonal activation. If neurohormonal activation is indeed underlying the above observations, the direct treatment implications are substantial. However, BUN/Cr is influenced by factors external to neurohormonal activation, and these non-neurohormonal factors may also be important in RD- associated mortality.
The aims of this proposal are to quantify the degree to which neurohormones are elevated in HF patients with RD and elevated BUN/Cr, investigate the influence of loop diuretics in the genesis of these neurohormonal abnormalities, and establish whether it is the neurohormonally dependent aspects of BUN/Cr that are driving these mortality observations. We will achieve these aims by: 1) Direct characterization of neurohormonal parameters in HF patients with RD and either a high or low BUN/Cr in the Clinical and Translational Research Center, before and after loop diuretic exposure. 2) Determination in a large prospective HF cohort, the Penn Heart Failure Study, if the fractional excretion of urea (which captures the neurohormonally mediated aspect of BUN/Cr) is responsible for the ability of BUN/Cr to differentiate high and low risk forms of RD. The results of this line of investigation will form the basis upon which future interventional trias in these high risk patients can be based. The combination of formal advanced research training and mentored patient-oriented research experience will ensure the PI emerges as a highly successful independent patient-oriented researcher in HF and cardio- renal interactions.

Public Health Relevance

Heart failure is a common condition and can cause dysfunction of other organs such as the kidneys. Recent studies have shown that people with kidney dysfunction from heart failure have a very high risk of death. An improved understanding of how heart failure causes kidney dysfunction could lead to important therapies for these patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23HL114868-01
Application #
8353910
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Scott, Jane
Project Start
2012-08-10
Project End
2017-06-30
Budget Start
2012-08-10
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Hanberg, Jennifer S; Rao, Veena S; Ahmad, Tariq et al. (2018) Inflammation and cardio-renal interactions in heart failure: a potential role for interleukin-6. Eur J Heart Fail 20:933-934
Costanzo, Maria Rosa; Barasch, Jonathan (2018) Creatinine and Cystatin C: Not the Troponin of the Kidney. Circulation 137:2029-2031
Bikdeli, Behnood; Testani, Jeffrey M; Ross, Joseph S et al. (2018) Older drugs with infantile evidence: the illustrative example of loop diuretics. Eur Heart J Qual Care Clin Outcomes 4:232-234
Ahmad, Tariq; Jackson, Keyanna; Rao, Veena S et al. (2018) Worsening Renal Function in Patients With Acute Heart Failure Undergoing Aggressive Diuresis Is Not Associated With Tubular Injury. Circulation 137:2016-2028
Saly, Danielle; Yang, Alina; Triebwasser, Corey et al. (2017) Approaches to Predicting Outcomes in Patients with Acute Kidney Injury. PLoS One 12:e0169305
Testani, Jeffrey M; Brisco-Bacik, Meredith A (2017) Worsening Renal Function and Mortality in Heart Failure: Causality or Confounding? Circ Heart Fail 10:
Soufer, Aaron; Riello, Ralph J; Desai, Nihar R et al. (2017) A Blueprint for the Post Discharge Clinic Visit after an Admission for Heart Failure. Prog Cardiovasc Dis 60:237-248
Grodin, Justin L; Sun, Jie-Lena; Anstrom, Kevin J et al. (2017) Implications of Serum Chloride Homeostasis in Acute Heart Failure (from ROSE-AHF). Am J Cardiol 119:78-83
Ahmad, Tariq; Testani, Jeffrey M (2017) What happens to stable heart failure patients when they don't take their medicines? Eur J Heart Fail 19:650-651
Hanberg, Jennifer S; Tang, W H Wilson; Wilson, F Perry et al. (2017) An exploratory analysis of the competing effects of aggressive decongestion and high-dose loop diuretic therapy in the DOSE trial. Int J Cardiol 241:277-282

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