Project Grant R01HL175306

BUILDING A KIDNEY MONITORING PANEL TO GUIDE THERAPY IN RESISTANT HYPERTENSION - PROJECT SUMMARY HYPERTENSION (HTN) IS THE MOST COMMON RISK FACTOR FOR CARDIOVASCULAR DISEASE (CVD) AND CAUSES MULTIPLE HEALTH PROBLEMS INCLUDING STROKE, HEART FAILURE, KIDNEY FAILURE, MYOCARDIAL INFARCTION, AND DEATH. RESISTANT HTN IS DEFINED BY FAILURE TO REACH BLOOD PRESSURE (BP) GOAL DESPITE THE USE OF 3 OR MORE HTN MEDICATIONS. AMONG THE MOST CHALLENGING POPULATIONS WITH RESISTANT HTN TO TREAT ARE PERSONS WITH RENAL ARTERY STENOSIS (RAS) SINCE HTN TREATMENT IN RAS OFTEN CAUSES CHANGES IN CREATININE (CR). FURTHERMORE, THESE INDIVIDUALS HAVE EXTREMELY HIGH CVD RISK, SO ACHIEVING BP CONTROL IS ESPECIALLY IMPORTANT. A MAJOR CHALLENGE THAT IMPAIRS HTN TREATMENT IS THE PERCEPTION OF WORSENING KIDNEY FUNCTION OR ACUTE KIDNEY INJURY (AKI) BASED ON CREATININE (CR) CHANGES DURING HTN TREATMENT. BLOOD PRESSURE LOWERING IS OFTEN ACCOMPANIED BY CHANGES IN CR, WHICH IN TURN, TYPICALLY LEADS TO INTERRUPTION OR CESSATION OF EFFECTIVE HTN MEDICATIONS; THIS CLINICAL RESPONSE IS HARMFUL TO PATIENTS BECAUSE THESE ELEVATIONS IN CR ARE TYPICALLY CAUSED BY BENIGN ACCOMMODATIONS TO HEMODYNAMIC CHANGES RATHER THAN ACUTE KIDNEY INJURY (AKI). THE GOAL OF THIS PROPOSAL IS TO DEVELOP A BETTER KIDNEY HEALTH MONITORING SYSTEM, A URINE-BASED KIDNEY TUBULE HEALTH PANEL (KTHP), THAT CAN ADJUDICATE AKI VS. BENIGN CR CHANGES DURING HTN TREATMENT, AND THUS ADDRESS A CRITICAL UNMET NEED. IN AIM 1, WE WILL DETERMINE WHETHER KTHP BIOMARKERS PREDICT THE MAGNITUDE OF BP LOWERING DURING TREATMENT WITH A COMPREHENSIVE AND STRUCTURED BP LOWERING INTERVENTION. IN AIM 2, WE WILL DETERMINE IF THE MAGNITUDE OF BP LOWERING IS ASSOCIATED WITH CHANGES IN KTHP MARKERS AT 1-YEAR; AND, WE WILL EVALUATE ASSOCIATIONS OF DECREASES IN EGFR WITH THE CHANGES IN THE INTRINSIC KIDNEY DAMAGE MARKERS (KTHP) AT 1-YEAR. THESE STUDIES WILL PROVIDE CRITICAL INSIGHTS INTO THE COMPARATIVE UTILITY OF KTHP BIOMARKERS VS. CREATININE DURING BP LOWERING. IN AIM 3, WE WILL EVALUATE ASSOCIATIONS OF BOTH BASELINE AND CHANGES IN 1-YEAR KTHP WITH CVD EVENTS. THESE AIMS WILL BE ACCOMPLISHED BY UTILIZING THE RICH AND DETAILED CLINICAL PHENOTYPING OF THE CARDIOVASCULAR OUTCOMES IN RENAL ATHEROSCLEROTIC LESIONS (CORAL) TRIAL, INCLUDING ADJUDICATED CLINICAL EVENTS. THE CORAL TRIAL BIOSPECIMEN BANK HAS BASELINE AND 1 YEAR URINE SPECIMENS THAT WILL ALLOW FOR KTHP BIOMARKER ASSESSMENT. THE METHODS IN THIS PROPOSAL WILL BUILD ON OUR PRIOR WORK IN THE SPRINT TRIAL AND WILL VALIDATE THE KTHP BIOMARKERS IN A HIGH-RISK HTN COHORT WITH FREQUENT CHANGES IN CR DURING BP LOWERING TREATMENT. TOGETHER, THESE STUDIES WILL PROVIDE DETAILED INVESTIGATION OF URINE KTHP BIOMARKERS FOR MONITORING DURING TREATMENT OF RESISTANT HTN. OVERALL, WE AIM TO IMPROVE OR REPLACE THE CURRENT CR-BASED KIDNEY HEALTH MONITORING SYSTEM, AND TO PROVE THE ACCURACY AND UTILITY OF THE PROPOSED KTHP BIOMARKERS FOR MONITORING DURING BOTH RESISTANT AND GENERAL HTN TREATMENT.