Modeling the Progression of Hypertensive Kidney Disease in African Americans
Authors: Clemmer John S. 
Published: May 2022

Chronic kidney disease (CKD) is associated with the progressive functional loss of nephrons and hypertension (HTN). Several clinical studies demonstrate calcium channel blocker (CCB) therapy mitigates the decline in renal function in humans with essential HTN, but there are few long‐term clinical studies that determine the impact of CCBs in patients with hypertensive CKD. African Americans (AA) have a faster progression to end stage renal disease as compared to the white population which may be partially explained by factors such as salt‐sensitive blood pressure (BP) and greater prevalence of uncontrolled HTN. Observational studies demonstrate BP to be a strong independent risk factor for CKD progression, yet intense BP lowering in AA does not diminish the renal function decline any more than standard therapy. The African American Study of Kidney Disease and Hypertension (AASK) trial suggests AA with proteinuric CKD may have detrimental responses to CCB as compared to an angiotensin converting enzyme (ACE) inhibitor. Therefore, using a large physiological model, we set out to replicate the AASK trial findings and predict the roles of the renin‐angiotensin system, salt intake, and intensive antihypertensive therapy in a virtual population during CCB therapy. Our current mathematical model, HumMod, is a large physiological simulator that is comprised of key systems that play an integral role in BP control such as neural, endocrine, circulatory, and renal systems. All of the parameters (n=335) that control these systems were randomly varied and resulted in over 3,000 unique models that we define as a virtual population. We calibrated this virtual population to patient level data from the AASK trial (BP and glomerular filtration rate [GFR] before and after 3 years of amlodipine). After matching the virtual population to individual level data, the virtual population (n=140) was associated with statistically similar BP and GFR before and after CCB therapy (Figure) as well as similar increases in glomerular damage. Baseline factors such as elevated single nephron GFR and increased tubuloglomerular feedback were correlated with greater declines in renal function and increased glomerulosclerosis after 3 years of CCB. Interestingly, when looking at the models with severe CKD (<35 mL/min), glomerulosclerosis and angiotensin II significantly increased with CCB despite significant falls in mean BP (‐7 ± 7 mmHg). Adding an ACE inhibitor decreased angiotensin II levels and abrogated the increase in glomerulosclerosis while further decreasing BP (‐12 ± 9 mmHg). Decreasing salt intake in addition to the CCB+ACE inhibitor therapy further benefited systemic and glomerular pressures but significantly decreased overall GFR independent of any glomerular damage. Finally, all antihypertensive therapies were associated with significant decreases in left ventricular mass. These data suggest the current clinical markers of renal function such as eGFR may not fully reflect the actual progression of CKD, especially with intensive antihypertensive treatment. Our simulation also supports that angiotensin system inhibitors are renoprotective and cardioprotective when combined with CCB therapy in African American CKD patients.