Questioning the renoprotective role of L-type calcium channel blockers in chronic kidney disease using physiological modeling.
Pubmed ID: 34486399
Pubmed Central ID: PMC8560404
Journal: American journal of physiology. Renal physiology
Publication Date: 10/01/2021
Affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.
MeSH Terms: Humans, Models, Biological, Hypertension, Treatment Outcome, Blood Pressure, Computer Simulation, Time Factors, Renal Insufficiency, Chronic, Antihypertensive Agents, Vasodilator Agents, Calcium Channel Blockers, Kidney Glomerulus, Calcium Channels, L-Type, Calcium Channels, T-Type
Grants: K99 MD014738, P01 HL051971, P20 GM104357, T32 HL105324
Authors: Moore KH, Clemmer JS
Cite As: Moore KH, Clemmer JS. Questioning the renoprotective role of L-type calcium channel blockers in chronic kidney disease using physiological modeling. Am J Physiol Renal Physiol 2021 Oct 1;321(4):F548-F557. Epub 2021 Sep 6.
Chronic kidney disease (CKD) is characterized by the progressive functional loss of nephrons and hypertension (HTN). Some antihypertensive regimens attenuate the progression of CKD (blockers of the renin-angiotensin system). Although studies have suggested that calcium channel blocker (CCB) therapy mitigates the decline in renal function in humans with essential HTN, there are few long-term clinical studies that have determined the impact of CCBs in patients with hypertensive CKD. Dihydropyridine (DHP) or L-type CCBs preferentially vasodilate the afferent arteriole and have been associated with glomerular HTN and increases in proteinuria in animal models with low renal function. Small clinical studies in vulnerable populations with renal disease such as African Americans, children, and diabetics have also suggested that DHP CCBs exacerbate glomerular injury, which questions the renoprotective effect of this class of antihypertensive drug. We used an established integrative mathematical model of human physiology, HumMod, to test the hypothesis that DHP CCB therapy exacerbates pressure-induced glomerular injury in hypertensive CKD. Over a simulation of 3 yr, CCB therapy reduced mean blood pressure by 14-16 mmHg in HTN both with and without CKD. Both impaired tubuloglomerular feedback and low baseline renal function exacerbated glomerular pressure, glomerulosclerosis, and the decline in renal function during L-type CCB treatment. However, simulating CCB therapy that inhibited both L- and T-type calcium channels increased efferent arteriolar vasodilation and alleviated glomerular damage. These simulations support the evidence that DHP (L-type) CCBs potentiate glomerular HTN during CKD and suggest that T/L-type CCBs are valuable in proteinuric renal disease treatment.<b>NEW & NOTEWORTHY</b> Our physiological model replicates clinical trial results and provides unique insights into possible mechanisms that play a role in glomerular injury and hypertensive kidney disease progression during chronic CCB therapy. Specifically, these simulations predict the temporal changes in renal function with CCB treatment and demonstrate important roles for tubuloglomerular feedback and efferent arteriolar conductance in the control of chronic kidney disease progression.