Questioning the renoprotective role of L-type calcium channel blockers in chronic kidney disease using physiological modeling.

Abstract

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). While studies suggest 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 determine 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, also suggest 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 three years, CCB therapy reduced mean blood pressure by ~14-16 mmHg in HTN both with and without CKD. Both impaired tubuloglomerular feedback (TGF) 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 T/L-type CCBs are valuable in proteinuric renal disease treatment.