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). 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.

NEW & NOTEWORTHY 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.

INTRODUCTION

Chronic kidney disease (CKD) is associated with hypertension (HTN) and increased cardiovascular morbidity and mortality. CKD leads to functional nephron loss, glomerular hypertrophy, and a decline in overall renal function despite a compensatory hyperfiltration of the remnant nephrons. However, evidence suggests that the concomitant hyperfiltration during decreased renal mass can damage glomeruli and accelerate the progression of CKD (1). The most effective therapeutic regimens not only aggressively target HTN in CKD but also play a role in slowing or preventing the progression of CKD to end-stage renal disease (2). Calcium channel blockers (CCB) are one of several first-line antihypertensive therapies currently used for the treatment of CKD (3).

Although CCB use in primary HTN results in improvements in blood pressure control and long-term renal function without signs of glomerular damage (4), the impact of CCB treatment in hypertensive CKD and the progression of kidney disease is unclear. Animal models of CKD have demonstrated that preglomerular vasodilation with CCBs potentiates proteinuria and glomerular sclerosis, even with reductions in blood pressure (5–9). Furthermore, experimental models of CKD suggest that low renal mass can exacerbate the transmission of high systemic pressures and accelerate glomerular capillary injury (6). Clinical studies have suggested that some classes of CCB may exacerbate proteinuria and CKD progression and increase the risk of mortality (10). For example, dihydropyridine (DHP) CCBs (e.g., amlodipine) block L-type calcium channels that are found primarily on the afferent arterioles. Despite successfully lowering blood pressure, these drugs have been associated with an accelerated decline in glomerular filtration rate (GFR), greater proteinuria, and worse renal outcomes in certain patients with CKD (11–14). However, the same is not true for patients with CKD receiving CCBs that block the T-type calcium channel, which vasodilate afferent and efferent arterioles (12). Because L-type calcium channels are only located on the afferent arterioles of the glomerular vasculature, whereas T-type calcium channels are located on the afferent and efferent arterioles, L- and T-type CCBs have differential effects on glomerular hemodynamics (15, 16). In addition, there are renoprotective effects from adjunctive renin-angiotensin system (RAS) blockade, which vasodilates the efferent arterioles, when given with L-type CCBs in CKD (17). These data suggest that efferent arteriolar vasodilation may mitigate glomerular HTN in patients with CKD. In this study, we present computer simulations detailing the cardiovascular and renal responses to 3 yr of CCB treatment. Two models of HTN were created: 1) essential HTN characterized by increases in sympathetic nerve activity (SNA) but with renal function intact (115 mL/min baseline GFR) and 2) CKD HTN (stage II) modeled by reducing functional renal mass by 75%.

We hypothesized that both low renal function and tubuloglomerular feedback (TGF) play important roles in determining the progression of glomerular damage. In addition, we hypothesized that during CKD, DHP (L-type) CCBs, but not T/L-type CCBs, increase the risk for glomerular HTN and decline in renal function. We tested these hypotheses using an integrative mathematical model of physiology, HumMod. To our knowledge, this is the first physiological model to investigate the chronic cardiovascular and renal responses to antihypertensive therapy over the course of several years.

METHODS

Model Description

The simulations presented in this study were performed using HumMod, a large well-validated model of human physiology composed of mathematical relationships derived from experimental and clinical studies reporting organ, tissue, and cellular function. Detailed analysis of the entire model is beyond the scope of this study. However, the model code, mathematical derivations, documentation, graphical user interface, and instructions on how to run simulations are available for academic download as a single ZIP file at http://hummod.org/hummod-ccb.zip. In addition, Supplemental Material describing additional simulations and a further model description is available online at https://doi.org/10.6084/m9.figshare.15204765.

In brief, the kidneys in HumMod are composed of both vascular and tubular components. Glomerular filtration is influenced by physical factors such as hydrostatic and osmotic pressures (Table 1). Renal hemodynamics and tubular functions are influenced by physical factors, the sympathetic nervous system, circulating hormones, and TGF. In the model, there is differential control of efferent neural outflow to the renal, hepatic, cardiac, adrenal, and splanchnic territories. In peripheral tissues, there is only an effect of SNA to cause vasoconstriction (Supplemental Fig. S3). The sympathetic effects in the kidney include increases in renin secretion, proximal tubular sodium reabsorption, and vasoconstriction. The determinants of renal vascular conductance are shown in Fig. 1. TGF is primarily determined by the delivery of filtered sodium to the macula densa with an additional positive effect from angiotensin II and negative effect from atrial natriuretic peptide (both minor effects) (Supplemental Fig. S4). Plasma levels of hormones are determined from rates of secretion/production, clearance rates, and volume of distribution. The organs and tissues that make up the model’s peripheral circulation include the kidneys, heart, skeletal muscle, gastrointestinal tract, liver, bone, brain, fat, and skin. Factors that determine the flow through peripheral tissues include factors such as oxygen partial pressures, the sympathetic nervous system, vasoconstrictor hormones such as antidiuretic hormone and angiotensin II, and vasodilatory effects from calcium channel blockade (Supplemental Fig. S3). The DHP CCB vasodilation effect was included in the kidneys, skeletal muscle, gastrointestinal tract, and fat tissue, all with the same function, as shown in Fig. 2.

Table 1.

Equations and model parameters for calculating glomerular filtration rate

Variable	Input
Colloid osmotic pressure =	Plasma osmotic pressure/(1 − FF)
Bowman’s capsule pressure =	SNGFR/PTconductance
Capillary hydrostatic pressure =	(RBF/efferent conductance) + renal venous pressure
GFR =	Kf (PC − PBC − Posm)
*FF =	GFR/RPF
*SNGFR =	GFR/nephron number
PTconductance = 2.55 × 10−6
Kf = 8.89 × nephron number (×Normal)

FF, filtration fraction; K_f, filtration coefficient; P_BC, Bowman’s capsule hydrostatic pressure; P_C, capillary hydrostatic pressure; P_osm, capillary colloid osmostic pressure; PTconductance, conductance of the proximal tubule; RBF, renal blood flow; RPF, renal plasma flow; SNGFR, single-nephron glomerular filtration rate (GFR). *Implicit equation.

Figure 1.

Determinants of afferent and efferent arteriolar conductance in the model.

Figure 2.

Model relationships describing vasodilatory effects from calcium channel blockade (CCB) (A), glomerular pressure-induced injury (B), and isradipine pharmacodynamics in the model (18) (C). The renal function decline after dihydropyridine CCB therapy is also shown (D). The chronic change in glomerular filtration rate (GFR) during CCB therapy was compared with clinical results (14, 19). *The GFR decline resembles the change from 1 yr to 3 yr of CCB therapy. AASK Trial, African American Study of Kidney Disease and Hypertension Study; ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; CKD, chronic kidney disease; HTN, hypertension.

To determine cardiovascular responses to CCB in a setting of HTN associated with increased SNA and impaired renal excretory function, baseline conditions were altered in two ways from the normal model. First, SNA was increased in specific regional beds based on the norepinephrine spillover and microneurography measurements in patients with essential HTN, which show increased SNA in the kidneys, heart, and skeletal muscle vasculature but not in the lungs or hepatomesenteric circulation (20, 21). SNA was increased in the kidneys and skeletal muscle vasculature by ∼70% and in the heart by ∼25%. Second, along with increasing SNA, kidney mass was reduced by 25% (to 0.9 million total nephrons/kidney). The CKD model was created by reducing nephrons 75% (0.3 million nephrons/kidney) and decreasing salt intake with SNA at normal levels to match the nondiabetic CKD population in the African American Study of Kidney Disease and Hypertension study (AASK Trial) (14).

Validation of CCB

The bioavailability of CCB in the model was based on the reported bioavailability of isradipine in humans (17%) (22). Gut permeability and the clearance rate of isradipine in the model were fit to match pharmacodynamics reported in human studies of an acute 5 mg dose of isradipine (18) and chronic 5 mg/day isradipine regimen (22) (Fig. 2C). The peripheral and renal hemodynamic effects of isradipine are based on chronic isradipine monotherapy in humans with essential HTN (Fig. 2) (23–25). Validation of isradipine’s reported effects on GFR, renal plasma flow (RPF), and total peripheral resistance (TPR) as well as its blood pressure-lowering effect were also based on isradipine treatment in humans with essential HTN (23–25). Finally, a T/L-type CCB was simulated in the CKD model by adding a CCB effect on the efferent arteriole (Fig. 1); these effects were based on a study of a third-generation CCB (efonidipine), which has inhibitory activity on both L-type and T-type calcium channels, the latter being found on afferent and efferent arterioles (26).

CKD and essential HTN responses [mean arterial pressure (MAP) and GFR] were compared with clinical data from the AASK trial and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), respectively (Fig. 3). ALLHAT data were directly extracted from research materials obtained from the National Heart, Lung, and Blood Institute. The inclusion criteria for ALLHAT patients were those who were Black with baseline HTN and without signs of renal dysfunction (≥60 mL/min baseline GFR).

Figure 3.

Comparison between mean arterial pressure (MAP) and glomerular filtration rate (GFR) responses to chronic dihydropyridine calcium channel blockade (CCB) treatment in essential hypertension (HTN) or chronic kidney disease (CKD) HTN. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) MAP (A) and GFR (B) responses are shown for Black patients with HTN (baseline MAP: 114 mmHg) without renal dysfunction [≥60 mL/min baseline estimated GFR (eGFR), average: 89 mL/min] on chronic dihydropyridine CCB monotherapy (2.5−10 mg/day amlodipine) (19). Changes in MAP (C) and GFR (D) are shown for the African American Study of Kidney Disease and Hypertension study (AASK trial), which consisted of patients with CKD (baseline eGFR: 46 mL/min) treated with 5−10 mg/day amlodipine (14).

Simulation Protocols

In the essential HTN model, sodium intake was fixed at a normal level of 180 meq/day; this was fixed slightly lower in the CKD HTN model at 160 meq/day, which corresponds to the salt intake reported in the AASK Trial (27). Water intake was ad libitum and based on the thirst mechanism in the model (i.e., serum osmolarity). In all simulations, functional nephron count decreased ∼1%/yr, corresponding to the loss due to aging (28). In addition, glomerulosclerosis (and loss of functional glomeruli) was determined by glomerular capillary pressure (Fig. 2B). Glomerulosclerosis was set to occur when glomerular pressure increases above 70 mmHg with a time delay of 120 days (T = 120) resulting in similar declines in overall renal function observed in clinical trials examining renal function after chronic DHP CCB treatment in patients with CKD (Fig. 3D) and corresponding to the 10–20% increase in baseline glomerular pressure that is needed to induce overt proteinuria and glomerular damage in animal models (29, 30).

After running each model for 12 mo to ensure steady-state conditions (only 3 mo are shown), 7.5 mg isradipine was given orally once per day for 3 yr. Responses to CCB or no drug (control) were simulated during essential HTN and CKD with different perturbations:

1. HTN control: essential HTN alone.

2. HTN + CCB: essential HTN with 7.5 mg isradipine daily.

3. HTN + CCB − TGF: essential HTN with 7.5 mg isradipine daily without effects from TGF.

4. CKD control: CKD HTN alone.

5. CKD + CCB: CKD HTN with 7.5 mg isradipine daily.

6. CKD + T/L CCB: CKD HTN with 7.5 mg isradipine daily with additional vasodilatory effects on the efferent arteriole.

RESULTS

Baseline cardiovascular, renal, and hormonal physiology in normal model conditions and in models of essential HTN and CKD are shown in Table 2. CCB therapy in the essential HTN model (HTN + CCB) decreased MAP and increased GFR within the range of clinical observations (19) (Fig. 3). CCB therapy in the CKD model (CKD + CCB) lowered MAP in a similar manner to patients with stages II−III CKD treated with DHP CCB (Fig. 3C). GFR in the CKD + CCB model, after initially increasing, progressively declined over the course of the 3-yr CCB treatment (Fig. 3D).

Table 2.

Baseline cardiovascular, renal, and hormonal physiology in normal model conditions and in models of essential hypertension and chronic kidney disease

	Normal	Essential Hypertension	Chronic Kidney Disease
MAP, mmHg	95	121	121
Sodium excretion, mmol/day	180	180	160
PV, L	3.5	2.9	3.8
RAP, mmHg	1.4	0.7	1.6
ANP, pmol/L	31	16	40
MSNA, Hz	1.5	2.6	1.5
RSNA, Hz	1.5	2.6	1.5
PRA, ng/mL/h	1.4	1.9	1.3
ANG II, pg/mL	14	19	13
Aldosterone, pmol/L	322	281	165
GFR, mL/min	126	115	45
RBF, mL/min	1,107	856	343
Afferent arteriolar resistance, mmHg/mL/min	0.06	0.11	0.23
Nephron number,* million	2.4	1.8	0.5
SNGFR, nL/min	53	65	88
Glomerular pressure, mmHg	52	66	76

ANG II, angiotensin II; ANP, atrial natriuretic peptide; GFR, glomerular filtration rate; MAP, mean arterial pressure; MSNA, mean sympathetic nerve activity; PRA, plasma renin activity; PV, plasma volume; RAP, right atrial pressure; RBF, renal blood flow; RSNA, renal sympathetic nerve activity; SNGFR, single-nephron glomerular filtration rate. *All listed factors are dependent variables with the exception of baseline nephron number, which is an independent variable (coefficient).

Table 3 shows the cardiovascular, renal hemodynamic, and hormonal changes after 3 yr of simulated CCB treatment in both essential HTN and CKD models compared with controlled, chronic, clinical studies (see references in Table 3). Plasma catecholamines were elevated in both essential HTN and CKD simulations. After CCB treatment, peripheral and renal SNA were increased in the HTN (5%) and CKD models (9%). RPF increased 5% and decreased 13% in the HTN and CKD models, respectively. In addition, peripheral blood flow increased ∼30% in both groups at the 3-yr time point compared with the respective baseline values.

Table 3.

Responses to chronic dihydropyridine CCB in essential HTN and during CKD with comparisons with available clinical data

	HTN + CCB	Range	Reference(s)	CKD + CCB	Range	Reference(s)
ΔMAP	−14 mmHg	−21 to −14 mmHg	(23, 31, 32)	−14 mmHg	−18 to −9 mmHg	(14, 33, 34)
CO, Δ	13%	5–20%	(23, 31, 32)	20%	?
TPR, Δ	−23%	−22% to −19%	(23, 31, 32)	−27%	?
SM blood flow, Δ	31%	30%	(35)	31%	?
ΔGFR, mL/min	5%	4−10%	(23, 36, 37)	−10 mL/min	−18 to 1 mL/min*	(14, 33, 34)
RPF, Δ	5%	0−18%	(23, 36)	−13%	?
Afferent arteriolar resistance, Δ	−34%	−24%	(36)	−27%	?
Efferent arteriolar resistance, Δ	−2%	−13%	(36)	18%	?
Glomerular pressure, Δ	4%	3%	(36)	5%	?
Glomerulosclerosis, %	1%/yr	?		10%/yr	?
Plasma NE, Δ	7%	27−61%	(31, 32)	8%	?
Plasma Epi, Δ	17%	0−77%	(32, 38)	7%	?

Comparative clinical studies in the literature that assessed chronic responses (≥6 wk) to dihydropyridine calcium channel blockade (CCB; 5−10 mg/day) either in essential hypertension (HTN) or during chronic kidney disease (CKD; stages II−III). Responses are changes (Δ) or percent changes unless noted otherwise. CO, cardiac output; epi, epinephrine; GFR, glomerular filtration rate; MAP, mean arterial pressure; NE, norepinephrine; RPF, renal plasma flow; SM blood flow, skeletal muscle blood flow; TPR, total peripheral resistance. *A decline in GFR of 18 mL/min was found in patients with CKD with an elevated baseline urinary protein-to-creatinine ratio of >0.22 (14).

Changes in MAP for both simulations are shown in Fig. 4. In the essential HTN model, MAP decreased 14 mmHg after 3-yr CCB therapy compared with baseline values. When TGF was impaired in HTN (HTN + CCB − TGF), MAP was decreased to 16 mmHg at the 3-yr time point. CCB resulted in initial falls in MAP in the CKD model (CKD + CCB: −21 mmHg and CKD + T/L CCB: −22 mmHg). Three years later, MAP was 13 and 18 mmHg below baseline in the CKD + CCB model and CKD + T/L CCB model, respectively.

Figure 4.

Blood pressure responses to 3-yr calcium channel blockade (CCB) in essential hypertension (HTN) and chronic kidney disease (CKD) models. Essential HTN + CCB, essential HTN with 7.5 mg isradipine daily; essential HTN + CCB − TGF, essential HTN with 7.5 mg isradipine daily without effects from tubuloglomerular feedback; CKD + CCB, CKD HTN with 7.5 mg isradipine daily; CKD + T/L CCB, CKD HTN with 7.5 mg isradipine daily with additional vasodilatory effects on the efferent arteriole.

Baseline afferent arteriolar resistance was 0.11 mmHg/mL/min in essential HTN and 0.23 mmHg/mL/min in CKD (Fig. 5A). Baseline TGF was 1.2 times normal in essential HTN and 0.9 times normal in CKD (Fig. 5D). CCB therapy resulted in similar effects on afferent arteriolar resistance in all models (Fig. 5C). Initially with CCB, the TGF effect on afferent arteriolar resistance increased 27% in essential HTN but only 17% in CKD. After 3 yr, afferent arteriolar resistance decreased 34% in the HTN + CCB simulation, decreased 27% in the CKD + CCB simulation, and decreased 51% in the CKD + T/L CCB simulation (Fig. 5A). In both essential HTN and CKD models, CCB therapy was met with activation of TGF (Fig. 5D), thus promoting an increase in afferent arteriolar resistance (Fig. 5A). However, in the TGF-impaired group (HTN + CCB − TGF), there were greater decreases in afferent arteriolar resistance with CCB therapy. TGF was also removed from the CKD model and resulted in greater glomerular pressure and glomerular damage, decreased GFR, and higher MAP after 3 yr of treatment (Supplemental Fig. S1). The afferent arteriolar vasodilation in the CKD + T/L CCB simulation was associated with virtually no change in TGF (Fig. 5D), due to the minimal increases in GFR and macula densa sodium delivery (Fig. 5B) that result from concomitant efferent arteriolar vasodilation.

Figure 5.

Afferent arteriolar resistance (A), macula densa sodium delivery (B), and the direct effects from calcium channel blockade (CCB) (C) and tubuloglomerular feedback (TGF) (D) on afferent arteriolar resistance are shown. CKD, chronic kidney disease; HTN, hypertension; essential HTN + CCB, essential HTN with 7.5 mg isradipine daily; essential HTN + CCB − TGF, essential HTN with 7.5 mg isradipine daily without effects from tubuloglomerular feedback (TGF); CKD + CCB, CKD HTN with 7.5 mg isradipine daily; CKD + T/L CCB, CKD HTN with 7.5 mg isradipine daily with additional vasodilatory effects on the efferent arteriole.

Figure 6 shows the renal responses to CCB or no therapy over the course of 3 yr in the essential HTN model. Overall baseline GFR was 115 mL/min (Fig. 6A), and baseline single-nephron GFR (SNGFR) was 65 nL/min (Fig. 6C). When CCB was first administered, there were large initial increases in GFR with an intact TGF and larger increases with TGF clamped at baseline levels (Fig. 6A). Over the next 3 yr of therapy, there were gradual decreases in GFR in all groups: −0.8 mL/min/yr (HTN control), −1.4 mL/min/yr(HTN + CCB), and −2.6 mL/min/yr (HTN + CCB − TGF) (Fig. 5A). At the 3-yr time point, SNGFR increased 10% and 22% in the HTN + CCB and HTN + CCB − TGF simulations, respectively. This was associated with an increase in glomerular pressure in both the HTN + CCB group (3 mmHg) and HTN + CCB − TGF group (7 mmHg) (Fig. 6B). Glomerular loss was exacerbated in the HTN + CCB − TGF group (9% of total glomeruli) compared with the HTN + CCB (4%) and untreated HTN (3%) groups after 3 yr (Fig. 6D).

Figure 6.

Renal responses and glomerular damage in essential hypertension (HTN) models with or without chronic calcium channel blockade (CCB). Glomerular filtration rate (GFR) (A), glomerular pressure (B), single-nephron GFR (SNGFR) (C), and total damaged glomerulli (D) are shown. Essential HTN, HTN alone; Essential HTN + CCB, essential HTN with 7.5 mg isradipine daily; Essential HTN + CCB − TGF, essential HTN with 7.5 mg isradipine daily without effects from tubuloglomerular feedback.

CKD simulations had a GFR of 45 mL/min (Fig. 7A) and SNGFR of 88 nL/min at baseline (Fig. 7C). Initially (after 1 wk of CCB therapy) in the CKD + CCB simulation, GFR and SNGFR increased to 48 mL/min and 95 nL/min, respectively, whereas these variables increased to 46 mL/min and 90 nL/min, respectively, in the CKD + T/L CCB simulation. The rate of overall GFR decline (from year 1 to year 3) in the CKD + CCB simulation (−2.8 mL/min/yr) was more rapid than in the T/L-type CCB (−0.8 mL/min/yr) and untreated CKD groups (−0.5 mL/min/yr) (Fig. 7A). At the 3-yr time point, SNGFR remained unchanged in the untreated CKD group, was increased 12% in the CKD + CCB group, and was only increased 4% in the CKD + T/L CCB group (Fig. 7C). In addition, glomerular pressure was unchanged in the untreated CKD group, increased 4 mmHg in the CKD + CCB group, and decreased 2 mmHg in the CKD + T/L CCB (Fig. 7B). The number of damaged glomeruli was three times higher in the CKD + CCB group (31% of baseline glomeruli) at 3 yr compared with the untreated CKD group (4% of baseline glomeruli) and the CKD + T/L CCB group (7% of baseline glomeruli) (Fig. 7D). The CKD model was also simulated with angiotensin-converting enzyme inhibitor treatment with and without DHP CCB, both of which resulted in decreased glomerular pressure and amelioration of glomerular damage (Supplemental Fig. S2).

Figure 7.

Renal responses and glomerular damage in chronic kidney disease (CKD) models with or without chronic calcium channel blockade (CCB). Glomerular filtration rate (GFR) (A), glomerular pressure (B), single-nephron GFR (SNGFR) (C), and total damaged glomerulli (D) are shown. The CKD + CCB model was treated with the L-type calcium channel blocker, and the T/L-type calcium channel blocker was used for the CKD + T/L CCB model.

DISCUSSION

The tremendous amount of information regarding the renoprotective effects of CCBs is complex, and clinical trials have reported conflicting data. There are few long-term clinical studies that have determined the impact of CCBs in patients with hypertensive CKD. Precision medicine in antihypertensive therapy does not exist, and the specific factors that determine the rate of CKD progression are unknown. Although some of the cardiovascular and renal responses to chronic L-type or T/L-type calcium channels have been previously demonstrated in humans (and were instrumental in validating the current model), our simulations provide novel results that, to our knowledge, have never been investigated or validated. For example, there have been no experimental or clinical studies that have directly measured afferent arteriolar responses, TGF, SNGFR, glomerular pressure, or glomerulosclerosis during chronic CCB therapies; although clinical studies have measured proteinuria as an index of glomerular damage, the levels of these factors in hypertensive CKD are unknown. Insights from our simulations suggest that L-type CCBs may potentiate glomerular HTN during impaired renal function. Our simulations also predict that dysfunctional renal autoregulation may accelerate glomerular damage and that T/L type CCBs, or other means of efferent arteriolar vasodilation, may be valuable tools for slowing or preventing the progression of CKD.

As functional nephrons are lost to either the natural aging process, kidney donation, or disease progression, the remaining nephrons hyperfilter to maintain overall GFR. With limited nephron loss, the remaining nephrons can adequately compensate without causing injury, as is seen in healthy kidney donors. However, when nephron number becomes critically low, glomerular capillaries are exposed to exacerbated pressures. In the current CKD model, CCB therapy immediately increased glomerular pressure despite the reduction in renal perfusion pressure (i.e., systemic blood pressure). This glomerular HTN resulted in gradual increases in glomerulosclerosis in the model and a decline in functional nephrons and subsequent fall in overall GFR (−10 mL/min) over the next 3 yr. In agreement with our data, CCBs that inhibit L-type calcium channels, found primarily on the preglomerular microvasculature, are associated with exacerbated decline in renal function and outcomes in diabetic and nondiabetic patients with CKD, despite successfully lowering blood pressure (11–14). For example, a 3-yr clinical trial of L-type CCB therapy in African American patients with CKD (AASK Trial) demonstrated an initial rise in GFR but greater increases in proteinuria compared with other antihypertensive classes (14). Furthermore, in patients with CKD with elevated proteinuria at baseline, there was an accelerated decline in GFR, warranting further investigation into the types of patients with CKD that may be vulnerable to DHP CCB therapy (14).

Clinical studies aimed at aggressively controlling HTN have shown significant amelioration of CKD progression (39). Although systemic pressure largely determines glomerular pressure, high pressures are not necessarily transmitted to the glomerular capillaries (40). Experimental models of HTN are sometimes associated with slight increases in glomerular pressures (40, 41), but these changes are much smaller than those seen in late-stage CKD. Clinical studies have demonstrated increases in GFR with L-type CCB treatment but have found little or no change in proteinuria in essential HTN without CKD (4). Similarly, GFR increased in the HTN + CCB model and was comparable to a clinical study (23), but there was only an increase of ∼20,000 damaged glomeruli above the HTN control simulation, unless TGF was disabled (∼100,000 damaged glomeruli). This level of damage was also observed in the CKD + CCB simulation (∼140,000 more damaged glomeruli than the CKD control). Although some clinical studies have suggested that L-type CCB may exacerbate proteinuria in proteinuric CKD and increase the risk of mortality in some populations (4, 10), the exact mechanisms as well as the glomerular hemodynamics, TGF responses, SNGFR, and extent of glomerular damage have never been assessed in these patients.

Glomerular HTN is likely the key driving force that contributes to the CCB-induced injury seen in animal models of CKD (5, 42). Experimental studies in rodents with low renal function have demonstrated elevated SNGFR (43) and increased susceptibility to increases in glomerular pressures (6). The current CKD model was associated with lower baseline TGF, lessened initial TGF responses, and higher glomerular pressures during CCB therapy compared with the essential HTN model (Fig. 5 and Table 3). TGF is a major renal autoregulatory mechanism that plays an important role in the maintenance of glomerular pressures and may become increasingly important as functional nephron numbers become compromised. In the essential HTN model, there were notable increases in glomerular pressure and glomerular loss without functional TGF. Interestingly, if the TGF mechanism is taken away completely from the CKD model, there are greater increases in glomerular pressure and damage (Supplemental Fig. S1). Our current simulation results paired with these existing experimental and clinical data suggest that the impairment of TGF in either essential HTN or CKD increases vulnerability to glomerular damage, albeit more so in CKD because of the already high glomerular pressures.

Efferent arteriolar vasodilation with T-type CCBs has been shown to play a significant role in ameliorating progressive renal injury in HTN, particularly during compromised renal function. For example, in a small clinical trial in patients with diabetic nephropathy, 2 yr of L-type CCB therapy was associated with a significant decrease in GFR, which was not true for T-type CCBs (11). T-type CCBs may not alter glomerular pressure significantly because T-type calcium channels are expressed on both afferent and efferent arterioles. In another trial, L-type CCBs increased proteinuria in patients with CKD, but T/L-type CCBs did not (12). Other clinical studies have shown that T/L-type CCBs reduce proteinuria more than L-type CCB in CKD (44–46). Our model predicted that the CKD + T/L CCB simulation increased total GFR without increasing glomerular pressures and was associated with similar glomerular damage as the CKD control model. In addition, the current model also predicted greater afferent arteriolar vasodilation with T/L CCB versus the DHP CCB simulation. This was due to minimal increases in GFR and macula densa sodium delivery with CCB administration, abrogating TGF activation (Fig. 5A).

Efferent arteriolar vasodilation with RAS blockers in addition to CCB therapy also provide superior renal protection in CKD compared with afferent vasodilation with L-type CCBs alone (47). However, there are very few clinical studies that have focused on the renoprotective effect of CCB/RAS inhibitor combination therapy in patients with CKD. The ACCOMPLISH Trial (n = 561) demonstrated that diabetics have a better retardation of CKD progression with CCB/RAS inhibition compared with diuretic/RAS inhibition (48), but this has not been a universal finding (49). In nondiabetic patients with CKD, L-type CCB treatment was associated with increased urinary protein excretion, whereas L-type CCBs used in combination with angiotensin-converting enzyme inhibitors were associated with decreased urinary protein excretion (34), similar to findings in children with CKD (17), suggesting that dual therapy may be key for blood pressure control and the slowing of CKD progression. Our model also demonstrates that RAS inhibition, either alone or in combination with DHP CCB treatment, results in better preservation of renal function and blunted glomerular damage (Supplemental Fig. S2). Other factors may also play a role in the favorable response to these therapies. For example, patients with CKD on a low-salt diet have increased activation of the RAS and thus enhance the ability of RAS blockers to control blood pressure and reduce proteinuria (50).

The physiological model, HumMod, reproduces many of the physiological responses to CCB therapy and the dysfunction seen in patients with primary HTN and hypertensive CKD. However, there are limitations that need to be addressed. Although these simulations and results are clinically relevant, the predictions presented in these simulations are to be considered hypotheses until confirmed with experimental and clinical investigation. Glomerular HTN has been associated with proteinuria in experimental models, whereas clinical studies have used proteinuria as an index of glomerular damage and/or glomerular pressure. HumMod’s predictions show glomerular pressure changes during pathological conditions and in response to treatment but do not currently include proteinuria. Although our model incorporates the medulla and vasa recta capillaries, CCBs do not directly affect these components in the current simulations, which may have underestimated the natriuretic effect of these drugs. These factors and analyses of other drugs such as loop diuretics and their impact on TGF and renal function in CKD will be the focus of future studies. Other clinical conditions associated with HTN or CKD that were not specifically examined in our simulations (e.g., primary aldosteronism or hypervolemia, heart failure, or renal artery stenosis) must await further development and testing of HumMod.

SUPPLEMENTAL DATA

All Supplemental Material and Supplemental Figs. S1–S4: https://doi.org/10.6084/m9.figshare.15204765.

GRANTS

This work was supported by National Institutes of Health Grants K99MD014738, P20GM104357, T32HL105324, and P01HL051971 and by The Joe and Dorothy Dorsett Brown Foundation.

DISCLAIMERS

This report was prepared using ALLHAT research materials obtained from the NHLBI Data Repository Information Coordinating Center and does not necessarily reflect the opinions or views of ALLHAT or the NHLBI.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

K.H.M. and J.S.C. conceived and designed research; J.S.C. performed experiments; K.H.M. and J.S.C. analyzed data; K.H.M. and J.S.C. interpreted results of experiments; J.S.C. prepared figures; K.H.M. and J.S.C. drafted manuscript; K.H.M. and J.S.C. edited and revised manuscript; K.H.M. and J.S.C. approved final version of manuscript.