Calcium Antagonists and Renal Failure Progression

Abstract

Although tighter blood pressure control is considered the main mechanism for preventing the progression of chronic renal failure, angiotensin-converting enzyme inhibitors and angiotensin receptors blockers seem to have an additional organ protective role. The effects of calcium antagonists in renal disease are not so clearly defined. Calcium antagonists have pleiotropic effects that might contribute to protect the kidney, such as attenuating mesangial entrapment of macromolecules, countervailing the mitogenic effect of platelet-derived growth factors and platelet-activating factors, and suppressing mesangial cell proliferation. They could also act as free radical scavengers and inhibit the renal effects of endothelin. Some evidence has been accumulated demonstrating that certain new dihydropyridinic calcium antagonists may affect postglomerular as well as preglomerular vessels, resulting in decreased filtration fraction and nephroprotective effect as renin-angiotensin axis-blocking drugs. Though there are few reports on the clinical renal effects of new calcium antagonists, they have rendered promising results. Manidipine does not increase proteinuria as do some classic calcium antagonists, and lercanidipine combined with renin-angiotesin axis-blocking drugs reduce proteinuria. Both drugs have been shown to decrease microalbuminuria when administered alone.

Keywords:

• calcium antagonists
• kidney disease
• nephroprotection

INTRODUCTION

There is a consistent message from published clinical trials indicating that treatment by calcium channel blockade reduces cardiovascular morbidity and mortality in hypertensive patients, including those with significant coronary artery disease and post-myocardial infarction.[1–8] In terms of clinical pharmacology and therapeutic use, there are fundamental differences between the dihydropyridine group of calcium antagonists (such as nifedipine) and other commonly used calcium antagonists (such as verapamil and diltiazem). Both verapamil and diltiazem have direct effects on cardiac contractility and conduction, and often are described as “rate-limiting” because of their shared tendency to reduce heart rate. This feature alone sets them apart from the dihydropyridine group to the extent that calcium antagonists should not be discussed as if they constituted a homogeneous group.[9]

Of even greater importance are the significant differences between agents within the dihydropyridine group. The development of new dihydropyridine calcium antagonists (numerically the most important group) has largely been focused upon obtaining longer elimination half-lives by the synthesis of alternative derivatives or the use of modified release formulations. The pharmacodynamic profile of these newer dihydropyridine calcium antagonists, particularly the duration of action, has been determined by the following pharmacokinetic characteristics:

• An extended elimination half-life. This is intrinsic in the case of amlodipine, with its plasma half-life of approximately 40 h.

• An apparent increase in elimination half-life due to modifications in the release characteristics of the drug formulation, such as nifedipine gastrointestinal therapeutic system (GITS).

• An increased degree of membrane binding in the case of the ‘lipophilic’ dihydropyridine calcium antagonists (e.g., lacidipine and lercanidipine), which have relatively short plasma half-lives but longer durations of action, attributed to a high membrane partition coefficient.[10]

Because hypertension is a major determinant of progression of renal disease, irrespective of cause, and the relative risk of developing end-stage renal disease in hypertensive patients (compared with that of patients with “optimal” BP) increases three-fold when diastolic BP increases to 90 mmHg,[11] this article seeks to highlight these differences, with a particular emphasis on the renoprotective effects of calcium channel blockers. Although tighter BP control is considered the main mechanism for preventing from the progression of chronic renal failure,[12],[13] some antihypertensive agents, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptors blockers (ARB), seem to have an additional organ protective role and are routinely used in renal disease.^[10] The effects of calcium antagonists in renal disease are not so clearly defined and will be discussed below.

EXPERIMENTAL RENOPROTECTIVE MECHANISM OF CALCIUM ANTAGONISTS

Calcium antagonists have pleiotropic effects that might contribute to protect the kidney against hypertension-induced damage. The calcium antagonist has been demonstrated to modulate macromolecular traffic through the mesangium and attenuate mesangial entrapment of macromolecules, which induce inflammatory and proliferative response.[14],[15] It has also been suggested that calcium antagonists may act to countervail the mitogenic effect of platelet-derived growth factors and platelet-activating factors, which seem to play an important role in renal lesion induced by hypertension.[12] Similarly, calcium antagonists suppress mesangial cell proliferation by inhibiting activator protein-1 (AP-1)[16] as well as the cell cycle transition from the G1 to S phase,[17] and modulate gene transcriptions that are involved in proinflammatory changes (interleukin-1ß and granulocyte/monocyte colony-stimulating factors).[18] In this regard, calcium antagonists have been shown to suppress the PMA-induced activation of nuclear factor kappa B in cultured human mesangial cells.[19]

Finally, calcium antagonists might act as free radical scavengers.[20],[21] They may reduce the activity of some intracellular free radicals sources (i.e., they could inhibit the activity of NADPH oxidase, xanthine oxidase, and cyclooxygenase, which are the main sources of intracellular reactive oxygen species).[22] Second, calcium channel blockers may decrease intracellular free radical concentration through its direct antioxidant capacity.[23] Third, calcium antagonists may protect the redox potential of the free radicals targets through their effect on nuclear factor kappa β and hence on the signaling pathways leading to its activation.[24]

Last, the inhibition of the renal effects of endothelin by calcium channel blockers has been showed under experimental conditions.[25] Endothelin-1 is a potent vasoconstrictor that has been implicated in the pathogenesis of kidney disease[26] and animal models of hypertension.[27],[28] It is therefore of considerable interest that endothelin appears preferentially to reduce blood flow in the renal cortex, with either only small reductions, or even increases, in medullary blood flow in anesthetized rats[29] and dogs.[30] Furthermore, treatments that reduce renal medullary blood flow cause hypertension, if administered chronically, and attenuate blood pressure-lowering mechanisms in the kidney.[31],[32] This phenomenon may have important implications in pathological conditions associated with increased circulating or local intrarenal levels of endothelin, such as acute and chronic renal failure,[26] advanced atherosclerosis,[33] and perhaps essential hypertension.[34]

EFFECTS ON RENAL HEMODYNAMICS

Angiotensin axis-blocking drugs are reputed to minimize hypertension-induced renal damage by preserving renal blood flow in the face of systemic blood pressure reduction.[35–37] It has been documented that calcium antagonists cause a preferential dilation of the glomerular afferent arteriole, with only modest action on the efferent arteriole.[38–40] Thus, whereas the depressor action of the calcium antagonist favors an attenuation of glomerular hypertension and subsequent renal protection,[41–44] the predominant activity of this agent on preglomerular vessels might cause glomerular hypertension that could finally be associated with the progression of renal diseases.[45–48]

The action of calcium antagonists varies depending on the agents used. Nifedipine in dogs caused a greater increase in glomerular filtration rate (GFR) than that in renal plasma flow (RPF), resulting in elevated filtration fraction.[49],[50] Nicardipine and verapamil are also reported to increase filtration fraction, suggesting a predominant action on the afferent arteriole.[50–52] In contrast, nicardipine and diltiazem are reported to have no effect on filtration fraction,[53],[54] although controversial results have been described with nicardipine.[55] Using direct visualization of the juxtamedullary nephron circulation, both verapamil and diltiazem, as well as nifedipine, potently inhibited the afferent arteriolar vasoconstriction, whereas efferent arterioles were relatively refractory to the vasodilator action of these agents.[36],[56] The isolated perfused rat kidney model allows constant renal perfusion pressure, whereby the unaltered myogenic tone of renal microvessels is unaltered. Studies with this technique have rendered similar results for nifedipine, nisoldipine, diltiazem, and amlodipine.[37],[57]

In contrast with the large number of investigations suggesting that the first and second generations of calcium antagonists have predominant action on preglomerular vessels, a growing body of evidence has been accumulated demonstrating that certain types of these agents may affect postglomerular as well as preglomerular vessels. The intravenous administration of manidipine caused a greater increase in RPF than that in GFR in spontaneously hypertensive rats (SHR), resulting in decreased filtration fraction.[58] Nilvadipine and efonidipine may elicit similar GFR changes in humans.[59],[60] In humans, manidipine, like benidipine, elicits both afferent and efferent arteriolar dilation.[61–63]

Hayashi et al. have demonstrated that several calcium antagonists, including manidipine, nilvadipine, benidipine, and efonidipine, can cause a substantial dilation of efferent arterioles in the isolated perfused rat hydronephrotic kidney. In contrast, in the same preparation, both dihydropyridine-class antagonists (nifedipine, nicardipine, and amlodipine) and non-dihydropyridine-class calcium antagonists (diltiazem) can cause predominant afferent arteriolar dilation.[64–67] Sabbatini et al. demonstrated the histological dilatation of efferent as well as afferent arteriolar lumen by 12-week treatment with lercanidipine in spontaneously hypertensive rats.[68]

The mechanisms for the efferent arteriolar vasodilation, however, remain undetermined. A role for nitric oxide and vasodilatory prostaglandins in mediating the efonidipine-induced efferent arteriolar dilation has been suggested, but neither nitro-L-arginine methylester nor indomethacin had any effect on efonidipine-induced efferent arteriolar vasodilation.[69] Hansen et al. have demonstrated that T-type calcium channels prevail at juxtamedullary efferent arterioles, as well as afferent arterioles of superficial and juxtamedullary nephrons.[70] It has been found that mibefradil decreased both afferent and efferent arteriolar resistance in SHR kidneys, using the micropuncture technique.[71] Efferent arteriolar dilation by calcium antagonists that possess the blocking activity on T-type calcium channels, such as mibefradil, efonidipine, nilvadipine and aranidipine,[72],[73] has been demonstrated. Thus, a critical role of T-type calcium channels in mediating the efferent arteriolar tone has been suggested.

On the other hand, it is established that angiotensin II-induced vasoconstriction is mediated by two main intracellular signaling pathways, protein kinase C (PKC) and inositol-1,4,5-triphosphate (IP3)-induced intracellular calcium release, and this latter pathway constitutes an important target for the action of mibefradil during the ANG II-induced arteriolar constriction.[74] It has also been reported that T-type calcium channel activation stimulates renin release, and mibefradil suppresses renin release.[75] This observation raises the possibility that T-type calcium channel blockade inhibits the angiotensin II production, and therefore would be anticipated to contribute in part to the efferent arteriolar vasodilation.

CALCIUM ANTAGONISTS NEPHROPROTECTION IN ANIMALS

The long-term effect of calcium antagonist on injured kidney is conflicting. Verapamil is reported to reduce proteinuria and protect against renal injury in remnant kidney models.[76] Although Dworkin et al. demonstrated that nifedipine reduced both urinary protein excretion and glomerular injury in several “in vitro” models,[77] there have been several reports suggesting deleterious effects of dihydropyridine-class calcium antagonists in renal diseases.[78] It has been demonstrated that nitrendipine did actually increase proteinuria and glomerulosclerosis in a two kidney/one clip model of hypertension.[79] Furthermore, in another report, amlodipine did not exhibit renoprotective action in DOCA-salt hypertensive rats.[80] Finally, felodipine impaired renal autoregulation more markedly than verapamil or diltiazem, which tended to parallel the degree of glomerulosclerosis.[81]

In contrast, the novel calcium antagonists, acting on both afferent and efferent arterioles, may correct glomerular hypertension, and could therefore exert salutary actions on the progression of renal injury, as has been shown with nilvadipine, efonidipine, and manidipine in SHR rats.[82–84] An eight-week treatment with calcium antagonists, including nicardipine, amlodipine, efonidipine, pranidipine, lercanidipine, and aranidipine, reduce BP and prevent the progression of renal injury in subtotally nephrectomized SHR. Furthermore, the histopathological changes and serum creatinine levels were also ameliorated, but the effects of these agents on proteinuria differ. Thus, nifedipine tended to decrease urinary protein excretion, and lercanidipine, pranidipine and efonidipine significantly reduced proteinuria.[57]

EFFECTS ON THE PROGRESSION OF HUMAN RENAL DISEASE

There is a great amount of information about the effects of calcium antagonists on human renal disease. Most of the reports have evaluated the changes on proteinuria or microalbuminuria (AER). That for which follow-up time was higher than 12 weeks has been taken into account in this review, a condition that excludes most comparisons against placebo. There is only one report about the renal effects of long-term treatment with nifedipine in normotensive type 1 diabetic patients with AER compared with placebo. Nifedipine treatment caused a significant reduction of AER after 6 and 12 months. GFR was significantly decreased by nifedipine treatment whereas RPF remained constant.[85] Also, data from the SYST-EUR study demonstrate a renoprotective effect of calcium channel blockers compared with placebo in hypertensive patients. Active treatment was initiated with nitrendipine with the possible addition of enalapril, hydrochlorothiazide, or both. In the patients assigned randomly to receive active treatment, the incidence of mild renal dysfunction decreased by 64%, and that of proteinuria by 33%.[86]

There are several reports on the protective effect of calcium antagonists when compared with diuretic treatment. In the National Intervention Cooperative Study in Elderly Hypertensives, fewer patients in the nicardipine group attained abnormally increased BUN concentrations.[87] Furthermore, in the SYST-EUR study, serum creatinine concentration did not change in patients continuing to receive monotherapy with nitrendipine, whereas it increased in patients who received hydrochlorothiazide. The results of the INSIGHT study suggest that antihypertensive treatment with nifedipine GITS also offers a renoprotective effect higher than do thiazides.[35],[88] Amlodipine is also demonstrated in the ALLHAT study to confer more substantial renal protective action than diuretics or ACE inhibitors when the systemic blood pressure is reduced to an optimal level.[89]

There is only one randomized study that compares the effects of verapamil with those of atenolol on the progression of diabetic renal disease. The primary end point of the study was a change in creatinine clearance slope. Thirty-four African Americans were randomized to one of the two groups. After a mean follow-up of 54 ± 6 months, the calcium channel blocker group demonstrated both a slower rate of decline in creatinine clearance (−1.7 ± 0.9 versus −3.7 ± 1.4 mL/min per year, p < 0.01) and a greater reduction in proteinuria. Additionally, a greater proportion of the atenolol group had a 50% or greater increase in serum creatinine compared with the verapamil group (32 ± 9% versus 16 ± 7%, p < 0.05). These between-group differences could not be explained by differences in blood pressure control.[90]

CALCIUM ANTAGONISTS VERSUS RENIN-ANGIOTENSIN AXIS-BLOCKING DRUGS

Non-Dihydropyridine Calcium Antagonists

The combination of trandolapril with verapamil produces a greater reduction in proteinuria due to type 2 diabetes nephropathy over either agent alone at one year.[91] Rubio-Guerra et al. compared the effect of fixed-dose trandolapril-verapamil with that of trandolapril alone on proteinuria in normotensive, type 2 diabetic patients with 24-h proteinuria >300 mg randomly assigned to two groups for open-label treatment. Both groups experienced a significant (p < 0.005) decrease in mean proteinuria from baseline, but a significantly greater reduction from baseline in proteinuria was observed in the combination group compared with the trandolapril group.[92]

More recently, the BENEDICT study failed to demonstrate any significant effect of verapamil to prevent overt microalbuminuria.[93] Again, the PROCOPA study compares proteinuria reduction when BP is lowered at the same level with calcium antagonists and ACE inhibitors. A significant fall in proteinuria was seen in the trandolapril and verapamil trandolapril groups; meanwhile, atenolol and verapamil alone could not get any reduction in this variable.[94] The TRAVEND study compared, at equal BP reduction, the effect of two different combinations on metabolic control and albuminuria in type 2 diabetic hypertensive patients with albuminuria. Overall BP was significantly reduced and albuminuria significantly decreased without significant differences between treatments.[95] Thus, verapamil did not enhance the antiproteinuric effect of the ACE inhibitor.

Boero et al. tested whether the combination of verapamil or amlodipine with trandolapril affected proteinuria differently from trandolapril alone in patients with nondiabetic nephropathies. Proteinuria diminished significantly after trandolapril treatment. In the randomized phase, there was a slight reduction in proteinuria in both groups without significant differences within and between treatments.[96]

Furthermore, it has been reported that verapamil may improve renal function in hypertensive patients when it has been impaired by the previous use of ACE inhibitors.[97],[98] As a conclusion, in spite of the promising initial results, verapamil has not shown any special ability to reduce proteinuria when compared with renin-angiotensin axis blocking drugs.

Dihydropyridine Calcium Antagonists

There is an enormous number of reports on the antiproteinuric or antimicroalbuminuric effect of dihydropyridine calcium antagonists compared with ACE inhibitor or angiotensin receptors blockers. This conclusion is clearly unfavorable to calcium channel blockers.

There are fewer trials about the long-term protective effect of calcium antagonists on renal function, and the results seem to be discouraging. The African American Study of Kidney Disease (AASK) showed striking results. However, compared with the metoprolol and amlodipine groups, the ramipril group manifested risk reductions in renal failure progression. Amlodipine significantly increase proteinuria compared with metoprolol and ramipril. Although AASK is the largest and longest trial of dihydropyridine calcium antagonists in renal protection, the results should be regarded with caution. First, African Americans constitute a special population highly prone to renal failure with a distinct response to cardiovascular drugs, as shown by the ALLHAT study. Second, other, shorter trials have not demonstrated such deleterious effects on proteinuria.[99]

The ESPIRAL study investigated the capacity of fosinopril and that of nifedipine GITS to modify the decay in renal function in hypertensive patients with primary renal disease, exhibiting a progressive increase in serum creatinine during the 24 months prior to entering the study. Renal survival was significantly better when fosinopril constituted the first step therapy. Proteinuria decreased at the end of the study in the fosinopril group and increased in the group receiving dihydropyridine. However, the patients receiving an ACE inhibitor showed lower SBP values; thus, the better BP control in the fosinopril arm could have resulted in a better outcome.[100] On the other hand, the J-MIND study showed no differences between enalapril and nifedipine retard with respect to progression from normoalbuminuria to microalbuminuria and from microalbuminuria to overt proteinuria. The incidence of this outcome was similar in both groups.[101]

Some studies have compared the possible beneficial effect of combining calcium antagonists and renin-angiotensin-blocking drugs for treating hypertension, but taken together, the published results are conflicting and inconclusive.[102–105]

New Calcium Antagonists

There are few reports on the clinical renal effects of new calcium antagonist, but they have rendered promising results. Bellinghieri et al. compared the effects of manidipine and nifedipine on blood pressure and renal function. Creatinine blood levels and creatinine clearance significantly increased in the manidipine group. Proteinuria did not significantly change in the manidipine group but increased in the nifedipine group.[106] The effect of long-term monotherapy with manidipine or lisinopril on albumin excretion rate (AER) has been compared. Both drugs provided a significant decrease in AER, but it was significantly more pronounced with lisinopril.[107] Del Vechio et al.[108] evaluated the efficacy and tolerability of manidipine in comparison with enalapril in patients with chronic renal disease secondary to primary renoparenchymal disease. Proteinuria remained unchanged with manidipine and decreased significantly with enalapril. No significant difference was observed in the rate of renal function decline in the two groups.

The Diabetes Ipertensione Albuminuria Lercanidipina (DIAL) study evaluated the effectiveness of lercanidipine in comparison with ramipril in mild-to-moderate hypertensive patients with Type 2 diabetes and persistent microalbuminuria. A reduction in AER was observed in both groups, without differences between the groups.[109] More recently, the ZAFRA study has shown a positive effect on proteinuria of the combination of the new calcium channel blocker lercanidipine and renin-angiotensin axis-blocking drugs. This is the only report on antiproteinuric effects on new calcium antagonists and suggests interesting properties compared with previously published results with classic calcium channel blockers.[110]

Thus, the new generation of calcium antagonists seems to have experimental and clinical renal protective effects, though there is still a limited amount of information on them.

CONCLUSIONS

Synthesizing the enormous amount of information about the renoprotective effects of calcium antagonist is complex in view of conflicting data coming from the reported trials. Nevertheless, the use of calcium antagonists in renal disease hypertensive patients is safe and has no deleterious effects on renal function. Calcium antagonists may be better than diuretics and beta-blockers to protect renal function against hypertension, although renin- angiotensin axis-blocking drugs are more effective than calcium channel blockers to reduce proteinuria and preventing from renal disease progression. The combination of calcium antagonists and renin-angiotensin axis-blocking drugs may be beneficial in order to improve the renal protective effects of ACE inhibitors and ARB administered alone. New generation calcium antagonists, with the property of vasodilator action on both afferent and efferent glomerular arterioles, may have interesting renoprotective effects as suggested by some recent reports. More clinical trials will be needed to confirm this possible effect.