Management of Hypertensive Chronic Kidney Disease: Role of Calcium Channel Blockers. Robert D. Toto, MD

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1 R e v i e w P a p e r Management of Hypertensive Chronic Kidney Disease: Role of Calcium Channel Blockers Robert D. Toto, MD Both the prevalence and incidence of end-stage renal disease have been increasing in the United States over the past two decades. Diabetes and hypertension are the attributable causes for more than three fourths of all new cases of end-stage renal disease. The overwhelming majority of diabetics with nephropathy are hypertensive, and lowering blood pressure is indicated in all patients with chronic kidney disease because of the increased risk for cardiovascular morbidity and mortality. Multiple studies indicate that reaching goal systolic blood pressure in patients with chronic kidney disease generally requires three to four antihypertensive agents. A number of medication combinations can effectively reduce blood pressure in the chronic kidney disease patient. In this regard, adding a calcium channel blocker to an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker helps in reaching goal blood pressure while preserving renal function in both diabetics and nondiabetics with proteinuria. (J Clin Hypertens. 2005;7(4 suppl 1):15 20) 2005 Le Jacq Ltd. Hypertension is common in patients with chronic kidney disease (CKD) and a major risk factor for both progression of CKD to end-stage renal disease (ESRD) as well as to an increase in cardiovascular (CV) morbidity and mortality. 1 More than 80% of patients with CKD have hypertension defined as a systolic blood pressure (BP) 140 mm Hg and a From the University of Texas Southwestern Medical Center, Dallas, TX Address for correspondence: Robert D. Toto, MD, Professor of Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX robert.toto@utsouthwestern.edu ID: 4471 diastolic BP 90 mm Hg. Both observational studies and clinical trials have demonstrated that systolic BP is a strong predictor of subsequent development of ESRD from many causes including essential hypertension, diabetes, and glomerulonephritis. 2 5 Taken together, epidemiologic and clinical trial evidence suggests that lowering BP slows progression of CKD and may also lower CV death risk. 6 This evidence has led to development of clinical practice guidelines for management of hypertension in CKD promulgated by the National Kidney Foundation. The National Kidney Foundation recommends a BP goal of <130 mm Hg/<80 mm Hg for all patients with CKD regardless of the cause. 7 However, it is well known that most patients with hypertension and CKD require multiple antihypertensive agents to bring BP to the recommended goals. Moreover, proteinuria is an important risk factor in patients with CKD and its reduction is an important goal of treatment for patients with hypertension and proteinuric forms of CKD The purpose of this review is to discuss the importance of BP control and proteinuria reduction in CKD patients with particular emphasis on the role of the calcium channel blocker (CCB) class of agents. This class of antihypertensive drugs is safe and effective at reducing risk of both CKD progression and CV events when used in combination with other agents. 13 Lowering BP to <130 mm Hg/80 mm Hg and reducing proteinuria (when present) are important goals in all patients with CKD. CCBs when combined with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), with or without diuretics, lower BP and proteinuria. In general, as a class CCBs are used as first-line antihypertensive agents in CKD patients if there is a contraindication (e.g., hyperkalemia) to an ACE inhibitor or an ARB. Also, in hypertensive proteinuric patients not treated with an ACE inhibitor SUPPL. 1 VOL. 7 NO. 4 APRIL 2005 THE JOURNAL OF CLINICAL HYPERTENSION 15

2 or an ARB nondihydropyridine CCBs significantly reduce proteinuria whereas dihydropyridine CCBs do not, despite similar BP lowering effects. This discussion focuses on the treatment of patients with CKD who have not reached ESRD; therefore, it does not pertain directly to those on dialysis or those who have undergone kidney transplant. These topics are discussed in detail elsewhere. 7,14 BP LOWERING AND PROGRESSION OF NEPHROPATHY Both the prevalence and incidence of ESRD have been increasing in the United States over the past two decades. Diabetes and hypertension are the attributable causes for more than three fourths of all new cases of ESRD. The overwhelming majority of diabetics with nephropathy are hypertensive, and lowering BP is indicated in all patients with CKD because of the increased risk for CV morbidity and mortality. Several clinical trials have demonstrated that lower systolic BP is associated with slowing in the rate of decline in glomerular filtration rate (GFR) in those with advanced stage CKD. Moreover, in type 2 diabetics with nephropathy, post hoc analyses of clinical trials indicate that those who achieved systolic BP >140 mm Hg increase their ESRD risk by two-fold as compared with those with an achieved systolic BP <140 mm Hg. 15,16 These and other studies indicate that achieving a systolic BP goal in patients with CKD generally requires three to four antihypertensive agents. Moreover, even diabetics without CKD typically require two to three antihypertensive agents to achieve the recommended BP goal. To this end, in a type 2 diabetic patient with nephropathy, the National Kidney Foundation recommends starting with an ACE inhibitor (or an ARB) followed by an appropriate diuretic (thiazide-type for those with estimated GFR of 50 ml/min and a loop diuretic for those with an estimated GFR <50 ml/ min), and then adding a long-acting CCB. 1 DIFFERENTIAL RENAL HEMODYNAMIC AND ANTIPROTEINURIC RESPONSES TO ACE INHIBITORS, ARBS, AND CCBS Proteinuria is an important marker for progression of CKD, and antihypertensive regimens that reduce proteinuria are more effective at slowing progression of CKD than those which do not reduce proteinuria. 12,17,18 Experimental animal models of proteinuric kidney disease, as well as studies in humans, have offered insights into the effects of different classes of antihypertensive agents on proteinuria (Table). 19 ACE inhibitors and ARBs predominantly lower efferent arteriolar resistance as a means by which they decrease glomerular capillary pressure. In addition, these agents reduce mesangial matrix protein accumulation, which otherwise can lead to sclerosis of the glomerular capillaries, and they decrease glomerular permeability to plasma proteins (reducing proteinuria) without altering renal blood flow autoregulation. Nondihydropyridine CCBs, such as verapamil and diltiazem, also reduce glomerular pressure, mesangial matrix accumulation, and glomerular permeability to proteins. However, these agents partially interfere with autoregulation of renal blood flow. In contrast to ACE inhibitors and ARBs, dihydropyridine CCBs have neutral effects on glomerular pressure, mesangial matrix accumulation, and membrane permeability to proteins and, because of their potent vasodilatory effect on the afferent arteriole, tend to abolish autoregulation of renal blood flow. These differential effects on the glomerular microcirculation in animal models, if true in humans, may explain some of the reported differences in antiproteinuric effects of CCB subclasses observed in patients with proteinuric kidney diseases. This subject has been the topic of a recent detailed review. 20 In summary, subclasses of dihydropyridine and nondihydropyridine CCBs lower BP to a similar extent, but have discrepant effects on the glomerular microcirculation in CKD. Nondihydropyridine CCBs consistently reduce proteinuria, whereas dihydropyridine CCBs do so less consistently. EFFECTS OF CCBS ON PROTEINURIA In patients with microalbuminuria (defined as mg albumin/g creatinine), some studies have demonstrated that dihydropyridine CCBs lower BP and microalbuminuria. In the Sysolic Hypertension in Europe (Syst-Eur) trial, 21 a placebo-controlled trial in elderly patients with isolated systolic hypertension, long-term administration of nitrendipine reduced Table. Differential Effects of ACE Inhibitors/ARBs and Subclasses of CCBs in Chronic Kidney Disease ACE INHIBITORS AND ARBS NONDIHYDROPYRIDINE CCB DIHYDROPYRIDINE CCB Glomerular pressure Decrease Decrease No change Mesangial matrix Decrease Decrease No change Proteinuria Decrease Decrease No change or increase Renal autoregulation No change Partly abolish Abolish ACE=angiotensin-converting enzyme; ARB=angiotensin receptor blocker; CCB=calcium channel blocker. Adapted from Curr Opin Nephrol Hypertens. 2004;13: THE JOURNAL OF CLINICAL HYPERTENSION SUPPL. 1 VOL. 7 NO. 4 APRIL 2005

3 albuminuria by 33% overall (compared with placebo), and among diabetics nitrendipine treatment reduced albuminuria by 71% (20% reduction with placebo). In addition, renal function (estimated from changes in serum creatinine) was better preserved in the nitrendipine-treated patients. However, it should be noted that BP was significantly lower in the nitrendipine-treated cohort. CCB therapy has also compared favorably to ACE inhibitor therapy as to a positive effect on microalbuminuria. For example, in the Appropriate Blood Pressure Control in Diabetes Study, 22 nisoldipine reduced microalbuminuria to a similar extent as the ACE inhibitor enalapril. However, many studies have found little to no decrease in albuminuria during long-term treatment with a dihydropyridine CCB. 23,24 There is a paucity of carefully controlled trials directly examining the differential effects of subclasses of CCBs on kidney function, in general, and proteinuria, in particular. To this end, in a small randomized double-blind comparator trial, the effects of long-acting diltiazem vs. long-acting nifedipine were evaluated in 24 type 2 diabetics with hypertension and macroalbuminuria (defined as 300 mg albumin/g creatinine) over a 24-month period. In this study, the confounding effects of ACE inhibitors and ARBs were avoided, as these agents were not included as part of the antihypertensive regimen in either CCB-treated group. BP was reduced similarly with either CCB; however, diltiazem reduced proteinuria 57% as compared with nifedipine gastrointestinal therapeutic system (Figure 1). In addition, this study demonstrated that long-acting diltiazem, but not long-acting nifedipine, improved glomerular barrier function as estimated by changes in the clearance of neutral dextrans. 25 In summary, both nondihydropyridines and dihydropyridines are effective antihypertensive agents in CKD, but these subclasses have differential effects on the glomerular microcirculation and urine protein excretion. 20,26 Based on currently available evidence from human studies, it appears that longterm administration of nondihydropyridine CCBs, such as verapamil and diltiazem, more consistently reduce proteinuria as compared with dihydropyridine CCBs, such as amlodipine and nifedipine, at similar degrees of systemic BP reduction. HOW DO ACE INHIBITORS AND CCBS COMPARE IN CKD? Few studies have directly compared the effects of ACE inhibitors to CCBs on kidney function. It is important to note that any such studies have not been head-to-head monotherapy comparisons in Change (%) Nifedipine (dihydropyridine) 4 Proteinuria Blood pressure 24 Diltiazem (Nondihydropyridine) Figure 1. Differential effects of calcium channel blockers on proteinuria in type 2 diabetics with nephropathy. Adapted with permission from Kidney Int. 1998;54: patients with CKD, since single antihypertensive agents seldom achieve adequate BP control (at least <140/90 mm Hg). Bakris et al. 27 compared the effects of verapamil, atenolol, and lisinopril-based regimens on the decline in GFR and proteinuria among a small cohort of type 2 diabetics with nephropathy and hypertension. They found that all three regimens lowered BP to a similar extent. There was no difference in the rate of decline in kidney function between the lisinopril and verapamil-based regimens. However, those assigned to the atenolol-based regimen had a faster rate of decline in renal function as compared with either lisinopril or verapamil-based regimens. A similar study also conducted in type 2 diabetics with nephropathy compared the ACE inhibitor trandolapril (average dose 5.5 mg/d), a long-acting nondihydropyridine CCB, verapamil (average dose 314 mg/d), and the combination of both agents (average trandolapril dose 2.9 mg/d and verapamil 219 mg/d). The doses of trandolapril and verapamil in combination were arrived at so as to achieve similar BP reduction to the monotherapy treatment limbs. Trandolapril and verapamil monotherapy each reduced protein excretion by about 30%, whereas the combination therapy achieved a 60% reduction in proteinuria. 28 The African-American Study of Kidney Disease and Hypertension (AASK) 23 was a double-blind, randomized, long-term trial in patients with hypertension and reduced renal function with an average GFR of about 50 ml/min. In this study, amlodipine- (5 10 mg/d) vs. ramipril- ( mg/d) vs. metoprolol- ( mg/d) based regimens were compared with participants further randomized to mean arterial pressure strata of either 92 mm Hg or mm Hg. There were no differences in rate of decline in GFR between either drug or BP control groups. However, the ramipril-based regimen reduced the risk for the combined end point of rapidly declining GFR or ESRD SUPPL. 1 VOL. 7 NO. 4 APRIL 2005 THE JOURNAL OF CLINICAL HYPERTENSION 17

4 With events (%) Amlodipine Ramipril Metoprolol Ramipril vs. metoprolol RR=22%, p=0.042 Metoprolol vs. amlodipine RR=20%, p=0.17 Ramipril vs. amlodipine RR=38%, p= Follow-up month Figure 2. Declining glomerular filtration rate event, end-stage renal disease, or death by drug group. RR=risk reduction. Adapted with permission from JAMA. 2002;288: Copyright 2002, American Medical Association. All rights reserved. or death from any cause (Figure 2). Compared with metoprolol, the relative risk reduction with ramipril was 22% (p<0.042), and compared with amlodipine, the relative risk reduction was 38% (p<0.004). 23 In addition, the median urinary protein excretion rate increased to a greater extent in the amlodipine as compared with the metoprolol- or ramipril-treated groups. Moreover, among those with a urine protein excretion rate 300 mg/d, ramipril as compared with amlodipine, slowed the decline in GFR by nearly 50% (p<0.006). 10 This protective effect of ramipril in comparison to amlodipine in African Americans with hypertensive, proteinuric CKD occurred despite a slightly lower systolic BP in the amlodipine group (amlodipine 133/81 mm Hg vs. ramipril 135/82 mm Hg). The slowing of GFR decline with an ACE inhibitor, as compared with a dihydropyridine CCB, established the importance of ACE-inhibitor use for BP control in this patient population. A comparison of the effects of CCBs and ACE inhibitors on renal function was undertaken in the secondary analyses of the Antihypertensive and Lipid Lowering to Prevent Heart Attack Trial (ALLHAT). 13 The study population in ALLHAT consisted of more than 44,000 complicated hypertensives, but largely excluded patients with CKD. There was no difference in the occurrence of ESRD comparing amlodipine (5 10 mg/d) or lisinopril (10 40 mg/d) to chlorthalidone mg/d. Analyses of these data indicated that renal function was slightly better preserved in the amlodipine and lisinopril groups compared with chlorthalidone; however, the differences in renal function were small, being on the order of 1 ml/min/yr. In summary, based on small studies of relatively short duration, nondihydropyridine CCBs are similar to ACE inhibitors in their capacity to reduce proteinuria and/or slow the decline in GFR in type 2 diabetic patients with nephropathy. 27,28 ACE inhibitors are superior to dihydropyridine CCBs in the management of African Americans with hypertensive nephrosclerosis marked by a mid-range decrease in GFR. 10 Finally, ACE inhibitors and dihydropyridine CCBs exhibit similar renal effects to those seen with a thiazide-based regimen among complicated hypertensives without CKD. 13 ACE INHIBITORS OR ARBS COMPARED WITH AND COMBINED WITH CCBS The Ramipril Efficacy in Nephropathy (REIN) trial 29 investigated the effects of ramipril (2.5 5 mg/d) as compared with placebo in 352 nondiabetic patients with proteinuric disease. The primary end point of the study was the rate of decline in GFR with an additional examination of the effect of reducing proteinuria on outcome. Ramipril proved to be superior to placebo for preserving GFR, increasing time to ESRD, and reducing proteinuria. 18 THE JOURNAL OF CLINICAL HYPERTENSION SUPPL. 1 VOL. 7 NO. 4 APRIL 2005

5 The effect of CCBs on proteinuria was examined in subgroups randomized to either placebo or ramipril and treated with or without a CCB for BP control. It was found that the effect of CCBs on proteinuria was dependent on BP control and concomitant treatment with the ACE inhibitor (ramipril). For example, in the absence of an ACE inhibitor, proteinuria was increased from baseline in CCB-treated patients with a mean arterial pressure maintained on average >100 mm Hg. Conversely, if mean arterial pressure was maintained <100 mm Hg, proteinuria decreased in CCB-treated patients not receiving an ACE inhihitor. 30 In the Reduction in Endpoints in NIDDM With the Angiotensin Antagonist Losartan (RENAAL) trial, 15 losartan was compared with placebo on a background of conventional antihypertensive treatments including CCBs. The study included 1513 type 2 diabetics with macroalbuminuria who were followed for an average of 3.4 years. The primary end point in the study was time to doubling of baseline serum creatinine, ESRD, or death from any cause. Despite similar BP control in losartan and placebo groups, losartan administration was associated with a 16% (p<0.01) risk reduction for the combined end point and a 28% risk reduction (p<0.002) for ESRD alone. Proteinuria decreased by 35% (p<0.0001) in the losartan treatment group, but did not diminish in the placebo group. Analysis of concomitant antihypertensive medications used in the study revealed that 90% of both the losartan and placebo-treated groups were administered CCBs of which two thirds received a dihydropyridine and one third a nondihydropyridine CCB during the course of the trial. Further analysis revealed that there was no apparent attenuation of the beneficial effect of losartan on the primary outcome with either class of CCB. The Irbesartan Diabetic Nephropathy Trial (IDNT) 18 was a double-blind, randomized, placebo-controlled trial among 1716 type 2 diabetics with hypertension and macroalbuminuria, comparing the effects of amlodipine (5 10 mg/d) vs. irbesartan ( mg/d) on a background of conventional antihypertensive agents. The primary end point in the study was time to doubling of baseline serum creatinine, ESRD, or death from any cause. The results indicated that irbesartan reduced the risk of the primary end point by 20% (p<0.024), compared with placebo and 23% (p<0.006), compared with amlodipine. Proteinuria was reduced by 33% in the irbesartan-treated group, while there was little or no change in either the amlodipine or placebo groups. Taking the RENAAL and IDNT trials together, the suggestion is that it is safe and effective to coadminister CCBs along with ARBs in the management of hypertensive type 2 diabetics with nephropathy. In summary, aggressive lowering of BP with dihydropyridine and nondihydropyridine CCBs in proteinuric nephropathies reduces proteinuria. Adding a CCB to an ACE inhibitor or an ARB helps in reaching goal BP, while preserving renal function in both diabetics and nondiabetics with proteinuria. REFERENCES 1 Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36: Klag MJ, Whelton PK, Randall BL, et al. Blood pressure and end-stage renal disease in men. N Engl J Med. 1996;334: Perry HM Jr, Miller JP, Fornoff JR, et al. Early predictors of 15-year end-stage renal disease in hypertensive patients. Hypertension. 1995;25: Young JH, Klag MJ, Muntner P, et al. Blood pressure and decline in kidney function: findings from the Systolic Hypertension in the Elderly Program (SHEP). 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