Introduction

Chronic kidney disease (CKD) is a growing health problem of epidemic proportions worldwide. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) guidelines define CKD as structural or functional abnormalities of the kidney for ⩾3 months, manifested by either pathological abnormalities or markers of kidney damage, including persistent proteinuria, with or without decreased glomerular filtration rate (GFR), or as decrease in GFR <60 ml min−1 per 1.73 m2 for ⩾3 months, with or without kidney damage.1 CKD may progress silently over many years.

Data from randomized clinical trials and epidemiological evidence identify systemic hypertension as the second most common modifiable risk factor for CKD progression after diabetes mellitus.2, 3, 4 High levels of hypertension have been strongly associated with faster decline of renal function in the Modification of Diet in Renal Disease (MDRD) study, especially in persons with higher baseline proteinuria.5 In addition, a strong relation between the estimated risk of end-stage renal disease (ESRD) and the elevations of BP was identified in the Multiple Risk Factor Intervention Trial (MRFIT), which followed up 332 544 men, 35–57 years of age, for 16 years.6 The United States Renal Data System (USRDS) data indicate that hypertension is the main cause for more than a quarter of the ESRD patients treated in the United States and although a variety of antihypertensive drugs are available, the rate of ESRD due to hypertension has grown by 8.7% since 2000.2

Patients with CKD are at increased risk for cardiovascular disease. It is well established that microalbuminuria and reduced GFR, in both diabetic and nondiabetic hypertensive patients, are major cardiovascular risk factors and many older patients develop or die from cardiovascular disease rather than progress to ESRD. Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) findings supported that chlorthalidone was superior to other agents in preventing one or more major forms of cardiovascular disease, although no significant difference was found in all-cause mortality.7 In addition, in participants with an estimated GFR <60 ml min−1, there was no significant difference in cardiovascular mortality between different treatment groups.8 Moreover, Staessen et al.9 in their meta-analysis showed that the level of blood-pressure control was a more significant predictor of cardiovascular disease outcomes than the use of newer antihypertensive agents.

According to the 2007 European Society of Hypertension and European Society of Cardiology (ESH–ESC) guidelines10 and the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC7),11 BP goal is set to <130/80 mm Hg in patients with renal dysfunction and <125/75 mm Hg if proteinuria is >1 g per day.12 However, this is not consistently supported by trial evidence, and on this basis, ESH changed BP goal to 130–139/80–85 mm Hg.13 Still, the optimal BP goals remain controversial.14 It is believed that any drug that lowers hypertension is renoprotective. However, some antihypertensive drugs have additional renoprotective effects that are independent to the BP lowering effect, like proteinuria reduction.15, 16

Proteinuria, including both microalbuminuria and clinical proteinuria, has been recognized as a key predictor of kidney disease progression in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study17, 18 and clearly has a pathogenic role in loss of renal function, through proinflammatory and profibrogenetic injury in tubular cells, which can facilitate the development of interstitial fibrosis and tubular atrophy.19 Clinical evidence to date suggest that appropriate therapy can reduce the rate of microalbuminuria progression to macroalbuminuria and CKD.5, 20 A large number of clinical studies have investigated the effect of antihypertensive treatment on renal function. The present article will review the latest data on the effect of each category of antihypertensive drugs on CKD.

Methods

Clinical studies of relevance to the effect of antihypertensive drugs on CKD were identified by searching the MEDLINE and the Cochrane databases. In addition, relevant ongoing clinical trials were searched in the ClinicalTrials.gov registry. The primary search terms were antihypertensive drugs and renal disease, renal function, renoprotective, CKD or renal protection. Secondary search terms were angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers, renin inhibitors, aldosterone antagonists, calcium channel blockers (CCBs), diuretics, α-blockers, β-blockers or centrally acting adrenergic drugs and CKD or renal function. Additional relevant publications were identified by searching the reference lists of obtained articles.

Renin-angiotensin system inhibitors

The pathophysiology of the RAS underpins the therapeutic renal benefit of ACEIsand angiotensin II type 1 receptor blockers (ARBs). Angiotensin II acts on the kidneys and produces vasoconstriction of efferent arteriole in the glomerulus, which increases capillary pressure and filtration fraction.21 Moreover, angiotensin II enhances ultrafiltration of proteins and is associated with podocyte injury, resulting in proteinuria.19 Chronic activation of the RAS perpetuates a cascade of proinflammatory, prothrombotic and atherogenic effects associated with end-organ damage.22

Diabetic nephropathy

One of the first studies that examined the effect of ACEIs on diabetic nephropathy was published in 1993 by the Collaborative Study Group and reported that in 409 patients with type 1 diabetes mellitus and overt nephropathy captopril 25 mg TID had a renoprotective effect compared with placebo that was independent of the BP reduction.23 The results of this study were later enhanced by larger studies, like the Microalbuminuria, Cardiovascular and Renal outcomes in the Heart Outcomes Prevention Evaluation study (MICRO-HOPE) that is a subset of the HOPE study, published in 2000, where the ACEI ramipril was shown to lower the risk of overt nephropathy by 24% (P=0.027) in 3577 patients with diabetes mellitus, who had at least one other cardiovascular risk factor and no clinical proteinuria.24

Likewise, MicroAlbuminuria Reduction with VALsartan (MARVAL) and Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) studies elucidated the beneficial effect of ARBs in patients with type 2 diabetes and microalbuminuria. The former showed that valsartan decreased albuminuria more than amlodipine (44 vs. 8%, P<0.001) during 6 months25 and the latter that only 5.2% of the group receiving 300 mg of irbesartan and 9.7% of those receiving 150 mg progressed to diabetic nephropathy during 2 years vs. 14.9% of the placebo group.26 IRMA 2 was followed by Irbesartan Diabetic Nephropathy Trial (IDNT), which involved subjects with overt nephropathy and showed a greater reduction of proteinuria in Irbesartan group than in amlodipine group (33 vs. 6%).27, 28 In a similar population, Reduction of Endpoints in Noninsulin-dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) study15 reproduced IDNT findings. The important role of ARBs in diabetic nephropathy was also underlined in Siebenhofer et al. meta-analysis.29 In addition, the more recent Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study showed that in a large sample of type 2 diabetics (n=4447), with at least one additional cardiovascular risk factor and normoalbuminuria, olmesartan delayed the onset of microalbuminuria by 23% compared with placebo group (P=0.01), at a median follow-up of 3.2 years, independently of baseline BP and the degree of BP reduction (Table 1).30, 31

Table 1 Diabetic nephropathy and RAS inhibitors
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Interpreting the results of important studies, NKF KDOQI guidelines on hypertension and antihypertensive agents in CKD12 suggest the use of ACEIs as first choice drugs for patients with type 1 diabetes mellitus and ARBs for subjects with type 2 diabetes mellitus. Diabetics Exposed to Telmisartan and Enalapril Trial (DETAIL)32 is the only long-lasting study that compares the two drug categories. According to the study results, ACEIs and ARBs did not differ significantly in reducing GFR decline in subjects with type 2 diabetes mellitus and nephropathy.33, 34 However, some limitations of the study design, like the small size of the study, the small number of patients with macroalbuminuria and the large number of subjects with normal GFR, may lead to precarious conclusions.

Nondiabetic (hypertensive) nephropathy

Randomized clinical trials have firmly established the benefit of RAS inhibition in hypertensive nephropathy. The effect of antihypertensive treatment on progression of renal insufficiency in nondiabetic patients (ESPIRAL) trial35 compared the effect of fosinopril and a long-acting gastrointestinal therapeutic system (GITS) formulation of nifedipine on CKD progression in 241 hypertensive nondiabetic subjects. After 3 years of follow-up, 21% of patients treated with fosinopril and 36% of those receiving nifedipine GITS presented a primary end point (double serum creatinine values and/or need to enter a dialysis program). In addition, proteinuria decreased at the end of the study by a mean of 57% in the fosinopril group and increased by 7% in the group receiving dihydropiridine. The larger African American Study of Kidney Disease and Hypertension (AASK) trial36 followed up on 1094 African Americans for 3 to 6.4 years and showed risk reductions in the clinical composite outcome of 22 (P=0.04) and 38% (P=0.004) in ramipril group compared with metoprolol and amlodipine groups, respectively. Both studies proved that ACE inhibition had a renoprotective effect that is independent to the reduction of BP. This notion is enhanced by Ramipril Efficacy in Nephropathy (REIN)37 and REIN-238 studies in nondiabetic proteinuric subjects (Table 2).

Table 2 Nondiabetic (hypertensive) nephropathy and RAS inhibitors
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In addition, a post-hoc analysis of the REIN trial showed that disease progression and response to ACE inhibition did not depend on the severity of renal insufficiency, although prevention of ESRD was found to be strongly dependent on treatment duration (P<0.0001) and was maximized when ACEIs were started in earlier stages.39 ACEIs were also shown to be effective in advanced nondiabetic nephropathy by Hou et al.,40 who followed up on 317 patients for a mean of 3.4 years and found that benazepril was beneficial in patients with stage 4 CKD. Nonetheless, patients with advanced CKD are particularly sensitive to the effects of ACEIs on the GFR and potassium excretion, thus renal function and serum potassium levels should be monitored carefully.

The meta-analysis conducted by Jafar et al.,41 which included 11 studies with a total of 1860 nondiabetic patients with renal disease, confirms the benefits of ACEIs in renal function protection, especially in patients with greater urinary protein excretion at baseline. To the same extent, Kent et al.42 suggest that there is no preferential benefit of ACEIs in nondiabetic patients with protein excretion <500 mg per day. In addition, the most recent meta-analysis of Sharma et al.43 demonstrates the lack of evidence of the effectiveness of ACEIs or ARBs in patients with stage 1–3 CKD who do not have diabetes mellitus. No published studies comparing ARBs with placebo were identified. It is notable that KDOQI hypertension guidelines do not have a preferred agent in nondiabetic CKD with spot urine total protein to creatinine <200 mg g−1.12

Combination treatment

As the findings of previous studies depicted the possibility of improved renal outcomes with dual RAS inhibition, newer trials examined this hypothesis. To date, the main study is the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET44), which investigated the effect of telmisartan plus ramipril compared with monotherapies in 25 620 patients with established atherosclerotic vascular disease or with diabetes with end-organ damage and found a reduction in albuminuria in telmisartan (P=0.004) and combination therapy groups (P=0.001) that persisted during the follow-up period (median 56 months). Notably, most patients had a normal baseline renal function and few (4%) exhibited overt proteinuria, which resulted in a very limited number of the renal end points that were significantly more frequent in combination therapy group (P=0.038). In addition, adverse events like acute dialysis and hyperkalemia were more often in combination therapy (P=0.02). An ongoing trial, VA NEPHRON-D, is expected to clarify whether combination therapy is beneficial or not. In this trial, losartan plus lisinopril combination compared with losartan alone is examined in 1850 patients with type 2 diabetes and overt proteinuria for a period of 2–5 years. The study is estimated to complete in 2014.45 Current evidence does not prove combination therapy to be superior. Conversely, it may increase adverse outcomes.

Recent ESH–ESC10 and JNC711 guidelines, based on the results of clinical trials and meta-analyses that clearly demonstrate the beneficial role of RAS-inhibitors on renal and cardiac protection, suggest ACEIs and ARBs as first choice for hypertension in patients with kidney disease, unless contraindicated, as it is in bilateral renal stenosis and pregnancy.

However, the majority of studies did not include patients above 70 years old. In addition, older patients with CKD are less likely to have proteinuria,46 thus, as discussed above, would not benefit from RAS inhibition.42 Moreover, elderly people are more prone to acute renal injury and hyperkalemia, due to a number of structural and functional changes characteristic of the ageing kidney.47 The above findings question the use of the RAS inhibition in the elderly.48

Calcium channel blockers

CCBs are classified in dihydropyridines, like amlodipine, felodipine and nifedipine, which are mainly peripheral vasodilators, and in non-dihydropyridines, like verapamil and diltiazem, which have adjunctive cardioprotective effect, as they decrease heart rate and myocardial contractility. First generation CCBs, like nifedipine, act exclusively on L-type calcium channels, and predominantly dilate afferent arterioles with the danger of glomerular hypertension and subsequent harm of the renal microcirculation. A good control of systemic BP, however, does not eliminate this risk. On the contrary, novel calcium antagonists, including efonidipine,49, 50 manidipine51, 52 and benidipine,53 which are predominantly licensed in Asian countries, block both L- and T-type calcium channels and elicit vasodilation of afferent and efferent arterioles. Moreover, T-type CCBs have been shown to inhibit renin release and inflammatory processes54 and attenuate oxidative stress.53 In support of these notions, Abe et al.55 and Ohta et al.56 showed that benidipine exerted antiproteinuric effect to a greater extent than amlodipine in hypertensive patients that was independent of the drug’s antihypertensive effects.

Larger studies have shown the beneficial effect of CCBs on renal outcomes. Intervention as a Goal in Hypertension Treatment (INSIGHT) study showed a small but significant GFR decline in the diuretic group compared with nifedipine, supporting the notion of a greater renoprotective effect of nifedipine.57 Likewise, a post-hoc analysis of Systolic Hypertension in Europe (SYST-EUR) trial for renal outcomes reported that the incidence of mild renal dysfunction decreased by 64% (P=0.04) in patients receiving active therapy with nitrendipine and the incidence of proteinuria decreased by 33% (P=0.03). Active treatment reduced the risk of proteinuria more in diabetic (71%) than in nondiabetic patients (20%) and decreased significantly serum creatinine in patients with baseline proteinuria (P<0.001).58 Unlike the above, a post-hoc analysis of ALLHAT trial for renal outcomes showed that in hypertensive patients with reduced GFR, there were no statistically significant differences between amlodipine, lisinopril and chlorthalidone in reducing the rate of development of ESRD or a 50% or greater decrement in GFR.59 Moreover, AASK study demonstrated less renoprotection and increase in proteinuria with amlodipine compared with ramipril (P<0.001).36

Several studies to date indicate that non-dihydropyridine CCBs decrease proteinuria in a greater extent than dihydropyridine CCBs in hypertensive patients, with or without diabetes. A systematic review of 28 randomized clinical trials was conducted by Bakris et al.,60 to assess the differential effects of these two subclasses on proteinuria, in hypertensive patients with proteinuria. The study revealed a 2% increase in proteinuria for dihydropyridine CCBs and a 30% reduction for non-dihydropyridine CCBs. On the other hand, in Bergamo Nephrologic Diabetes Complications Trial (BENEDICT), which involved hypertensive patients with type 2 diabetes, albeit verapamil plus trandolapril combination therapy was shown to reduce microalbuminuria, adding verapamil did not improve the renoprotective effects of RAS inhibition with trandolapril.16, 61 In addition, Verapamil Versus Amlodipine in Nondiabetic Nephropathies Treated with Trandolapril (VVANNTT) trial, which involved patients with nondiabetic proteinuric nephropathy treated with an ACEI, showed that the addition of a non-dihydropyridine or a dihydropyridine CCB did not significantly increase its antiproteinuric effect62 (Table 3).

Table 3 Calcium channel blockers
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CCBs have a great heterogeneity and as a result, their effect to kidney disease progression is variable. Notably, short-acting formulations may increase sympathetic activity and activate RAS, due to acute peripheral vasodilation, wheras long-acting CCB agents might be beneficial in CKD patients that belong to non-dippers, whose nocturnal decrease of mean BP is <10% of daytime BP.63

β-blockers

In patients with chronic renal failure, afferent signals from diseased kidneys to integrative structures in the brain result in activation of sympathetic outflow.64 In addition, reduced expression and secretion of renalase, an enzyme that metabolizes catecholamines and is predominantly expressed in glomeruli and proximal tubules, may have a causative role in increased plasma catecholamine levels.65 Sympathetic nervous system acts on the kidney through its β-1, β-2 and α-1 receptors and affects the vasomotor tone of renal arterioles, in order to maintain a constant glomerular filtration.66 β-1 receptors cause renin release and increase in cardiac output, β-2 receptors induce vasodilation and increase glycogenolysis, whereas α-1 receptors induce vasoconstriction.66 In the case of CKD, the efferent arterioles are constricted more than the afferents, thereby increasing intraglomerular pressure.

Propanolol, a classic agent of this group, together with carvedilol and labetalol belong to non-selective β-blockers, as they exert blocking action both on β-1 and β-2 receptors. β-1-selective or cardio-selective blockers include metoprolol, atenolol and nebivolol. Carvedilol and labetalol mediate vasodilation through additional blockade of the α-1-adrenergic receptors.67 Nebivolol may also exert vasodilation via stimulation of nitric oxide.68 In addition, carvedilol and nebivolol have antioxidant effect69, 70, 71, 72, 73 and a safer metabolic profile.74, 75, 76, 77 Thus, newer β-blockers carvedilol and nebivolol are more beneficial. However, β-blockers are underused and this is in large part due to tolerability of these agents.78 Traditional β-blockers, like propranolol, atenolol and metoprolol, reduce GFR and renal blood flow,79 as a result of the decreased cardiac output they cause and the elevation of peripheral vascular resistance due to unblocked α-1 receptors. The USRDS Dialysis Morbidity and Mortality Study found that only 20% of chronic dialysis patients were receiving β-blocker therapy.80 A similar trend occurs in the predialysis patients (with mild to moderate renal insufficiency).81

When it comes to comparing β-blockers with other antihypertensive drugs, in terms of renal protection, unfortunately, a few studies on long-term renal outcomes are available. AASK trial compared ramipril with metoprolol and amlodipine and showed that the first one reduced progression of hypertensive renal disease to a greater extent than either of the two other drugs; however, patients in metoprolol group had significantly lower ESRD or death rate comparing with those receiving amlodipine.36 A major meta-analysis was conducted in 2005 that included 13 trials comparing a β-blocker with active treatment and seven studies comparing a β-blocker with placebo. This meta-analysis showed 16% increase of strokes and 3% of total mortality in β-blockers group compared with other antihypertensive drugs.82 In the light of these results β-blockers use as first choice antihypertensive drugs was challenged.83

However, the importance of sympathetic nervous system activation in hypertension, CKD pathogenesis and the increased cardiovascular morbidity and mortality seen in CKD patients, justify β-blockers, especially the newer vasodilating ones, as an adjunctive antihypertensive treatment in CKD that can provide cardiorenal protection.84

Diuretics

Extracellular volume expansion due to fluid and sodium retention is a substantial contributing factor to hypertension seen in chronic renal failure. Diuretics are therefore a useful tool to manage volume overload and to achieve strict blood pressure control in these patients.85, 86 Thiazide diuretics, especially chlorthalidone, have a longer antihypertensive effect than the loop diuretics. Loop diuretics are less effective in patients with normal renal function, unless they are given in multiple daily doses. However, as thiazide diuretics are less effective at low levels of GFR, a loop diuretic is preferred in patients with more advanced CKD (GFR<30 ml min−1), as well as in acute renal failure.12, 87

Several studies have shown the substantial role of diuretics in CKD. De Nicola et al.88 assessed control rates and treatment of hypertension in 1200 patients with CKD from Italy and found that, although 70% received multidrug antihypertensive therapy including RAS inhibitors, BP target was achieved in only 12% of patients. Notably, diuretic treatment was prescribed in a minority of patients (37%) and at insufficient doses in half the cases. Researchers concluded that the main barrier to guideline implementation was possibly the inadequate treatment of extracellular volume expansion. Moreover, Abe et al.85 proposed that a low dose of hydrochlorothiazide should be administered to those patients in whom BP is not controlled well by intensive RAS inhibition therapy using the maximum recommended doses of ARBs and ACEIs. In this study, hydrochlorothiazide was shown to have a renoprotective effect in hypertensive patients with stage 3–4 CKD, as it significantly decreased BP and urinary protein/creatinine ratio. In addition, ALLHAT trial showed that chlorthalidone reduced systolic BP more than either amlodipine or lisinopril,7 while a post-hoc analysis found no statistically significant differences in ESRD incidence rate between the three treatment groups.59

Diuretic use as monotherapy is controversial. Although European10 and US11 guidelines on hypertension recommend the use of thiazide diuretics as first-line therapy,89 some researchers have a different opinion.90 Arguments are based on the fact that diuretics induce RAS stimulation, as well as metabolic alterations in glucose and lipids,91, 92 that may have negative impact on cardiovascular outcomes. The results of numerous large intervention trials support the concept that long-term therapy with diuretics, especially when diuretics are combined with β-blockers, reduce glucose tolerance and increases new-onset diabetes risk. Examples of such studies are the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation trial (ALPINE),93 INSIGHT trial57 and Captopril Prevention Project (CAPPP) trial.94 Furthermore, despite increasing diuretic therapy in the US, Hawkins and Houston95 also observed increasing incidence of ESRD and examined the possibility that these two parameters are related to each other. The study synthesized data from different national databases for the decade 1990–2001 with data fusion technique and the results showed a positive correlation between changes in the use of diuretics and the increase the occurrence of ESRD, with a time lag of 2 years.

The majority of studies so far have limited duration and middle to long-term diuretic efficacy in renal protection has not been sufficiently assessed. However, control of volume retention remains the most important key to hypertension treatment in patients with chronic renal failure and, for the most part, cannot be adequately regulated without the use of a diuretic.

Aldosterone receptor blockers

Accumulating evidence suggests that aldosterone per se is an important mediator of renal injury, while elevated levels have been found in CKD.96, 97 Aldosterone may induce inflammation and fibrosis in the kidney by stimulating plasminogen activator inhibitor-1 expression,98 generating reactive oxygen species and transforming growth factor-β expression.99 Albeit ACEIs and ARBs suppress RAS, their action is not enough to control plasma aldosterone levels, owing to aldosterone escape during long-term blockade of the renin-angiotensin-aldosterone system.100 As a result, aldosterone receptor blockers therapy could enhance antihypertensive treatment.101

Aldosterone antagonists are classified in the non-selective, like spironolactone, and in the newer selective antagonists, like eplerenone. Both substances have been proved to reduce albuminuria in patients with diabetic nephropathy. Rossing et al.102 have shown that 25 mg of spironolactone, when added to maximum ACEI or ARB treatment, resulted in 33% reduction of albuminuria (P<0.001) in patients with type 2 diabetes and nephropathy. In addition, Epstein et al.103 showed that adding 50–100 mg of eplerenone in ACEI therapy in patients with type 2 diabetes and nephropathy resulted in 41% reduction of albuminuria (P<0.001) comparing with placebo group. Conversely, hyperkalemia, an important side effect of aldosterone antagonist therapy, can be aggravated by concurrent renal insufficiency, diabetes mellitus, severe heart failure, old age and other potassium-sparing drugs. Aldosterone antagonists are not recommended when serum creatinine is >2.5 mg dl−1 or creatinine clearance is <30 ml min−1 or serum potassium is >5 mmol l−1.11, 104 Unfortunately, there are not yet studies comparing non-selective to selective aldosterone antagonists, neither studies evaluating the long-term effects of aldosterone antagonists combined to other RAS inhibitors, in terms of kidney function. Therefore, aldosterone antagonists cannot be yet recommended as a routine additional therapy in patients with CKD.

α-blockers

Alpha1-adrenergic blockers, including doxazosin, terazosin and prazosin, inhibit vasoconstriction that is induced by sympathetic nervous system through noradrenaline and cause vasodilation, reduction of peripheral resistances and BP decrease. To date, studies have not shown a special benefit of these drugs in cardiovascular and renal protection. The ALLHAT study showed that cardiovascular and renal outcomes were not significantly reduced in α-blocker group (doxazosin) comparing with diuretic group in patients with metabolic syndrome, including those without diabetes mellitus (RR=1.18).105 α-blockers lack potent antihypertensive effect, especially when used as monotherapy, but they are usually given in combination with other antihypertensive drugs in CKD patients that have resistant hypertension.106 In addition, they are of benefit in men with symptomatic benign prostatic hyperplasia. Their most common adverse effect is sudden occurrence of orthostatic hypotension after first dose, which can be avoided if treatment is initialized in low dose. Other known adverse effects, like headache, dry mouth and weakness, have been eliminated with newer components.

Centrally acting antihypertensives

Centrally acting drugs, like clonidine, a-methyldopa, guanfacine and the newer moxonidine, cross the blood–brain barrier and act centrally by activating α-2-adrenergic receptors in the vasomotor center in the brain stem and hypothalamus, resulting in reduction of peripheral sympathetic tone and hence vasodilation and a fall in BP, heart rate and cardiac output.107 No adverse metabolic effects have been mentioned, but a numerous of other side effects, like dry mouth, fatigue, drowsiness and sedation. Cessation of therapy with clonidine, and to a lesser extent with methyldopa and guanfacine, may result in a severe withdrawal syndrome characterized by restlessness, sweating, anxiety, tremor, palpitations, headache and a rebound rise in BP. Moxonidine and rilmenidine (not available in the United States), the newer substances of this group, have a more selective action on I1-imidazoline receptors, located in the nucleus reticularis lateralis, and therefore their side-effect profile is more favorable.108 There is a lack of studies on the impact of centrally acting antihypertensives on CKD, however, there is a long experience especially with clonidine use and these agents may be added to an existing regimen in cases of resistant hypertension.

Renin inhibitors

The most recent agents of renin-angiotensin-aldosterone system inhibitors are renin inhibitors. The blockade of renin is a very attractive idea, as the interaction of renin with its physiological substrate angiotensinogen is the rate-limiting step in the renin-angiotensin-aldosterone system cascade. The first commercially available orally active renin inhibitor is aliskiren.109 Aliskiren acts by binding to the active site of renin, thereby inhibiting catalytic activity, and reduces angiotensin II levels and plasma renin activity without stimulating compensatory increases in plasma renin activity, angiotensin I and angiotensin II, as seen with ACEIs and ARBs.110 In addition, it is well tolerated and effective in lowering BP in both the general population of hypertensive patients and specific patient groups, such as obese people.111 Studies in animal models have shown that aliskiren has renoprotective, cardioprotective and anti-atherosclerotic properties, which are independent of BP reduction.111

In terms of proteinuria reduction in diabetic patients, Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) trial has shown positive results. The study compared the combination of aliskiren/losartan with losartan as monotherapy in 599 hypertensive patients with type 2 diabetes and nephropathy for a period of 6 months. According to the results, proteinuria in the combined therapy group was reduced by 20% more than in the control group, while adverse events were similar in both treatment groups.112 However, the longer Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE)113 was early terminated when an interim review of data showed an increased risk for non-fatal stroke, renal complications, hyperkalemia and hypotension in patients taking aliskiren in combination with an ACEI or an ARB after 18–24 months. Further studies to evaluate the renoprotective effect of aliskiren are required.

Endothelin-1 receptor antagonists

Endothelin-1 is a strong vasoconstrictor peptide, 30–50 times more potent than equimolar quantities of norepinephrine and angiotensin II.114 It is notable that the medulla of the kidney has the highest concentration of endothelin receptors in the body, while in the cortex 70% of receptors are type B.115 Activation of ET-B receptor results in vasodilation through the release of nitric oxide, prostacyclin, atrial natriuretic peptide and adrenomeduline.116, 117 Moreover, it induces natriuresis and diuresis118, 119 and participates in the clearance of endothelin-1.120 In contrast, ET-A receptors cause vasoconstriction and inflammatory reactions. A double-blind randomized multicenter study of Weber et al.,121 which included 379 patients with resistant hypertension, showed that the substance darusentan, a selective ET-A receptor antagonist, offered additional reduction of BP. In addition, Wenzel et al.122 followed up 286 patients with diabetic nephropathy, macroalbuminuria and hypertension for 12 weeks, and showed a significant decrease in albuminuria in the group where the substance avosentan, a non-selective antagonist, was added in the already given treatment with ACEIs or ARBs. In both studies, the main side effect was fluid retention, while a dose-dependent hepatotoxicity was also reported. Although endothelin receptor antagonists have already been approved for the treatment of pulmonary hypertension,123 the available studies on arterial hypertension and CKD are still inefficient.124

Conclusions

It is clear that the goal of antihypertensive therapy should be to obtain optimal BP control. A variety of BP lowering agents is available for clinical use. Usually, a combination of two or more antihypertensive drugs is required in order to control hypertension. In fact, antihypertensive treatment is individualized to each patient depending on the tolerance, compliance and specific clinical features.

ACEIs and ARBs have been undoubtedly studied the most. Their ability to induce dilation of efferent arterioles in renal glomerulus, resulting in reduced intraglomerular pressure, and to inhibit proinflammatory and proliferative actions exerted by angiotensin II, makes them the most commonly used drugs in CKD patients, particularly in those with diabetes, as they have neutral metabolic effects and they have been shown to significantly reduce proteinuria. Less data are available for the long-term effects of other agents on CKD. CCBs have been proved to control BP effectively, β-blockers to regulate sympathetic nervous system overactivity observed in chronic renal failure and diuretics to control expansion of intravascular volume caused by fluid retention. Notably, β-blockers reduce insulin sensitivity, except for some newer substances, and therefore they should be avoided in patients with diabetes or impaired glucose tolerance. Moreover, CCBs may increase proteinuria, unless BP is well controlled, because they dilate the afferent arteriole and increase intraglomerular pressure. Clinical studies have shown that especially diltiazem and verapamil appear to have greater renoprotective role than dihydropyridines.

To achieve the desired levels of BP, an ACEI or ARB can be combined with a thiazide diuretic or loop diuretic, and, if necessary, a CCB or a β-blocker can be added. The combination of ACEIs with ARBs appears to reduce further the proteinuria in CKD. However, a significant risk for hyperkalemia and acute renal failure has been attributed to this combination. Continuous research has found new substances that might contribute to optimal BP control, such as renin inhibitors, the newest RAS blockers, and inhibitors of endothelin-1, which have beneficial effects when combined with ACEIs.