**4. Considerations about hypertension treatment in CKD**

The treatment of hypertension in CKD has three main goals: blood pressure control; delaying the progression of CKD itself; decreasing the risk of cardiovascular complications in this particular population. The role of non-drug therapy is frequently underestimated. However, salt restriction and lifestyle modifications are invaluable to achieve the goals defined above. Drug therapy is fundamental, and at later stages of CKD, double or multiple drug associations are often needed. RAS antagonists should the preferred drugs and their association with diuretics mandatory.

## **4.1 Salt restriction and life style modifications**

Given that one of the main causes of CKD related hypertension is increased extracellular volume (or exchangeable sodium), dietary sodium restriction makes every sense. Excess dietary salt, typical of Western Countries, is clearly associated with the massive number of hypertensive patients in modern societies and, in the other extreme, it is well known that in primitive civilizations with low sodium intake, the prevalence of hypertension is irrelevant (Carvalho et al, 1989). Guidelines on CKD recommend a low sodium ingestion (70– 100mmol/day) in patients with CKD (KDOQI, 2004; Joint Specialty Committee Guidelines, 2006; Levin et al, 2008). This suggestion is based on the evidence that a lower sodium intake is associated with a reduction of the blood pressure values (Sacks et al, 2001), increases the protective effect of ACE inhibitors in patients with proteinuria (Heeg et al, 1989) and, possibly, declines the progression of renal failure (Ciancaruso et al, 1998). Concerning life style changes, it is recommended to CKD patients to have a healthy life. Cigarette smoking, a well known cardiovascular risk factor also works as a renal risk factor. Smoking increases blood pressure by stimulating the sympathetic nervous system and also by rising plasma endothelin levels (Orth, 2003; Halimi & Mimran, 2000). The related excessive production of oxygen-free radicals can produce endothelial dysfunction and consequently be another factor implicated in the increase of blood pressure. It is critical to stop smoking, because this preventable risk factor can hasten the progression of chronic renal insufficiency in diabetic and non-diabetic nephropathies, independently of gender and race (Orth, 2003). Reduction of alcohol ingestion is also another useful decision, not because it is related with worsening of the renal function itself, but rather because it can be associated with smoking and obesity (Suter & Schutz, 2008). Weight loss in hypertensive obese patients is associated with reductions of the blood pressure, proteinuria and left ventricular hypertrophy, with benefits in terms of total cardiovascular outcomes. In CKD patients a favorable impact was also demonstrated: a decrease in proteinuria and better blood pressure control (Praga & Morales, 2006). Weight reduction may improve insulin resistance and decreases inflammation and oxidative stress beyond positive actions on the RAS and sympathetic nervous system. Furthermore, it may also slow down the progression to ESRD. The regular practice of exercise also has a beneficial effect on CKD patients. A high-quality exercise program can improve many indicators of physical performance, as well as all cardiovascular indices. Exercise may improve the control of blood pressure and endothelial function and decrease

Hypertension and Chronic Kidney Disease:

Cause and Consequence – Therapeutic Considerations 53

more than 30 years ago, using diuretics and a Beta Blocker in type I diabetic patients with nephropathy (Mogensen, 1976). Notwithstanding, in the last decades, the superiority of the ACE inhibitors, and lately of the angiotensin receptor blockers (ARB), in terms of preventing the progression of CKD and also in terms of reducing cardiovascular morbidity and mortality have been widely reported in medical literature. The benefits of ACE inhibitors and ARB are far beyond and independent of blood pressure control. The mechanisms of renal protection result from hemodynamic and non-hemodynamic actions: decrease of intraglomerular hydrostatic pressure, decrease of protein excretion, and decrease of AII activity (Sica, 2003). This octapeptide is also a powerful cytokine with nonhemodynamic properties such as proinflammatory and profibrotic actions. AII upregulates the production of adhesion molecules, cytokines and chemokines, increasing the number of inflammatory cells in the kidney. It also stimulates extracellular matrix accumulation through the production of profibrotic factors, such as transforming growth factor-β. The decrease of AII activity observed with these drugs explains, in part, the extra advantages of their use in CKD patients. Several RCT and meta-analysis, in type 1 and 2 diabetic patients as well as in non-diabetic patients, confirmed that ACE inhibitors and ARB must be first choice drugs in renal patients, since they effectively slow the progression of CKD (Jafar et al, 2003; Lewis et al, 1993; Lewis et al, 2001; Brenner et al, 2001; Jafar et al, 2001). In addition, these particular drugs have the ability to reduce cardiovascular morbidity and mortality. In a post hoc analysis of the HOPE study, treatment with ramipril in patients with slight to moderate CKD decreased significantly the number of cardiovascular events (Mann et al, 2001). In the PEACE trial, trandolapril reduced the mortality in 27 % only in the subgroup of patients with renal insufficiency (Solomon et al, 2006) and in a recent meta-analysis, Balamuthusamy and coworkers found that RAS blockade in patients with non-diabetic renal disease was associated with a significant reduction in cardiovascular outcomes (Balamuthusamy et al, 2007). Concerning the secondary effects of these anti-hypertensive agents in renal patients, special attention must be given to: possible slight increase of the creatinine level (< 25 %), reflecting a decrease of the glomerular hyperfiltration, which means good news on the long run; a major increase of the creatinine level is suggestive of volume depletion (concomitant use of diuretics) or of bilateral renal artery stenosis; hyperkalemia is usually insignificant, but when severe it might be fatal; we must be aware of the potassium intake and of the use of other potentially hyperkalemic drugs, like aldosterone antagonists or non-steroid anti-inflammatory drugs; finally, we must also take into consideration that these drugs may also increase the need for

higher dose of erythropoiesis stimulating agents (Neves et al, 2007).

As stated previously, most patients will need two or more drugs to control hypertension and a stepwise approach should be pursued. After the prescription of an ACE inhibitor or an ARB, if there are no contra-indications, the choice of another anti-hypertensive agent must be dictated by any specific conditions of each patient. Diuretics are very useful and almost always mandatory, mainly in later stages of the disease, because of the presence of fluid overload. Thiazides can be used when the GFR > 30 ml/min/1,73 m2 body surface area, being ineffective beyond this level. Then, we should rather use a loop diuretic such as indapamide or furosemide (KDOQI, 2004). Diuretics have the ability to diminish sodium reabsorption, thereby reversing hypervolemia and reducing the blood pressure. By reducing

**4.2.3 Which drug association must we favor?** 

inflammation and insulin resistance (Johansen, 2007). Moreover, physical exercise has no untoward effect on progression of CKD. However, since this population has a potential bigger risk of musculoskeletal injuries and cardiac events it is mandatory to perform an accurate medical checkout before enrolling any exercise program.

## **4.2 Pharmacological therapy**

The need to employ anti-hypertensive drugs mainly in the late stages of the disease is mandatory in almost all CKD patients. It is, often, necessary to use multiple drug regimens to control the blood pressure levels adequately and a constant evaluation of patient compliance and frequent medical reassessment meetings are required.

## **4.2.1 What should be the target blood pressure?**

Nearly all guidelines concerning CKD patients support that blood pressure should be targeted to less than 130/80 mmHg (Chobanian et al, 2003; KDOQI, 2004; Levin et al, 2008). Despite major well designed randomized controlled trials (RCT) (Klahr et al, 1994; Estacio et al, 2000; Wright et al, 2002; Ruggenenti et al, 2005), there is no clear evidence that a blood pressure target < 130/80 mmHg is better, in terms of renal disease progression in CKD patients. A recently published systematic review did not show any advantage, regarding progression of CKD, in keeping blood pressure < 130/80 mmHg (Upadhyay et al, 2011). Post-hoc analysis of the MDRD and ABCD studies showed some benefits in the group of patients with a better control of the blood pressure, and two meta-analyses (Makki et al, 1995; Casas et al, 2005) also showed a protracted progression of the CKD in patients with lower blood pressure levels. Furthermore, another meta-analysis including 11 RCT with non-diabetic CKD patients, showed that those with systolic blood pressure between 110-119 mmHg, had the lowest risk of progression of CKD, and that this risk was greatly increased in patients with systolic blood pressure > 130 mmHg (Jafar et al, 2003). Finally, Appel and co-workers demonstrated that in African-American patients with CKD and proteinuria, intensive blood pressure treatment decreased the risk of progression of renal failure (Appel et al, 2010). Secondary analysis from large RCT with antagonists of the RAS, such as the HOPE, IDNT and ADVANCE studies, proved that hypertension treatment in CKD patients can reduce the risk of cardiovascular events (Mann et al, 2001; Pohl et al, 2005; Heerspink et al, 2010). However, insofar no RCT was able to prove that a blood pressure < 130/80 mmHg is better in terms of cardiovascular outcomes. On the other hand, it must be kept in mind that lowering the blood pressure < 120/70 mmHg, mainly in older patients, can increase the progression of renal failure (van Bemmel et al, 2006) and enhance the probability of a cardiovascular event (Pohl et al, 2005; Hirsh et al, 2008). In brief, there is no strong evidence to have a blood pressure target < 130/80 mmHg, and we should maintain the goal of blood pressure < 140/90 mmHg, mostly in the elderly. However, in patients under 60 years with proteinuria a lower target might be allowed.

#### **4.2.2 Which anti-hypertensive drug must we choose?**

We must choose a drug to control the blood pressure, with the ability to slow down the inexorable progression of CKD and decrease the cardiovascular risk of this population. Hypertension control, by itself, can delay the progression of CKD, as Mogensen reported

inflammation and insulin resistance (Johansen, 2007). Moreover, physical exercise has no untoward effect on progression of CKD. However, since this population has a potential bigger risk of musculoskeletal injuries and cardiac events it is mandatory to perform an

The need to employ anti-hypertensive drugs mainly in the late stages of the disease is mandatory in almost all CKD patients. It is, often, necessary to use multiple drug regimens to control the blood pressure levels adequately and a constant evaluation of patient

Nearly all guidelines concerning CKD patients support that blood pressure should be targeted to less than 130/80 mmHg (Chobanian et al, 2003; KDOQI, 2004; Levin et al, 2008). Despite major well designed randomized controlled trials (RCT) (Klahr et al, 1994; Estacio et al, 2000; Wright et al, 2002; Ruggenenti et al, 2005), there is no clear evidence that a blood pressure target < 130/80 mmHg is better, in terms of renal disease progression in CKD patients. A recently published systematic review did not show any advantage, regarding progression of CKD, in keeping blood pressure < 130/80 mmHg (Upadhyay et al, 2011). Post-hoc analysis of the MDRD and ABCD studies showed some benefits in the group of patients with a better control of the blood pressure, and two meta-analyses (Makki et al, 1995; Casas et al, 2005) also showed a protracted progression of the CKD in patients with lower blood pressure levels. Furthermore, another meta-analysis including 11 RCT with non-diabetic CKD patients, showed that those with systolic blood pressure between 110-119 mmHg, had the lowest risk of progression of CKD, and that this risk was greatly increased in patients with systolic blood pressure > 130 mmHg (Jafar et al, 2003). Finally, Appel and co-workers demonstrated that in African-American patients with CKD and proteinuria, intensive blood pressure treatment decreased the risk of progression of renal failure (Appel et al, 2010). Secondary analysis from large RCT with antagonists of the RAS, such as the HOPE, IDNT and ADVANCE studies, proved that hypertension treatment in CKD patients can reduce the risk of cardiovascular events (Mann et al, 2001; Pohl et al, 2005; Heerspink et al, 2010). However, insofar no RCT was able to prove that a blood pressure < 130/80 mmHg is better in terms of cardiovascular outcomes. On the other hand, it must be kept in mind that lowering the blood pressure < 120/70 mmHg, mainly in older patients, can increase the progression of renal failure (van Bemmel et al, 2006) and enhance the probability of a cardiovascular event (Pohl et al, 2005; Hirsh et al, 2008). In brief, there is no strong evidence to have a blood pressure target < 130/80 mmHg, and we should maintain the goal of blood pressure < 140/90 mmHg, mostly in the elderly. However, in patients under 60 years with

We must choose a drug to control the blood pressure, with the ability to slow down the inexorable progression of CKD and decrease the cardiovascular risk of this population. Hypertension control, by itself, can delay the progression of CKD, as Mogensen reported

accurate medical checkout before enrolling any exercise program.

compliance and frequent medical reassessment meetings are required.

**4.2.1 What should be the target blood pressure?** 

proteinuria a lower target might be allowed.

**4.2.2 Which anti-hypertensive drug must we choose?** 

**4.2 Pharmacological therapy** 

more than 30 years ago, using diuretics and a Beta Blocker in type I diabetic patients with nephropathy (Mogensen, 1976). Notwithstanding, in the last decades, the superiority of the ACE inhibitors, and lately of the angiotensin receptor blockers (ARB), in terms of preventing the progression of CKD and also in terms of reducing cardiovascular morbidity and mortality have been widely reported in medical literature. The benefits of ACE inhibitors and ARB are far beyond and independent of blood pressure control. The mechanisms of renal protection result from hemodynamic and non-hemodynamic actions: decrease of intraglomerular hydrostatic pressure, decrease of protein excretion, and decrease of AII activity (Sica, 2003). This octapeptide is also a powerful cytokine with nonhemodynamic properties such as proinflammatory and profibrotic actions. AII upregulates the production of adhesion molecules, cytokines and chemokines, increasing the number of inflammatory cells in the kidney. It also stimulates extracellular matrix accumulation through the production of profibrotic factors, such as transforming growth factor-β. The decrease of AII activity observed with these drugs explains, in part, the extra advantages of their use in CKD patients. Several RCT and meta-analysis, in type 1 and 2 diabetic patients as well as in non-diabetic patients, confirmed that ACE inhibitors and ARB must be first choice drugs in renal patients, since they effectively slow the progression of CKD (Jafar et al, 2003; Lewis et al, 1993; Lewis et al, 2001; Brenner et al, 2001; Jafar et al, 2001). In addition, these particular drugs have the ability to reduce cardiovascular morbidity and mortality. In a post hoc analysis of the HOPE study, treatment with ramipril in patients with slight to moderate CKD decreased significantly the number of cardiovascular events (Mann et al, 2001). In the PEACE trial, trandolapril reduced the mortality in 27 % only in the subgroup of patients with renal insufficiency (Solomon et al, 2006) and in a recent meta-analysis, Balamuthusamy and coworkers found that RAS blockade in patients with non-diabetic renal disease was associated with a significant reduction in cardiovascular outcomes (Balamuthusamy et al, 2007). Concerning the secondary effects of these anti-hypertensive agents in renal patients, special attention must be given to: possible slight increase of the creatinine level (< 25 %), reflecting a decrease of the glomerular hyperfiltration, which means good news on the long run; a major increase of the creatinine level is suggestive of volume depletion (concomitant use of diuretics) or of bilateral renal artery stenosis; hyperkalemia is usually insignificant, but when severe it might be fatal; we must be aware of the potassium intake and of the use of other potentially hyperkalemic drugs, like aldosterone antagonists or non-steroid anti-inflammatory drugs; finally, we must also take into consideration that these drugs may also increase the need for higher dose of erythropoiesis stimulating agents (Neves et al, 2007).

#### **4.2.3 Which drug association must we favor?**

As stated previously, most patients will need two or more drugs to control hypertension and a stepwise approach should be pursued. After the prescription of an ACE inhibitor or an ARB, if there are no contra-indications, the choice of another anti-hypertensive agent must be dictated by any specific conditions of each patient. Diuretics are very useful and almost always mandatory, mainly in later stages of the disease, because of the presence of fluid overload. Thiazides can be used when the GFR > 30 ml/min/1,73 m2 body surface area, being ineffective beyond this level. Then, we should rather use a loop diuretic such as indapamide or furosemide (KDOQI, 2004). Diuretics have the ability to diminish sodium reabsorption, thereby reversing hypervolemia and reducing the blood pressure. By reducing

Hypertension and Chronic Kidney Disease:

retention induced by the former (KDOQI, 2004).

**4.2.4 What about the dual blockade of the RAS?** 

moment this association cannot be recommended.

**5. Conclusion** 

Cause and Consequence – Therapeutic Considerations 55

hyperkaliemia. The association of aldosterone antagonists with AII antagonists is justified by the called aldosterone escape phenomenon. The hypothetical advantage of this add-on therapy is attributed to the anti-fibrotic and anti-hypertensive properties of aldosterone antagonists. Although there are some beneficial effects in terms of proteinuria , the addition of an aldosterone antagonist to an ACE inhibitor or to an ARB does not slow the progression of renal failure. Besides, the risk of hyperkalemia is markedly increased. Renin Inhibitors, a new class of antagonists of the RAS that blocks the conversion of angiotensinogen to angiotensin I, have recently started to be used worldwide. Aliskiren, the first compound of the class, shows an effective blood pressure control and reduces albuminuria successfully in type 2 diabetic patients, when given alone (Persson et al, 2009) or in combination with losartan (Parving et al, 2008). This renoprotection is independent of its blood pressure lowering effect. Further studies are needed to determine if aliskiren, alone or in association, is able to reduce hard renal and cardiovascular end-points in CKD patients. The utilization of α-adrenergic agents or the potent vasodilator minoxidil is only justified if blood pressure control was still not achieved with the previous described classes of anti-hypertensive drugs. They are extremely potent agents but present many adverse side effects. Furthermore, minoxidil must always be associated with a Beta-Adrenergic Blocker and a diuretic in order to control the reflex tachycardia and the fluid

The rational for using two antagonists of the RAS is sustained by the existence of the AII escape phenomenon. After long-term ACE inhibition, it was demonstrated that AII synthesis via non-ACE pathways increases. Moreover, there are some limitations of ACE inhibitors in decreasing the local production of AII (Arici & Erdem, 2009). The ARB blocks the binding of AII to its receptors, reducing both its systemic and local effects (Arici & Erdem, 2009). There are advantages and drawbacks of combination therapy (Wolf & Ritz, 2005), but, in clinical terms, the aim of combination therapy is to block of the RAS more effectively (Arici & Erdem, 2009). Although several studies showed a greater decrease of albuminuria with the dual blockade (Mogensen et al, 2000; Campbell et al, 2003; Jennings et al, 2007), there are no RCT demonstrating a true slow down of CKD with combination therapy. In the ONTARGET study, the group of patients under ramipril plus telmisartan presented a higher renal impairment - doubling of serum creatinine or dialysis - and there were no differences in respect to cardiovascular outcomes (Yusuf et al, 2008). The ValHeFT and the VALIANT studies also showed more kidney dysfunction in the combination groups (Conn et al, 2001; Pfeffer et al, 2003), despite better cardiovascular results in the ValHeFT (Conn et al, 2001). In summary, concerning CKD progression, despite the theoretical advantages of combination therapy, presently there are no RCT demonstrating such benefit. Furthermore, the dual blockade is not harmless, and is associated with the risk of hyperkalemia and of greater renal impairment. Probably, studies with selected patients (with proteinuria > 1g/24h) or a different type of dual blockade with a renin inhibitor, will demonstrate a clear superiority of an association of two antagonists of the RAS. At the

Hypertension and CKD are both the chicken and the egg in this story. CKD resulting from hypertension and hypertension resulting from CKD are complex and multifactorial. A better

the blood volume and stimulating the renin activity, diuretics intensify the effect of ACE inhibitors and ARB. Potassium sparing agents must be avoided or used very carefully due to the risk of life threatening hyperkalemia, particularly if the patient is also under an ACE inhibitor or ARB (KDOQI, 2004). For all these reasons, in the CKD patient, diuretics should be the first class of anti-hypertensive drugs to be added to an ACE inhibitor or an ARB. Calcium Channel Blockers (CCB) are potent vasodilators and also have a relevant role in the control of the blood pressure in CKD patients. They are particularly indicated if the patient has angina or heart failure secondary to diastolic dysfunction (KDOQI, 2004). Due to distinct renal hemodynamic effects, the type CCB to use should not be indiscriminate. In fact, dihydropyridines by inhibiting the renal auto-regulatory capacity and by increasing the glomerular permeability, intensifying proteinuria (Nathan et al, 2005), are harmful in terms of CKD progression. This observation was well demonstrated in the AASK and IDNT trials (Wright et al, 2002, Lewis et al, 2001), where the dihydropyridine amlodipine was worse than the ACE inhibitor or the ARB regimen. However, the non-dihydropyridines, do not interfere with glomerular auto-regulation, and therefore do not exhibit deleterious effect in terms of proteinuria and renal function (Nathan et al, 2005; Bakris et al, 1996). In renal patients with proteinuria, the non-dihydropyridine CCB are a good choice to add to an ACE inhibitor to an ARB. On the contrary, they should be avoided in patients with second and third degree heart block or with congestive heart failure due to systolic dysfunction (KDOQI, 2004). Once the dihydropiridines have detrimental effects on renal function, it is recommended that they must be given in combination with kidney protecting drugs, such as the AII antagonists. In fact, in the ACCOMPLISH trial, the risk of progression of the CKD was lower in the group of patients treated with a combination of an ACE inhibitor with amlodipine than in the group treated with the ACE inhibitor and a diuretic (Bakris et al, 2010).. This study may support, at least in some patients, the use of a CCB as the first drug to add to an AII axis antagonist. It has been shown that this association may have a greater anti-inflammatory effect. Beta-Adrenergic Blockers comprise a heterogeneous group of drugs organized in classes according to their receptor selectivity, lipid-solubility, intrinsic sympathetic activity and membrane stabilizing capacity (Kaplan, 2006a). The use of a Beta-Adrenergic Blocker, in a renal patient, is almost always justified by the coexistence of ischemic heart disease. This class of drugs is specially indicated in patients with prior angina or myocardial infarction or with atrial tachycardia or fibrillation (KDOQI, 2004). The water soluble Beta-Adrenergic Blockers (atenolol, sotalol) are excreted by the kidney and may accumulate in CKD; the lipid soluble ones (propranolol, metoprolol) are metabolized in the liver and may be associated with central nervous system side effects. Both types can cause hyperkalemia. Beta-Adrenergic Blockers do not worsen renal function but, beyond blood pressure control, they do not protect the kidney (Hannedouche et al, 1994). Carvedilol is a Beta-Adrenergic Blocker with non-selective α1 activity that displays some advantages: beneficial effects on lipid profile (Stafylas & Sarafidis, 2008), increase of insulin sensitivity, and the capacity to reduce albumin excretion (Bakris et al, 2004). Respecting renal hemodynamics, carvedilol preserves the renal blood flow and the glomerular filtation rate (GFR), whereas decreases the renal vascular resistance. Furthermore, has anti-oxidant activity. Contradictory results concerning the favorable effect of Beta-Adrenergic Blocker on cardiovascular morbidity and mortality of CKD patients have been reported in medical literature. Prospective RCT are needed to ascertain whether these anti-hypertensive drugs really do have a positive influence on the survival of renal patients or not. Aldosterone antagonists can be used in renal patients, but with great caution if the GFR is below 30 ml/min, the patient is taking an ACE inhibitor or an ARB, or has additional risk factors for

the blood volume and stimulating the renin activity, diuretics intensify the effect of ACE inhibitors and ARB. Potassium sparing agents must be avoided or used very carefully due to the risk of life threatening hyperkalemia, particularly if the patient is also under an ACE inhibitor or ARB (KDOQI, 2004). For all these reasons, in the CKD patient, diuretics should be the first class of anti-hypertensive drugs to be added to an ACE inhibitor or an ARB. Calcium Channel Blockers (CCB) are potent vasodilators and also have a relevant role in the control of the blood pressure in CKD patients. They are particularly indicated if the patient has angina or heart failure secondary to diastolic dysfunction (KDOQI, 2004). Due to distinct renal hemodynamic effects, the type CCB to use should not be indiscriminate. In fact, dihydropyridines by inhibiting the renal auto-regulatory capacity and by increasing the glomerular permeability, intensifying proteinuria (Nathan et al, 2005), are harmful in terms of CKD progression. This observation was well demonstrated in the AASK and IDNT trials (Wright et al, 2002, Lewis et al, 2001), where the dihydropyridine amlodipine was worse than the ACE inhibitor or the ARB regimen. However, the non-dihydropyridines, do not interfere with glomerular auto-regulation, and therefore do not exhibit deleterious effect in terms of proteinuria and renal function (Nathan et al, 2005; Bakris et al, 1996). In renal patients with proteinuria, the non-dihydropyridine CCB are a good choice to add to an ACE inhibitor to an ARB. On the contrary, they should be avoided in patients with second and third degree heart block or with congestive heart failure due to systolic dysfunction (KDOQI, 2004). Once the dihydropiridines have detrimental effects on renal function, it is recommended that they must be given in combination with kidney protecting drugs, such as the AII antagonists. In fact, in the ACCOMPLISH trial, the risk of progression of the CKD was lower in the group of patients treated with a combination of an ACE inhibitor with amlodipine than in the group treated with the ACE inhibitor and a diuretic (Bakris et al, 2010).. This study may support, at least in some patients, the use of a CCB as the first drug to add to an AII axis antagonist. It has been shown that this association may have a greater anti-inflammatory effect. Beta-Adrenergic Blockers comprise a heterogeneous group of drugs organized in classes according to their receptor selectivity, lipid-solubility, intrinsic sympathetic activity and membrane stabilizing capacity (Kaplan, 2006a). The use of a Beta-Adrenergic Blocker, in a renal patient, is almost always justified by the coexistence of ischemic heart disease. This class of drugs is specially indicated in patients with prior angina or myocardial infarction or with atrial tachycardia or fibrillation (KDOQI, 2004). The water soluble Beta-Adrenergic Blockers (atenolol, sotalol) are excreted by the kidney and may accumulate in CKD; the lipid soluble ones (propranolol, metoprolol) are metabolized in the liver and may be associated with central nervous system side effects. Both types can cause hyperkalemia. Beta-Adrenergic Blockers do not worsen renal function but, beyond blood pressure control, they do not protect the kidney (Hannedouche et al, 1994). Carvedilol is a Beta-Adrenergic Blocker with non-selective α1 activity that displays some advantages: beneficial effects on lipid profile (Stafylas & Sarafidis, 2008), increase of insulin sensitivity, and the capacity to reduce albumin excretion (Bakris et al, 2004). Respecting renal hemodynamics, carvedilol preserves the renal blood flow and the glomerular filtation rate (GFR), whereas decreases the renal vascular resistance. Furthermore, has anti-oxidant activity. Contradictory results concerning the favorable effect of Beta-Adrenergic Blocker on cardiovascular morbidity and mortality of CKD patients have been reported in medical literature. Prospective RCT are needed to ascertain whether these anti-hypertensive drugs really do have a positive influence on the survival of renal patients or not. Aldosterone antagonists can be used in renal patients, but with great caution if the GFR is below 30 ml/min, the patient is taking an ACE inhibitor or an ARB, or has additional risk factors for hyperkaliemia. The association of aldosterone antagonists with AII antagonists is justified by the called aldosterone escape phenomenon. The hypothetical advantage of this add-on therapy is attributed to the anti-fibrotic and anti-hypertensive properties of aldosterone antagonists. Although there are some beneficial effects in terms of proteinuria , the addition of an aldosterone antagonist to an ACE inhibitor or to an ARB does not slow the progression of renal failure. Besides, the risk of hyperkalemia is markedly increased. Renin Inhibitors, a new class of antagonists of the RAS that blocks the conversion of angiotensinogen to angiotensin I, have recently started to be used worldwide. Aliskiren, the first compound of the class, shows an effective blood pressure control and reduces albuminuria successfully in type 2 diabetic patients, when given alone (Persson et al, 2009) or in combination with losartan (Parving et al, 2008). This renoprotection is independent of its blood pressure lowering effect. Further studies are needed to determine if aliskiren, alone or in association, is able to reduce hard renal and cardiovascular end-points in CKD patients. The utilization of α-adrenergic agents or the potent vasodilator minoxidil is only justified if blood pressure control was still not achieved with the previous described classes of anti-hypertensive drugs. They are extremely potent agents but present many adverse side effects. Furthermore, minoxidil must always be associated with a Beta-Adrenergic Blocker and a diuretic in order to control the reflex tachycardia and the fluid retention induced by the former (KDOQI, 2004).

#### **4.2.4 What about the dual blockade of the RAS?**

The rational for using two antagonists of the RAS is sustained by the existence of the AII escape phenomenon. After long-term ACE inhibition, it was demonstrated that AII synthesis via non-ACE pathways increases. Moreover, there are some limitations of ACE inhibitors in decreasing the local production of AII (Arici & Erdem, 2009). The ARB blocks the binding of AII to its receptors, reducing both its systemic and local effects (Arici & Erdem, 2009). There are advantages and drawbacks of combination therapy (Wolf & Ritz, 2005), but, in clinical terms, the aim of combination therapy is to block of the RAS more effectively (Arici & Erdem, 2009). Although several studies showed a greater decrease of albuminuria with the dual blockade (Mogensen et al, 2000; Campbell et al, 2003; Jennings et al, 2007), there are no RCT demonstrating a true slow down of CKD with combination therapy. In the ONTARGET study, the group of patients under ramipril plus telmisartan presented a higher renal impairment - doubling of serum creatinine or dialysis - and there were no differences in respect to cardiovascular outcomes (Yusuf et al, 2008). The ValHeFT and the VALIANT studies also showed more kidney dysfunction in the combination groups (Conn et al, 2001; Pfeffer et al, 2003), despite better cardiovascular results in the ValHeFT (Conn et al, 2001). In summary, concerning CKD progression, despite the theoretical advantages of combination therapy, presently there are no RCT demonstrating such benefit. Furthermore, the dual blockade is not harmless, and is associated with the risk of hyperkalemia and of greater renal impairment. Probably, studies with selected patients (with proteinuria > 1g/24h) or a different type of dual blockade with a renin inhibitor, will demonstrate a clear superiority of an association of two antagonists of the RAS. At the moment this association cannot be recommended.
