**3.2 The Renin-Angiotensin System**

The relevance of the RAS, in physiological terms, is based on its capacity to regulate arterial pressure and sodium balance. When the blood pressure or perfusion fall, or the sympathetic activity increases, the juxtaglomerular cells secrete renin, which cleaves angiotensinogen, leading to an increase in angiotensin II (AII) levels. This octapeptide is a powerful vasoconstrictor and stimulates the production of aldosterone, which, in turn, increases renal sodium reabsorption, and closes the regulatory feedback loop. However, if the blood volume is normal, the increased activity of the RAS produces an abnormal rise in the blood pressure.

Only a small proportion of CKD patients have a measurable increase of the RAS (Acosta, 1982). However, this activity in most of these patients is inappropriately high in the volumeexpanded milieu of CKD (Davies et al, 1973; Mailloux, 2001). Furthermore, in CKD, mainly secondary to vascular disease, diabetes or PKD, in areas of renal injury or ischemia there is a greater production of local and intra-renal AII which then exacerbates systemic hypertension (Acosta, 1982;Rosenberg et al, 1994).

#### **3.3 Oxidative stress and nitric oxide antagonism**

"Oxidative stress is an imbalance between oxidants and anti-oxidants in favor of the oxidants, potentially leading to damage"( Sies, 1997). In CKD there is an excess of oxidant molecules such as superoxide and hydrogen peroxide and a decrease of anti-oxidant ones,

Hypertension and Chronic Kidney Disease:

association with diuretics mandatory.

**4.1 Salt restriction and life style modifications** 

population.

Cause and Consequence – Therapeutic Considerations 51

(Hamlyn et al, 1996; Komiyama et al, 2005), secondary to an increased sodium content and expanded blood volume, may also contribute to the hypertension commonly seen in this

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

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

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

such as catalase, superoxide dismutase and glutathione dismutase (Vaziri et al., 2002). The excess of reactive oxygen species may directly stimulate vascular contraction or reduce nitric oxide, contributing to hypertension in CKD (Hu et al., 1998). In addition, it is known that anti-oxidant agents can reduce the blood pressure in animal models of hypertension (Vaziri et al., 1997). The endothelial-derived nitric oxide has the capacity to maintain the vascular tone and to produce vasodilatation, through the activation of guanylate cyclase. In CKD, there is an increase of asymmetric dimethylarginine, an inhibitor of nitric oxide synthase (Leone et al., 1992). Moreover, has we pointed out before, the increase amount of reactive oxygen species in CKD impair nitric oxide effects. These two factors are responsible for a decrease nitric oxide activity in CKD which contribute to endothelial dysfunction and increased blood pressure.
