**3.1 Sodium and volume status**

48 Antihypertensive Drugs

could not be explained by the higher prevalence and greater severity of hypertension in African-American patients or by socioeconomic determinants (Freedman 1993, 1995). Furthermore, in African-American patients progression for ESRD is faster across all levels of blood pressure (Klag et al., 1997; Shulman et al., 1989). Biopsy-proven hypertensive nephrosclerosis occurs earlier and is more severe in African-American than in Caucasian patients independently of blood presure values and proteinuria (Tracy et al., 1991; Perneger et al., 1995; Marcantoni et al., 2002). Traditionally, this excess of kidney damage has been associated with genetically or environmentally induced impairment of renal auto-regulation and amplification of profibrotic mechanisms (Campese et al., 1991; Duru et al., 1994;

Early studies from animal models with Dahl salt-sensitive rats, Spontaneous Hypertensive Rats, Fawn-hooded rats and Brown and Norway rats as well as the results of the AASKD trial suggested a genetic susceptibility to hypertensive vascular damage (Brown et al., 1996; Churchill et al., 1997; Freedman et al., 1998; Zarif et al., 2000; Agodoa et al., 2001). Several genetic alterations have been associated to a more rapid decline of renal function in African-American patients with hypertensive nephrosclerosis. Polymorphisms of the kallikrein (KLK1) gene promoter were associated with a higher risk of ESRD in the presence of hypertension in a population of African-American patients (Yu et al., 2002). Different genetic polymorphisms of the RAS have been linked to a greater progression to ESRD across a wide spectrum of populations and causes of CKD (Wong et al., 2008). Polymorphisms of TGF-β have also been implicated in hypertension and progressive fibrosis (August et al., 2000). Non-muscle myosin heavy chain 9 gene (MYH9) polymorphisms, leading to disruption of normal podocyte function, brought attention to the role of podocyte injury as a mechanism of kidney damage in hypertensive glomerulosclerosis (Freedman et al., 2009). Genetic variation within the loci of the adrenergic beta-1 receptor (ADRB1) gene is associated with increased adrenergic activity and an increased risk of progressive renal disease (Fung et al., 2009). Specific polymorphisms in the C - reactive protein gene predicted a higher risk for CKD progression, resistant to the action of ACE inhibitors in African-American patients (Hung et al., 2010). Finally, mutations in the human methylenetetrahydrofolate reductase (MTHFR) gene were associated with elevated levels of homocysteine and a faster decline of renal function over time in African-American patients (Fung et al., 2011). Very recently a study, conducted in a population of Hispanic descent reported an association between polymorphisms of vascular endothelial growth factor (VEGF) and hypertensive nephropathy

Suthanthiran et al., 1998).

with subsequent progression to ESRD (Yang et al., 2011).

**3. Pathogenesis of hypertension in chronic kidney disease** 

Although the kidney is also involved in essential or primary hypertension, its insufficiency causes high BLOOD PRESSURE, contributing to 2-5 % of all cases of hypertension or half the cases of all forms of secondary hypertension (Kaplan, 2006b). The pathogenesis of hypertension-related to CKD is complex and multifactorial, mainly in the late stages of the renal disease. In addition to the classical factors, such as increased intravascular volume and excessive activity of the RAS, there are new recognized players such as increased activity of the sympathetic nervous system, endothelial dysfunction and alterations of several humoral and neural factors that promote an increase of the blood pressure. Hypertension is highly prevalent in CKD, being related with the level of renal function, the etiology of the kidney disease and the age of the patient. Patients with vascular disease, diabetes and polycystic The fundamental role of the kidney in the control of sodium and volume homeostasis is well acknowledged since the seminal studies of Dahl and Guyton. During the last decades, a bulk of evidence shows that volume expansion is the first and major pathogenic mechanism for hypertension in CKD. In the early stages of CKD, patients have already an increased exchangeable sodium and blood volume, which are correlated with the blood pressure level (Beretta-Piccoli et al, 1976).

According to the Guyton's whole-body auto-regulation concept, many organs, including the kidney and the brain, have the ability to maintain a relatively constant blood flow in the presence of variations of the perfusion pressure (Coleman & Guyton, 1969). Guyton proposed that this auto-regulation could be responsible for the secondary increase of the peripheral resistance in the presence of blood volume expansion, as it occurs in CKD (Guyton et al, 1980). Therefore, initially, an augment of the blood volume increases the cardiac output and simultaneously the peripheral vascular resistance fell. Later, the autoregulatory increase of the vascular resistance causes a pressure natriuresis (Navar, & Majid, 1996), with normalization of the cardiac output and maintenance of high blood pressure values.
