**2.2 Epidemiology of hypertensive nephrosclerosis**

The general term "nephrosclerosis", both benign and malignant, has been used to describe these lesions since the beginning of the 20th century. The causal relationship between malignant hypertension with fibrinoid necrosis and renal failure is consensual. On the other hand, the evidence for a relationship between milder degrees of hypertension and either benign nephrosclerosis and ESRD remains controversial (Zucchelli & Zuccala, 1995; Freedman et al., 1995; Kincaid-Smith, 1999).

In the past 30 years, at the start of dialysis, an increasing number of patients have been labeled as having hypertension-related ESRD (USRDS 2003). Although, only few of them have undergone a kidney biopsy (Weisstuch & Dworkin, 1992) making it impossible to exclude other causes of ESRD, such as atheroembolic disease, ischemic nephropathy secondary to atheromatous disease, or glomerulonephritis (Zucchelli & Zuccala, 1998; Freedman et al., 1995). On the other hand, the increased life expectancy of the general population, due to better anti-hypertensive control and better survival from cardiovascular events, providing a longer time for hypertensive renal disease to progress, could in fact account for this increased prevalence (Caetano et al., 1999). The MRFIT study established a consistent relationship between increasing levels of systolic and diastolic blood pressure and ESRD that was independent of several other relevant variables. Nevertheless, several other literature reports originating in studies conducted in the US and in the United Kingdom concluded that benign nephrosclerosis did not significantly progress to ESRD (Tomson et al., 1999; Kincaid-Smith, 1982, 1999). However, the exception was provided by Africa-American patients in whom a higher risk of progression to ESRD was widely demonstrated in all age groups (Rostand, 1982; Fogo, 1997; Marcantoni et al., 2002). This disproportion

Hypertension and Chronic Kidney Disease:

(Ridao et al., 2001, USRDS, 2010).

**3.1 Sodium and volume status** 

(Beretta-Piccoli et al, 1976).

**3.2 The Renin-Angiotensin System** 

hypertension (Acosta, 1982;Rosenberg et al, 1994).

**3.3 Oxidative stress and nitric oxide antagonism** 

values.

pressure.

Cause and Consequence – Therapeutic Considerations 49

kidney disease (PKD) are more prone to be hypertensive (Ridao et al., 2001). It is also known that as renal function worsens the prevalence of hypertension increases. Therefore, more than 80 % of the patients beginning renal replacement therapy have high blood pressure

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

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

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

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

"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,

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; Suthanthiran et al., 1998).

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