**1. Introduction**

44 Antihypertensive Drugs

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There is a strong relationship between hypertension and Chronic Kidney Disease (CKD). Hypertension is an important cause of End-Stage Renal Disease (ESRD), contributing to the disease itself or, most commonly, contributing to its progression. On the other hand, hypertension is highly prevalent in CKD patients, playing a role in the high cardiovascular morbidity and mortality of this particular population. This chapter will focus on the pathogenesis of hypertension-related CKD and its role on the progression of renal disease itself. The pathogenesis and treatment of hypertension resulting from CKD will also be addressed.

## **2. Hypertension as a cause of CKD**

The relationship between abnormal blood pressure and kidney dysfunction was first established in the 19th century. The prevalence of both, and of the associated burden of cardiovascular morbidity and mortality, has been dramatically increasing worldwide (Kearney et al., 2005; Kearney et al., 2004; Ong et al., 2007; Schoenborn & Heyman, 2009; USRDS 2010; Meguid El Nahas & Bello, 2005). Data from several renal databases identifies systemic hypertension as the second most common cause of ESRD, with Diabetes mellitus being the first. In the United States (US), hypertension is the leading cause of ESRD in African-American patients (USRDS 2010; Klag et al., 1996; Hsu et al., 2005). Additionally, for any given cause of CKD, the elevation in systemic blood pressure accelerates the rate at which the glomerular filtration rate (GFR) declines (Perry et al., 1995). This is particularly true for patients with proteinuric nephropathies (Jafar et al., 2003).

#### **2.1 Pathogenesis of hypertensive renal damage**

The exact mechanisms of kidney damage in patients with hypertension still remain elusive. Two complementary pathogenic mechanisms ultimately ending in kidney fibrosis and scarring have been proposed. One starts with the changes in systemic and renal macro and microvasculature leading to the loss of renal auto-regulation with elevation of intraglomerular capillary pressure and the consequent hyperfiltration-mediated injury.

Hypertension and Chronic Kidney Disease:

retention (Carlos & Jeanneret, 2003).

Freedman et al., 1995; Kincaid-Smith, 1999).

Zoja et al., 1998; Takase et al., 2003; Alvarez et al., 2002).

**2.2 Epidemiology of hypertensive nephrosclerosis** 

Cause and Consequence – Therapeutic Considerations 47

oxidative stress and epithelial-to-mesenchimal transdifferentiation eventually culminating in fibrosis (Ruggenenti & Remuzzi, 2000; Mayer et al., 1993; Abbate et al., 1998; Fine et al., 1998; Sánchez-Lozada et al., 2003; Higgins et al., 2007; Tian et al., 2008; Leh et al., 2011; Dussaule et al., 2011). The involvement of inflammation in the progression of CKD was widely demonstrated in experimental models of non-imunologic kidney disease (Bottinger & Bitzer, 2002; Müller, 2000, 2001; Fujihara, 1998, 2000; Romero et al., 1999; Mazzali et al., 2001; Eddy & Giachelli, 1995; Largo et al., 1999; Gómez-Garre et al., 2001;

Traditionally, the glomeruli have been in the centre of attention particularly in view of the hyperfiltration hypothesis involving the degradation and sclerosis of the remaining nephrons. However, the notion that tubulointerstitial fibrosis might rather cause than result from decreased glomerular function has gained strong evidence (Ong & Fine, 1994; Luft & Haller, 1995). Tubulointerstitial proliferation with incoming of inflammatory monocytes and macrophages, resulting from mechanical damage to the postglomerular interstitial vasculature, were also described, establishing the tubules and the interstitium as additional sites of early hypertensive damage (Eng et al., 1994). Furthermore, the up-regulation of the intrarrenal RAS, hypothetically mediated by local ischemia, is associated with increased expression of Angiotensin Converting Enzyme (ACE) in proximal tubules and peri-tubular interstitium. Here, ACE can cleave angiotensinogen and bradykinins creating an imbalance in favor of the former with the consequent stimulation of proliferation, fibrosis and salt

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;

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

Hyperfiltration leads to transglomerular loss of proteins which promotes the release of cytokines and growth factors by mesangial cells and downstream tubular epithelial cells. The second mechanism proposes endothelial dysfunction and loss of endogenous vasodilators as precipitating factors of hypoxic-ischemic injury. The consequent activation of the intrarrenal Renin Angiotensin System (RAS) and the increased release of cytokines and growth factors with recruitment of inflammatory cells stimulate apoptosis causing loss of normal kidney cells and increased matrix production, finally leading to progressive glomerular and interstitial fibrosis and scarring.

Evidence to support, this apparently straightforward, chain of events starting in systemic hypertension and culminating in ESRD, has been accumulating since the beginnings of the 20th century when Goldblatt conducted his first experiments in dogs driven hypertensive by the clipping of one renal artery: the two-kidney one clip model of hypertension (Goldblatt, 1964). The brilliancy of this model rests on the existence of a control organ: the clipped kidney was protected from the deleterious effects of blood pressure. In fact, vascular damage was not found in the clipped kidneys. More recently, other authors reported that the clipped kidney is also protected from the effects of immunological mediators (Wenzel et al., 2002).

Extension of this model to rats and rabbits confirmed Goldblatt findings ( Eng et al., 1994; Wenzel et al., 2002). These later experiments also documented the pivotal role of changes in renal macro and microvasculature to induce and maintain a vicious cycle, where hypertension causes vascular lesions which in turn will further increase blood pressure, even after its primary cause has been removed (Rettig et al., 1990).

Further investigation on animal models, as well as on genetic models of hypertension, allowed the description of three different stages of preglomerular vascular change. The histopathological resemblance between these experimentally induced vascular lesions and those observed in benign and malignant nephrosclerosis in human kidneys have long been documented. Medial thickening with narrowing of the lumen resulting from hypertrophy of smooth muscle cells (Nordborg et al., 1983; Hampton et al., 1989; Vial & Boyd 1989; Lee, 1987; Mulvany & Aalkjaar 1990; Owens & Schartz, 1982; Chobanian et al., 1984; Ross, 1993) is followed by segmental hyalinosis of the vessel wall of interlobular arteries and afferent arterioles. In humans studies using light microscopy and imunofluorescence these lesions were better characterized and termed "benign nephrosclerosis" (Valenzuela, 1980; Fisher,1966). Finally, the most severe type of hypertensive renal vascular lesion, similar to "malignant nephrosclerosis", is proliferation of the intima resulting in the typical onion-like appearance and extremely narrow vessels predominantly affecting the interlobular arteries and afferent arterioles (Klemperer & Otani, 1931). The previous existence of medial hypertrophy and, or, increased collagen content in the arterial wall were pre-requisites for the development of this final stage (Helmchen et al., 1984, Bidani et al., 1994). However, in humans even the early lesions of malignant nephrosclerosis affect the intima (Ellis, 1942; Heptinstal, 1953; Somers, 1958).

After this initial chain of events, increased glomerular perfusion and elevation of glomerular capillary pressure resulting in hyperfiltration, lead to further damage of the affected glomerulus (Brenner, 1985; Klahr et al., 1988) and to increased filtration of proteins to the tubular lumen. Enhanced tubular reabsorption induces the synthesis of inflammatory and fibrotic factors, resulting in tubulointerstial ischemia, inflammation, up-regulation of

Hyperfiltration leads to transglomerular loss of proteins which promotes the release of cytokines and growth factors by mesangial cells and downstream tubular epithelial cells. The second mechanism proposes endothelial dysfunction and loss of endogenous vasodilators as precipitating factors of hypoxic-ischemic injury. The consequent activation of the intrarrenal Renin Angiotensin System (RAS) and the increased release of cytokines and growth factors with recruitment of inflammatory cells stimulate apoptosis causing loss of normal kidney cells and increased matrix production, finally leading to progressive

Evidence to support, this apparently straightforward, chain of events starting in systemic hypertension and culminating in ESRD, has been accumulating since the beginnings of the 20th century when Goldblatt conducted his first experiments in dogs driven hypertensive by the clipping of one renal artery: the two-kidney one clip model of hypertension (Goldblatt, 1964). The brilliancy of this model rests on the existence of a control organ: the clipped kidney was protected from the deleterious effects of blood pressure. In fact, vascular damage was not found in the clipped kidneys. More recently, other authors reported that the clipped kidney is also protected from the effects of immunological mediators (Wenzel et

Extension of this model to rats and rabbits confirmed Goldblatt findings ( Eng et al., 1994; Wenzel et al., 2002). These later experiments also documented the pivotal role of changes in renal macro and microvasculature to induce and maintain a vicious cycle, where hypertension causes vascular lesions which in turn will further increase blood pressure,

Further investigation on animal models, as well as on genetic models of hypertension, allowed the description of three different stages of preglomerular vascular change. The histopathological resemblance between these experimentally induced vascular lesions and those observed in benign and malignant nephrosclerosis in human kidneys have long been documented. Medial thickening with narrowing of the lumen resulting from hypertrophy of smooth muscle cells (Nordborg et al., 1983; Hampton et al., 1989; Vial & Boyd 1989; Lee, 1987; Mulvany & Aalkjaar 1990; Owens & Schartz, 1982; Chobanian et al., 1984; Ross, 1993) is followed by segmental hyalinosis of the vessel wall of interlobular arteries and afferent arterioles. In humans studies using light microscopy and imunofluorescence these lesions were better characterized and termed "benign nephrosclerosis" (Valenzuela, 1980; Fisher,1966). Finally, the most severe type of hypertensive renal vascular lesion, similar to "malignant nephrosclerosis", is proliferation of the intima resulting in the typical onion-like appearance and extremely narrow vessels predominantly affecting the interlobular arteries and afferent arterioles (Klemperer & Otani, 1931). The previous existence of medial hypertrophy and, or, increased collagen content in the arterial wall were pre-requisites for the development of this final stage (Helmchen et al., 1984, Bidani et al., 1994). However, in humans even the early lesions of malignant nephrosclerosis affect the intima (Ellis, 1942;

After this initial chain of events, increased glomerular perfusion and elevation of glomerular capillary pressure resulting in hyperfiltration, lead to further damage of the affected glomerulus (Brenner, 1985; Klahr et al., 1988) and to increased filtration of proteins to the tubular lumen. Enhanced tubular reabsorption induces the synthesis of inflammatory and fibrotic factors, resulting in tubulointerstial ischemia, inflammation, up-regulation of

even after its primary cause has been removed (Rettig et al., 1990).

glomerular and interstitial fibrosis and scarring.

al., 2002).

Heptinstal, 1953; Somers, 1958).

oxidative stress and epithelial-to-mesenchimal transdifferentiation eventually culminating in fibrosis (Ruggenenti & Remuzzi, 2000; Mayer et al., 1993; Abbate et al., 1998; Fine et al., 1998; Sánchez-Lozada et al., 2003; Higgins et al., 2007; Tian et al., 2008; Leh et al., 2011; Dussaule et al., 2011). The involvement of inflammation in the progression of CKD was widely demonstrated in experimental models of non-imunologic kidney disease (Bottinger & Bitzer, 2002; Müller, 2000, 2001; Fujihara, 1998, 2000; Romero et al., 1999; Mazzali et al., 2001; Eddy & Giachelli, 1995; Largo et al., 1999; Gómez-Garre et al., 2001; Zoja et al., 1998; Takase et al., 2003; Alvarez et al., 2002).

Traditionally, the glomeruli have been in the centre of attention particularly in view of the hyperfiltration hypothesis involving the degradation and sclerosis of the remaining nephrons. However, the notion that tubulointerstitial fibrosis might rather cause than result from decreased glomerular function has gained strong evidence (Ong & Fine, 1994; Luft & Haller, 1995). Tubulointerstitial proliferation with incoming of inflammatory monocytes and macrophages, resulting from mechanical damage to the postglomerular interstitial vasculature, were also described, establishing the tubules and the interstitium as additional sites of early hypertensive damage (Eng et al., 1994). Furthermore, the up-regulation of the intrarrenal RAS, hypothetically mediated by local ischemia, is associated with increased expression of Angiotensin Converting Enzyme (ACE) in proximal tubules and peri-tubular interstitium. Here, ACE can cleave angiotensinogen and bradykinins creating an imbalance in favor of the former with the consequent stimulation of proliferation, fibrosis and salt retention (Carlos & Jeanneret, 2003).
