Hypertension and Renal Failure

Hypertension and Renal Failure
Background
Hypertension or sustained elevated blood pressure is a major and an independent risk factor for various cardiovascular diseases (Mennuni et al., 2013). Almost 72 million U.S. citizens are affected with different stages of hypertension. Hypertension is also the 2nd leading cause of end-stage renal disease (ESRD) in the U.S. Almost 30% incidences of ESRD are attributed to a hypertensive crisis (Mennuni et al., 2013). The prevalence of ESRD has dramatically increased over the past two decades. Hypertension is considered both a cause and a consequence of ESRD. ESRD represents end organ failure of the kidneys (Mennuni et al., 2013). Studies indicate that prevalence of hypertension among patients undergoing hemodialysis is as high as 90%. Patients suffering from a pre-existing renal disease or diabetes mellitus are predisposed to the risk of hypertension mediated renal failure (Shankland, 2006).
Hypertension mediated renal failure is also associated with left ventricular hypertrophy, microalbuminuria, and cognitive dysfunction. Hence, hypertension mediated renal failure is associated with various complications and comorbidity. Therefore, it is extremely essential for preventing the mortality and morbidity associated with hypertension (Mennuni et al., 2013). Appropriate and aggressive control of hypertension is recommended by different guidelines for preventing the risk of ESRD. Hypertension mediated renal failure is broadly classified as benign and malignant nephrosclerosis (Fofi, Pecci &Galliani, 2001).

The present article focuses on the etiology of renal failure as a consequence of uncontrolled blood pressure. The etiology of hypertension is based on various histological, cellular molecular and genetic mechanisms.
Histological and Cellular Mechanisms
Different auto-regulatory mechanisms protect the kidneys from a systemic elevation in blood pressure. The auto-regulatory mechanisms which operate in the kidneys are glomerulotubular feedback and tubuloglomerular feedback (Shankland, 2006). Autoregulation helps to maintain the glomerular filtration rate and the renal arterial pressure. The extent of renal damage due to hypertension is directly proportional to the sustained elevation of blood pressure within the renal microvasculature (Romagnani & Remuzzi, 2013). If the afferent arterioles are intact, the auto-regulatory mechanisms prevent damage to the renal microvasculature. Such protective mechanisms prevent the formation of acute lesions within the glomeruli (Shankland, 2006). However, an increase in renal arterial pressure beyond the range of autoregulation leads to glomerular and vascular injuries. These injuries are associated with the formation of fibrinoid necrosis at the afferent arterioles. Fibroid necrosis leads to the genesis of malignant nephrosclerosis (Mennuni et al., 2013).
The alterations in renal microvasculature play an important role in the persistence of hypertension. Different vascular changes are witnessed as a result of the hypertensive injury. There is a significant increase in medial wall thickness and narrowing of the lumen of renal arteries. Such changes represent homeostatic alterations for preventing vascular damage. However, these changes further amplify renal arterial pressure (RAP). Increased RAP leads to hypertrophy of afferent blood vessels. The resultant hypertrophy is a homeostatic adjustment for negating the stress that arises in the vessel walls due to chronic elevations in renal arterial pressure (Mennuni et al., 2013).
On the other hand, vessel wall hypertrophy increases the diffusion distance of oxygen across the smooth muscle wall of renal arteries. Increased diffusion distance of oxygen leads to reduced oxygen supply in the glomerulus and tubulointerstitial structures. The reduction in oxygen supply causes ischemic injury in both glomeruli and tubulointerstitial structures. Glomerular hypertension causes stretching of glomerular arteries, damage to the endothelium and increased protein filtration at the glomerulus.
Proteins are usually not filtered in the glomerulus and Bowman’s capsule. This is due to the physical properties of the pores in the Bowman’s capsule. Although the pore size is larger than the plasma proteins, they are not permeable. These pores are lined by sialic acid which carries a negative charge. On the other hand, the plasma proteins are also negatively charged. Such attribute leads to repulsion between the pores lined with sialic acid and the plasma proteins. Hence, proteins are prevented from filtration. However, in conditions like glomerulonephritis, the pore size of the Bowman’s capsule increases manifold. As a result, repulsion between the pores lined with sialic acid and plasma proteins is reduced. Such a situation results infiltration of plasma proteins. Decreased perfusion leads to the collapse of glomerular arteries, while increased perfusion leads to glomerular necrosis. On the other hand, the filtered plasma proteins lead to tubulointerstitial inflammation and glomerular sclerosis (Mennuni et al., 2013).
Molecular and Genetic Mechanisms
Stretch causes proliferation and change in shape of endothelial and mesangial cells. These changes activate the Renin-Angiotensin-Aldosterone-System (RAAS) and increase vascular permeability (Ruster & Wolf, 2006). Such changes lead to glomerular sclerosis. Binding of Angiotensin-II to its receptor (AT-1) activate endocytic processes (Mennuni et al., 2013). Endocytosis causes internalization of Angiotensin-II into the cytoplasm, which leads to stimulation of cytoplasmic and nuclear AT-1 receptors. Such stimulation causes an intracellular influx of Ca++ ions. Calcium ions increase the transcription of nuclear factor-kappa-beta (NFKB) and pro-inflammatory cytokines. NFKB and pro-inflammatory cytokines lead to apoptosis of endothelial cells (Pavenstadt, Kriz & Kretzler, 2003). On the other hand, Aldosterone exerts a pro-oxidant action by activating NADPH oxidase. Such pro-oxidant actions lead to the generation of reactive oxygen species (ROS) (Mennuni et al., 2013).
Genesis of apoptotic signals and production of ROS are responsible for glomerular necrosis. On the other hand, aldosterone also activates the mitogenic activity of TGF-B (Tumor growth factor beta). Such mechanisms lead to renal fibrosis and glomerular sclerosis. Aldosterone also causes increased transcription of endothelin-1 (ET-1) peptide. ET-1is a potent vasoconstrictor peptide and causes inflammation and fibrosis. ET-1 stimulates NFKB and TGF-B that leads to acute ischemic damage. The risk of renal dysfunction is strongly associated with genetic factors (Mennuni et al., 2013). Two genes (MYH9 and APOL1) have been associated with increased risk of renal failure. These genes are located on chromosome 22 and encode a non-muscle myosin heavy chain protein. These proteins are highly expressed in the foot processes beneath the podocytes (Mennuni et al., 2013). Such proteins are thought to influence the contractile properties of foot processes (Shankland, 2006).
Discussion and Conclusion
Hypertension is the 2nd leading cause of end-stage renal disease (ESRD) in the U.S. Almost 30% incidences of ESRD are attributed to hypertension. The prevalence of ESRD has dramatically increased over the past two decades. Hypertension is considered both a cause and a consequence of ESRD. ESRD signifies renal failure which implicates loss of anatomical and functional properties of the kidneys. Patients suffering from a pre-existing renal disease or metabolic diseases (like diabetes mellitus) are predisposed to the risk of hypertension-induced renal failure. The article indicated that hypertension mediated renal failure is driven by complex mechanisms. Different histological, cellular, molecular and genetic changes are associated with the genesis of ESRD.
Hypertension causes damage to the vascular endothelium and apoptosis of renal cells. Such mechanisms alter the structural integrity of the glomerular and mesangial cells. RAAS and ROS-mediated factors underpin the molecular mechanisms of damage. These mechanisms often interact with each other and aggravate the pathogenesis of renal failure. Metabolic disorders and genetic factors increase the risk of hypertensive nephropathy. Hence, appraising the etiology of hypertension-induced renal failure, is essential for planning appropriate therapeutic interventions.
References
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