Etiology and Management of Hypertension in Chronic Kidney Disease

Med Clin N Am 89 (2005) 525–547

Etiology and Management of Hypertension in Chronic Kidney Disease Martin J. Andersen, MD, Rajiv Agarwal, MBBS, MD, DNB, FASN, FAHA* Division of Nephrology, Department of Medicine, Indiana University School of Medicine and Richard L. Roudebush Veterans Affairs Medical Center, 1481 West 10th Street, 111N, Indianapolis, IN 46202, USA

The kidneys are vital in the pathogenesis of hypertension and are also pathologically affected by the presence of hypertension. Hypertension affects 24% of the adult United States population [1]. According to data from the Third National Health and Nutrition Examination Survey, 3% of the adult population has an elevated serum creatinine and 70% of these patients have hypertension defined as blood pressure greater than or equal to 140/90 mm Hg [2]. The prevalence of hypertension in chronic kidney disease (CKD) depends on age, the severity of renal failure, and proteinuria [3]. It also depends on the underlying renal disease; nearly 90% of patients with diabetes and renovascular disease have hypertension. As patients with CKD progress to end-stage renal disease (ESRD), 86% are diagnosed with hypertension [4]. The intricate and inextricable relationship between CKD and hypertension seems to cause cardiovascular disease that has assumed epidemic proportions. This article discusses the etiology and treatment of hypertension in CKD so that it can be better controlled. Etiology of hypertension Sodium and water It has been recognized for at least 50 years that increasing sodium intake leads to a variable but consistent increase in blood pressure in animals. This Dr. Agarwal gratefully acknowledges the research support from National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases Grant 5 RO1-062030-02. Dr. Andersen is supported by NIH training Grant 5T32DK062711-02. * Corresponding author. E-mail address: [email protected] (R. Agarwal). 0025-7125/05/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2004.12.001 medical.theclinics.com

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heterogeneity in response was thought to be the interaction between genetic and environmental factors by Dahl et al [5], and by ingenious inbreeding experiments in Sprague Dawley rats fed a high-sodium diet, they could create colonies within three generations that were hypertensive. Feeding a sodiumpoor diet, even in the predisposed animals, did not increase blood pressure, but caused an elevation in blood pressure in the sodium-sensitive animals confirming the importance of sodium in causing hypertension. The most definitive experiments on the role of sodium being etiologically significant for hypertension in primates were performed over a span of 2.5 years in chimpanzees fed a high-sodium diet [6]. Chimpanzees, who typically consume a vegetarian, potassium-rich, sodium-poor diet, were gradually supplemented with dietary sodium to a level of 15 g/d that was sustained over 16 months. At the end of supplementation period blood pressure increased 33/10 mm Hg together with suppression of plasma renin. Within 20 weeks of stopping sodium supplementation, blood pressure returned to baseline. Human data support the animal findings noted previously. In primitive societies, such as the New Guinea Highlanders, Yanomamo Indians in the Amazon rain forest [7], Bushmen of Kalahari, or Kenyan tribal farmers, sodium content in the diet is extremely low (1–10 mEq/d). Hypertension and age-related blood pressure increase in these populations is not seen. In contrast, the mean dietary intake of sodium in Akita, Japan, is 450 mEq/d (26 g/d) and a high incidence of hypertension and strokes are seen. Furthermore, dietary sodium increase in preliterate societies associated with urban migration is associated with rapid increase in blood pressure. A meta-analysis of trials of sodium restriction in normotensive and hypertensive individuals concluded that 50 mEq/d reduction in dietary sodium (that can simply be achieved by taking away table salt) leads to fall in systolic blood pressure of 5 mm Hg on average and by 7 mm Hg in those who are more hypertensive [8]. Furthermore, at least 5 weeks of sodium restriction are required to see such an effect. The reciprocal relationship between sodium intake and blood pressure is regulated by the kidney [9]. The kidneys, in response to increased dietary sodium intake, decrease sodium and water reabsorption in the proximal tubule and loop of Henle. This increases urinary sodium and water output, a phenomenon recognized as ‘‘pressure natriuresis,’’ and normalizes the blood pressure [10]. In people with hypertension, the pressure natriuresis curve is shifted to the right. The concept of volume overload in the genesis of hypertension was popularized by Guyton et al [11,12]. Recognizing that mean arterial pressure is the product of cardiac output and peripheral vascular resistance, it is evident that an increase in mean arterial pressure can be either caused by an increase in cardiac output or peripheral vascular resistance. Guyton’s group was amongst the first to demonstrate the central importance of the kidneys in modulating systemic hemodynamics via sodium retention [11,12]. By removing 40% of one kidney in dogs and infusing isotonic saline for 13 days, Guyton’s colleagues created a model of hypertension. During the first 3 days

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of saline administration, blood pressures increased together with a rise in cardiac output; however, peripheral vascular resistance fell. Subsequently, cardiac output dropped while peripheral vascular resistance increased. These results were explained by an increase in blood volume, an increase in mean circulatory filling pressure, and a higher cardiac output at the initial stages of volume expansion. This was followed by autoregulatory vasoconstriction that resulted in increased peripheral vascular resistance. Perfusion of kidneys at higher pressures caused pressure natriuresis, and restoration of cardiac output. Hypertension was sustained even after the fall in cardiac output, because of a persistently elevated peripheral vascular resistance.

The renin–angiotensin system Reduced volume, perfusion, or increased sympathetic tone is sensed by the juxtaglomerular cells of the renal afferent arteriole, which secrete renin. Renin, in turn, cleaves angiotensinogen to the decapeptide angiotensin I, which angiotensin-converting enzyme (ACE) converts to the octapeptide angiotensin II (Ang II). Ang II increases systemic vascular resistance by activation of the Ang II subtype 1 receptors on vascular smooth muscle. Ang II also causes efferent renal arteriolar vasoconstriction that increases glomerular hydrostatic pressure. Ang II stimulates the adrenal glands to release aldosterone, which stimulates renal sodium absorption. In the sodium-depleted state, these actions preserve blood pressure and maintain glomerular filtration rate, but in the sodium-replete state can result in renal injury and hypertension. In addition to the well-known hemodynamic actions of Ang II, endothelial, mesangial, and renal tubular activation; oxidative stress (discussed later); and inflammation and fibrosis can occur with elevated levels of this hormone in a variety of kidney diseases. For example, in areas of renal injury, ACE activity can be even higher than in noninjured areas [13]. The resultant overexpression of Ang II can lead to progressive renal damage and hypertension [14].

Oxidative stress Reactive oxygen species, such as superoxide and hydrogen peroxide, are important signaling molecules. Their production is regulated by Ang II– sensitive enzymes, such as the vascular NAD(P)H oxidases, and their catabolism by antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase [15,16]. Both superoxide and hydrogen peroxide serve as second messengers to activate multiple intracellular proteins and enzymes that, in turn, activate redox-sensitive transcription factors. Reactive oxygen species participate in vascular smooth muscle cell growth and migration; modulation of endothelial function, including endotheliumdependent relaxation and expression of adhesion molecules, chemoattractant

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compounds, and cytokines rendering a proinflammatory phenotype; and modification of the extracellular matrix. Haugen et al [17] examined three models to assess the direct effect of Ang II on the structure and function of the kidney by oxidative stress. In the first model, Ang II was administered by miniosmotic pumps to rats maintained on standard diets. Oxidative stress and hypertension were observed. In the second model, rats were made hypertensive with deoxycorticosterone acetate and salt, but they were not given Ang II. In this model, the renin– angiotensin system is expected to be suppressed, and hypertension without oxidative stress was noted. In the third model, rats maintained on antioxidant-deficient diets were studied while infused with Ang II. Proteinuria and decreased creatinine clearance were noted in addition to oxidative stress and hypertension. Kawada et al [18] studied the relationship between prolonged and graded infusions of Ang II and blood pressure. In mice, high-dose Ang II infusions caused a rapid increase in systolic blood pressure. Intermediate doses of Ang II led to increased postglomerular resistance, followed by elevated preglomerular resistance and hypertension. Renal oxidative stress was increased at a later time point (Day 12 of infusion), and administration of an antioxidant-reduced oxidative stress, blood pressure, and renal vascular resistance. Others have demonstrated that rats with renin-mediated hypertension have AT1 receptor–mediated endothelial dysfunction associated with increased oxidative stress and increased vascular xanthine oxidase activity [19]. In contrast, knockout mice that are genetically deficient in gp91(phox), an NADPH oxidase subunit protein, show lower baseline blood pressures and demonstrate less oxidative stress–mediated vascular injury in response to Ang II [20]. Nishiyama et al [21] have demonstrated that the blood pressure–elevating effect of Ang II is partly caused by inactivation of nitric oxide (NO) through the generation of oxygen-derived free radicals. In humans with CKD, the authors have found that blockade of renin–angiotensin system can reduce oxidative stress [22] and profibrotic cytokines [23] independent of reduction in proteinuria or blood pressure [24]. Taken together, these experiments offer direct evidence that Ang II induces oxidative stress in vivo, which contributes to renal injury. This injury seems to be predominantly localized to the renal proximal tubules. NADPH oxidase-derived superoxide anion seems to be important for the regulation of basal blood pressure and in the pathogenesis of hypertension. Furthermore, these studies reveal a pressure-independent vascular hypertrophic response to Ang II and implicate that oxidative stress is causally important in the genesis of renal parenchymal hypertension. Nitric oxide and circulating inhibitors of nitric oxide Endothelial-derived NO plays a critical role in the maintenance and regulation of vascular tone and modulates key processes mediating vascular

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disease including leukocyte adhesion, platelet aggregation, and vascular smooth muscle proliferation [25]. Endothelial NO synthase enzymatically produces NO from the substrate L-arginine. NO vasodilates the vasculature by activation of guanylate cyclase, which subsequently produces cyclic guanosine monophosphate [26]. Cyclic guanosine monophosphate activates a protein kinase enzyme that phosphorylates and activates a calciumdependent potassium channel, leading to potassium efflux and vasodilation [27]. In hypertensive patients, this mechanism has been found to be defective [28–30]. Also, L-arginine supplementation can partially reverse renal failure– associated endothelial dysfunction [31]. Reactive oxygen species can impair the activity of NO. Superoxide quenches NO to produce peroxynitrite, which is itself devoid of vasodilating activity [32]. Peroxynitrite, in turn, reacts with tyrosine to produce nitrotyrosine, a marker of oxidative stress [32]. In animals with induced oxidative stress through glutathione depletion, blood pressures and nitrotyrosine levels are elevated, indicating the interaction of superoxide with NO and the inhibition of vasodilation [33]. Studies further show that endothelial-dependent vasodilation improves in hypertensive patients after receiving antioxidant therapy [34]. A circulating inhibitor of NO synthase, asymmetric dimethylarginine, competes with L-arginine for NO synthase. In humans with salt-sensitive hypertension, administration of a high-salt diet increases plasma asymmetric dimethylarginine and blood pressure [35]. Circulating asymmetric dimethylarginine is increased in subjects with CKD [36] and ESRD [37] and may contribute to endothelial dysfunction and increased blood pressure. In patients with ESRD, asymmetric dimethylarginine is correlated with increased left ventricle thickness and reduced ejection fraction, consistent with its ability to increase systemic vascular resistance [38]. As reviewed by Cooke [39], of the 300 lmol/d asymmetric dimethylarginine normally generated, only 50 lmol/d is excreted by the kidneys in healthy volunteers, whereas the remaining amount is degraded enzymatically by dimethylarginine dimethylaminohydrolase. Pharmacologic inhibition of dimethylarginine dimethylaminohydrolase with a small molecule, 4124W, causes accumulation of asymmetric dimethylarginine and generalized vasoconstriction. In contrast, overexpression of dimethylarginine dimethylaminohydrolase in genetically engineered mice reduces asymmetric dimethylarginine, improves NO bioavailability, and reduces systolic blood pressure. Oxidative stress that impairs dimethylarginine dimethylaminohydrolase activity by oxidizing a sulfhydryl moiety critical to its enzymatic activity leads to accumulation of asymmetric dimethylarginine and promotes endothelial dysfunction. Inflammation, increased homocysteine levels, reduced antioxidant defenses, and increased free radicals in ESRD may provide an explanation for the relationship between oxidative stress, endothelial dysfunction, and the generation of hypertension [37].

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The sympathetic nervous system The sympathetic nervous system in the kidney stimulates the juxtaglomerular cells to release renin by b-adrenergic receptors and stimulates sodium and water reabsorption. The sympathetic nervous system constricts the vascular smooth muscle cells by a-adrenergic and dilates by the b-adrenergic receptors [40]. In the heart, activation by the sympathetic nervous system of b receptors leads to increased cardiac inotropy, cardiomyocyte hypertrophy, and arrhythmogenicity [40]. Strong evidence has emerged that implicates enhanced sympathetic activity as a cause of hypertension in patients with CKD and ESRD [41]. Microvascular and tubulointerstitial damage induced by repeated injections of phenylephrine in animals leads to the development of sodium-sensitive hypertension [42]. There is also ample evidence that sympathetic nervous system is activated in CKD. Diminished vascular response to norepinephrine in animals with chronic renal failure provided initial indirect evidence of increased sympathetic nerve activity that down-regulated adrenergic receptors [43]. Later studies, however, provided more direct evidence of elevated sympathetic tone in patients with ESRD [41]. This was made possible by direct measurement of efferent sympathetic nerve activity [44]. Using microneurography, investigators have demonstrated that the sympathetic activity is increased in those patients on chronic hemodialysis who still have their native kidneys. In contrast, those patients with bilateral nephrectomy have reduced sympathetic activity, lower calf vascular resistance, and lower mean arterial pressure [41]. The kidney, although devoid of excretory function, serves as an afferent organ to signal the midbrain region to increase sympathetic activity. The central mechanisms of increased sympathetic activity may involve dopaminergic neuronal transmission. Experiments in hypertensive hemodialysis patients show that administration of the dopamine-releasing drug bromocriptine decreased plasma norepinephrine and lowered mean arterial pressure [45]. In animals with chronic renal failure, norepinephrine turnover rate is increased in the posterior hypothalamic nuclei, and endogenous NO may be an important regulator of sympathetic activity [46]. NO inactivation in the central nervous system by an arginine analogue resulted in higher blood pressures and increased renal sympathetic nerve activity in rabbits [47]. Baroreceptor desensitization has also long been recognized in hypertensive patients with ESRD and may contribute to elevated blood pressure [48]. Hormones Endothelin Endothelin-1 binds to endothelin-A and endothelin-B receptors in vascular smooth muscle cells to initiate vasoconstriction [49]. Conversely, endothelin-1 binds to endothelin-B receptors on endothelial cells to mediate vasodilation [49]. Infusion of Ang II increases both endothelin-1 plasma

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levels and blood pressure in animals [50]. Because NO prevents the expression of endothelin-1 [51], these effects seem to be secondary to oxidative stress–induced NO quenching by Ang II. Vasoconstriction and blood pressure elevation are the end results. As expected, endothelin-A receptor blockade reduces blood pressure. Human studies have also shown the importance of endothelin-1 in hypertension. Compared with normotensive patients, endothelin-1–dependent vasoconstriction is higher in obese, hypertensive patients [52], whereas black, hypertensive patients show increased endothelin-1 and vascular smooth muscle endothelin-B receptor expression [53]. Treatment with bosentan, an endothelin-A receptor blocker, in hypertensive patients lowers blood pressure [54]. Parathyroid hormone In a study of 123 elderly patients that compared 24-hour ambulatory blood pressures (ABPs) and parathyroid hormone (PTH) levels, PTH levels strongly correlated with mean 24-hour systolic blood pressures [55]. Duprez et al [56] noted that PTH levels significantly correlated to mean 24-hour diastolic blood pressures and left ventricular hypertrophy in hypertensive patients. Jorde et al [57] showed that PTH levels in middleaged women also correlated with both elevated systolic and diastolic blood pressures. The role of PTH in the pathogenesis of hypertension, however, has been controversial. PTH can increase intracellular calcium and aggravate hypertension [58], and parathyroidectomy may improve blood pressure control [59]. Conversely, others have reported that elevated PTH levels can reduce the pressor response to norepinephrine in animals with chronic renal failure [60], and parathyroidectomy may not correct hypertension [61]. Two studies from Japan showed that sodium loading in hypertensive patients caused increase in blood pressure, intracellular calcium, and PTH levels [62,63]. Furthermore, the change in PTH levels with sodium loading correlated significantly with the elevations in blood pressure and intracellular calcium levels. The authors suggested that elevated intracellular calcium levels may be caused by the elevated PTH levels. Because vascular smooth muscle cells use calcium to initiate vasoconstriction [64], this in turn may lead to the higher blood pressures. A recent study, however, has disputed the ability of PTH to raise intracellular calcium levels [65]. Others have suggested that the increase in PTH levels were secondary to the lower calcium levels that resulted from hemodilution from saline infusion [66]. When calcium levels were held stable by infusing calcium during saline infusion, blood pressures increased despite a fall in PTH. In fact, PTH infusion in hypertensive patients actually had vasodilatory and natriuretic effects [67], and the higher urinary calcium levels and serum PTH levels in hypertensive patients may simply reflect defects in renal calcium handling [68,69].

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To resolve these contradictions, Pang et al [70] have proposed that the parathyroid glands, in addition to secreting PTH, may also secrete parathyroid hypertensive factor. Parathyroid hypertensive factor may cause vasoconstriction by increasing intracellular calcium levels, thereby leading to elevated blood pressures. In contrast, the effects of PTH, the authors argue, are vasodilatory. This model at least sets the stage for a testable hypothesis that may help resolve the role of PTH in the pathogenesis of hypertension. Drugs and toxins Erythropoietin Erythropoietin can cause hypertension in around 20% of patients [71]. It has also been noted to cause hypertensive urgency [72]. Originally, erythropoietin-induced hypertension was attributed to the rise in hematocrit and blood viscosity that occurred with treatment [73,74]. Yet, in both animal and human studies, results have consistently shown that the rise in blood pressure with erythropoietin administration is independent of hematocrit [75–78]. For example, Vaziri et al [79] have shown that if erythropoietin is administered to anemic animals with chronic renal failure, but hemoglobin is kept stable by feeding these animals an iron-deficient diet, hypertension still occurs. In blood vessels harvested from these animals treated with erythropoietin, vasodilatory responses to NO donors were impaired, but response to several vasoconstrictors was normal. Erythropoietin increases the release of endothelin-1 from bovine endothelial cells [80] and raises the blood pressures in spontaneously hypertensive rats through endothelin-1–mediated mechanisms [81]. This has not, however, been consistently seen [82]. Vascular smooth muscle cells use intracellular calcium to initiate vasoconstriction [64]. Platelet cytosolic calcium concentrations have been shown to correlate with vascular smooth muscle cytosolic calcium concentrations and blood pressures [83]. Platelet cytosolic calcium serves as a surrogate for smooth muscle calcium concentration. In this context, erythropoietin increases platelet cytosolic calcium in animals [79] and in hypertensive patients [84]. Erythropoietin can activate calcium channels by tyrosine kinase [85]. Felodipine, a calcium channel blocker, lowered platelet cytosolic calcium concentrations and blood pressures in rats treated with erythropoietin [86]. Lead Low-level lead exposure is associated with impaired renal function [87] and hypertension [88–91]. Oxidative stress and impaired endothelial vasodilation seem to be important in the mechanism of lead-induced hypertension. Lead-exposed rats had hypertension and biomarkers of oxidative stress that improved with the administration of an antioxidant [92].

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Similarly, tempol, an antioxidant that reduces superoxide levels, lowered blood pressures in lead-exposed rats while having no effect in the control rats [93]. Finally, lead-exposed rats, in addition to having hypertension, have reduced endothelial guanylate cyclase expression suggesting endothelial dysfunction [94]. Cocaine Cocaine blocks the uptake of catecholamines in presynaptic sympathetic nerves [95], leading to peripheral vasoconstriction and elevated blood pressure. Cocaine infusions in laboratory rats raised blood pressure in a biphasic manner: after a rapid initial increase in blood pressure, a more sustained response ensued [96]. Treatment with phentolamine, an aadrenergic receptor blocker, or pentolinium, a ganglionic blocker, in these rats prevented cocaine-induced elevations in blood pressures. Furthermore, although the vasoconstrictive effects of norepinephrine were unaffected, those of cocaine were attenuated when isolated carotid artery preparations were stripped of endothelium or pretreated with a NO synthase inhibitor, NGmonomethyl-L-arginine [97]. These results indicate that the blood pressure– raising effect of cocaine is at least in part caused by its ability to impair endothelial function. Cyclosporine Cyclosporine, a calcineurin immunosuppressive agent, causes afferent arteriolar vasoconstriction and tubulointerstitial fibrosis [98] that can lead to hypertension and reduced glomerular filtration rate. NO deficiencies may play a primary role in the pathogenesis of cyclosporine’s toxicity. Cyclosporine increases the production of ROS (primarily superoxide and hydrogen peroxide) in vitro that can be reduced by free radical scavengers [99]. Cyclosporine administration to laboratory rats increased Ang II superoxide levels and blood pressure [100]. Nephrotoxicity of cyclosporine can be abrogated in laboratory rats by antioxidant therapy [101]. Nonsteroidal anti-inflammatory drugs Prostaglandins promote vasodilation and enhance natriuresis [102]. Nonsteroidal anti-inflammatory drugs block the synthesis of prostaglandins and lead to an elevation in blood pressure of about 5 mm Hg [102,103]. The elderly, the hypertensive, and those with CKD carry an increased risk of developing hypertension with nonsteroidal anti-inflammatory drugs. Aspirin and sulindac seem to have the least effect on increasing blood pressure [103]. Increased vascular resistance and expanded extracellular volume have both been incriminated in the genesis of nonsteroidal anti-inflammatory drug–induced hypertension. Like nonsteroidal antiinflammatory drugs, the coxcibs can also increase blood pressure and cause renal injury [104,105].

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Summary of pathophysiology of hypertension and chronic kidney disease The pathophysiology of hypertension and CKD can be summarized as follows: renal injury occurs because of a variety of reasons that include activation of the renin–angiotensin–aldosterone axis, the sympathetic nervous system, and toxins (Fig. 1). Some of these factors (eg, renin– angiotensin system, sympathetic system, cocaine use) can by themselves aggravate hypertension. Tubulointerstitial inflammation results in the release of oxidants by the invading inflammatory cells, the inactivation of local NO, and the heterogeneous activation of the intrarenal renin– angiotensin system. Tubular and vascular barotrauma characterized by afferent arteriolopathy leads to a right-shifted pressure natriuresis curve. This relieves the renal ischemia, but at the expense of higher blood pressure, leading to the development of hypertension that causes further renal injury. Dietary sodium excess, by inactivation of dimethylarginine dimethylaminohydrolase, can reduce NO activity and further accelerate tubular and microcirculatory damage. Extracellular volume expansion by sodium

Fig. 1. The pathophysiology of hypertension and CKD. CVD, cardiovascular disease; DDAH, dimethylarginine dimethylaminohydrolase; ECF, extracellular fluid volume; NSAIDs, nonsteroidal anti-inflammatory drugs; RAAS, renin–angiotensin–aldosterone system; ROS, reactive oxygen species; SNS, sympathetic nervous system.

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overload can by itself aggravate hypertension. Renal inflammation eventually leads to fibrosis, progressive CKD, and ESRD. CKD is accelerated by underlying CVD and is a known risk factor for CVD. Johnson et al [106] have suggested that subtle acquired renal injury is an essential part of all salt-sensitive hypertension, whereas Brenner’s hypothesis that low nephron dose is central to the pathogenesis of essential hypertension is finding growing support [107]. Essential hypertension may simply be a disease of the nephrons (low numbers or impaired function) and may account for a significant proportion of salt-sensitive hypertension seen in the general population [108].

Management of hypertension Assessment of blood pressures Blood pressure obtained in the physician’s office (clinic blood pressures [CBPs]), has been the basis of most clinical trials and most physicians guide antihypertensive therapy based on CBP. Accurate readings of CBP, however, are often not obtained. According to the Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), CBP should be obtained only from patients who have been sitting for at least 5 minutes and who have had their feet on the floor and arms at heart level [109]. Bladders of blood pressure cuffs should encircle greater than or equal to 80% of patients’ arms to avoid spuriously high CBP values. Finally, two measurements, taken at least 2 minutes apart, should be obtained and averaged to determine the patients’ CBP. These recommendations are often not followed. Home blood pressures (HBP) are another way to assess blood pressure in patients with CKD. Concern has been noted in the past about the reliability of patients being able to perform and record their HBP accurately [110]. A study by Mengden et al [111] revealed that more than half of hypertensive patients incorrectly record their HBP values into diaries. HBP monitors that electronically store the HBP data are preferred [112]. Finger and wrist HBP devices are to be avoided because they tend to be inaccurate. Instead, appropriately sized arm cuffs should be used, and the patients should take their HBP over a 7-day period with at least a total of 12 readings recorded during that time [112]. According to prior studies, HBP should be performed at least twice a day with two measurements made at each sitting [113,114]. Furthermore, because of their likelihood of being inaccurate, the first day’s HBP should not be considered when making clinical judgments. ABP recordings provide even more information on the diurnal nature of the blood pressure variation. The European Society of Hypertension recommends that ABP monitoring be performed with an appropriately sized cuff over a 24-hour period with readings made every 20 to 30 minutes, a timeline that prevents interference with daily activities, but allows for

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a sufficient amount of readings to be made [112]. At least 14 ABP measurements should be made during the day, and at least seven measurements should be made during the night to obtain a minimal amount of data. If there are fewer recordings, the ABP monitoring should be repeated. Daytime and nighttime divisions can be determined either from patient diaries or arbitrarily set time periods devised by the physicians. When measuring CBP, ABP, or HBP, it is important to use validated devices (ie, those approved by the American Association for the Advancement of Medical Instrumentation and the British Hypertension Society) [115]. It is recommended that physicians use only those cuffs that have successfully passed the testing criteria of both societies. Treatment decisions: clinic blood pressures, ambulatory blood pressures, and home blood pressures Currently, all guidelines for antihypertensive therapy are based on CBP [109] because all major studies on the cardiovascular risks of hypertension use CBP exclusively [116–118]. Other blood pressure measurement techniques, however, offer advantages over CBP. Repeated measurements of blood pressure, with ABP or HBP, allow better assessment of patients’ true blood pressures [112]. Furthermore, those patients who have elevated blood pressure only in the physician’s office (white coat hypertension) may be correctly identified. Also, those patients who have a normal blood pressure in the physician’s office but elevated blood pressure at home (masked hypertension) can be recognized. ABP allows the assessment of diurnal blood pressure trends. Observational studies show that nocturnal, nondipping blood pressures, defined as less than 10% reduction of nocturnal systolic blood pressure, are associated with increased cardiovascular risk [119]. CBP, unable to measure nighttime blood pressures and subject to measurement error, may underestimate this association between blood pressure and cardiovascular risk [120]. Most importantly, studies reveal that ABP correlate better with cardiovascular disease than CBP [121– 123]. In one such study [124], hypertensive patients were divided by CBP into JNC VI classes of hypertension (stages I, II, or III). Within each class, there were patients with normotension on ABP monitoring, defined by a systolic ABP less than 135 mm Hg. The normotensive patients had significantly fewer cardiovascular events than those patients who did not. In multivariable analysis, ABP emerged as an independent predictor of cardiovascular risk even after accounting for CBP. Data are also emerging that the lack of nocturnal dipping in patients with type 1 diabetes mellitus may be a marker of future diabetic nephropathy [125]. HBP monitoring provides a cost-effective tool for the assessment of blood pressure [126]. HBP are generally lower than CBP; CBP of 140/90 mm Hg generally correlates with HBP of 135/85 mm Hg [113,127–131]. Additionally, HBP is more reproducible over time compared with CBP,

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making HBP more useful in predicting cardiovascular disease [132]. For example, Mule et al [133] reported that both ABP and HBP were superior to CBP in predicting target organ damage (as measured by left ventricular mass index, albumin excretion rate, and an index of cardiac, renal, and retinal parameters) in hypertensive patients. Furthermore, Ohkubo et al [134] performed a population-based, observational study of 1789 Japanese subjects, aged greater than or equal to 40 years, who were followed for a mean 6.6 years. HBP and CBP were obtained in these subjects at baseline. After adjusting for cardiovascular risk factors, the authors found that only the average of multiple (taken more than three times) systolic HBP values were significantly and strongly related to cardiovascular mortality risk, indicating that HBP had a stronger predictive power for cardiovascular mortality than did screening CBP. Because of the growing data supporting ABP and HBP, all three blood pressure measurements are important in managing hypertension. ABP monitoring, however, currently is only reimbursed for the evaluation of white coat hypertension. White coat hypertension occurs in patients who have elevated CBP, but normal 24-hour ABP [112]. Approximately 10% of all patients diagnosed with hypertension have white coat hypertension [112]. These discrepancies between blood pressures may be caused possibly by increased sympathetic activity in these patients during clinic visits [135]. Whatever the etiology underlying white coat hypertension, these patients’ cardiovascular risk is essentially the same as the normotensive population [136]. Diagnosing white coat hypertension prevents inappropriate antihypertensive therapy. A distinction needs to be made between white coat hypertension and the white coat effect. The white coat effect occurs in patients with hypertensive CBP whose ABP, although lower than their CBP, are still abnormally high [112]. The white coat effect is quite common in hypertensive patients, occurring in greater than 70% [112]. The importance of diagnosing the white coat effect is that patients diagnosed with severe hypertension by CBP may only have moderate hypertension on ABP monitoring. This provides patients with a better prognosis. The magnitude of the white coat effect does not correlate with left ventricular hypertrophy, attesting to its benign nature [136]. Blood pressure goals The goals of treatment of hypertension are to reduce cardiovascular morbidity and mortality. Whereas effective hypertensive treatment has resulted in the decline of the prevalence of left ventricular hypertrophy and cardiovascular mortality [137], the absolute risks for cardiovascular mortality are still high in the industrialized world [138]. A meta-analysis of cardiovascular morbidity and mortality in 1 million hypertensive adults revealed that cardiovascular disease occurs in a continuous and graded manner with higher blood pressures, starting from at least a threshold of

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usual blood pressure of 110/70 mm Hg and a single blood pressure of 115/ 75 mm Hg even among the very old [116]. JNC VII has delegated reduced glomerular filtration rate as an independent cardiovascular risk factor. At the extreme end of the spectrum are ESRD patients who have very high cardiovascular morbidity and mortality: 40% have coronary artery disease; 75% have left ventricular hypertrophy; and 9% die every year from cardiovascular causes [139]. Data show that even mild renal failure (serum creatinine
1.4 mg/dL but \ 2.4 mg/dL) in high-risk patients (namely patients with vascular disease or diabetes mellitus and one other risk factor) had a 40% increase in the risk of cardiovascular death, myocardial infarction, or stroke compared with those patients with lower serum creatinine [140]. Whereas large data sets are not available for vascular protection with blood pressure control in patients with CKD, data nevertheless strongly support the need for blood pressure control at least for reducing progression of kidney disease [141,142]. JNC VII guidelines recommend that patients with diabetes mellitus or CKD, defined as a glomerular filtration rate less than 60 mL/min/1.73 m2 or albuminuria greater than 300 mg/d, have CBP targeted to less than 130/ 80 mm Hg [109]. Data from the Modification in Diet in Renal Disease Study, a study in which patients with CKD were randomized to various protein restriction and blood pressure groups, revealed that those patients with greater than 1 g/d of proteinuria had better outcomes when their blood pressures were lowered to less than 125/75 mm Hg [143]. The National Kidney Foundation has recommended this lower CBP goal in CKD patients with proteinuria [144]. Although guidelines for ABP and HBP are not as clearly defined for hypertensive CKD patients, ABP and HBP greater than 135/85 mm Hg are considered hypertensive by JNC VII [109]. The European Society of Hypertension notes that ABP in high-risk groups should be less than 130/80 mm Hg [112]. It is worth noting that systolic hypertension is of central importance for blood pressure management. In a retrospective of patients with hypertension, systolic blood pressures correlated more strongly for cardiovascular outcomes than diastolic blood pressures [117,145]. In the Multiple Risk Factor Intervention Trial, a study developed in the 1970s to reduce cardiovascular disease in men, relative risks for coronary heart disease mortality in patients were increased with higher systolic blood pressures compared with those with higher diastolic blood pressures. In the Cardiovascular Health Study, a study that evaluated the cardiovascular event rate of 5888 patients greater than or equal to 65 years in relationship to blood pressure [118], higher systolic blood pressures, diastolic blood pressures, and pulse pressures were all associated with increased cardiovascular events; however, systolic blood pressures had higher relative risks for stroke and myocardial infarction than either diastolic blood pressures or pulse pressures. Also, only systolic blood pressures in this study were associated with total mortality.

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Blood pressure management Lifestyle modifications, such as restriction of dietary sodium intake, exercise, weight loss, limitation of alcohol intake, and cessation of smoking, are of great importance but are often neglected in the management of hypertensive CKD patients. Each of these modifiable factors (high sodium intake [146,147], increased body mass index [148], smoking [149,150], and excessive alcohol intake [151]) has been independently linked to kidney disease. The goal of antihypertensive therapy in CKD patients is to slow the progression of renal disease and reduce cardiovascular morbidity and mortality. Despite the general recognition that blood pressure control is the single most effective method to delay progression of chronic kidney disease, only 75% of patients with CKD are treated and only 11% controlled to a goal blood pressure of less than 130/80 mm Hg. Forty-eight percent of such individuals are prescribed only one antihypertensive drug. ACE inhibitors and angiotensin receptor blockers (ARBs) are the backbone of antihypertensive therapy in patients with CKD [109]. A meta-analysis of 1860 patients with nondiabetic kidney disease also showed that ACE inhibitor use reduced the risk for progression to ESRD by 31% [152]. ACE inhibitors have been shown to slow the progression of diabetic nephropathy in type I and II patients [153– 155]. In addition, ARB use in type II diabetic patients has been shown to be effective in slowing the progression of diabetic nephropathy [153,154,156]. These data indicate that disruption of the renin–angiotensin–aldosterone axis is beneficial in high-risk patients with kidney disease because these agents, besides lowering blood pressures, favorably alter glomerular hemodynamics [153,157]. ACE inhibitors, in addition, abrogate sympathetic activation seen in CKD [158]. Furthermore, reduction in proteinuria is considered beneficial for reduction of cardiorenal risk [159]. A meta-analysis of the major antihypertensive trials of the past decade shows improved outcomes with better blood pressure control in patients with essential hypertension [160]. Similar data are emerging that demonstrate reduction in renal risk with lower blood pressure achieved in patients with nephropathy. Control of blood pressure seems critical to the success of any antihypertensive program. The National Kidney Foundation recommends that when CKD patients have blood pressures greater than 15/10 mm Hg above their goal blood pressures, two different agents should be started [144]. A good combination in this situation is a thiazide diuretic combined with either an ACE inhibitor or an ARB. If the creatinine is high (glomerular filtration rate \ 30 mL/min), a loop diuretic should be substituted in lieu of a thiazide [161,162]. If blood pressures continue to be high, calcium channel blockers or b-blockers can be sequentially added to the regimen followed by other agents, such as clonidine, and vasodilators like minoxidil or hydralazine. If patients have substantial proteinuria, both ACE inhibitors and ARBs can be combined to reduce the proteinuria [163–165]. This strategy, however, needs to be tested in prospective trials to evaluate its risk-benefit ratio.

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