Hypertension in Chronic Kidney Disease



Hypertension in Chronic Kidney Disease


Peter N. Van Buren

Robert D. Toto



INTRODUCTION

The prevalence of hypertension in patients with chronic kidney disease (CKD) exceeds that of the general population. Although hypertension is believed to be the etiology of kidney disease in many of these patients, hypertension is often the consequence of kidney disease stemming from any etiology. The pathophysiology of hypertension in CKD is related to multiple factors, including expanded extracellular volume from sodium retention, activation of the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS), and imbalances in vasoconstrictor and vasodilator substances that regulate peripheral vascular resistance. Untreated or poorly controlled hypertension in CKD patients is associated with adverse outcomes including deterioration of renal function, development of left ventricular hypertrophy (LVH), and increased mortality. Recent clinical trials have investigated the role of various antihypertensive treatments and blood pressure targets in preventing these outcomes. The purpose of this chapter is to review the epidemiology, pathophysiology, and management of hypertension in patients with CKD. Because diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) in the United States, the unique aspects of its pathophysiology and the treatment of hypertension in this setting warrant a separate discussion. Although mentioned briefly herein, the reader is referred to a recent extensive review of this topic.1


EPIDEMIOLOGY


Chronic Kidney Disease

Hypertension is a prevalent comorbidity associated with CKD. The prevalence of hypertension in the overall U.S. population, according to the National Health and Nutrition Examination Survey (NHANES) data from 2007 to 2008, is 29%.2 Data published by the United States Renal Data System (USRDS) according to NHANES data collected from 1999 to 2006 indicate that the prevalence of hypertension in the non-CKD population is 23.3%.3 In contrast, the prevalence of hypertension in the CKD population is much higher. The prevalence of hypertension increases with each stage of CKD and is estimated to be 35.8%, 48.1%, 59.9%, and 84.1% in patients with stage I, II, III, and IV/V CKD, respectively. Although the awareness of hypertension among patients with stage III and IV CKD was similar to that in the non-CKD population, the failure to control hypertension (defined as blood pressure [BP] 130/80 mm Hg for those with CKD and 140/90 mm Hg for those without CKD) is higher among the CKD patients.

The Chronic Renal Insufficiency Cohort (CRIC) is a National Institutes of Health (NIH) sponsored prospective observational study among 3,612 patients with an estimated glomerular filtration rate (GFR) of 20 to 70 mL per minute designed to better understand factors responsible for CKD progression and cardiovascular disease.4 Although the sample population for CRIC is smaller than NHANES, the detailed ascertainment of individual demographics, comorbidities, medication use, and laboratory analysis provides useful information for understanding the relationship between CKD and hypertension control in a population that is established in the health care system. In this population, 85.7% of patients are hypertensive based on the definition of a BP > 140/90 mm Hg or with the use of an antihypertensive medication. The percentage of patients from CRIC that are aware of their diagnosis of hypertension (98.9%) and who are treated for hypertension (98.3%) is higher than in the NHANES data. However, the control of hypertension in CRIC patients is still suboptimal, with 67.1% having BP > 130/80 mm Hg and 46.7% having BP > 140/90 mm Hg. The CRIC data indicate that older age, African American race, and a greater amount of proteinuria are risk factors for a failure to control BP to either 140/90 or 130/80 mm Hg.5 Overall, the epidemiologic evidence from NHANES and CRIC identifies that hypertension is a significant burden for patients with CKD and the health care providers responsible for managing these patients.

The long-term consequences of uncontrolled hypertension highlight the significance of this disease in CKD patients. Studies have reported that elevated systolic BP increases the incidence of CKD,6,7 the progression of CKD,8 and the incidence of ESRD.9 Furthermore, hypertension is reported to be the second leading cause of ESRD in the
United States based on USRDS data.10 However, it has been difficult to establish the independent effect of BP in CKD from effects related to the degree of baseline proteinuria.11

Elevated BP is also a risk factor for cardiovascular events, including stroke and myocardial infarction among CKD patients; however, the exact relationship between BP and outcomes is not consistent among studies. A J-shaped relationship between cardiovascular morbidity and BP has been shown,12 suggesting that the highest risk for an outcome occurs at the highest and lowest BP, whereas the lowest risk for an outcome occurs at an intermediate BP. In one longitudinal study of patients with stage III and IV CKD, systolic BP >130 mm Hg was a predictor for an incident stroke; however, those with systolic BP < 120 mm Hg had a greater risk than those with a systolic BP between 120 and 129 mm Hg.12 In contrast, a post hoc analysis of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a prospective randomized placebo controlled trial of the effects of perindopril on stroke among patients with a prior history of cerebrovascular disease, CKD patients had a reduced risk for a recurrent stroke across all strata of systolic BP. Moreover, there was no increase in the risk for recurrent stroke in those who achieved a systolic BP <120 mm Hg compared to higher achieved BP levels.13

When considering mortality as an outcome, some observational data confirm the association with low BP and events.14,15 One study showed an increased mortality risk in subjects with baseline systolic BP in the lowest quartile (<133 mm Hg) compared to the other quartiles, and another study showed the highest mortality risk with a systolic BP < 110 mm Hg and >180 mm Hg in a cohort of CKD patients inclusive of both diabetic and nondiabetic CKD. The effect from the latter study was strongest in older patients with advanced CKD and without proteinuria, thus limiting the generalizability of this finding.

In summary, observational studies demonstrate an increased risk for cardiovascular morbidity and mortality at BP levels considered hypertensive for the general population. However, it is unclear if an aggressive reduction of BP translates into decreased cardiovascular morbidity and mortality in the CKD population. The evidence from randomized clinical trials on specific BP targets is discussed in the treatment section of the chapter.


Ambulatory Blood Pressure Measurements and Chronic Kidney Disease

Although CKD patients frequently have BP measured in an office setting, it is important to recognize some of the limitations that can arise in this context. Of utmost importance to the topic of hypertension is the relationship between home and clinic BP measurements. Home and ambulatory measurements better predict the presence of end organ damage such as proteinuria compared to clinic measurements.16 Ambulatory BP measurements also predict which CKD patients with an elevated clinic BP have a greater risk for progression to ESRD or reaching the composite outcome of ESRD or death.17 Thus, a comprehensive ascertainment of BP burden requires the consideration of more than measurements obtained in the office.


Hemodialysis Patients

ESRD patients on hemodialysis (HD) have an annual mortality rate close to 20%, with cardiovascular disease and infections accounting for the highest percentage of deaths.18 Although the prevalence of hypertension in the HD population is near 90%,19 a target BP to improve outcomes has yet to be identified. Early epidemiologic studies showed that for BP measurements obtained in the HD unit, low systolic BP and systolic BP in excess of 200 mm Hg were associated with the highest mortality, particularly in older patients and diabetics.20,21 However, it has also been shown that uncontrolled hypertension with systolic BP in excess of 140 mm Hg results in the increased incidence of LVH, de novo ischemic heart disease, and de novo cardiac failure.22 It must be considered that low systolic BP can be a manifestation of decreased cardiac output, resulting from the structural and functional consequences of long-standing uncontrolled hypertension, which would explain its association with increased mortality.

Similar to pre-ESRD CKD patients, the timing and location of BP measurements are also important considerations in HD patients. Home and ambulatory BP measurements during the interdialytic time period, in comparison to individual HD-unit measurements, are better predictors of mortality.23 The significance of BP changes during HD treatments has also been recently investigated. Intradialytic hypertension, increases in BP from pre- to post-HD, has been associated with increased short-term (6 month) morbidity and mortality in prevalent HD patients and decreased 2-year survival in incident HD patients.24,25 There is evidence that mechanisms responsible for the phenomenon include extracellular volume overload26 or increased vasoconstriction related to intradialytic endothelin-1 surges as a manifestation of endothelial cell dysfunction.27,28,29 Patients with intradialytic hypertension have also been shown to have increased ambulatory blood pressure and greater impairment in underlying endothelial cell function during the interdialytic time period.30,31 Additional mechanisms that have been proposed, but that have yet to be confirmed, include increased activity of the RAAS and SNS, changes in electrolytes during HD, and removal of antihypertensive medications during the course of HD.32



ENDOTHELIAL CELL DYSFUNCTION AND HYPERTENSION

Because the increase in peripheral vascular resistance also contributes to the elevated BP in patients with kidney disease, it is important to understand the mechanisms responsible for vasoconstriction. Blood vessels are lined with endothelial cells, which release mediators that exert their actions on VSMC receptors. The balance between vasoconstricting mediators and vasodilating mediators dictates the ultimate response of the VSMC and the amount of resistance. Endothelial nitric oxide synthase (eNOS) uses arginine as a substrate to produce the vasodilator nitric oxide (NO). This process is dependent on the presence of the cofactor tetrahydrobiopterin (BH4), and production of NO can be inhibited by the arginine analog asymmetric dimethylarginine (ADMA). One of the primary vasoconstrictive agents is endothelin-1 (ET-1), but the ultimate response of the vascular tone is dependent on which ET receptor is being bound. The interplay between all of these mediators is complex. Substances such as Ang II modify the activity of ET-1, and NO release is sensitive to the relative state of oxidative stress and inflammation.


Endothelin

ET-1 is a 21 amino acid mitogenic peptide that is produced ubiquitously, but to a large extent in vascular endothelial cells. Its original description demonstrated that it had more potent vasoconstrictive effects than other vasoconstrictive peptides including Ang II, vasopressin, and neuropeptide Y while having a longer lasting effect on vascular tone than the endothelial-derived relaxing factor NO.81 Additionally, ET-1 has been shown to promote vascular cell hypertrophy and increase nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, resulting in oxidative stress and endothelial cell dysfunction.82 There are two primary receptors for ET-1: ET-A and ET-B. ET-1 binding to ET-A and ET-B receptors found on VSMC causes vasoconstriction, whereas binding to ET-B receptors on the endothelial cells causes vasodilation, suggesting a mechanism for feedback inhibition to stimulation by ET-1. Because ET-1 has paracrine behavior and migrates from the endothelial cells to VSMC (away from the lumen), plasma levels of ET-1 have proven to be unreliable in establishing a clear causal relationship with hypertension. However, mRNA expression of ET-1 in the endothelium of resistance vessels is higher in patients with moderate-to-severe hypertension compared to those with mild hypertension
or controls.83 Its role in hypertension in humans is further implicated by its effects on arterial tone. Following an infusion of ET-1, forearm blood flow decreases (increased tone) in both hypertensive and healthy humans, although the effect is greater in hypertensive patients. The pharmacologic inhibition of ET-A receptors alone or the combined inhibition of ET-A and ET-B receptors results in significant increases in forearm blood flow in the hypertensive patients, but not the healthy subjects.84 The administration of a nonselective ET receptor blocker in a dose of >500 mg per day resulted in reductions in systolic and diastolic office and ambulatory BP as compared to placebo; the BP reduction from the drug was similar to that achieved with the ACE inhibitor enalapril.85

In patients with CKD, both systemic and local renal effects are proposed to contribute to hypertension in this population. Partial nephrectomy Sprague-Dawley rat models suggest that there is an imbalance of ET expression and degradation in the uremic state. In these animals, there were increased ET-1 levels (related to increased expression) in the endothelial cells of the thoracic aorta and renal cortex.86 It was also found that the number of ET-B receptors was decreased in these locations, but there was a mild increase in ET-A receptor expression in the VSMC. Downregulation of ET-B receptors disables a mechanism for ET-1 degradation and can further contribute to the increased presence and action of ET-1.87,88

In CKD, there is also increased urinary and plasma levels of ET-1, independent of BP.89,90 The renal excretion rate of ET-1 is increased in hypertensive CKD patients, but not in subjects with normal renal function who have increased plasma ET-1 levels accompanying essential hypertension. These findings suggest that renal production of ET-1 increases as renal function declines and contributes to hypertension in CKD.91

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May 29, 2016 | Posted by in NEPHROLOGY | Comments Off on Hypertension in Chronic Kidney Disease

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