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Hypertension in Chronic Dialysis Patients: Pathophysiology, Monitoring, and Treatment
Hypertension in Chronic Dialysis Patients: Pathophysiology, Monitoring, and Treatment STEPHEN A. MORSE, DO; AN DANG, MD; VASHU THAKUR, MD; RUBIN ZHANG, MD; EFRAIN REISIN, MD
ABSTRACT: The prevalence of hypertension in the population with ESRD is very high, approaching 100% in some populations, and may account for the fact that cardiovascular disease continues to be the leading cause of morbidity and mortality in ESRD. The pathophysiology of hypertension in ESRD is reviewed, suggesting multifactorial causes; a dominant cause is that of volume expansion and an inappropriate increase in systemic vascular resistance because of activation of the renin-angiotensin system. The
primary goal in the treatment of hypertension should be to attain a dry-weight and maintain volume control through limiting salt and fluid intake and ultrafiltration of excess fluids. If this approach is unsuccessful, an array of antihypertensive medications are available to help control blood pressure in patients with ESRD. KEY INDEXING TERMS: End stage renal disease; Hemodialysis; Hypertensive mechanisms; Antihypertensive therapy. [Am J Med Sci 2003;325(4):194–201.]
ypertension is not only a leading cause of kidney failure but also remains a common and vexing health issue in dialysis patients, by causing or contributing to cardiovascular disease, the most frequent cause of death in these subjects.1,2 Hypertension has been shown to cause or contribute to the development of left ventricular (LV) hypertrophy, cardiac chamber dilation, increased ventricular wall stress, redistribution of coronary blood flow, myocardial ischemia, myocardial fibrosis, heart failure, and arrhythmias.3 The prevalence of hypertension in the hemodialysis (HD) population has been estimated to be 80%, but that may approach 100% depending on the population studied.4,5 The prevalence of hypertension in the peritoneal dialysis population is estimated at about 50%, which is less than that reported in the HD population.6 Using ambulatory blood pressure monitoring (ABPM), which has been shown to correlate with cardiovascular outcomes, Coomer et al7 reported that the pre- and postdialysis blood pressure (BP) correlated significantly with the 48-hour mean interdialytic blood pressure and that there were no variations of more than 10% (nondipping) in the mean blood pressure during the daily measurements in the blood pressure of endstage renal disease (ESRD) patients. Despite these findings, the significance of systolic or diastolic pressures or whether to use pre- or postdialysis blood
H
pressures for the diagnosis of hypertension in dialysis patients remains controversial. In addition to the high prevalence of nondipping in patients with ESRD, it has also been noted that patients with ESRD are more likely to have isolated systolic hypertension with an increased pulse pressure,8 which in turn has been associated with cardiovascular disease and early death.9 Conversely, good blood pressure control has been shown to dramatically improve survival.10 Low blood pressure levels, however, were also associated with high mortality in patients with ESRD.11 Zager et al12 describe a bimodal “U-shaped” association of mortality with both high and low blood pressure. These findings have created contradictory recommendations for BP goals in patients with ESRD, with some authors proposing normal and others high normal values for blood pressure treatment goals.13,14 In this article, we will summarize the pathophysiological mechanisms involved in the development of hypertension, review the on-going discussion about the different monitoring techniques and recommended goals of blood pressure controls, and discuss the best proposed pharmacological approach for patients with ESRD.
From the Section of Nephrology, Department of Medicine, Louisiana State University Health Science Center, New Orleans, Louisiana. Correspondence: Efrain Reisin, M.D., Professor of Medicine and Chief Section of Nephrology, 1542 Tulane Ave., New Orleans, LA 70112 (E-mail: [email protected]).
The normal physiologic response to intravascular volume expansion in the healthy person is to increase glomerular filtration via a rise in cardiac output, enhance urinary sodium excretion by suppression of the renin-angiotensin-aldosterone sys-
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Pathophysiology of Hypertension in ESRD Excess Extracellular Volume and the ReninAngiotensin-Aldosterone System.
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tem, and increase natriuresis as a result of the effects of atrial natriuretic peptide (ANP) and an endogenous digitalis-like factor.15 ANP is a 28-amino-acid peptide from the C-terminal end of pro-ANP, 1 of several active fragments, which acts as a peripheral dilator to decrease systemic blood pressure and as a natriuretic/diuretic hormone.16 The result of these physiologic adaptations is natriuresis and diuresis, and restoration of normal plasma volume. In contrast, excess extracellular fluid volume and increases in total body exchangeable sodium are common in patients with ESRD, because of diminished sodium and fluid excretory capacity.17 It has been shown that normotensive patients have significantly less total body water than hypertensive hemodialysis patients, demonstrating the importance of intravascular volume in the pathogenesis of hypertension in patients with ESRD.18 Volume expansion in hypertensive patients with ESRD results in a rise in cardiac output.19 The abnormally increased systemic vascular resistance seen in volume-expanded patients with ESRD may be caused by activation of the renin-angiotensin system. Angiotensin II levels may be inappropriately increased in relation to volume and exchangeable sodium or from the ouabain-like inhibitors of vascular smooth muscle Na⫹,K⫹-ATPase, resulting in increased intracellular sodium (less sodium is extruded from inside the cell) and increased intracellular calcium, which in turn causes vasoconstriction.20 In addition to the mechanisms described previously, the renin-angiotensin-aldosterone system can become activated as a result of primary vascular disease or regional ischemia and nephrosclerosis. The group of patients who remain hypertensive after achieving their dry weight may be reacting to the renin-angiotensin system, because they have been found to respond to angiotensin-converting enzyme (ACE) inhibition treatment.21 Sympathetic Overactivity. Increased sympathetic activity may also contribute to hypertension in ESRD.22 Converse et al23 found evidence of long-term sympathetic overactivity that correlates with the increase in both vascular resistance and systemic BP but was not correlated with plasma catecholamine or renin levels. Because heightened sympathetic activity is not seen in anephric patients, it has been suggested that the afferent signal resulting in increased sympathetic tone originates from the kidney. Volume overload greater than 6% of total body weight results in activation of sympathetic nervous system.24 Postdialysis plasma volume contraction and negative sodium balance may stimulate sympathetic activity as well.25 This may partially explain the blood pressure increase that is seen at the end of dialysis in some patients. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Impaired Endothelium-Dependent Vasodilation. The vascular endothelium produces vasoactive compounds that can relax vascular smooth muscle cells or cause vasoconstriction. One of the first substances to be identified was initially called endothelium-derived relaxing factor and later characterized as nitric oxide (NO). Nitric oxide causes both vasodilation and inhibition of vascular smooth muscle cell proliferation.26 NO deficiency occurs in ESRD and is associated with hypertension.27 An endogenous compound, asymmetrical dimethylargine (ADMA), inhibits NO production and accumulates in ESRD.28 ADMA levels are reduced up to 65% during HD.29 Ritz et al30 hypothesized that depletion of the amino acid L-arginine because of protein malnutrition would result in loss of substrate for nitric oxide production, which could then enhance the effect of ADMA on NO synthesis. Plasma ADMA levels in patients with ESRD may not actually be high enough to cause vasoconstriction but may still be responsible for impaired vasodilation in patients with ESRD.31 Elevated levels of the potent vasoconstrictor endothelin-1 have been found in patients with ESRD.32 The importance of endothelin and the other vasoactive compounds and their physiologic role in patients with ESRD will require further investigation. Use of Recombinant Human Erythropoietin. Nearly one third of renal failure patients treated with erythropoietin develop an increase in BP of 10 mm Hg or more.33 It has been reported that there is a significant correlation between hypertension and erythropoietin therapy, especially when used intravenously.34 Other studies, however, have shown no effect on blood pressure by the administration of erythropoietin.5,7 Different mechanisms of recombinant human erythropoietin-induced hypertension have been proposed, including increased blood viscosity, enhanced pressor responsiveness to endogenous vasoactive compounds, vascular endothelial dysfunction, and direct vasoconstrictor effects of recombinant human erythropoietin.35 Secondary Hyperparathyroidism. Secondary hyperparathyroidism stimulates calcium entry into smooth muscle cells of the blood vessels, which can then lead to vasoconstriction and hypertension.36 Parathyroid hormone infusion results in increased BP and intracellular calcium in healthy subjects,37 and the treatment of secondary hyperparathyroidism with alfacalcidol, an active vitamin D analog, resulted in decreased mean arterial pressure and decreased intracellular calcium.38 How to Monitor Blood Pressure: Blood Pressure Targets and Goals The automated blood pressure monitoring devices used in the dialysis units are useful for looking at 195
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trends and for monitoring patients during dialysis but probably do not conform to the exacting standards set in the various guidelines for the measurement of blood pressure. Normally, blood pressure measurements should be obtained using a correct cuff size and in the sitting position, as recommended by the JNC VI.39 ABPM has been effectively used to measure interdialytic BP and may be especially indicated in patients refractory to antihypertensive treatments. Home blood pressure measurements by patients should be used with caution, because studies using ABPM have shown that casual BP measurements either overestimate or underestimate the degree of hypertension.40 Previous studies were contradictory in the recommendations of whether systolic or diastolic blood pressure and predialysis or postdialysis measurement should be considered when diagnosing and treating hypertension in patients with ESRD. Mittal et al5 examined the pre- and postdialysis and midweek BP of hemodialysis patients over a 3-month period, and they concluded that most of the patients moderately controlled by antihypertensive medications were those with predialysis systolic hypertension.5 Other studies that included antihypertensive and normotensive subjects using ABPM found that the postdialysis BP was better than the predialysis BP at predicting the average BP during the interdialytic period. We agree with the recommendations of Mailloux and Haley41; they concluded that the understanding of the relationship of different important related factors like circadian BP patterns, race, sex, age, and cardiac status should be under consideration to reach the best therapeutic decision. Consequently, they considered the importance of obtaining pre-, intra-, and postdialysis BP measurement as well as interdialytic manual and ambulatory BP in all the patients with ESRD with hypertension and especially in those patients who are refractory to antihypertensive treatment.41 London14 has recommended that the optimum predialysis BP of patients with ESRD with systolicdiastolic hypertension should be 150 to 160/85 to 90 mm Hg.14 He believes that guidelines for the general population do not apply to the majority of hemodialysis patients, who mainly have isolated systolic hypertension. Schömig et al13 have countered that the same principles and goals established for the general population (⬍120/80 mm Hg) should apply to the hemodialysis population and that an optimal BP should be the lowest pressure that is well tolerated. The question arises then as to the definition of “well tolerated,” because some patients with ESRD strongly resist efforts to lower their BP to the recommended levels. Mailloux and Haley,41 in their excellent review, concluded that the optimal BP level may be different in patients with ESRD and should be based on the individual patient’s overall cardiovascular profile, including age, previous and 196
concurrent complications, and comorbid diseases. Despite these conflicting reports, the National Kidney Foundation Task Force on Cardiovascular Disease supported that a target predialysis blood pressure of 140/90 mm Hg or less may be best unless symptomatic hypotension becomes a complicating factor.42 We believe that an extensive effort should be devoted to educate nephrologists, nurses, and patients concerning the importance of obtaining accurate blood pressure measurements in the dialysis units, the patient’s own home BP measurements, or through ABPM to help determine the lowest “welltolerated” blood pressure for the patient. These findings will help nephrologists to plan for each patient’s BP goal in accordance with the previously mentioned recommendations.42 Nonpharmacologic Management of Hypertension in ESRD Patients Dietary Sodium and Water Restriction. Dietary sodium chloride restriction may be the most effective way to control hypertension in ESRD.43 It has been proposed that salt restriction of 750 to 1000 mg/day helps decrease thirst and control interdialytic fluid gain.44 Some authors have observed that there is a lag period of weeks to months when BP continues to decrease without further decrease in extracellular fluid volume after a dry weight has been attained.45 It is thought that during this “lag time,” the extracellular space is slowly stabilizing and the patient is converting from a catabolic state to an anabolic state. In addition, the decrease in BP is associated with a decrease in peripheral vascular resistance, which may be induced by a decrease in intracellular calcium concentration.46 Compliance of patients with ESRD on a low-sodium diet can be monitored by observing their weight. Dry weight is notoriously difficult to assess because there is no single parameter, and the many nonclinical techniques for accurately assessing dry weight may not be practical for use in the dialysis clinic.47 It is interesting to note that high temperature and low humidity also facilitate BP control in patients with ESRD.48 Dialysis Techniques. The use of programmed variable sodium dialysis helped to reduce antihypertensive medications in a randomized crossover study evaluating the effects of programmed, decreased, in-dialysate sodium concentration from 155 to 135 mEq/L compared with the standard stable sodium dialysate concentration of 140 mEq/L.49 Long (8hour) hemodialysis as practiced in Tassin, France, has been shown to optimally control hypertension and reduce LV hypertrophy.50 It is suggested that the superior quality of dialysis and ultrafiltration performed over a longer period of time may be involved in better removal of uremic toxins, ultimately April 2003 Volume 325 Number 4
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resulting in decreased sympathetic tone.51 Changing dialysis modalities from HD to peritoneal dialysis has been recommended in patients who still have significant residual renal function but have uncontrolled hypertension while on HD.52 Lifestyle Changes. Other lifestyle changes should include increasing exercise, losing weight if overweight, limiting alcohol intake, stopping the use of medications that increase blood pressure, and discontinuation of tobacco use.53 Pharmacologic Management of Hypertension in ESRD Patients Antihypertensive medications are effective in decreasing BP in patients with ESRD, and previous studies have shown that calcium channel blockers, ACE inhibitors, and ␣- and -adrenergic receptor blockers are the most commonly used antihypertensive medications in dialysis patients.5,54 The type of antihypertensive medications used also depends on the underlying comorbid conditions and the target population.53 Suboptimal antihypertensive therapy is not an uncommon problem in patients with ESRD because of conflicting instructions from physicians and dialysis staff. In addition, patient noncompliance with fluid and dietary sodium chloride intake recommendations contribute to the problem.55 Blood pressure control often requires a combination of therapeutic modalities and treatment regimens because of the many underlying mechanisms involved in the development of hypertension in ESRD. ACE Inhibitors and Angiotensin II Receptor Blockers. The inappropriately increased angiotensin II levels in relation to the increased volume previously described in patients with ESRD justify the use of ACE inhibitors or angiotensin II receptor blockers (ARBs) as the first line of therapy in ESRD. ACE inhibitors or ARBs are recommended in patients with ESRD with increased LV mass index and normal or reduced LV volume, whereas reduction of hypervolemia should be the choice in patients with elevated LV volume.56 Diastolic function improved and LV mass index regression were noted with ACE inhibitor monotherapy.57 In another study, ACE inhibition was found not only to control hypertension in chronic renal disease but also to decrease sympathetic hyperactivity as well.58 ACE inhibitors are known to cause hyperkalemia, cough, angioedema, and rash, and are contraindicated in pregnancy. In hemodialysis patients, ACE inhibitors may cause the development of erythropoietin resistance59 and anaphylactoid reaction in patients dialyzed with an AN69 dialyzer.60 The anaphylactoid reaction during hemodialysis is thought to be mediated by the blockade of bradykinin degradation by ACE inhibitors and may be dose-dependent. The interference with bradykinin breakdown THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
by ACE inhibitors may amplify the anaphylactoid reaction. Except for fosinopril, a dose reduction of 50% is recommended in ESRD of all the ACE inhibitors; cilazapril, lisinopril, and ramipril should be further decreased to 25% of normal dose.61 Dosing of ACE inhibitors after HD may be preferred. A recent report has pointed out the advantage of lisinopril, a water-soluble ACE inhibitor, given 3 times a week after HD in varying doses of 20 to 40 mg for the treatment of hypertension in noncompliant patients with ESRD.62 ARBs are being widely used at this time for the treatment of hypertension, but extensive experience is limited in patients with ESRD. ARBs have also been found useful in patients with congestive heart failure (CHF),63 and 1 study showed a good blood pressure response with no important side effects in a group of patients on maintenance hemodialysis.64 In another study of 100 patients, 2 patients (2%) had possible anaphylactoid reactions when losartan was used with AN69 dialyzers.65 Except for candesartan (decrease dose by 50%), no dosing adjustments are necessary. Calcium Channel Blockers. CCBs have been found to be an effective antihypertensive medication in patients with ESRD and may be uniquely more so in volume-expanded patients.66 They are also the most frequently used antihypertensive medication. As in the general population, CCBs are useful in patients with LV hypertrophy and diastolic dysfunction. Other than the dihydropyridines (nifedipine), some are particularly useful in patients with coronary artery disease, peripheral vascular disease (PVD), and supraventricular tachycardia, especially verapamil (phenylakylamines) and diltiazem (benzothiazepines). Side effects include headaches, constipation, and edema. Diltiazem and verapamil should be avoided in CHF. Theoretically, the mechanisms of action of CCBs and ACE inhibitors complement each other and may be more effective in combination.67 CCBs generally do not require dosing adjustments with hemodialysis.52,61 Adrenergic Receptor Blockers. Peripheral adrenergic receptor blockers (␣-blockers, ␣/-blockers, and -blockers) have been indicated for patients with hypertension (ESRD), recent myocardial infarctions, coronary artery disease, and arrhythmias. Some -blockers have shown cardioprotective effects in patients with myocardial ischemia or infarction and may induce regression of LV hypertrophy. -Blockers have been shown to lower angiotensin levels by lowering plasma renin activity. Side effects of -blockers include central nervous system depression, bradycardia, possible exacerbation of heart failure, and exacerbation of asthma and chronic obstructive pulmonary disease; they may have an additive negative chronotropic and inotropic effect when combined with certain CCBs. They should be avoided in patients with type 1 diabetes, CHF, PVD, 197
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and heart block. Atenolol is a long acting -blocker and is cleared with dialysis. One study has shown that it is effective in controlling blood pressure when dosed after hemodialysis on a 3 times per week basis.68 Aluminum salts can reduce the bioavailability of metoprolol and propranolol and so they should not be taken at the same time.69 Acebutatolol, atenolol, and nadolol require a dose adjustment to less than 25% of normal and should be given after hemodialysis.52,61 Two drugs that combine ␣- and -blockade properties, labetalol and carvedilol, can be used in patients with ESRD. Dose adjustments are not needed. Carvedilol has been shown to reduce morbidity and mortality in patients with LV systolic failure.70 ␣-Blockers can be used safely in patients with ESRD in the treatment of hypertension and have been used to treat PVD and prostatic hypertrophy as well. Side effects include orthostatic hypotension, syncope, headache, and palpitations. The initial ␣-blocker dose should be reduced and taken at bedtime to avoid complications. Central Sympatholytic Agents. The use of central sympatholytic agents, which inhibit sympathetic outflow from the brainstem, is useful in dialysis patients because there is increased sympathetic activity in patients with ESRD, as discussed previously.23 These drugs have also been used for the treatment of diarrhea caused by autonomic neuropathy and in patients undergoing narcotic withdrawal. Side effects include sedation, dry mouth, postural hypotension, rebound hypertension after rapid tapering (clonidine), rash, hemolysis (positive Coombs test), and liver damage (␣-methyldopa). Because most of these drugs are excreted by the kidneys, reduction in dosing should be considered.61 In this category, guanabenz is the only drug metabolized by the liver and does not require dosing adjustments.52,61 Vasodilators. This class of medications includes hydralazine and minoxidil and has been particularly effective in the treatment of resistant or refractory hypertension in association with other antihypertensive agents. Hydralazine or minoxidil is generally used in combination with a -blocker to reduce the effect of reflex tachycardia. Minoxidil is very useful in the treatment of refractory hypertension. Side effects for hydralazine include headaches, tachycardia, positive anti-nuclear antibodies, and lupus-like syndrome; for minoxidil, they include hypertrichosis, sodium retention, worsening edema, and pericardial effusion. Doses should be decreased in hemodialysis patients because the drugs are normally excreted by the kidney.52,61 Refractory Hypertension. Blood pressure control can be achieved with salt restriction and volume control by dialysis manipulations. If adequate salt and water restriction are not achieved, hypertension 198
may persist and become refractory to the antihypertensive medications. As in the general population, secondary causes of hypertension should be sought in cases in which the patient does not respond to effective volume control and reduced consumption of dietary salt and fluids. Some secondary causes include concurrent use of medications that can raise the BP or renovascular hypertension. If secondary causes of hypertension are ruled out, an individualized approach using the wide arsenal of antihypertensive medications (Table 1) will help to control blood pressure in most of the hemodialysis patients. Hypertensive Emergencies and Urgencies. When severe hypertension occurs with acute or progressing end organ damage, it is considered a hypertensive emergency that often requires parenteral medications. Nitroprusside can be used to effectively lower blood pressure in such situations but requires careful monitoring and early weaning to prevent thiocyanate toxicity. Thiocyanate levels should be monitored every 24 hours. Thiocyanate toxicity may be indicated if nausea, vomiting, or myoclonic movements and seizures occur. Nitroprusside and its metabolites are removed with dialysis. Nitroglycerin given as a continuous IV infusion has also been used effectively to reduce blood pressure and may be preferred over nitroprusside but should not be used in patients with inferior wall myocardial infarction or right ventricular infarction. Other alternative choices include labetalol, esmolol, nicardipine, enalaprilat, and hydralazine. Labetalol is contraindicated in patients with heart failure, asthma, or heart block, and hydralazine is contraindicated in ischemic heart disease. Esmolol is a short-acting, cardioselective -blocker that can be used intravenously and has been particularly useful in patients with aortic dissection. Nicardipine is a CCB that can be used intravenously but can cause headaches, flushing, reflex tachycardia, and venous irritation. Enalaprilat is an ACE inhibitor that can be given intravenously but may cause hypotension in patients with high renin levels. Fenoldopam is a peripherally acting dopamine-1agonist that reduces blood pressure secondary to arterial vasodilation. Previous studies have shown the drug to be very effective in reducing blood pressure in hypertensive urgencies or emergencies, but it does not reduce right ventricular filling pressures or pulmonary capillary wedge pressure. The drug is not indicated in patients with congestive heart failure, but can be used in patients with ESRD to avoid the toxicity of nitroprusside.71 Conclusions Hypertension and other long-standing risk factors for cardiovascular disease are at the root of the high mortality rate in patients with ESRD. The optimal April 2003 Volume 325 Number 4
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Table 1. Benefits and Side Effects of Antihypertensive Medications in Dialysis Patients According to Coexisting Diseases Group
Benefits
Side Effects
ACEIs
LVH; CHF; LV diastolic dysfunction
ARBs
LVH; CHF; does not require dose adjustments (except candesartan) LVH; LV diastolic dysfunction; does not require dose adjustments; useful in SVT (verapamil and diltiazem only) Cardioprotection (-blockers); LVH (␣blockers); useful in PVD (␣-blockers); prostatic hypertrophy (␣-blockers); CHF (-blockers or ␣/-blockers)
CCBs Adrenergic receptor blockers
Central sympathetic agonists
Useful in diabetic gastropathy
Vasodilators
Useful in resistant hypertension
Cough, angioedema, anaphylactoid reactions, dose adjustments (except lisinopril) Not enough experience Headaches, constipation, can exacerbate CHF (verapamil and diltiazem) CNS depression, bradycardia, CHF (blockers); contraindicated in COPD; avoid in DM-1, PVD, heart block (-blockers); cleared by dialysis (atenolol); some require dose adjustments; postural hypotension (␣-blockers) Sedation, dry mouth, postural hypotension, rebound hypertension, hemolysis, liver damage (alpha-methyldopa); requires dose adjustments Headaches, tachycardia, worsening edema, pleural and pericardial effusions (minoxidil), drug-induced SLE (hydralazine); requires dose adjustments
ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers; CCB, calcium channel blockers; LVH, left ventricular hypertrophy; CHF, congestive heart failure; CNS, central nervous system; PVD, peripheral vascular disease; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; SVT, supraventricular tachycardia; SLE, systemic lupus erythematosis.
blood pressure recommendations of 120/80 mm Hg made by the JNC VI may be difficult to achieve in the ESRD population but provide an ideal target for blood pressure control.39 A universally acceptable target BP has yet to be established for the ESRD population but the National Kidney Foundation Task Force has recommended a target predialysis BP of 140/90 mm Hg or less.42 In patients with a tendency for symptomatic postdialysis hypotension, a predialysis blood pressure that is greater than 140/90 may be required to avoid symptoms and other complications.52 Salt restriction is often overlooked as a means of controlling BP in patients with ESRD.44 An effort should be made to withdraw antihypertensive medications slowly once dialysis is started and during the process of determining the patient’s dry weight. On the other hand, if blood pressure remains uncontrolled, it may be necessary to add antihypertensive medications. In light of the pathophysiology of hypertension in ESRD, ACE inhibitors, ARBs, adrenergic receptor blockers, and CCBs have been found to be effective in lowering BP and may have the potential added benefit of improving cardiovascular morbidity and mortality. References 1. Burt VL, Cutler JA, Higgins M, et al. Trends in the prevalence, awareness, treatment, and control of hypertension in the adult US population. Data from the health examination surveys, 1960 to 1991. Hypertension 1995;26:60 –9.
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2. US Renal Data System. USRDS 2001 Annual Data Report. Atlas of end-stage renal disease in the United States. Bethesda (MD): National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2001. 3. Rostand SG, Brunzell JD, Cannon RO III, et al. Cardiovascular complications in renal failure. J Am Soc Nephrol 1991;2:1053– 62. 4. Tomita J, Kimura G, Inoue T, et al. Role of systolic BP in determining prognosis of hemodialyzed patients. Am J Kidney Dis 1995;25:405–12. 5. Mittal SK, Kowalski E, Trenkle J, et al. Prevalence of hypertension in a hemodialysis population. Clin Nephrol 1999;51:77– 82. 6. Rocco MV, Flanagan MJ, Beaver S, et al. Report from the 1995 Core Indicators for Peritoneal Dialysis study group. Am J Kidney Dis 1997;30:165–73. 7. Coomer RW, Schulman G, Breyer JA, et al. Ambulatory blood pressure monitoring in dialysis patients and estimation of mean interdialytic blood pressure. Am J Kidney Dis 1997; 29:678 – 84. 8. London G, Guerin A, Pannier B, et al. Increased systolic pressure in chronic uremia: role of arterial wave reflections. Hypertension 1992;20:10 –9. 9. Covic A, Goldsmith DJ. Ambulatory blood pressure monitoring in nephrology: focus on BP variability. J Nephrol 1999;12:220 –9. 10. Charra B, Calemard E, Ruffet M, et al. Survival as an index of adequacy of dialysis. Kidney Int 1992;41:1286 –91. 11. Mazzuchi N, Carbonell E, Fernancez-Cean J. Importance of blood pressure control in hemodialysis patient survival. Kidney Int 2000;58:2147–54. 12. Zager PG, Nikolic J, Brown RH, et al. “U” curve association of blood pressure and mortality in hemodialysis patients. Kidney Int 1998;54:561–9.
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13. Schömig M, Eisenhardt A, Ritz E. Controversy on optimal blood pressure on hemodialysis: Normotensive blood pressure values are essential for survival. Nephrol Dial Transplant 2001;16:469 –74. 14. London GM. Controversy on optimal blood pressure on haemodialysis: lower is not always better. Nephrol Dial Transplant 2001;16:475–9. 15. Rose BD. Natriuretic hormones: atrial peptides and ouabain-like hormone. UpToDate 2000;8:2. 16. Vesely DL, Douglass MSA, Dietz JR, et al. Three peptides from the atrial natriuretic factor prohormone amino terminus lower blood pressure and produce diuresis, natriuresis, and/or kaliuresis in humans. Circulation 1994;90:1129 –34. 17. Cannella G, Castellani A, Mioni G, et al. Blood pressure control in end-stage renal disease in man: indirect evidence of a complex pathogenic mechanism besides renin or blood volume. Clin Sci Mol Med 1977;52:19 –21. 18. Lins RL, Elseviers M, Rogiers P, et al. Importance of volume factors in dialysis related hypertension. Clin Nephrol 1997;48:29 –33. 19. Campese VM, Chanana A. Hypertension in dialysis patients. In: Henrich WI, editor. Principles and practice of dialysis, 2nd ed. Baltimore: Lippincott Williams & Wilkins; 1999. p. 209 –34. 20. Glatter KA, Graves SW, Hollenberg NK, et al. Sustained volume expansion and (Na-K) ATPase inhibition in chronic renal failure. Am J Hypertens 1994;7:1016 –24. 21. Vaughn ED Jr, Carey RM, Ayers CR, et al. Hemodialysisresistant hypertension: control with an orally active inhibitor of angiotensin-converting enzyme. J Clin Endocrinol Metab 1979;48:869 –71. 22. Campese VM, Romoff MS, Levitan D, et al. Mechanisms of autonomic nervous system dysfunction in uremia. Kidney Int 1981;20:246 –53. 23. Converse RL Jr, Jacobsen TN, Toto RD, et al. Sympathetic overactivity in patients with chronic renal failure. N Engl J Med 1992;327:1912–28. 24. Odar-Cederlof I, Ericsson F, Theodorsson E, et al. Is neuropeptide Y a contributor to volume-induced hypertension? Am J Kidney Dis 1998;31:803– 8. 25. London G, Marchais S, Guerin AP. Blood pressure control in chronic hemodialysis patients. In: Jacobs C, Kjellstrand CM, Koch KM, et al, editors. Replacement of renal function by dialysis. London: Kluwer; 1997. p. 966 – 89. 26. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524 – 6. 27. Schmidt RJ, Domico J, Samsell LS, et al. Indices of activity of the nitric oxide system in hemodialysis patients. Am J Kidney Dis 1999;34:228 –34. 28. Vallance P, Leone A, Calver A, et al. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 1992;339:572–5. 29. Kielstein JT, Böger RH, Bode-Böger SM, et al. Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease. J Am Soc Nephrol 1999; 10:594 – 600. 30. Ritz E, Vallance P, Nowicki M. The effect of malnutrition on cardiovascular mortality in dialysis patients: is L-arginine the answer? Nephrol Dial Transplant 1994;9:129 –30. 31. Anderstam B, Katzarski K, Bergstrom J. Serum levels of NG,NG-dimethyl-L-arginine, a potential endogenous nitric oxide inhibitor in dialysis patients. J Am Soc Nephrol 1997; 7:2453– 60.
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32. Shichiri M, Hirata Y, Ando K, et al. Plasma endothelin levels in hypertension and chronic renal failure. Hypertension 1992;15:493. 33. Eschbach JW, Kelly MR, Haley NR, et al. Treatment of anemia of progressive renal failure with recombinant human erythropoietin. N Engl J Med 1989;321:158 – 63. 34. Raine AE, Roger SD. Effects of erythropoietin on blood pressure. Am J Kidney Dis 1991;18(Suppl 1):76 – 83. 35. Hörl MP, Hörl WH. Hemodialysis-associated hypertension: Pathophysiology and therapy. Am J Kidney Dis 2002;39:227– 44. 36. Massry SG, Iseki K, Campese VM. Serum calcium, parathyroid hormone and blood pressure. Am J Nephrol 1986;6: 119 –28. 37. Fliser D, Franek E, Fode P, et al. Subacute infusion of physiological doses of parathyroid hormone raises blood pressure in humans. Nephrol Dial Transplant 1997;12:933– 8. 38. Goldsmith DJ, Covic AA, Venning MC, et al. Blood pressure reduction after patients for secondary hyperparathyroidism: Further evidence implicating calcium homeostasis in blood pressure regulation. Am J Kidney Dis 1996;27:819 – 25. 39. Anonymous. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1997;157:2413– 46. 40. Agarwal R. Role of home blood pressure monitoring in hemodialysis patients. Am J Kidney Dis 1999;33:682–7. 41. Mailloux LU, Haley WE. Hypertension in the ESRD patient: pathophysiology, therapy, outcomes and future directions. Am J Kidney Dis 1998;32:705–19. 42. Levey AS, Beto JA, Coronado BE, et al. Controlling the epidemic of cardiovascular disease in chronic renal disease: What do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease Am J Kidney Dis 1998;32(Suppl):853– 906. 43. Shaldon S. Can antihypertensive medications control BP in haemodialysis patients [letter]? Nephrol Dial Transplant 2000;15:736. 44. Mailloux LU. The overlooked role of salt restriction in dialysis patients [editorial]. Semin Dial 2000;13:150. 45. Charra B, Bergström J, Scribner BH. Blood pressure control in dialysis patients. The importance of the lag phenomenon. Am J Kidney Dis 1998;32:720 – 4. 46. Donohoe P, Farmer C, Dallyn P, et al. Low sodium haemodialysis without fluid removal improves blood pressure control in chronic dialysis patients [abstract]. Kidney Int 1997;52:1110. 47. Jaeger JQ, Mehta RL. Assessment of dry weight in hemodialysis: an overview. J Am Soc Nephrol 1999;10:392– 403. 48. Argiles A, Mourad G, Mion C. Seasonal changes in blood pressure in patients with end-stage renal disease treated with hemodialysis. N Engl J Med 1998;339:1364 –70. 49. Flanigan MJ, Khairullah QT, Lim VS. Dialysate sodium delivery can alter chronic blood pressure management. Am J Kidney Dis 1997;29:383–91. 50. Luik AJ, Charra B, Katzarski K, et al. Blood pressure control and hemodynamic changes in patients on long time dialysis treatment. Blood Purif 1998;16:197–209. 51. Chazot C, Charra B, Laurent G, et al. Interdialysis blood pressure control by long haemodialysis sessions. Nephrol Dial Transplant 1995;10:831–7. 52. Mailloux LU, Levey AS. Hypertension in patients with chronic renal disease. Am J Kidney Dis 1998;32(Suppl): S120 – 41.
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53. Reisin E. Nonpharmacologic approaches to hypertension: weight, sodium, alcohol, exercise, and tobacco considerations. Med Clin N Am 1997;81:1289 –303. 54. Zazgornik J, Biesenbach F, Forstenlehner M, et al. Profile of antihypertensive drugs in hypertensive patients on renal replacement therapy (RRT). Clin Nephrol 1997;48:337– 440. 55. Rahman M, Dixit A, Donley V, et al. Factors associated with inadequate blood pressure control in hypertensive hemodialysis patients. Am J Kidney Dis 1999;33:498 –506. 56. Klingbeil AU, Schmieder RE. Not all left ventricular hypertrophy is created equal. Nephrol Dial Transplant 1999;14: 2803–5. 57. Dyadyk AI, Bagriy AE, Lebed IA, et al. ACE inhibitors captopril and enalapril induce regression of left ventricular hypertrophy in hypertensive patients with chronic renal failure. Nephrol Dial Transplant 1997;12:945–51. 58. Ligtenberg G, Blankestijn PJ, Oey PL, et al. Reduction of sympathetic hyperactivity by enalapril in patients with chronic renal failure. N Engl J Med 1999;340:1321– 8. 59. Dhondt AW, Vanholder RC, Ringoir SM. Angiotensinconverting enzyme inhibitors and higher erythropoietin requirements in chronic hemodialysis patients. Nephrol Dial Transplant 1995;10:2107–9. 60. Verresen L, Waer M, Vanrenterghem Y, et al. Angiotensin-converting-enzyme inhibitors and anaphylactoid reactions to high-flux membrane dialysis. Lancet 1990;336: 1360 –2. 61. Aronoff GR, Berns JS, Brier ME, et al. Drug prescribing in renal failure: dosing guidelines for adults, 4th ed. Philadelphia: American College of Physicians; 1999.
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62. Agarwal R, Lewis R, Davis JL, et al. Lisinopril therapy for hemodialysis hypertension: hemodynamic and endocrine responses. Am J Kidney Dis 2001;38:1245–50. 63. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial—the Losartan Heart Failure Survival Study ELITE II. Lancet 2000;355:1582–7. 64. Toto R, Shultz P, Raij L, et al. Efficacy and tolerability of losartan in hypertensive patients with renal impairment. Collaborative Group. Hypertension 1998;31:684 –91. 65. Saracho R, Martin-Malo A, Martinez I, et al. Evaluation of the Losartan in Hemodialysis (ELHE) Study. Kidney Int 1998;68(Suppl):S125–9. 66. London GM, Marchais SJ, Guerin AP, et al. Salt and water retention and calcium blockade in uremia. Circulation 1990;82:105–13. 67. Preston RA. Renoprotective effects of antihypertensive drugs. Am J Hypertens 1999;12(Suppl):S19 –S32. 68. Agarwal R. Supervised atenolol therapy in management of hemodialysis hypertension. Kidney Int 1999;55:1528 –35. 69. Barbour MM, McKindley DS. Pharmacology and pharmacotherapy of cardiovascular drugs in patients with chronic renal disease. Semin Nephrol 2001;21:66 –78. 70. Packer M, Bristow MR, Cohn JN, al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334:1349 –55. 71. Calhoun D, Oparil S, Mathur V, et al. Fenoldopam: a novel peripherally acting dopamine-1-agonist for parenteral treatment of hypertension. Drugs Today 1997;33:729 –34.
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ABSTRACT: The prevalence of hypertension in the population with ESRD is very high, approaching 100% in some populations, and may account for the fact that cardiovascular disease continues to be the leading cause of morbidity and mortality in ESRD. The pathophysiology of hypertension in ESRD is reviewed, suggesting multifactorial causes; a dominant cause is that of volume expansion and an inappropriate increase in systemic vascular resistance because of activation of the renin-angiotensin system. The
primary goal in the treatment of hypertension should be to attain a dry-weight and maintain volume control through limiting salt and fluid intake and ultrafiltration of excess fluids. If this approach is unsuccessful, an array of antihypertensive medications are available to help control blood pressure in patients with ESRD. KEY INDEXING TERMS: End stage renal disease; Hemodialysis; Hypertensive mechanisms; Antihypertensive therapy. [Am J Med Sci 2003;325(4):194–201.]
ypertension is not only a leading cause of kidney failure but also remains a common and vexing health issue in dialysis patients, by causing or contributing to cardiovascular disease, the most frequent cause of death in these subjects.1,2 Hypertension has been shown to cause or contribute to the development of left ventricular (LV) hypertrophy, cardiac chamber dilation, increased ventricular wall stress, redistribution of coronary blood flow, myocardial ischemia, myocardial fibrosis, heart failure, and arrhythmias.3 The prevalence of hypertension in the hemodialysis (HD) population has been estimated to be 80%, but that may approach 100% depending on the population studied.4,5 The prevalence of hypertension in the peritoneal dialysis population is estimated at about 50%, which is less than that reported in the HD population.6 Using ambulatory blood pressure monitoring (ABPM), which has been shown to correlate with cardiovascular outcomes, Coomer et al7 reported that the pre- and postdialysis blood pressure (BP) correlated significantly with the 48-hour mean interdialytic blood pressure and that there were no variations of more than 10% (nondipping) in the mean blood pressure during the daily measurements in the blood pressure of endstage renal disease (ESRD) patients. Despite these findings, the significance of systolic or diastolic pressures or whether to use pre- or postdialysis blood
H
pressures for the diagnosis of hypertension in dialysis patients remains controversial. In addition to the high prevalence of nondipping in patients with ESRD, it has also been noted that patients with ESRD are more likely to have isolated systolic hypertension with an increased pulse pressure,8 which in turn has been associated with cardiovascular disease and early death.9 Conversely, good blood pressure control has been shown to dramatically improve survival.10 Low blood pressure levels, however, were also associated with high mortality in patients with ESRD.11 Zager et al12 describe a bimodal “U-shaped” association of mortality with both high and low blood pressure. These findings have created contradictory recommendations for BP goals in patients with ESRD, with some authors proposing normal and others high normal values for blood pressure treatment goals.13,14 In this article, we will summarize the pathophysiological mechanisms involved in the development of hypertension, review the on-going discussion about the different monitoring techniques and recommended goals of blood pressure controls, and discuss the best proposed pharmacological approach for patients with ESRD.
From the Section of Nephrology, Department of Medicine, Louisiana State University Health Science Center, New Orleans, Louisiana. Correspondence: Efrain Reisin, M.D., Professor of Medicine and Chief Section of Nephrology, 1542 Tulane Ave., New Orleans, LA 70112 (E-mail: [email protected]).
The normal physiologic response to intravascular volume expansion in the healthy person is to increase glomerular filtration via a rise in cardiac output, enhance urinary sodium excretion by suppression of the renin-angiotensin-aldosterone sys-
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Pathophysiology of Hypertension in ESRD Excess Extracellular Volume and the ReninAngiotensin-Aldosterone System.
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tem, and increase natriuresis as a result of the effects of atrial natriuretic peptide (ANP) and an endogenous digitalis-like factor.15 ANP is a 28-amino-acid peptide from the C-terminal end of pro-ANP, 1 of several active fragments, which acts as a peripheral dilator to decrease systemic blood pressure and as a natriuretic/diuretic hormone.16 The result of these physiologic adaptations is natriuresis and diuresis, and restoration of normal plasma volume. In contrast, excess extracellular fluid volume and increases in total body exchangeable sodium are common in patients with ESRD, because of diminished sodium and fluid excretory capacity.17 It has been shown that normotensive patients have significantly less total body water than hypertensive hemodialysis patients, demonstrating the importance of intravascular volume in the pathogenesis of hypertension in patients with ESRD.18 Volume expansion in hypertensive patients with ESRD results in a rise in cardiac output.19 The abnormally increased systemic vascular resistance seen in volume-expanded patients with ESRD may be caused by activation of the renin-angiotensin system. Angiotensin II levels may be inappropriately increased in relation to volume and exchangeable sodium or from the ouabain-like inhibitors of vascular smooth muscle Na⫹,K⫹-ATPase, resulting in increased intracellular sodium (less sodium is extruded from inside the cell) and increased intracellular calcium, which in turn causes vasoconstriction.20 In addition to the mechanisms described previously, the renin-angiotensin-aldosterone system can become activated as a result of primary vascular disease or regional ischemia and nephrosclerosis. The group of patients who remain hypertensive after achieving their dry weight may be reacting to the renin-angiotensin system, because they have been found to respond to angiotensin-converting enzyme (ACE) inhibition treatment.21 Sympathetic Overactivity. Increased sympathetic activity may also contribute to hypertension in ESRD.22 Converse et al23 found evidence of long-term sympathetic overactivity that correlates with the increase in both vascular resistance and systemic BP but was not correlated with plasma catecholamine or renin levels. Because heightened sympathetic activity is not seen in anephric patients, it has been suggested that the afferent signal resulting in increased sympathetic tone originates from the kidney. Volume overload greater than 6% of total body weight results in activation of sympathetic nervous system.24 Postdialysis plasma volume contraction and negative sodium balance may stimulate sympathetic activity as well.25 This may partially explain the blood pressure increase that is seen at the end of dialysis in some patients. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Impaired Endothelium-Dependent Vasodilation. The vascular endothelium produces vasoactive compounds that can relax vascular smooth muscle cells or cause vasoconstriction. One of the first substances to be identified was initially called endothelium-derived relaxing factor and later characterized as nitric oxide (NO). Nitric oxide causes both vasodilation and inhibition of vascular smooth muscle cell proliferation.26 NO deficiency occurs in ESRD and is associated with hypertension.27 An endogenous compound, asymmetrical dimethylargine (ADMA), inhibits NO production and accumulates in ESRD.28 ADMA levels are reduced up to 65% during HD.29 Ritz et al30 hypothesized that depletion of the amino acid L-arginine because of protein malnutrition would result in loss of substrate for nitric oxide production, which could then enhance the effect of ADMA on NO synthesis. Plasma ADMA levels in patients with ESRD may not actually be high enough to cause vasoconstriction but may still be responsible for impaired vasodilation in patients with ESRD.31 Elevated levels of the potent vasoconstrictor endothelin-1 have been found in patients with ESRD.32 The importance of endothelin and the other vasoactive compounds and their physiologic role in patients with ESRD will require further investigation. Use of Recombinant Human Erythropoietin. Nearly one third of renal failure patients treated with erythropoietin develop an increase in BP of 10 mm Hg or more.33 It has been reported that there is a significant correlation between hypertension and erythropoietin therapy, especially when used intravenously.34 Other studies, however, have shown no effect on blood pressure by the administration of erythropoietin.5,7 Different mechanisms of recombinant human erythropoietin-induced hypertension have been proposed, including increased blood viscosity, enhanced pressor responsiveness to endogenous vasoactive compounds, vascular endothelial dysfunction, and direct vasoconstrictor effects of recombinant human erythropoietin.35 Secondary Hyperparathyroidism. Secondary hyperparathyroidism stimulates calcium entry into smooth muscle cells of the blood vessels, which can then lead to vasoconstriction and hypertension.36 Parathyroid hormone infusion results in increased BP and intracellular calcium in healthy subjects,37 and the treatment of secondary hyperparathyroidism with alfacalcidol, an active vitamin D analog, resulted in decreased mean arterial pressure and decreased intracellular calcium.38 How to Monitor Blood Pressure: Blood Pressure Targets and Goals The automated blood pressure monitoring devices used in the dialysis units are useful for looking at 195
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trends and for monitoring patients during dialysis but probably do not conform to the exacting standards set in the various guidelines for the measurement of blood pressure. Normally, blood pressure measurements should be obtained using a correct cuff size and in the sitting position, as recommended by the JNC VI.39 ABPM has been effectively used to measure interdialytic BP and may be especially indicated in patients refractory to antihypertensive treatments. Home blood pressure measurements by patients should be used with caution, because studies using ABPM have shown that casual BP measurements either overestimate or underestimate the degree of hypertension.40 Previous studies were contradictory in the recommendations of whether systolic or diastolic blood pressure and predialysis or postdialysis measurement should be considered when diagnosing and treating hypertension in patients with ESRD. Mittal et al5 examined the pre- and postdialysis and midweek BP of hemodialysis patients over a 3-month period, and they concluded that most of the patients moderately controlled by antihypertensive medications were those with predialysis systolic hypertension.5 Other studies that included antihypertensive and normotensive subjects using ABPM found that the postdialysis BP was better than the predialysis BP at predicting the average BP during the interdialytic period. We agree with the recommendations of Mailloux and Haley41; they concluded that the understanding of the relationship of different important related factors like circadian BP patterns, race, sex, age, and cardiac status should be under consideration to reach the best therapeutic decision. Consequently, they considered the importance of obtaining pre-, intra-, and postdialysis BP measurement as well as interdialytic manual and ambulatory BP in all the patients with ESRD with hypertension and especially in those patients who are refractory to antihypertensive treatment.41 London14 has recommended that the optimum predialysis BP of patients with ESRD with systolicdiastolic hypertension should be 150 to 160/85 to 90 mm Hg.14 He believes that guidelines for the general population do not apply to the majority of hemodialysis patients, who mainly have isolated systolic hypertension. Schömig et al13 have countered that the same principles and goals established for the general population (⬍120/80 mm Hg) should apply to the hemodialysis population and that an optimal BP should be the lowest pressure that is well tolerated. The question arises then as to the definition of “well tolerated,” because some patients with ESRD strongly resist efforts to lower their BP to the recommended levels. Mailloux and Haley,41 in their excellent review, concluded that the optimal BP level may be different in patients with ESRD and should be based on the individual patient’s overall cardiovascular profile, including age, previous and 196
concurrent complications, and comorbid diseases. Despite these conflicting reports, the National Kidney Foundation Task Force on Cardiovascular Disease supported that a target predialysis blood pressure of 140/90 mm Hg or less may be best unless symptomatic hypotension becomes a complicating factor.42 We believe that an extensive effort should be devoted to educate nephrologists, nurses, and patients concerning the importance of obtaining accurate blood pressure measurements in the dialysis units, the patient’s own home BP measurements, or through ABPM to help determine the lowest “welltolerated” blood pressure for the patient. These findings will help nephrologists to plan for each patient’s BP goal in accordance with the previously mentioned recommendations.42 Nonpharmacologic Management of Hypertension in ESRD Patients Dietary Sodium and Water Restriction. Dietary sodium chloride restriction may be the most effective way to control hypertension in ESRD.43 It has been proposed that salt restriction of 750 to 1000 mg/day helps decrease thirst and control interdialytic fluid gain.44 Some authors have observed that there is a lag period of weeks to months when BP continues to decrease without further decrease in extracellular fluid volume after a dry weight has been attained.45 It is thought that during this “lag time,” the extracellular space is slowly stabilizing and the patient is converting from a catabolic state to an anabolic state. In addition, the decrease in BP is associated with a decrease in peripheral vascular resistance, which may be induced by a decrease in intracellular calcium concentration.46 Compliance of patients with ESRD on a low-sodium diet can be monitored by observing their weight. Dry weight is notoriously difficult to assess because there is no single parameter, and the many nonclinical techniques for accurately assessing dry weight may not be practical for use in the dialysis clinic.47 It is interesting to note that high temperature and low humidity also facilitate BP control in patients with ESRD.48 Dialysis Techniques. The use of programmed variable sodium dialysis helped to reduce antihypertensive medications in a randomized crossover study evaluating the effects of programmed, decreased, in-dialysate sodium concentration from 155 to 135 mEq/L compared with the standard stable sodium dialysate concentration of 140 mEq/L.49 Long (8hour) hemodialysis as practiced in Tassin, France, has been shown to optimally control hypertension and reduce LV hypertrophy.50 It is suggested that the superior quality of dialysis and ultrafiltration performed over a longer period of time may be involved in better removal of uremic toxins, ultimately April 2003 Volume 325 Number 4
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resulting in decreased sympathetic tone.51 Changing dialysis modalities from HD to peritoneal dialysis has been recommended in patients who still have significant residual renal function but have uncontrolled hypertension while on HD.52 Lifestyle Changes. Other lifestyle changes should include increasing exercise, losing weight if overweight, limiting alcohol intake, stopping the use of medications that increase blood pressure, and discontinuation of tobacco use.53 Pharmacologic Management of Hypertension in ESRD Patients Antihypertensive medications are effective in decreasing BP in patients with ESRD, and previous studies have shown that calcium channel blockers, ACE inhibitors, and ␣- and -adrenergic receptor blockers are the most commonly used antihypertensive medications in dialysis patients.5,54 The type of antihypertensive medications used also depends on the underlying comorbid conditions and the target population.53 Suboptimal antihypertensive therapy is not an uncommon problem in patients with ESRD because of conflicting instructions from physicians and dialysis staff. In addition, patient noncompliance with fluid and dietary sodium chloride intake recommendations contribute to the problem.55 Blood pressure control often requires a combination of therapeutic modalities and treatment regimens because of the many underlying mechanisms involved in the development of hypertension in ESRD. ACE Inhibitors and Angiotensin II Receptor Blockers. The inappropriately increased angiotensin II levels in relation to the increased volume previously described in patients with ESRD justify the use of ACE inhibitors or angiotensin II receptor blockers (ARBs) as the first line of therapy in ESRD. ACE inhibitors or ARBs are recommended in patients with ESRD with increased LV mass index and normal or reduced LV volume, whereas reduction of hypervolemia should be the choice in patients with elevated LV volume.56 Diastolic function improved and LV mass index regression were noted with ACE inhibitor monotherapy.57 In another study, ACE inhibition was found not only to control hypertension in chronic renal disease but also to decrease sympathetic hyperactivity as well.58 ACE inhibitors are known to cause hyperkalemia, cough, angioedema, and rash, and are contraindicated in pregnancy. In hemodialysis patients, ACE inhibitors may cause the development of erythropoietin resistance59 and anaphylactoid reaction in patients dialyzed with an AN69 dialyzer.60 The anaphylactoid reaction during hemodialysis is thought to be mediated by the blockade of bradykinin degradation by ACE inhibitors and may be dose-dependent. The interference with bradykinin breakdown THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
by ACE inhibitors may amplify the anaphylactoid reaction. Except for fosinopril, a dose reduction of 50% is recommended in ESRD of all the ACE inhibitors; cilazapril, lisinopril, and ramipril should be further decreased to 25% of normal dose.61 Dosing of ACE inhibitors after HD may be preferred. A recent report has pointed out the advantage of lisinopril, a water-soluble ACE inhibitor, given 3 times a week after HD in varying doses of 20 to 40 mg for the treatment of hypertension in noncompliant patients with ESRD.62 ARBs are being widely used at this time for the treatment of hypertension, but extensive experience is limited in patients with ESRD. ARBs have also been found useful in patients with congestive heart failure (CHF),63 and 1 study showed a good blood pressure response with no important side effects in a group of patients on maintenance hemodialysis.64 In another study of 100 patients, 2 patients (2%) had possible anaphylactoid reactions when losartan was used with AN69 dialyzers.65 Except for candesartan (decrease dose by 50%), no dosing adjustments are necessary. Calcium Channel Blockers. CCBs have been found to be an effective antihypertensive medication in patients with ESRD and may be uniquely more so in volume-expanded patients.66 They are also the most frequently used antihypertensive medication. As in the general population, CCBs are useful in patients with LV hypertrophy and diastolic dysfunction. Other than the dihydropyridines (nifedipine), some are particularly useful in patients with coronary artery disease, peripheral vascular disease (PVD), and supraventricular tachycardia, especially verapamil (phenylakylamines) and diltiazem (benzothiazepines). Side effects include headaches, constipation, and edema. Diltiazem and verapamil should be avoided in CHF. Theoretically, the mechanisms of action of CCBs and ACE inhibitors complement each other and may be more effective in combination.67 CCBs generally do not require dosing adjustments with hemodialysis.52,61 Adrenergic Receptor Blockers. Peripheral adrenergic receptor blockers (␣-blockers, ␣/-blockers, and -blockers) have been indicated for patients with hypertension (ESRD), recent myocardial infarctions, coronary artery disease, and arrhythmias. Some -blockers have shown cardioprotective effects in patients with myocardial ischemia or infarction and may induce regression of LV hypertrophy. -Blockers have been shown to lower angiotensin levels by lowering plasma renin activity. Side effects of -blockers include central nervous system depression, bradycardia, possible exacerbation of heart failure, and exacerbation of asthma and chronic obstructive pulmonary disease; they may have an additive negative chronotropic and inotropic effect when combined with certain CCBs. They should be avoided in patients with type 1 diabetes, CHF, PVD, 197
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and heart block. Atenolol is a long acting -blocker and is cleared with dialysis. One study has shown that it is effective in controlling blood pressure when dosed after hemodialysis on a 3 times per week basis.68 Aluminum salts can reduce the bioavailability of metoprolol and propranolol and so they should not be taken at the same time.69 Acebutatolol, atenolol, and nadolol require a dose adjustment to less than 25% of normal and should be given after hemodialysis.52,61 Two drugs that combine ␣- and -blockade properties, labetalol and carvedilol, can be used in patients with ESRD. Dose adjustments are not needed. Carvedilol has been shown to reduce morbidity and mortality in patients with LV systolic failure.70 ␣-Blockers can be used safely in patients with ESRD in the treatment of hypertension and have been used to treat PVD and prostatic hypertrophy as well. Side effects include orthostatic hypotension, syncope, headache, and palpitations. The initial ␣-blocker dose should be reduced and taken at bedtime to avoid complications. Central Sympatholytic Agents. The use of central sympatholytic agents, which inhibit sympathetic outflow from the brainstem, is useful in dialysis patients because there is increased sympathetic activity in patients with ESRD, as discussed previously.23 These drugs have also been used for the treatment of diarrhea caused by autonomic neuropathy and in patients undergoing narcotic withdrawal. Side effects include sedation, dry mouth, postural hypotension, rebound hypertension after rapid tapering (clonidine), rash, hemolysis (positive Coombs test), and liver damage (␣-methyldopa). Because most of these drugs are excreted by the kidneys, reduction in dosing should be considered.61 In this category, guanabenz is the only drug metabolized by the liver and does not require dosing adjustments.52,61 Vasodilators. This class of medications includes hydralazine and minoxidil and has been particularly effective in the treatment of resistant or refractory hypertension in association with other antihypertensive agents. Hydralazine or minoxidil is generally used in combination with a -blocker to reduce the effect of reflex tachycardia. Minoxidil is very useful in the treatment of refractory hypertension. Side effects for hydralazine include headaches, tachycardia, positive anti-nuclear antibodies, and lupus-like syndrome; for minoxidil, they include hypertrichosis, sodium retention, worsening edema, and pericardial effusion. Doses should be decreased in hemodialysis patients because the drugs are normally excreted by the kidney.52,61 Refractory Hypertension. Blood pressure control can be achieved with salt restriction and volume control by dialysis manipulations. If adequate salt and water restriction are not achieved, hypertension 198
may persist and become refractory to the antihypertensive medications. As in the general population, secondary causes of hypertension should be sought in cases in which the patient does not respond to effective volume control and reduced consumption of dietary salt and fluids. Some secondary causes include concurrent use of medications that can raise the BP or renovascular hypertension. If secondary causes of hypertension are ruled out, an individualized approach using the wide arsenal of antihypertensive medications (Table 1) will help to control blood pressure in most of the hemodialysis patients. Hypertensive Emergencies and Urgencies. When severe hypertension occurs with acute or progressing end organ damage, it is considered a hypertensive emergency that often requires parenteral medications. Nitroprusside can be used to effectively lower blood pressure in such situations but requires careful monitoring and early weaning to prevent thiocyanate toxicity. Thiocyanate levels should be monitored every 24 hours. Thiocyanate toxicity may be indicated if nausea, vomiting, or myoclonic movements and seizures occur. Nitroprusside and its metabolites are removed with dialysis. Nitroglycerin given as a continuous IV infusion has also been used effectively to reduce blood pressure and may be preferred over nitroprusside but should not be used in patients with inferior wall myocardial infarction or right ventricular infarction. Other alternative choices include labetalol, esmolol, nicardipine, enalaprilat, and hydralazine. Labetalol is contraindicated in patients with heart failure, asthma, or heart block, and hydralazine is contraindicated in ischemic heart disease. Esmolol is a short-acting, cardioselective -blocker that can be used intravenously and has been particularly useful in patients with aortic dissection. Nicardipine is a CCB that can be used intravenously but can cause headaches, flushing, reflex tachycardia, and venous irritation. Enalaprilat is an ACE inhibitor that can be given intravenously but may cause hypotension in patients with high renin levels. Fenoldopam is a peripherally acting dopamine-1agonist that reduces blood pressure secondary to arterial vasodilation. Previous studies have shown the drug to be very effective in reducing blood pressure in hypertensive urgencies or emergencies, but it does not reduce right ventricular filling pressures or pulmonary capillary wedge pressure. The drug is not indicated in patients with congestive heart failure, but can be used in patients with ESRD to avoid the toxicity of nitroprusside.71 Conclusions Hypertension and other long-standing risk factors for cardiovascular disease are at the root of the high mortality rate in patients with ESRD. The optimal April 2003 Volume 325 Number 4
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Table 1. Benefits and Side Effects of Antihypertensive Medications in Dialysis Patients According to Coexisting Diseases Group
Benefits
Side Effects
ACEIs
LVH; CHF; LV diastolic dysfunction
ARBs
LVH; CHF; does not require dose adjustments (except candesartan) LVH; LV diastolic dysfunction; does not require dose adjustments; useful in SVT (verapamil and diltiazem only) Cardioprotection (-blockers); LVH (␣blockers); useful in PVD (␣-blockers); prostatic hypertrophy (␣-blockers); CHF (-blockers or ␣/-blockers)
CCBs Adrenergic receptor blockers
Central sympathetic agonists
Useful in diabetic gastropathy
Vasodilators
Useful in resistant hypertension
Cough, angioedema, anaphylactoid reactions, dose adjustments (except lisinopril) Not enough experience Headaches, constipation, can exacerbate CHF (verapamil and diltiazem) CNS depression, bradycardia, CHF (blockers); contraindicated in COPD; avoid in DM-1, PVD, heart block (-blockers); cleared by dialysis (atenolol); some require dose adjustments; postural hypotension (␣-blockers) Sedation, dry mouth, postural hypotension, rebound hypertension, hemolysis, liver damage (alpha-methyldopa); requires dose adjustments Headaches, tachycardia, worsening edema, pleural and pericardial effusions (minoxidil), drug-induced SLE (hydralazine); requires dose adjustments
ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers; CCB, calcium channel blockers; LVH, left ventricular hypertrophy; CHF, congestive heart failure; CNS, central nervous system; PVD, peripheral vascular disease; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; SVT, supraventricular tachycardia; SLE, systemic lupus erythematosis.
blood pressure recommendations of 120/80 mm Hg made by the JNC VI may be difficult to achieve in the ESRD population but provide an ideal target for blood pressure control.39 A universally acceptable target BP has yet to be established for the ESRD population but the National Kidney Foundation Task Force has recommended a target predialysis BP of 140/90 mm Hg or less.42 In patients with a tendency for symptomatic postdialysis hypotension, a predialysis blood pressure that is greater than 140/90 may be required to avoid symptoms and other complications.52 Salt restriction is often overlooked as a means of controlling BP in patients with ESRD.44 An effort should be made to withdraw antihypertensive medications slowly once dialysis is started and during the process of determining the patient’s dry weight. On the other hand, if blood pressure remains uncontrolled, it may be necessary to add antihypertensive medications. In light of the pathophysiology of hypertension in ESRD, ACE inhibitors, ARBs, adrenergic receptor blockers, and CCBs have been found to be effective in lowering BP and may have the potential added benefit of improving cardiovascular morbidity and mortality. References 1. Burt VL, Cutler JA, Higgins M, et al. Trends in the prevalence, awareness, treatment, and control of hypertension in the adult US population. Data from the health examination surveys, 1960 to 1991. Hypertension 1995;26:60 –9.
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