Ebook Kaplan’s clinical hypertension (10/E): Part 2

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Part 1 book "Kaplan’s clinical hypertension" includes content: Hypertensive crises, renal parenchymal hypertension, renovascular hypertension, primary aldosteronism, pheochromocytoma (with a preface about incidental adrenal masses), hypertension induced by cortisol or deoxycorticosterone, other forms of identifiable hypertension, hypertension with pregnancy and the pill, hypertension in childhood and adolescence.

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CCH A PPTTEERR HA 8 Hypertensive Crises lthough only a small spot in the large status, reversible by reduction of BP. Encephalopathy is A panorama of hypertension, hypertensive crises represent, on one hand, the most more common in previously normotensive individuals whose pressures rise suddenly, such as during pregnancy immediate danger to those afﬂicted and, on the with eclampsia; the accelerated-malignant course often other, the most dramatic proof of the life-saving appears without encephalopathy in individuals with potential of antihypertensive therapy. Such crises are more chronic hypertension whose pressures progres- now less likely to be the end result of chronic hyper- sively rise. tension but may be seen at any age, representing the manifestations of suddenly developing hypertension from such diverse causes as substance abuse, immu- nosuppressive drugs, and human immunodeﬁciency ACCELERATED-MALIGNANT virus infection (Ewen et al., 2009). HYPERTENSION Mechanisms When BP reaches some critical level—in experimen- DEFINITIONS tal animals at a mean arterial pressure of 150 mm A hypertensive emergency is a situation that requires Hg—lesions appear in arterial walls, and the syn- immediate reduction in blood pressure (BP) with drome of accelerated-malignant hypertension begins parenteral agents because of acute or progressing tar- (Fig. 8-1). This may be provoked by one or more get organ damage (Table 8-1). vasoactive factors, but the accelerated-malignant A hypertensive urgency is a situation with mark- phase is likely to be a nonspeciﬁc consequence of edly elevated BP but without severe symptoms or very high BP (Beilin & Goldby, 1977). Any form of progressive target organ damage, wherein the BP hypertension may progress to the accelerated- should be reduced within hours, often with oral malignant phase, some without activation of the agents. Some of the circumstances listed in Table 8-1 renin-angiotensin system or other known humoral may be urgencies rather than emergencies if of lesser mechanisms (Gavras et al., 1975). severity, including some patients with accelerated- malignant hypertension, perioperative or rebound Structural Changes hypertension, less severe body burn, or epistaxis. The In animal models, the level of the arterial pressure distinction between an emergency and an urgency is correlates closely with the development of ﬁbrinoid often ambiguous. necrosis, the experimental hallmark of accelerated- Accelerated-malignant hypertension represents malignant hypertension (Byrom, 1974). In humans, markedly elevated BP with papilledema (grade 4 ﬁbrinoid necrosis is rare, perhaps because those who Keith-Wagener retinopathy) and/or hemorrhages die from an acute attack have not had time to and exudates (grade 3 Keith-Wagener retinopathy). develop the lesion and those who live with therapy The clinical features and prognosis are similar with are able to repair it. The typical lesions, best seen in grade 3 or grade 4 retinopathy. (Ahmed et al., 1986). the kidney, are hyperplastic arteriosclerosis and Hypertensive encephalopathy is a sudden, marked accelerated glomerular obsolescence (Kitiyakara & elevation of BP with severe headache and altered mental Guzman, 1998). 274 Chap08.indd 274 8/28/2009 1:02:44 PM
Chapter 8 • Hypertensive Crises 275 TABLE 8.1 accelerated-malignant hypertension in humans, found Hypertensive Emergencies in 20% to 35% of patients with this form of hyperten- Accelerated-malignant hypertension with papilledema sion (Davis et al., 1979; Webster et al., 1993). Cerebrovascular conditions Evidence for the pathway shown on the left side of Figure 8-1 includes the presence of circulating Hypertensive encephalopathy Atherothrombotic brain infarction with severe hypertension endothelial and platelet microparticles in patients Intracerebral hemorrhage with severe uncontrolled hypertension (Preston et al., Subarachnoid hemorrhage 2003) and markers of endothelial dysfunction and Head trauma platelet activation in patients with malignant hyper- Cardiac conditions tension (Lip et al., 2001). Acute aortic dissection Acute left ventricular failure Clinical Features Acute or impending myocardial infarction Accelerated-malignant hypertension may be accom- After coronary bypass surgery panied by various symptoms and signs (Table 8-2). Renal conditions However, it is not uncommon to see patients, partic- Acute glomerulonephritis ularly young black men, who deny any prior symp- Renovascular hypertension toms when seen in the end stages of the hypertensive Renal crises from collagen-vascular diseases process, with their kidneys destroyed, heart failing, Severe hypertension after kidney transplantation and brain function markedly impaired. Even in the Excess circulating catecholamines elderly, hypertension may initially present in the Pheochromocytoma crisis accelerated-malignant phase (Lip et al., 2000). Food or drug interactions with monoamine oxidase Less common clinical presentations include: inhibitors Sympathomimetic drug use (cocaine) • Aortic dissection with giant cell arteritis (Smulders & Rebound hypertension after sudden cessation of Verhagen, 2008) antihypertensive drugs • Fibrinoid necrosis within abdominal arteries produc- Automatic hyperreﬂexia after spinal cord injury ing major gastrointestinal tract infarction with an Eclampsia acute abdomen (Padﬁeld, 1975) Surgical conditions • Rapidly progressive necrotizing vasculitis as a feature Severe hypertension in patients requiring immediate of lupus (Mitchell, 1994) or polyarteritis nodosa surgery (Blaustein et al., 2004) Postoperative hypertension • Hematospermia or hematuria (Fleming et al., 2008) Postoperative bleeding from vascular suture lines Severe body burns Funduscopic Findings Severe epistaxis The effects of the markedly elevated BP are displayed in the optic fundi (Fig. 8-2). Acute changes may include arteriolar spasm, either segmental or diffuse; Humoral Factors retinal edema, with a sheen or ripples; retinal There is support, however, for the involvement of factors besides the level of the BP in setting off the accelerated-malignant phase (Kincaid-Smith, 1991). As shown on the right side of Figure 8-1, in both rats TABLE 8.2 Clinical Characteristics (Gross et al., 1975) and dogs (Dzau et al., 1981) with of Accelerated-Malignant unilateral renal artery stenosis, the accelerated-malignant Hypertension phase was preceded by natriuresis that markedly acti- vated the renin-angiotensin system. The progression Blood pressure: usually >140 mm Hg diastolic Funduscopic ﬁndings: hemorrhages, exudates, papilledema was delayed by giving saline loads after the natriuresis. Neurologic status: headache, confusion, somnolence, Whether these animal models involving a major stupor, vision loss, focal deﬁcits, seizures, coma insult to renal blood ﬂow are applicable to most human Renal status: oliguria, azotemia accelerated-malignant hypertension is uncertain; how- Gastrointestinal status: nausea, vomiting ever, renal artery stenosis is a common cause of Chap08.indd 275 8/28/2009 1:02:45 PM
276 Kaplan’s Clinical Hypertension FIGURE 8-1 Scheme for initiation and progression of accelerated- malignant hypertension. hemorrhages, either superﬁcial and ﬂame-shaped or deep and dot-shaped; retinal exudates, either hard and waxy from resorption of edema or with a raw cot- ton appearance from ischemia; and papilledema and engorged retinal veins (Foguet et al., 2008). Similar retinopathy with hemorrhages and even papilledema rarely occurs in severe anemia, collagen diseases, and subacute bacterial endocarditis. Some patients have pseudopapilledema associated with congenital anomalies, hyaline bodies (drusen) in the disc, or severe farsightedness. Fluorescein fundus photography will distinguish between the true and the pseudo states. In addition, benign intracranial hypertension may produce real papilledema but is usually a minimally symptomatic and self-limited process (Jain & Rosner, 1992). Evaluation FIGURE 8-2 Funduscopic photography showing typical In addition to an adequate history and physical exam- features of accelerated-malignant hypertension. ination, a few laboratory tests should be done imme- diately to assess the patient’s status (Table 8-3). Chap08.indd 276 8/28/2009 1:02:45 PM
Chapter 8 • Hypertensive Crises 277 TABLE 8.3 Initial Evaluation of Patients with a Hypertensive Emergency History Prior diagnosis and treatment of hypertension Intake of pressor agents: street drugs, sympathomimetics Symptoms of cerebral, cardiac, and visual dysfunction Physical examination Blood pressure Funduscopy Neurologic status Cardiopulmonary status Body ﬂuid volume assessment Peripheral pulses Laboratory evaluation Hematocrit and blood smear Urine analysis Automated chemistry: creatinine, glucose, electrolytes Electrocardiogram Plasma renin activity and aldosterone (if primary aldosteronism is suspected) Plasma renin activity before and 1 h after 25 mg captopril (if renovascular hypertension is suspected) Spot urine or plasma for metanephrine (if pheochromocytoma is suspected) Chest radiograph (if heart failure or aortic dissection is suspected) Laboratory Findings Evaluation for Identiﬁable Causes In 27% of patients with malignant hypertension, van Once causes for the presenting picture other than den Born et al. (2008) found thrombotic microan- severe hypertension are excluded and necessary giopathy, characterized by thromboses of small ves- immediate therapy is provided, an appropriate evalu- sels, intravascular hemolysis with fragmented red ation for identiﬁable causes of the hypertension blood cells, elevated lactic dehydrogenase, and con- should be performed as quickly as possible. It is pref- sumption of platelets. They postulate that endothelial erable to obtain necessary blood and urine samples damage from high BP triggers release of the pro- for required laboratory studies before institution of thrombotic van Willebrand factor that activates factor therapies that may markedly complicate subsequent which activates intravascular coagulation. evaluation. None of these procedures should delay The urine contains protein and red cells. In a few effective therapy. patients, acute oliguric renal failure may be the Renovascular hypertension is by far the most presenting manifestation (Lip et al., 1997). likely secondary cause and, unfortunately, the one Various features of renal insufﬁciency may be that may be least obvious by history, physical exami- present. Approximately half of patients have nation, and routine laboratory tests. It should be par- hypokalemia, reﬂecting secondary aldosteronism ticularly looked for in older patients with extensive from increased renin secretion induced by intrarenal atherosclerosis (see Chapter 10). ischemia (Kawazoe et al., 1987). Hyponatremia is If there are suggestive symptoms of phenochro- usual and can be extreme (Trivelli et al., 2005), in mocytoma, blood for a plasma metanephrine assay contrast to the hypernatremia found in primary should be collected (see Chapter 12). aldosteronism. Primary aldosteronism should be considered, The electrocardiogram usually displays evidence particularly if signiﬁcant hypokalemia is noted on the of left ventricular hypertrophy, strain, and lateral isch- initial blood test. A plasma renin and aldosterone level emia. Echocardiography may show incoordinate con- should be obtained. In most cases of primary aldoster- tractions with impaired diastolic function and delayed onism presenting with malignant hypertension, mitral valve opening (Shapiro & Beevers, 1983). plasma renin activity has initially been elevated, Chap08.indd 277 8/28/2009 1:02:46 PM
278 Kaplan’s Clinical Hypertension later being suppressed as the intrarenal necrotizing HYPERTENSIVE ENCEPHALOPATHY process subsides (Suzuki et al., 2002) (see Chapter 11). With or without the structural defects of accelerated- malignant hypertension, progressively higher BP can Prognosis lead to hypertensive encephalopathy. If untreated, most patients with accelerated-malignant hypertension will die within 6 months. The 1-year survival rate was only 10% to 20% without therapy Pathophysiology (Dustan et al., 1958). With current therapy, 5-year Breakthrough Vasodilation survival rates of greater than 70% are usual (Lip et al., With changes in BP, cerebral vessels dilate or constrict 2000; Webster et al., 1993), clearly showing the major to maintain a relatively constant level of cerebral blood protection provided by antihypertensive therapy. ﬂow (CBF), the process of autoregulation that is regu- Many patients when ﬁrst seen with accelerated- lated by sympathetic nervous activity (Tuor, 1992). malignant hypertension have signiﬁcant renal damage, Figure 8-3 shows direct measurements taken in cats, which markedly worsens their prognosis (van den Born with progressive vasodilation as pressures are lowered et al., 2005). In one series of 100 consecutive patients and progressive vasoconstriction as pressures rise with malignant hypertension (Bing et al., 2004), the (MacKenzie et al., 1976). Note, however, that when 5-year survival rate of those without renal impairment mean arterial pressures reach a critical level, approxi- (serum creatinine
Chapter 8 • Hypertensive Crises 279 FIGURE 8-4 Idealized curves of CBF at varying levels of systemic BP in normotensive and hyperten- sive subjects. Rightward shift in autoregulation is shown with chronic hypertension. (Adapted from Strandgaard S, Olesen J, Skinhøj E, et al. Autoregulation of brain circulation in severe arterial hypertension. Br Med J 1973;1: 507–510.) Breakthrough vasodilation has also been demon- These symptoms may appear at levels of BP that are strated in humans (Strandgaard et al., 1973). Figure 8-4 still well within the normal range of autoregulation shows curves of autoregulation constructed by measur- and well tolerated by normotensives. The reason is ing CBF repetitively while arterial BP was lowered by that the entire curve of autoregulation shifts, so that vasodilators or raised by vasoconstrictors. CBF is con- the lower end also is moved, with a falloff of CBF at stant between mean arterial pressures of 60 and 120 mm levels of 100 to 120 mm Hg mean arterial pressure Hg in normotensive subjects. However, when pressure (Fig. 8-4). Moreover, chronic hypertensives may lose was raised beyond the limit of autoregulation, break- their ability to autoregulate, increasing their risk of through hyperperfusion occurred. cerebral ischemia when BP is lowered acutely (Jansen Pressures such as these are handled without obvi- et al., 1987). ous trouble in chronic hypertensives, whose blood ves- As detailed in Chapter 7, if the BP is lowered sels adapt to the chronically elevated BP with structural gradually, the curve can shift back toward normal so thickening, presumably mediated by sympathetic that greater reductions in pressure can eventually be nerves (Tuor, 1992). Thereby the entire curve of auto- tolerated. However, maneuvers that increase CBF regulation is shifted to the right (Fig. 8-4). Even with further and thereby increase intracranial pressure, this shift, breakthrough will occur if mean arterial pres- such as CO2 inhalation or cerebral vasodilators (e.g., sures are markedly raised to levels beyond 180 mm Hg. hydralazine and nitroprusside), may be harmful in These ﬁndings explain a number of clinical patients with encephalopathy. observations. Previously normotensive people who suddenly become hypertensive may develop enceph- Central Nervous System Changes alopathy at relatively low levels of hypertension, Encephalopathic patients have many of the same which are nonetheless beyond their upper limit of laboratory ﬁndings seen in patients with malignant autoregulation. These include children with acute hypertension, but they have more central nervous glomerulonephritis and young women with eclamp- system manifestations. The cerebrospinal ﬂuid rarely sia. On the other hand, chronically hypertensive shows pleocytosis (McDonald et al., 1993) but is usu- patients less commonly develop encephalopathy and ally under increased pressure. Computed tomography only at much higher pressures. or magnetic resonance imaging shows a characteristic In regard to the lower portion of the curve, when posterior leukoencephalopathy predominantly affect- the BP is lowered by antihypertensive drugs too ing the parietooccipital white matter, often the cere- quickly, chronic hypertensives often are unable to tol- bellum and brainstem (Karampekios et al., 2004), erate the reduction without experiencing cerebral and occasionally other areas as well (Vaughan & hypoperfusion, manifested by weakness and dizziness. Delanty, 2000). Chap08.indd 279 8/28/2009 1:02:47 PM
280 Kaplan’s Clinical Hypertension TABLE 8.4 worsen and the lack of autoregulation in ischemic Conditions that May Mimic a brain tissue may result in further increases in the vol- Hypertensive Emergency ume of the ischemic tissue, which may cause either Acute left ventricular failure acute herniation or more gradual compression of End-stage renal disease normal brain. Cerebrovascular accident On the other hand, the shift to the right of the Subarachnoid hemorrhage curve of cerebral autoregulation in most patients Brain tumor who develop encephalopathy exposes them to the Head injury hazards of a fall in CBF when systemic pressure is Reversible cerebral vasoconstriction syndromes lowered abruptly by more than approximately 25%, Epilepsy (postictal) Collagen diseases, particularly systemic lupus, with even though these levels are not truly hypotensive cerebral vasculitis (Immink et al., 2004; Strandgaard & Paulson, 1996) Encephalitis (Fig. 8-4). Drug ingestion: sympathomimetics (e.g., cocaine) Acute intermittent porphyria Hypercalcemia Initiating Therapy Acute anxiety with hyperventilation syndrome or With encephalopathy or evidence of progressive myo- panic attack cardial ischemia, no more than a very few minutes should be taken to admit a patient to an intensive care unit, set up intravenous access, and begin fre- quent monitoring of the BP, usually with an intra- Differential Diagnosis arterial line. The initial blood and urine samples There are clinical situations in which the BP is ele- should be obtained, and antihypertensive therapy vated and the patient has ﬁndings that suggest hyper- should begin immediately thereafter. tension-induced target organ damage wherein the ﬁndings are unrelated to the elevated BP. Table 8-4 lists conditions that may mimic a hypertensive emer- Monitoring Therapy gency. A less aggressive approach to lowering of the Abrupt falls in pressure should be avoided, and the BP is indicated in such patients. Particular caution is goal of immediate therapy should be to lower the warranted after a stroke, when a rapid decrease in BP diastolic pressure only to approximately 110 mm may shunt blood away from the ischemic area and Hg. The reductions may need to be even less if signs extend the lesion (Adams et al., 2007). of tissue ischemia develop as the pressure is lowered. In addition to the two speciﬁc presentations of Most of the catastrophes seen with treatment of accelerated-malignant hypertension and hypertensive hypertensive emergencies were related to overly encephalopathy, hypertension may be life threatening aggressive reduction of the BP (Jansen et al., when it accompanies other acute conditions wherein 1987). a markedly elevated BP contributes to the ongoing Particular care should be taken in elderly tissue damage (Table 8-1). The role of hypertension patients and in patients with known cerebrovascu- in most of these conditions is covered in Chapter 4, lar disease, who are even more vulnerable to sud- and some of the other speciﬁc circumstances (e.g., den falls in systemic BP (Fischberg et al., 2000). In pheochromocytoma crises and eclampsia) are covered patients with recent ischemic stroke, the American in their respective chapters. Stroke Association recommends cautious reduc- tion of BP by 10% to 15% if systolic levels are above 220 mm Hg or diastolic above 120 mm Hg THERAPY FOR HYPERTENSIVE (Adams et al., 2007). EMERGENCIES If the neurologic status worsens as treatment proceeds, urgent computed tomography of the brain The majority of patients with the conditions shown should be obtained and, if potentially life-threatening in Table 8-1 require immediate reduction in BP. In cerebral edema is identiﬁed, osmotic diuresis with those patients with hypertensive encephalopathy, if mannitol, often plus intravenous furosemide, can be the pressure is not reduced, cerebral edema will effective (Brott & Bogousslavsky, 2000). It may be Chap08.indd 280 8/28/2009 1:02:47 PM
Chapter 8 • Hypertensive Crises 281 possible to monitor intracranial pressure and cerebral data to document which of these drugs is best or, autoregulation noninvasively (Schmidt et al., 2003). more importantly, whether their use is followed by decrease in morbidity or mortality. As described by Perez and Musini (2008) in their Cochrane systematic Parenteral Drugs review of 5,413 identiﬁed citations, only 15 were Table 8-5 lists the choices of parenteral therapy now acceptable as a randomized control trial (RCT), and available. All are capable of inducing hypotension, a only one of these was of good quality. Perez and risk that mandates careful monitoring of BP. They are Musini (2008) could ﬁnd no adequate evidence to covered in the order shown in Table 8-5. ask the question, “Does antihypertensive therapy, as Before examining the various parenteral agents, compared to placebo or no treatment, change an important fact must be recognized: There are no mortality and morbidity in patients with hypertensive TABLE 8.5 Parenteral Drugs for Treatment of Hypertensive Emergency Onset of Duration Druga Dose Action of Action Adverse Effectsb Special Indications Vasodilators Nitroprusside 0.25–10.00 mg/ Immediate 1–2 min Nausea, vomiting, Not preferred for kg/min IV muscle twitching, most hypertensive thiocyanate emergencies and cyanide toxicity Nitroglycerin 5–100 mg/min 2–5 min 5–10 min Headache, vomiting, Not preferred but methemoglobinemia, may be useful with tolerance with coronary ischemia prolonged use Fenoldopam 0.1–0.6 mg/ 4–5 min 10–15 min Tachycardia, May be indicated (Corlopam) kg/min IV increased intraocular with renal pressure, insufﬁciency Nicardipinec 5–15 mg/h 5–10 min 1–4 h Headache, nausea, Most hypertensive (Cardene IV) ﬂushing, tachycardia emergencies Clevidipine 1–2 mg IV, 2–4 min 5–15 min Most hypertensive (Cleviprex) rapidly emergencies increasing dose to 16 mg maximum Hydralazine 5–20 mg IV 10–20 min 1–4 h Tachycardia, ﬂushing, Eclampsia. Not for headache, vomiting, aortic dissection 10–40 mg IM 20–30 min 4–6 h aggravation of angina Adrenergic inhibitor Phentolamine 5–15 mg IV 1–2 min 3–10 min Tachycardia, ﬂushing, Catecholamine headache excess Esmolol 250–500 mg/kg/min 1–2 min 10–20 min Hypotension, nausea Aortic dissection (Brevibloc) for 4 min, then after surgery 50–300 mg/kg/min IV Labetalol 20–80 mg IV bolus 5–10 min 3–6 h Vomiting, scalp Most hypertensive (Normodyne, every 10 min tingling, burning in emergencies Trandate) throat, dizziness, except acute nausea, heart block, heart failure orthostatic 2 mg/min IV infusion hypotension a In order of rapidity of action. b Hypotension may occur with any. c Intravenous formulations of other CCBs are also available. Chap08.indd 281 8/28/2009 1:02:48 PM
282 Kaplan’s Clinical Hypertension emergencies?… We feel it is important for physicians 2008). These effects are potentially detrimental in to know that this is one of the clinical settings where patients with hypertensive encephalopathy or after a treatment is not supposed by RCT evidence.” stroke. As noted by Varon (2008): “considering the The authors further note the absence of data to potential for severe toxicity with nitroprusside, this inform clinicians as to which drug class provides drug should be used only when other intravenous more beneﬁt than harm. They state: “Neither did we antihypertensive agents are not available and then, ﬁnd RCTs that compared different strategies to only in speciﬁc clinical circumstances in patients with reduce blood pressure. Thus, how fast or how much normal renal and hepatic function.” blood pressure should be lowered in hypertensive emergencies remains unknown.” Nitroglycerin In the absence of evidence, clinicians must con- Nitroglycerin as a potent venodilator reduces BP, tinue to administer parenteral drugs to lower markedly decreasing preload and cardiac output, both undesir- elevated BP in patients with hypertensive emergency. able effects in patients with compromised cerebral However, we must do so carefully, with close supervi- perfusion (Varon, 2008). Therefore, it is not an sion, choosing drugs that allow for gradual reduction acceptable ﬁrst choice for hypertensive emergencies, of BP, that have no inherent toxicity, and provide the but it may be helpful as an adjunct in patients with ability to back down if target organ functions deterio- acute coronary ischemia. rate. With current criteria, the use of nitroprusside Fenoldopam can no longer be defended though it was the ﬁrst Fenoldopam, a peripheral dopamine-I agonist, unlike truly effective agent used in such patients (Gifford, other parenteral antihypertensive agents, maintains 1959). or increases renal perfusion while it lowers BP (Murphy et al., 2001). It maintains most of its efﬁ- cacy for 48 hours of constant rate infusion without Nitroprusside rebound hypertension when discontinued. Although The BP always falls when nitroprusside is given, theoretically attractive in maintaining renal perfusion, although it occasionally takes much more than the it was no better than nitroprusside when compared in usual starting dose of 0.25 mg/kg/minute for a response. a sequential study of 43 patients with hypertensive The antihypertensive effect disappears within minutes emergencies (Devlin et al., 2004). after the drug is stopped. Obviously, the drug should be used only with constant monitoring of the BP. The nitric oxide that is part of the nitroprusside Nicardipine structure induces immediate arteriolar and venous When given by continuous infusion, the intravenous dilation with no effects on the autonomic or central formulations of various dihydropyridine calcium nervous system (Mansoor & Frishman, 2002). Nitro- channel blockers (CCBs) produce a steady, progres- prusside is metabolized to cyanide by sulfhydryl sive fall in BP with little change in heart rate and a groups in red cells, and the cyanide is rapidly metabo- small increase in cardiac output (Mansoor & Frishman, lized to thiocyanate in the liver (Schulz, 1984). If 2002). Nicardipine has been found to provide high levels of thiocyanate (>10 mg/dL) remain for responses virtually equal to those seen with nitroprus- days, toxicity may be manifested as fatigue, nausea, side, with few side effects (Neutel et al., 1994). disorientation, and psychosis. If cyanide toxicity is suspected because of metabolic acidosis and venous Clevidipine hyperoxemia, nitroprusside should be discontinued, This dihydropyridine CCB has recently been approved and 4 to 6 mg of 3% sodium nitrite given intrave- for intravenous use in treating severe hypertension. nously over 2 to 4 minutes, followed by an infusion Unlike nicardipine, clevidipine has a very fast onset of 50 mL of 25% sodium thiosulfate (Friederich & of action and a short duration of action of about Butterworth, 1995). 15 minutes, as it is rapidly metabolized by red blood Beyond its inherent potential toxicity and the cell esterases. It reduces blood pressure by selective need for constant surveillance with its use, nitroprus- arterial dilation, reducing afterload without affecting side poses an even greater hazard: It reduces CBF cardiac ﬁlling pressure or causing a reﬂex tachycardia while increasing intracranial pressure (Immink et al., (Varon, 2008). Chap08.indd 282 8/28/2009 1:02:48 PM
Chapter 8 • Hypertensive Crises 283 Hydralazine Criteria for Drug Selection The direct vasodilator hydralazine can be given by Because no clinical comparisons are available of the repeated intramuscular injections as well as intravenously eventual outcome after the use of various agents, the with a fairly slow onset and prolonged duration of action, choice of therapy is based on rapidity of action, ease of allowing for less intensive monitoring. Signiﬁcant com- administration, and propensity for side effects. Although pensatory increases in cardiac output preclude its use as nitroprusside has been most widely used and continues a sole agent except in young patients, as with preeclamp- to be preferred for most hypertensive emergencies by sia, who can handle the increased cardiac work without most authors, its propensity to increase intracranial the likelihood that coronary ischemia will be induced. pressure and the need for constant monitoring support Hydralazine’s primary use is for severe hypertension dur- the wider use of other effective parenteral agents such as ing pregnancy, as noted in Chapter 15. labetalol, nicardipine, and fenoldopam. The management of hypertensive emergencies in Phentolamine a number of special circumstances is considered in The a-blocker phentolamine is speciﬁcally indicated other chapters of this book: renal insufﬁciency, for pheochromocytoma or tyramine-induced cate- Chapter 9; pheochromocytoma, Chapter 12; drug cholamine crisis. abuse, Chapter 14; eclampsia, Chapter 15; and, in children and adolescents, Chapter 16. Esmolol Esmolol, a relatively cardioselective b-blocker, is rap- idly metabolized by blood esterases and has a short (approximately 9-minute) half-life and total duration THERAPY FOR HYPERTENSIVE of action (approximately 30 minutes). Its effects begin URGENCIES almost immediately, and it has found particular use during anesthesia to prevent postintubation hemody- Hypertensive urgencies can usually be managed with namic perturbations (Oxorn et al., 1990). oral therapy, including some cases of accelerated- malignant hypertension or perioperative or rebound Labetalol hypertension. The management of the overwhelming The combined a- and b-blocker labetalol has been majority of patients who are found to have a very found to be both safe and effective when given intra- high BP but who are asymptomatic and in little dan- venously either by repeated bolus (Huey et al., 1988) ger of rapidly progressive target organ damage, or by continuous infusion (Leslie et al., 1987). It starts referred to as uncontrolled severe hypertension rather acting within 5 minutes, and its effects last for 3 to than a hypertensive urgency, is considered at the end of 6 hours. Labetalol can likely be used in almost any this chapter. situation requiring parenteral antihypertensive ther- In particular, patients in a surgical recovery room apy, except when left ventricular dysfunction could be or a nursing home whose BP is found to be above worsened by the predominant b-blockade. Caution is some arbitrary danger level such as 180/110 mm Hg needed to avoid postural hypotension if patients are should not automatically be given sublingual nife- allowed out of bed. Nausea, itching, tingling of the dipine or any other antihypertensive drug. This prac- skin, and b-blocker side effects may be noted. tice has been widespread. In a 2-month survey in three hospitals, 3.4% of all patients had been given Diuretic sublingual nifedipine: 63% of the orders were given A diuretic may be needed after other antihyperten- over the telephone for arbitrary and asymptomatic sives are used, because reactive renal sodium retention BP elevations and 98% with no bedside evaluation usually accompanies a fall in pressure and may blunt (Rehman et al., 1996). the efﬁcacy of nondiuretic agents. On the other hand, Rather than such inappropriate prescribing, the if the patient is volume depleted from pressure- proximate causes for abrupt increases in BP should be induced natriuresis and prior nausea and vomiting, identiﬁed and managed (e.g., hypoxia, pain, or vol- additional diuresis could be dangerous, and volume ume overload in the postoperative patient; a distended expansion may be needed to restore organ perfusion bladder, disturbed sleep, or arthritic pain in the nurs- and prevent an abrupt fall in BP when antihyperten- ing home patient). Only if the BP remains above sives are given (Varon, 2008) 180/110 mm Hg after 15 to 30 minutes may there be Chap08.indd 283 8/28/2009 1:02:48 PM
284 Kaplan’s Clinical Hypertension a need for additional antihypertensive therapy but there is no place for such short-acting formulations in not for rapid and precipitous reduction of BP as the chronic treatment of hypertension, but if the BP induced by sublingual nifedipine. If such rises in BP needs to be lowered over a few hours, short-acting are frequent, appropriate increases in long-term nifedipine is an acceptable choice. Other slower and, therapy may be indicated. therefore, possibly safer oral CCB formulations such as short-acting diltiazem, felodipine, or verapamil can be used (Shayne & Pitts, 2003). Choice of Oral Agents Virtually, every available antihypertensive drug with a Captopril fairly short onset of action has been shown to be Captopril is the fastest acting of the oral ACEIs now effective in patients with uncontrolled, severe hyper- available, and it can also be used sublingually in tension. None is clearly better than the rest, and a patients who cannot swallow (Angeli et al., 1991). As combination will often be needed for long-term con- noted earlier in this chapter, an ACEI may be particu- trol. Those most widely used are listed in Table 8-6; larly attractive because it shifts the entire curve of cere- complete information about them is provided in bral autoregulation to the left, so CBF should be well Chapter 7. maintained as the systemic BP falls (Barry, 1989). Abrupt and marked ﬁrst-dose hypotension after Nifedipine an ACEI has been rarely observed, usually in patients The rapidly acting formulation of the CCB nife- with an activated renin-angiotensin system (Postma dipine has been widely used for the treatment of et al., 1992). Caution is advised in patients who have hypertensive urgencies (Grossman et al., 1996). Liq- signiﬁcant renal insufﬁciency or who are volume uid nifedipine in a capsule will usually lower BP after depleted. Despite the small potential for hypoten- a single 5- or 10-mg oral dose (Maharaj & van der sion, oral captopril may be the safest of nonparenteral Byl, 1992). The drug is effective even more quickly agents for urgent hypertension. when the capsule is chewed and the contents are swal- lowed than when it is squirted under the tongue (van Clonidine Harten et al., 1987). Clonidine, a central a-agonist, has been widely used As might be expected with any drug that induces in repeated hourly doses to reduce very high BP safely such a signiﬁcant and rapid fall in BP, with no way to and effectively (Jaker et al., 1989). Signiﬁcant seda- titrate or overcome the response, occasional symp- tion is the major side effect that contraindicates its tomatic hypotension can occur, resulting in severe use in patients with central nervous system involve- cerebral or cardiac ischemia (Grossman et al., 1996). ment. Because it has a greater proclivity than other Grossman et al. (1996) therefore recommended that drugs to cause rebound hypertension if it is suddenly the use of short-acting nifedipine be abandoned. discontinued, it should not be used by patients who However, if taken in the unbroken capsule, it seems have demonstrated poor compliance with therapy. no more likely to cause a precipitous fall in BP than Despite its past popularity, clonidine seems to be a other short-acting agents (e.g., captopril). Certainly, most unattractive drug for such patients. TABLE 8.6 Oral Drugs for Hypertensive Urgencies Drug Class Dose Onset Duration (h) Captopril Angiotensin-converting 6.5–50.0 mg 15 min 4–6 enzyme inhibitor Clonidine Central a-agonist 0.2 mg initially, then 0.1 mg/h, 0.5–2.0 h 6–8 up to 0.8 mg total Furosemide Diuretic 20–40 mg 0.5–1.0 h 6–8 Labetalol a- and b-Blocker 100–200 mg 0.5–2.0 h 8–12 Nifedipine Calcium channel blocker 5–10 mg 5–15 min 3–5 Propranolol b-Blocker 20–40 mg 15–30 min 3–6 Chap08.indd 284 8/28/2009 1:02:48 PM
Chapter 8 • Hypertensive Crises 285 Labetalol should probably be given. The 180/115 mm Hg level The a- and b-blocker labetalol has been given in hourly is chosen with no basis for deciding that this is the oral doses ranging from 100 to 200 mg. It has reduced “critical” level, but because it is the level used by neu- elevated pressures as effectively as repeated doses of oral rologist to preclude thrombolysis for acute ischemic nifedipine; it works somewhat more slowly and, perhaps, stroke, as valid a reason as any. more safely (McDonald et al., 1993). Thereafter, enough medication should be sup- plied to cover the time until appropriate follow-up Diuretics can be obtained in a primary care facility. This will, at Diuretics, speciﬁcally furosemide or bumetanide, the least, relieve the ED physician from concern over often are needed in patients with hypertensive urgen- not taking some action, as if such action could be cies, both to lower the BP by getting rid of excess lifesaving. However, as the American College of volume and to prevent the loss of potency from non- Emergency Physician Clinical Policy (Decker et al., diuretic antihypertensives because of their tendency 2006) states, “we could ﬁnd no evidence demonstrat- to cause ﬂuid retention as they lower BP. However, ing improved patient outcomes or decreased mortal- volume depletion may be overdone, particularly in ity or morbidity with acute management of elevated patients who start off with a shrunken ﬂuid volume. blood pressure in the ED.” Their policy statement Thereby, renin secretion may be further increased, concludes with these three recommendations: producing more intensive vasoconstriction and wors- 1. Initiating treatment for asymptomatic hyperten- ening the hypertension. sion in the ED is not necessary when patients have follow-up. Management After Acute Therapy 2. Rapidly lowering blood pressure in asymptomatic patients in the ED is unnecessary and may be After the patient is out of danger, a careful search harmful to some patient. should continue for possible identiﬁable causes, as 3. When ED treatment for asymptomatic hyperten- delineated earlier in the section “Evaluation” in this sion in initiated, blood pressure management chapter. Identiﬁable causes, in particular renovascular should attempt to gradually lower blood pressure hypertension, are much more likely in patients with and should not expect to be normalized during the severe hypertension. initial ED visit. After control of the acute presentation, most patients will likely require multiple drug therapy and We will now leave the realm of primary chronic treatment should likely begin with a diuretic hypertension and examine the various identiﬁable and an appropriate second agent. The guidelines (secondary) forms of hypertension, starting with the delineated in Chapter 7 should be followed to ensure most common: renal parenchymal disease. adherence to effective therapy. REFERENCES UNCONTROLLED SEVERE HYPERTENSION Adams HP Jr, del ZG, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: A guideline from the Most patients who are diagnosed and treated as a American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology hypertensive urgency are not in the immediate dan- and Intervention Council, and the Atherosclerotic Peripheral ger of uncontrolled hypertension that this diagnosis Vascular Disease and Quality of Care Outcomes in Research connotes. Many such patients have come to an emer- Interdisciplinary Working Groups: The American Academy of Neurology afﬁrms the value of this guideline as an educational gency department (ED) for unrelated acute problems, tool for neurologists. Circulation 2007;115: e478–e534. but whose BP is elevated in response to pain, anxiety, Ahmed MEK, Walker JM, Beevers DG, et al. Lack of difference or an understandable white-coat effect from being in between malignant and accelerated hypertension. Br Med J 1986;292:235–237. an inhospitable surrounding. Angeli P, Chiesa M, Caregaro L, et al. Comparison of sublingual If there is no evidence of trouble from the ele- captopril and nifedipine in immediate treatment of hyperten- vated BP, additional readings should be obtained after sive emergencies. A randomized, single-blind clinical trial. Arch Intern Med 1991;151:678–682. the pain or anxiety is alleviated. If the BP remains Barry DI. Cerebrovascular aspects of antihypertensive treatment. above 180/115 mm Hg, an oral antihypertensive drug Am J Cardiol 1989;63:14C–18C. Chap08.indd 285 8/28/2009 1:02:48 PM
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Chapter 8 • Hypertensive Crises 287 Rehman F, Mansoor GA, White WB. “Inappropriate” physician Trivelli A, Ghiggeri GM, Canepa A, et al. Hyponatremic- habits in prescribing oral nifedipine capsules in hospitalized hypertensive syndrome with extensive and reversible renal patients. Am J Hypertens 1996;9:1035–1039. defects. Pediatr Nephrol 2005;20:101–104. Schmidt B, Czosnyka M, Raabe A, et al. Adaptive noninvasive Tuor UI. Acute hypertension and sympathetic stimulation: Local assessment of intracranial pressure and cerebral autoregulation. heterogeneous changes in cerebral blood ﬂow. Am J Physiol Stroke 2003;34:84–89. 1992;263:H511–H518. Schulz V. Clinical pharmacokinetics of nitroprusside, cyanide, thio- van den Born BJ, van der Hoeven NV, Groot E, et al. Associa- sulphate and thiocyanate. Clin Pharmacokinet 1984;9:239–251. tion between thrombotic microangiopathy and reduced Shapiro LM, Beevers DG. Malignant hypertension: Cardiac struc- ADAMTS13 activity in malignant hypertension. Hypertension ture and function at presentation and during therapy. Br Heart J 2008;51:862–866. 1983;49:477–484. van den Born BJH, Honnebier UPF, Koopmans RP, et al. Microan- Shayne PH, Pitts SR. Severely increased blood pressure in the giographic hemolysis and renal failure in malignant hyperten- emergency department. Ann Emerg Med 2003;41:513–529. sion. Hypertension 2005;45:246–251. Smulders YM, Verhagen DW. Giant cell arteritis causing aortic van Harten J, Burggraaf K, Danhof M, et al. Negligible sublingual dissection and acute hypertension. Br Med J 2008;337:a426. absorption of nifedipine. Lancet 1987;2:1363–1365. Strandgaard S, Olesen J, Skinhøj E, et al. Autoregulation of brain Varon J. Treatment of acute severe hypertension: current and newer circulation in severe arterial hypertension. Br Med J 1973;1: agents. Drugs 2008;68:283–297. 507–510. Vaughan CJ, Delanty N. Hypertensive emergencies. Lancet 2000; Strandgaard S, Paulson OB. Cerebral blood ﬂow and its pathophys- 356:411–417. iology in hypertension. Am J Hypertens 1989;2:486–492. Webster J, Petrie JC, Jeffers TA, et al. Accelerated hypertension— Strandgaard S, Paulson OB. Antihypertensive drugs and cerebral patterns of mortality and clinical factors affecting outcome in circulation. Eur J Clin Invest 1996;26:625–630. treated patients. Q JM 1993;86:485–493. Suzuki H, Asano K, Eiro M, et al. Recovery from renal failure in malignant hypertension associated with primary aldoster- onism: Effect of an ACE inhibitor. Q JM 2002;95:128–130. Chap08.indd 287 8/28/2009 1:02:48 PM
CHAPTER 9 Renal Parenchymal Hypertension enal parenchymal diseases are the most factor, obesity-induced diabetes. Between them, they R common secondary or reversible cause of hypertension and their incidence will con- represent by far the most common risk factors across the entire spectrum of renal disease (Whaley-Connell tinue to increase as the population grows older and et al., 2008) (Fig. 9-1). In addition, low hemoglobin, fatter (Bakris & Ritz, 2009). Before covering them, higher serum uric acid, history of nocturia, and ﬁnally speciﬁcally, and in reverse order, from acute to the history of kidney disease are independent risk fac- chronic to transplant, some general issues about their tors for ESRD (Hsu et al., 2009). overall signiﬁcance deserve mention. As the incidence of both hypertension and obesity- Those who desire more information on all issues induced diabetes is growing rapidly, the burden of relating to kidney disease should peruse the KDOQI CKD promises to expand even beyond its currently Clinical Practice Guidelines published in the Ameri- bloated share of health care resources. Moreover, as can Journal of Kidney Diseases. The guidelines on RRT keeps many ESRD patients alive longer, they end diabetes and chronic kidney disease (CKD) (KDOQI, up as major contributors to cardiovascular disease, 2007) cover areas that go beyond the focus of this both heart attacks and stroke (McCullough et al., chapter on hypertension in both acute and CKD. 2008). Some speciﬁc data about the overall situation: The web site of U.S. Renal Data System provides • As noted in early 2008 (MMWR, 2008a): yearly statistics on CKD and end-stage renal disease (ESRD). The British National Institute for Clinical Thirteen percent of U.S. adults (i.e., 26 million adults) Excellence (NICE) has also recently published guide- were estimated to have chronic kidney disease in 2000, lines for the identiﬁcation and management of CKD and most of these adults were not aware of their condi- (Crowe et al., 2008). tion (Coresh et al., 2007).… In 2005, approximately CKD is one of the many factors that can lead to 100,000 persons began treatment for ESRD in the United States, nearly half a million persons were living resistant hypertension. The approach that should be on chronic dialysis or with a kidney transplant, and taken to elucidate the causes and improve the man- total Medicare expenditures for ESRD reached approxi- agement of resistant hypertension is covered in mately $20 billion, accounting for 6.4% of the total Chapter 7. Additional information directed to CKD Medicare budget (U.S. Renal Data System, 2007). Of and resistant hypertension is provided in the Core the new cases of ESRD in 2005, 71% had diabetes or Curriculum in Nephrology (Parker, 2008). hypertension listed as the primary cause. By 2020, with the aging of the population and the increasing prevalence of diabetes, nearly 150,000 per- sons in the U.S. are projected to begin therapy for THE SCOPE OF THE PROBLEM ESRD, nearly 800,000 will be living on chronic dialysis or with a kidney transplant, and costs for ESRD are One of the major crises facing health care in the projected to reach $54 billion. United States and all developed societies is the need to provide renal replacement therapy (RRT) to the • The overall prevalence of CKD has risen from 10% of rapidly growing number of people with kidney dam- the adult population in 1988 to 13% in 2004 and has age that progresses into ESRD. Hypertension is reached 38% of people over the age of 70 years (Coresh responsible for much of this progressive damage, et al., 2008). The deﬁnition and clariﬁcation of CKD playing a major role as well in the other major risk used in these surveys include both microalbuminuria 288 Chap09.indd 288 8/28/2009 7:13:34 PM
Chapter 9 • Renal Parenchymal Hypertension 289 100 Obesity DM HTN 75 CVD Percentage 50 25 0 Stage 1 Stage 2 Stage 3 Stage 4 Stage 5 FIGURE 9-1 The prevalence of four risk factors (obesity, diabetes, hypertension, and cardiovascular disease) in patients screened in the Kidney Early Evaluation Program, grouped by the stage of chronic renal disease. (Reproduced from Whaley- Connell AT, Sowers JR, Stevens LA, et al. CKD in the United States: Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) 1999–2004. Am J Kidney Dis 2008;51:S13–S20.) (more than 30 mg/g creatinine) and an estimated stage 3, 38% with stage 4, and 47% with stage 5 glomerular ﬁltration rate (eGFR) below 60 mL per (Saab et al., 2008). minute per 1.73 m2 (Table 9-1). These increases from • Most major trials on treatment of either hyperten- 1988 to 2004 pertain to both the milder stages, i.e., sion or cardiovascular disease either exclude patients 1 and 2, and the more serious stages, 3 and 4, of CKD. with CKD or provide little data on their course Similar, or even higher, prevalences have been found in (Coca et al., 2006). other developed societies (Tsukamoto, 2008; Wen et al., 2008). As developing countries become more developed, their burden will also grow: by 2030, it is estimated that 70% of ESRD will be among their resi- TABLE 9.1 Classiﬁcation of Chronic dents, while they possess only 15% of the world econ- Kidney Disease omy (Barsoum, 2006). Albuminuria • At least in the United States and Japan, the increas- (calculated ing incidence of new ESRD has slowed, but the GFR (estimated from urine number of patients receiving RRT continues to rise from MDRD albumin/ rapidly (U.S. Renal Data System, 2008). This likely equation in creatinine Percent reﬂects two opposing forces: the adequate treatment mL/min/1.73 m2) rate in mg/g) of CKD of more (though still only a fraction) of susceptible Stage 1 >90 >30 20 patients before they progress into ESRD versus the Stage 2 60–89 >30 27 continually expanding population whom nephrolo- Stage 3 30–59 — 50 gists are willing to enter into chronic dialysis. Stage 4 25–29 — (4 and 5) 3 • Most patients in the United States with CKD are Stage 5
290 Kaplan’s Clinical Hypertension Although some argue that this scenario does not unwilling to pay hundreds to prevent their reﬂect an epidemic of CKD (Glassock & Winearls, progression into ESRD. The waste, in both money 2008), even they would agree that it is “endemic at a and suffering inherent in the U.S. system, is seen relatively constant and unacceptably high prevalence” when our data are compared to countries with uni- (Coresh et al., 2008). versal access to care: Norway has the same prevalence of CKD as the United States, but the rate of progres- sion from stage 3 to stage 4 and to ESRD is threefold The Role of Hypertension higher in the United States (Hallan et al., 2006). Hypertension is second only to diabetes as the pri- To the credit of nephrologists and their profes- mary cause of ESRD. Unfortunately, few CKD sional organizations, the inequities of current care for patients have their blood pressure (BP) adequately CKD have been recognized and attempts are being controlled to 130/80 mm Hg or lower: only 13.2% of made to rectify them (DuBose, 2007; Jurkovitz et al., over 10,000 people screened in the Kidney Early 2008; Vassalotti et al., 2007). Evaluation Program, although 80% of these partici- pants were aware of their hypertension and 70% were being given antihypertensive medication (Saraﬁdis Practical Solutions et al., 2008a). Those who were poorly controlled As societal changes are being sought, two simple more likely had elevated systolic pressure and were changes in current practices need implementation: more likely elderly, obese, black, and male. First, increase the performance of spot urine These data are likely related to two factors. First, testing for albuminuria and estimated glomerular ﬁl- since RRT for ESRD is totally compensated by tration rate (eGFR) from a serum creatinine (Lee et al., Medicare, black men have unrestricted access to 2009). Now fewer than 20% of primary care practitio- RRT (Duru et al., 2008) and actually do better than ners obtain these tests, even on elderly patients with Caucasian men when they start dialysis (Norris et al., diabetes (Minutolo et al., 2008) and only 38% of U.S. 2008). On the other hand, black men are much less clinical labs report eGFR when they measure serum likely to receive medical care that could prevent their creatinine (Accetta et al., 2008). progressing into ESRD (Duru et al., 2008). This Second, encourage primary caregivers to treat obviously reﬂects the absence of a rational health those with stage 1 or 2 disease more intensely. There care system in the United States (Wesson, 2008). are not enough nephrologists to care even for those Unfortunately, black men in particular, and poor with stage 3 disease, which is the level of CKD that is people in general, will continue to suffer the conse- now the criterion for referral to a nephrologist. quences of a skewed health care delivery system will- Table 9-2 provides a nine-item list for prevention of ing to pay millions to keep ESRD patients alive but the progression of kidney damage (Graves, 2008). TABLE 9.2 Measures to Prevent Progression of Kidney Disease 1. Control hypertension to a level < 130/80 mm Hg 2. Control diabetes to a hemoglobin A1c level < 7.0 3. Control lipid levels to an LDL-C level < 100 mg/dL 4. Use antiproteinuric antihypertensive agents: Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone inhibitors, diltiazem 5. Avoid NSAIDs 6. Recommend dietary modiﬁcation: Low fat, low salt, fewer calories if overweight 7. Avoid radio-contrast radiographic tests and premedicate the patient if required 8. Advise patients to discuss their condition with any physician who intends to prescribe a new medication 9. Encourage regular visits to a nephrologist (every 6–12 months) SI conversion factor: To convert LDL-C values to mmol/L, multiply by 0.0259. LDL-C, low-density lipoprotein cholesterol; NSAIDs, nonsteroidal anti-inﬂammatory drug. Modiﬁed from Graves JW. Diagnosis and management of chronic kidney disease. Mayo Clin Proc 2008;83:1064–1069. Chap09.indd 290 8/28/2009 7:13:34 PM
Chapter 9 • Renal Parenchymal Hypertension 291 We will now examine the speciﬁc varieties of renal The reported mortality rate for those who develop disease and how they relate to hypertension, starting AKI varies from 36% to 71%. Among survivors, from acute renal insults and progressing eventually to those over age 65 have less recovery of kidney func- posttransplantation. Renovascular hypertension is cov- tion (Schmitt et al., 2008). ered in the next chapter. It should always be kept in mind as a potentially curable form of CKD. Gadolinium and Nephrogenic Systemic Fibrosis Contrast agents have long been known to reduce renal function (Weisbord et al., 2008), but a more ACUTE KIDNEY DISEASE speciﬁc syndrome—nephrogenic systemic ﬁbrosis— A rapid decline in renal function may appear from has recently been identiﬁed as a serious consequence various causes: prerenal (e.g., volume depletion), of the use of gadolinium as contrast for magnetic intrinsic (e.g., glomerulonephritis), or postrenal (e.g., resonance imaging (MRI) in patients with preexisting obstructive uropathy). Nonsteroidal anti-inﬂamma- ESRD (Kallen et al., 2008). tory drugs (NSAIDs) are among the most common causes of acute renal failure, particularly in patients whose already reduced renal perfusion depends on Recognition of AKI prostaglandin-mediated vasodilation. Hypertension is The need for an early recognition of AKI is obvious, rarely a problem because most of these patients are since immediate correction of causative factors is crit- also volume contracted from prior therapy with ical for survival. Among many markers that have been diuretics and ACEI or ARB therapy (Braden et al., proposed, the plasma and urine measurements of 2004). However, hypertension is frequent in most neutrophil gelatinase-associated lipocalin (NGAL) intrinsic and postrenal conditions. are the most promising. NGAL is one of the most rapidly induced proteins in the kidney after acute injury (Mishra et al., 2003) and it can easily be mea- Acute Kidney Injury sured in one drop of blood or 0.2 mL of urine A striking increase in hospitalizations for acute kidney (Devarajan, 2008). In a prospective cohort study of injury (AKI) has been recorded in the U.S. National 635 patients with suspected AKI, the urinary NGAL Hospital Discharge Survey (MMWR, 2008b). In provided a 90% sensitivity and a 99.5% speciﬁcity, 2004, there were 221,000 hospitalizations for AKI ver- superior to other markers and highly predictive of sus 19,000 for CKD, a reversal from 1980 when there clinical outcomes (Nickolas et al., 2008). was a ﬁvefold greater rate for CKD than for AKI. Hypotension, rather than hypertension, is fre- AKI is deﬁned differently in different studies quent in many AKI patients because vasodilation and (Zappitelli et al., 2008). Perhaps the best is the RIFLE volume depletion may occur at the onset of the injury. classiﬁcation, which provides a gradation of severity, If hypertension supervenes, it often reﬂects iatrogenic starting with stage 1 or “risk” as oliguria for more volume overload in an attempt to increase renal per- than 6 hours or an increase in serum creatinine of fusion. Renin released from hypoperfused kidneys more than 50% and proceeding to stage 2 as “injury” may also be involved. and stage 3 as “failure” with greater disease severity (Kellum et al., 2008). Acute Glomerulonephritis Waikar et al. (2008), in their review of AKI, list The classic presentation of acute glomerulonephritis is these as the most common precipitations, all more common in the elderly, the diabetic, and those with a child with recent streptococcal pharyngitis or impe- preexisting CKD (Hsu et al., 2008): tigo who suddenly passes dark urine and develops facial edema. The renal injury represents the trapping of • Sepsis antibody-antigen complexes within the glomerular • Coronary interventions: catheterization, angioplasty, capillaries. Although the syndrome has become less and bypass surgery common, it still occurs, sometimes in adults past mid- • Aortic aneurysm repair dle age. Typically, in the acute phase, patients are hyper- • Intravenous contrast for radiologic examinations tensive, and there is a close temporal relation between • Nephrotoxic antibiotics oliguria, edema, and hypertension. On occasion, Chap09.indd 291 8/28/2009 7:13:35 PM
292 Kaplan’s Clinical Hypertension hypertension of a severe, even malignant, nature may Other Causes of Acute Renal Disease be the overriding feature. Other causes of acute renal disease with hypertension The hypertension should be treated by salt and include: water restriction and, in mild cases, diuretics and other oral antihypertensives. In keeping with an • Bilateral renal artery occlusion, either by emboli or apparent role of renin, ACEI and ARB therapies have thromboses (Svarstad et al., 2005). been effective (Catapano et al., 2008). In the classic • Removal of angiotensin II support of blood ﬂow disease, the patient is free of edema and hypertension with ACEI or ARB therapy in the presence of bilat- within days, of proteinuria within weeks, and of eral renal artery disease (Saﬁan & Textor, 2001). hematuria within months. Hypertension was found • Trauma to the kidney (Watts & Hoffbrand, 1987). in only three of 88 children followed up for 10 to • Cholesterol emboli, which may shower the kidney 17 years (Popovic-Rolovic et al., 1991). after radiologic or surgical procedures, producing More common than poststreptococcal glomeru- rapidly worsening renal function and hypertension lonephritis are a variety of primary renal diseases (e.g., (Vidt, 1997). IgA nephropathy) and systemic diseases (e.g., sys- • Extracorporeal shock wave lithotripsy for kidney temic lupus erythematosus), which may present with stones is only rarely followed by rises in BP (Eassa acute renal crises marked by hypertension (Haas et al., 2008). et al., 2008). The hypertension may be effectively treated with an ACEI, with or without an ARB (Catapano et al., 2008). Renal Donors Various viral infections may precipitate renal damage, more likely chronic than acute (Berns & Removal of half of a living donor’s renal mass could Bloom, 2008). HIV-infected patients may have be looked upon as an acute injury, but in normal only microalbuminuria (Baekken et al., 2008) or humans, the removal of a kidney does not usually severe antiglomerular basement membrane disease result in hypertension, likely because of downward (Wechsler et al., 2008), manifested by heavy protei- adjustments in glomerular hemodynamics to main- nuria (Rhee et al., 2008) or malignant hypertension tain normal ﬂuid volume (Guidi et al., 2001). How- (Morales et al., 2008). ever, the possibility of subsequent damage to the remaining kidney has been raised, since the removal of one kidney could lead to hyperperfusion and pro- Urinary Tract Obstruction and Reﬂux gressive glomerulosclerosis in the other. Vesicoureteric reﬂux is seen in 1% to 2% of other- In a meta-analysis of 48 studies with 5,145 donors wise normal children and can lead to hypertension, whose average age at donation was 41 years and whose renal scarring, and ESRD (Gargollo & Diamond, BP averaged 121/77, follow-up for at least 5 years 2007). Among 157 hypertensives in India over the revealed a 6/4 mm Hg increase in BP (Boudville et al., age of 18 years, vesicoureteral reﬂux was found in 30 2006). However, at a mean follow-up of 12.2 years, (19.1%) without overt evidence of renal parenchy- the survival and incidence of ESRD were similar in mal damage (Barai et al., 2004). 255 donors compared to those in the general popula- Hypertension may develop after unilateral (Shin tion (Ibrahim et al., 2009). et al., 2008) or bilateral (Kiryluk et al., 2008) obstruction to the urinary tract. Unilateral hydro- nephrotic mice have enhanced reactivity of afferent CHRONIC KIDNEY DISEASE arterioles in both kidneys accompanied by reduced NO availability (Carlstrom et al., 2008). In most Of the various discernable primary causes of ESRD patients, the hypertension is fairly mild, but signiﬁ- among patients starting dialysis in the United States, cant hypertension and severe renal insufﬁciency may diabetic nephropathy is the most common, com- occur with hydronephrosis from prostatic obstruc- prising about 40%, followed by vascular diseases, tion (Sacks et al., 1989). Catheter drainage of the including hypertensive nephrosclerosis (20%), pri- residual urine may lead to rapid resolution of the mary glomerular disease (18%), tubulointerstitial hypertension and circulatory overload (Ghose & diseases (7%), and cystic diseases (5%) (Whaley- Harindra, 1989). Connell et al., 2008). Chap09.indd 292 8/28/2009 7:13:35 PM
Chapter 9 • Renal Parenchymal Hypertension 293 There are some differences in the prevalence of observed slowing of the progression of established hypertension and the responses to antihypertensive CKD as initially elevated BPs are lowered. This therapy among these various causes of kidney disease: was demonstrated ﬁrst for patients with diabetic chronic pyelonephritis may be less commonly associ- nephropathy (Mogensen, 1976) and subsequently for ated with hypertension (Goodship et al., 2000); those with other causes of CKD, as in the Modiﬁca- polycystic diseases may be more commonly associ- tion of Diet in Renal Disease Study (MDRD) (Lazarus ated (Grantham, 2008), even before signiﬁcant renal et al., 1997). In the MDRD trial, 585 patients with a dysfunction develops (Reed et al., 2008). Patients GFR between 25 and 55 mL per minute and with these various causes of CKD may start at either 255 patients with a GFR between 13 and 24 mL per end of the spectrum: hypertension without overt minute were studied. Among those with proteinuria renal damage on the one end and severe renal insuf- of more than 1 g per day at baseline, the rate of decline ﬁciency without hypertension on the other. Eventu- in GFR was signiﬁcantly less over a mean follow-up ally, however, both groups move toward the middle— of 2.2 years in both the groups whose BPs remained renal insufﬁciency with hypertension—so that an average of 5 mm Hg lower as a result of more hypertension is found in approximately 85% of intensive therapy. patients with CKD of diverse causes (Saraﬁdis et al., Along with their higher prevalence of hyperten- 2008a) and is closely related to the progression of sion, African Americans have an increased suscepti- nephropathy. Renal insufﬁciency as a consequence of bility to CKD and ESRD. Non-diabetic CKD in primary hypertension is described in Chapter 4 with African Americans has been attributed to “hyper- coverage of the recently published data incriminating tensive neprosclerosis,” i.e. hypertension causing genetic polymorphism, at least in Blacks and nondia- CKD. The diagnosis is usaually made by exclusion betics, and not preexisting hypertension as the cause with non-speciﬁc focal segmental glomerulosclero- of the focal segmental glomerulosclerosis underlying sis (FSGS) on biopsy. what has been called “hypertensive nephrosclerosis” Two studies in the October 2008 issue of Nature (Freedman & Sedor, 2008). Genetics report a genetic locus, MYH9, that explains This section examines the development of hyper- much of the increased risk of FSGS in African Amer- tension as a secondary process in the presence of pri- icans (Kao et al., 2008; Kopp et al., 2009). mary renal disease or diabetes. The special features of In patients with CKD, ambulatory BP moni- diabetic nephropathy are covered separately, but most toring, which often identiﬁes a loss of nocturnal dip- cases of CKD are similar in their course and treat- ping, is better than ofﬁce readings in predicting ment. Moreover, almost half of patients clinically progression of renal damage and mortality (Pogue deﬁned as having diabetic nephropathy have been et al., 2009). Nondipping in CKD has been attrib- shown to actually have nondiabetic renal disease by uted to a compensation for diminished natriuresis kidney biopsy (Zhou J et al., 2008). during the daytime and to enhanced pressure- Patients whose underlying problem is bilateral natriuresis during the night (Kimura, 2008). Out- renovascular disease may present with refractory of-ofﬁce BP measurements in patients with CKD are hypertension and renal insufﬁciency (Guo et al., also critical to identify the considerable proportion 2007). The recognition of the renovascular etiology with white-coat hypertension, 32% in one series of these patients’ condition is critical because revascu- (Minutolo et al., 2007a), to avoid unnecessary and larization may relieve their hypertension and improve potentially harmful overtreatment. their renal function. More about this important group of patients with ischemic nephropathy is provided in the next chapter, as well as hypertension associated Mechanisms with renal tumors. Hypertension develops and progresses in patients with renal diseases for multiple reasons (Table 9-3). Most of these funnel into a common path: Impaired The Role of Hypertension renal autoregulation that normally attenuates Hypertension accelerates the progression of renal the transmission of elevated systemic pressure to damage, regardless of the cause. Perhaps the best evi- the glomeruli, resulting in high perfusion pressure dence for this tight relationship is the repeatedly (Mori et al., 2008). The resultant glomerular Chap09.indd 293 8/28/2009 7:13:35 PM