AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

According to the 2003 US Renal Data System (USRDS), hypertensive nephrosclerosis (HN) accounts for at least 26 % of patients reaching end-stage renal disease (ESRD) each year in the United States. HN is the second most common cause of ESRD in white people (24%) and is the leading cause of ESRD in black people (33%).

The term HN has traditionally been used to describe a clinical syndrome characterized by long-term essential hypertension, hypertensive retinopathy, left ventricular hypertrophy, minimal proteinuria, and progressive renal insufficiency. Most cases are diagnosed based solely on clinical findings. In fact, most of the literature dedicated to HN is based on the assumption that progressive renal failure in a patient with long-standing hypertension, moderate proteinuria, and no evidence suggesting an alternative diagnosis characterizes HN. The lack of firm criteria on which to base a histologic diagnosis and the lack of a clear demonstration that hypertension initiates the development of renal failure likely indicate that the true prevalence of HN has been overestimated.

As reported by Zuccalà and Zucchelli (1996), part of the confusion in the classification of HN stems from the use of the word nephrosclerosis. Coined almost a century ago by Theodor Fahr, nephrosclerosis simply means hardening of the kidney. In the United States and Europe, the terms HN, benign nephrosclerosis, and nephroangiosclerosis are commonly used to describe the same clinical condition. These terms refer more to the pathologic changes attributed to the effects of hypertension than to the clinical picture of the disease in question. Unfortunately, the pathologic changes are not specific to hypertensive renal injury; they are also observed in kidney biopsy specimens of patients who are normotensive, particularly those of advanced age or with diabetes.

Unlike morbidity and mortality of stroke and coronary disease, incident cases of ESRD attributed to hypertension continue to increase. Some authors suggest that many of these cases are more likely related to other factors, including small vessel injury related to aging, diabetes, or obesity-related kidney injury.

A couple of important points have been made in recent studies. First, among an unselected sample of community-based participants in the Framingham Heart Study, the combination of hypertension and a mild reduction in the glomerular filtration rate (GFR) was found to be an important risk factor for the development of new-onset kidney disease. Other factors noted were diabetes, obesity, smoking, and a low high-density lipoprotein cholesterol level. Second, systolic blood pressure (BP) is a strong, independent predictor of a decline in kidney function among older persons with isolated systolic hypertension. This is a significant finding because most cases of uncontrolled hypertension in the United States are due to systolic hypertension among older adults.

Most patients reaching ESRD from any cause are hypertensive, with nephrosclerosis being the classic finding in end-stage kidneys. Regardless of the etiology, once hypertension develops, a cycle of renal injury, nephrosclerosis, worsening of hypertension, and further renal injury is established. As a result, in a patient presenting with ESRD, determining whether nephrosclerosis is the cause or the consequence of chronic renal injury may be difficult.

Pathophysiology

Two pathophysiologic mechanisms have been proposed for the development of HN. One mechanism suggests that glomerular ischemia causes HN. This occurs as a consequence of chronic hypertension resulting in narrowing of preglomerular arteries and arterioles, with a consequent reduction in glomerular blood flow. Alternatively, glomerulosclerosis occurs because of glomerular hypertension and glomerular hyperfiltration. According to this theory, hypertension causes some glomeruli to become sclerotic. As an attempt to compensate for the loss of renal function, the remaining nephrons undergo vasodilation of the preglomerular arterioles and experience an increase in renal blood flow and glomerular filtration. The result is glomerular hypertension, glomerular hyperfiltration, and progressive glomerular sclerosis. These mechanisms are not mutually exclusive, and they may operate simultaneously in the kidney.

Furthermore, Tracy and Ishii (2000) postulate that nephrosclerosis may not be a single disease entity in the sense of responding to a single etiology such as hypertension or aging. Rather, nephrosclerosis appears to be multifactorial. It may, in part, be a consequence of fibroplasias in microscopic arteries causing ischemic damage to some nephrons; however, it also may be the end product of a mixture of converging separate pathologic conditions, ie, "second hits," of which only some are known.

Genetically mediated animal models of hypertension, including the Dahl rat and the spontaneous hypertensive rat (SHR), have been used to investigate the role of hypertension in the development of nephrosclerosis. Fundamental differences exist among the strains and between rat and human hypertension. The SHR most closely resembles human essential hypertension. The SHR becomes hypertensive without exposure to salt. Micropuncture studies in hypertensive rats demonstrate an increased preglomerular vasoconstriction that is effective in preventing the development of intraglomerular hypertension. In fact, the SHR develops little renal damage, unless uninephrectomized. In these animals, rigorous BP control does not prevent the development of proteinuria and the pathologic changes of HN. The Dahl salt-sensitive rat develops proteinuria before hypertension and before a high-sodium diet is administered. Of note, no glomerular hypertension occurs.

In patients with essential hypertension, hemodynamic studies frequently show a reduction in renal blood flow. The increased preglomerular vasoconstriction of the afferent arteriole and interlobular artery is thought, at least initially, to exert a protective effect in the glomerulus. With time, sclerosis of the preglomerular vessels causes further reduction in renal blood flow. The GFR is maintained because of increased intraglomerular pressure secondary to efferent arteriolar vasoconstriction and systemic hypertension. Eventually, glomerular ischemia and tubular ischemia develop. Considered together, these data suggest that hypertension precedes and accelerates arteriolar changes in the renal vessels.

Genetics

A genetic link for hypertension and related renal failure is supported by studies demonstrating familial clustering of HN in black people and, to the same extent, in white people. The idea of a genetic predisposition to renal injury in black people is also supported by reports of clinical trials.

In the Multiple Risk Factor Intervention Trial (MRFIT), no changes in the reciprocal creatinine slope were observed in white people, but a significant loss in kidney function was observed in black people despite similar levels of BP control. Similarly, secondary analyses from the Modification of Diet in Renal Diseases (MDRD) study demonstrated that at equivalent mean arterial pressures greater than 98 mm Hg, black patients had a reduction in their GFR at a rate of approximately 1 mL/min/y more than white patients. These observations have led to investigations into genetic factors predisposing to renal damage.

In different populations, polymorphism in the angiotensin-converting enzyme (ACE) gene, the DD genotype is associated with a higher prevalence of progressive renal disease. This genotype is more common in the black population than the white population. Black people with hypertension also have increased angiotensinogen mutations compared with white people with hypertension. Homozygous D polymorphism is associated with an enhanced pressor response to angiotensin I. In patients with immunoglobulin A nephropathy, homozygous D polymorphism appears to influence the rate of progression of renal diseases and the response to ACE inhibitors; thus, ACE polymorphism could be an important modulator for the renal response to injury and the response to treatment in persons with HN. Whether these data are also applicable to the black population remains to be determined.

Frequency

United States

Over the last 2 decades, ESRD attributed to HN has contributed significantly to the 7-11% per year increase in new patients starting dialysis in the United States. According to the 2003 USRDS, rates of ESRD caused by hypertension increased almost 50%, while the increase was 11% for glomerulonephritis and 21% for cystic kidney disease. When patients are separated according to race, hypertension is the leading cause of ESRD in black people, accounting for 34% of patients initiating dialysis during this period.

International

In Europe, according to the European Dialysis and Transplant Association registry, HN is a less common cause of ESRD, accounting for 12% of new patients starting renal replacement therapy. However, the reported prevalence varies among different countries, with France and Italy reporting HN as being responsible for ESRD in 21% and 27% of patients starting dialysis, respectively. In Asia, hypertension appears to be a relatively infrequent cause of ESRD, with both Japanese and Chinese registries reporting 6% and 7%, respectively. Establishing whether these differences are real or reflect differences in accuracy of diagnosis or criteria for diagnosis in different countries is difficult.

Mortality/Morbidity

According to the 2003 USRDS, the annual mortality rate for patients on hemodialysis in the United States is 23.3%. HN accounts for more than one third of patients on hemodialysis.

Race

Marked differences exist in the prevalence of HN among patients of different ethnic backgrounds. Although black people make up 12% of the US population, they account for 28% of the patients on renal replacement therapy. With perhaps the exception of atherosclerotic renal disease, black people are at an increased risk of renal diseases from any cause, especially HN. In black people, HN occurs earlier, is more severe, and more often causes ESRD (36.8% in black patients vs 26% in white patients).

• In persons of all age groups, ESRD is more common in black people. The increased susceptibility of black patients with hypertension to develop progressive renal failure cannot be explained solely by the higher prevalence of hypertension, severity of hypertension, or socioeconomic factors. The MRFIT indicated that effective BP control was associated with stable renal function in white people but not in black people. Socioeconomic differences alone among races do not explain the higher prevalence of HN in black people because stroke and cardiovascular mortality rates have decreased equally in both white and black populations.
• Several renal, hormonal, and physiologic differences, including increased BP sensitivity to a high-salt diet, increased renal vascular resistance, and decreased renal blood flow, are suggested as an explanation for the susceptibility of black people to HN. A decreased nephron number secondary to low birth weight, which is more common in black people, is also suggested to be a part of the increased risk for progressive renal failure in this patient population. In addition, renal angiograms of black patients with hypertension and normal renal function show increased tortuosity and occlusion in the interlobular and arcuate arteries compared with those of white patients with similar BPs and renal function.

Age

The diagnosis of HN increases with advancing age. The peak age for the development of ESRD in white patients is 65 years and older, while the peak age is 45-65 years in black people. In most cases, the diagnosis of HN in older patients is made clinically because of the reluctance to perform a renal biopsy in this elderly population. Even when a renal biopsy specimen is available, distinguishing vascular lesions due to aging from those due to hypertension may be difficult. In this respect, atheromatous renal vascular disease has been increasingly recognized as a common finding in patients older than 50 years.

• Rimmer and Gennari (1993) estimate that atheromatous renal vascular disease accounts for 5-15% of all patients who develop ESRD each year. In addition, cholesterol embolism resulting from atheromatous plaque disruption with subsequent shedding of cholesterol crystals into the renal circulation is frequently diagnosed in this patient population. Both renal artery stenosis and cholesterol embolism are associated with renal microvascular lesions and with glomerular sclerosis. Neither of these findings should be underestimated because patients older than 65 years represent at least 45% of the total population of patients on dialysis in the United States.
• Similarly, Appel et al (1995) found bilateral renal artery stenoses in 11% of patients on hemodialysis who are older than 50 years. After extrapolating their results to the total number of cases of ESRD, multiplying by the number of patients aged 50 years or older, and multiplying by the number of patients with ischemic renal disease, Appel et al concluded that more than 3500 cases of ischemic renal disease remain undiagnosed each year in the United States. If these predictions are correct, ischemic renal disease is likely the fourth most common cause of ESRD in patients older than 50 years.
• More recently, Hansen et al (2002) provided the first population-based estimate of the prevalence of renovascular disease among free-living elderly American participants of the Cardiovascular Health Study (CHS). This is a multicenter, longitudinal cohort study of cardiovascular disease risk factors, morbidity, and mortality among free-living adults older than 65 years. CHS participants numbered 870, and each underwent renal duplex sonography to assess for the presence or absence of renovascular disease, defined as greater than or equal to 60% diameter-reducing renal artery stenosis or occlusion. The results of this study show that renovascular disease is present in 6.8% of all individuals, regardless of race (6.9% of white participants and 6.7% of black participants).

CLINICAL

Section 3 of 11  

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• Clinical
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• Follow-up
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History

Patients may present with hypertension, its complications (eg, heart failure, stroke), and/or symptoms of uremia. In most patients, hypertension is present for many years (usually >10 y), with evidence of periods of accelerated or poorly controlled BP. Features suggesting the diagnosis of HN are as follows:

• Black race
• Hypertensive retinal changes
• Left ventricular hypertrophy
• Long-standing or very severe hypertension
• Proteinuria less than 0.5 g/d
• Hypertension diagnosed prior to the onset of proteinuria
• Hypertension preceding renal dysfunction
• No evidence of another renal disease
• Biopsy findings compatible with the diagnosis

Physical

Upon physical examination, evidence of hypertension-related target organ damage includes hypertensive changes in the retinal vessels and signs of left ventricular hypertrophy. Hemorrhages or exudates are characteristic of accelerated hypertension, and papilledema is a feature of malignant hypertension.

Causes

No causes for HN are known. See Pathophysiology. A gene that predisposes to hypertensive renal injury has been identified in rats. To date, however, no specific hypertensive ESRD-associated gene has been identified in humans. Correct identification of HN susceptibility genes requires accurate HN phenotyping. The major impediment to establishing a reliable HN phenotype is the absence of strong clinical criteria to distinguish HN from other renal diseases. Genetic approaches to HN require careful scrutiny of clinical diagnoses before assigning phenotypes to study subjects.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Renal atherosclerotic disease
Cholesterol microembolization
Malignant hypertension
Mildly active primary renal disease

Hypertension and atherosclerotic renal artery disease

Hypertension is frequently associated with atheromatous renal artery disease (RAS), especially in elderly patients. A recent population-based study estimated the prevalence of atherosclerotic RAS among free-living, black and white Americans older than 65 years to be approximately 7% (Hansen et al, 2002). The prevalence can increase up to 20-45% of patients older than 50 years who have had an angiography performed because of peripheral or coronary artery disease.

Approximately 2.4% of cases of ESRD in the United States are attributed primarily to vascular disease. These data, however, need to be interpreted with caution since they are subjective and the result of assigning a diagnosis without evidence of causation.

On the other hand, recent follow-up studies of patients with known RAS treated conservatively indicate that progression to renal failure is rare. Pillay et al (2002) reported on 85 subjects observed for at least 2 years and indicated that although mortality was high, both for those treated with or without renal revascularization, death was rarely directed to renovascular disease. Although progressive disease can sometimes threaten renal function and/or result in the development of accelerated hypertension, clinically progressive disease develops in 10-15% of subjects over a 5-year period. These figures are central to estimating the risks and benefits of revascularization in patients with RAS, particularly if they are asymptomatic.

The predominant clinical manifestations of atherosclerotic RAS include hypertension, renal failure (ischemic nephropathy), recurrent episodes of congestive heart failure, and flash pulmonary edema. Sudden worsening of renal function in a patient who is hypertensive and who was started on an ACE inhibitor is also suggestive of renal vascular disease.

Not all patients with RAS are hypertensive. Olin et al (2002) studied 395 consecutive patients who had undergone arteriography as part of an evaluation for aortoiliac or peripheral vascular disease and who did not have the usual clues to suggest RAS and found greater than or equal to 50% stenosis in approximately 35% of nondiabetic patients and in up to approximately 50% of diabetic patients.

Goals for identifying RAS include improving BP control and preserving renal function. The diagnosis of RAS can be established with the use of Doppler ultrasound scanning, magnetic resonance (MR) angiography using gadolinium as the contrast agent, CT angiography, or intra-arterial renal angiography. Comparative studies on patients undergoing several tests indicate that both captopril renogram and Doppler studies can fail to detect significant lesions. Both tests are less reliable than either MR angiography or CT angiography. Doppler ultrasound can be highly accurate when stenosis is present. However, Doppler ultrasound studies are highly operator dependent, and failure to locate the critical vessel segment or an adverse body habitus can easily lead one to overlook high-grade lesions leading to false-negative tests. As a result, such studies are most useful when positive.

By contrast, MR angiogram can provide excellent detail regarding location and severity of atherosclerotic vascular lesion. CT angiography can provide excellent imaging comparable with intra-arterial renal angiography but has the drawbacks of requiring iodinated contrast.

Most patients are treated medically, and they should include the use of an ACE inhibitor or ARB. Although there may be a concern that the use of these agents can result in deterioration of kidney function in patients with RAS, clinically important changes in kidney function are remarkably rare, even when these agents are applied to subjects at high risk for undetected RAS. A substudy of the Heart Outcomes Prevention Trial (HOPE) examining 980 patients with serum creatinine levels of 1.4-2.3 mg/dL demonstrated reduced combined cardiovascular endpoints in the group randomized to receive ramipril. These benefits were obtained with no excessive change in kidney function as compared with the placebo arm. Thus, the benefits of angiotensin II blockade regarding both cardiovascular outcomes and preservation of renal function favor using ACE inhibitors or ARBs despite elevated creatinine levels.

To minimize the potential hazard of these agents in patients with RAS, it is recommended that diuretic agents should be temporarily withheld on initiation of an ACEi/ARB and serum creatinine and potassium values rechecked at frequent intervals until a stable dose is achieved without a significant change in renal function. It is also important to avoid volume depletion in these patients.

When progressive hypertension, renal insufficiency, or circulatory congestion develops, renal revascularization should be considered. Renal revascularization (ie, percutaneous transluminal angioplasty/stent, surgery) may result in improvement in BP control in 50-80% of patients, but cure is unusual in patients with long-standing hypertension. Vascular intervention (percutaneous transluminal angioplasty or surgery) may also improve or stabilize renal function in selected patients. Dorros et al recently reported on a multicenter registry regarding 1058 patients subjected to angiography and stenting observed for at least 6 months. The procedure was successful in 100% of cases. The mean age was 69 years, and 59% (n=629) had preprocedure serum creatinine levels greater than or equal to 1.5 mg/dL. These data indicate that follow-up systolic blood pressure was reduced by approximately 20 mm Hg and antihypertensive requirements fell from 2.4 to 2.0 medications per patient. The overall 4-year survival was 74%.

For patients with serum creatinine levels greater than or equal to 2.0 mg/dL, survival at 4 years was less in those with bilateral disease, despite successful revascularization (55% unilateral vs 36% bilateral, p <0.05). Serum creatinine levels improved or remained unchanged in 74% and were considered worse in 27% of those with bilateral disease.

The complication rate for renal artery stenting varies considerably between centers, and complications include hematomas, retroperitoneal hemorrhage, arterial dissections, pseudoaneurysm formation, arteriovenous fistula, rupture of the renal artery, vessel occlusion, or infection. Restenosis occurs in 14-20% of cases. Treatment failures or restenosis can be treated with repeat endovascular procedures or in some cases by surgical endarterectomy. Some patients may develop contrast-induced acute renal failure and cholesterol embolism. As a result, approximately 20% of patients who undergo vascular intervention experience a worsening of renal function or develop ESRD; additionally, BP is not improved in 20-50% of patients. For some individuals, the actual risk of complications and restenosis may be higher than the true risk of clinical disease progression.

Management of renal arterial disease should be part of an integrated program of cardiovascular risk reduction, including blood pressure and lipid control, in addition to withdrawal of smoking. Patients with worsening hypertension, declining renal function, or history "flush" pulmonary edema unexplained by cardiac function alone warrant further diagnostic studies and intervention. Whether renal revascularization changes the natural history and mortality of patients with RAS is not clear. To date, no randomized trial has shown a survival benefit for either endovascular or surgical revascularization compared with medical management in patients with RAS. It should be recognized that prospective interventions trials typically exclude those patients at higher risk and those with evident disease progression. Those patients with rapid loss of renal function are most likely to benefit from renal revascularization.

Recognizing RAS and identifying patients who will benefit from revascularization remains a significant challenge for clinicians. For a review on this subject, see the 2003 article by S.C. Textor.

Cholesterol microembolization

Besides renal artery stenosis, cholesterol microembolization can also mimic HN. Cholesterol embolization is frequently found at autopsy in white patients older than 50 years, at a rate varying from 4.7-17.7%. This condition is also observed in black patients; it was present in 2 of 39 patients in the African American Study of Kidney Disease and Hypertension (AASK). Making the diagnosis is not difficult when patients present acutely following an angiographic procedure, transluminal angioplasty, or anticoagulant treatment or as a complication of vascular surgery. However, in many cases, the disease is chronic, patients are relatively asymptomatic, and, presumably, the disease is the result of a spontaneous renal cholesterol embolism. These patients may present with nephrotic-range proteinuria. Renal biopsy specimens show classic needle-shaped crystals in the glomeruli or renal arteries.

Malignant hypertension

Malignant hypertension is relatively uncommon, occurring in approximately 1% of patients with hypertension. Men are more frequently affected than women, and the patients' ages range from infants to the elderly. It may occur in patients with preexisting hypertension or in a previously normotensive patient. The incidence of malignant hypertension has been decreasing in Caucasians and may be related to improvement in BP control with antihypertensive medications and better understanding of the need for treatment. The incidence remains higher in African American and Asian patients.

The clinical presentation reflects the deleterious effects of high BP on target organs. Systolic BP can range from 150-290 mm Hg while diastolic BP can vary from 100-180 mm Hg. Keith-Wagener grade III (hemorrhages and exudates) and grade IV retinal changes (papilledema) are the hallmarks of malignant hypertension. Acute heart failure and pulmonary edema can be the presenting signs in approximately 10% of patients. Left ventricular hypertrophy is present in as many as 75% of patients at presentation.

At presentation, greater than 60% of patients complain of headaches with a cerebrovascular event (eg, focal cerebral ischemia, cerebral/subarachnoid hemorrhage) occurring in close to 5-10% of patients. True hypertensive encephalopathy is characterized by headache, nausea, vomiting, and visual blurring, together with impaired cognitive function, generalized seizures, or cortical blindness. Renal involvement is common, but the degree of severity varies. Proteinuria is common, but overt nephrotic syndrome is unusual. More than 30% of patients will have an elevated serum creatinine level at presentation. A microangiopathic hemolytic anemia (schistocytes, thrombocytopenia, increased fibrin degradation products, and increased fibrinogen) is frequently present. Other symptoms include weakness, malaise, fatigue, and weight loss.

Untreated, the outcome is extremely poor, with 1-year survival of less than 25% in patients with grade IV retinopathy. In studies from 1950s-1960s, uremia was the major cause of death (50-60%), with heart failure and cerebrovascular diseases accounting for the remaining 30-40% of deaths. This dismal outcome has improved thanks to better antihypertensive therapy and the availability of dialysis. African American patients have higher mortality and greater degree of renal impairment.

Malignant hypertension complicated by organ failure (eg, hypertensive encephalopathy, intracranial hemorrhage, congestive heart failure and pulmonary edema, acute myocardial infarction, unstable angina, dissecting aortic aneurysm, eclampsia) is a medical emergency and requires rapid reduction in BP. Rapid normalization of BP is not necessary and should be avoided because it can precipitate end-organ ischemia (eg, stroke, acute renal failure). In uncomplicated malignant hypertension, rapid BP reduction is not as critical as in the previous group with BP reduction by up to 20% of the presenting values, or a systolic BP of greater than 170 mm Hg in the first 24 hours has been an acceptable target. For a review of this subject, see Kitiyakara and Guzman (1998).

Renal biopsy findings

Renal biopsy findings that mimic HN can be observed in various clinical conditions, even in the absence of hypertension. These conditions include hemolytic uremic syndrome, postpartum renal failure, scleroderma, chronic radiation nephritis, and obesity. Reaching an accurate diagnosis can be difficult in patients presenting late in the course of renal failure.

WORKUP

Section 5 of 11  

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• Clinical
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• Follow-up
• Miscellaneous
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Lab Studies

• Laboratory evaluation includes the following:
• • Baseline complete blood cell count
  • Creatinine level
  • Electrolyte status
  • Urinalysis
  • Either a spot urine test for albumin or creatinine ratio or a 24-hour urine collection - To determine total protein excretion
• In a large series of patients, most had urine protein excretion of lower than 1 g/d; however, in some patients with biopsy-proven HN, a 24-hour urinary protein excretion greater than 1 g/d was been described. When secondary changes of focal segmental glomerulosclerosis (FSGS) related to hyperfiltration develop, proteinuria can increase to the nephrotic range.
• Innes et al (1993) reviewed 185 cases of patients with renal biopsy specimens that were classified solely as HN. In 40% of these patients, urinary protein excretion was greater than 1.5 g/d, with 22% excreting more than 3 g/d and 18% having serum albumin values less than 3 g/dL. Similar findings were reported by Harvey et al (1992). Freedman et al (1994) questioned these findings because many biopsy specimens showed segmental and diffuse glomerulosclerosis. Harvey et al attributed these lesions to the effect of hypertension, but Freedman et al felt that these patients had idiopathic FSGS, not HN.
• The contrasting conclusions of Harvey et al and Freedman et al highlight the problems of distinguishing HN from primary glomerular disease purely on clinical grounds. Nevertheless, in black people who are hypertensive, do not have diabetes, and have mild-to-moderate renal failure and proteinuria less than 2 g/d, renal biopsy specimens are likely to show morphological lesions consistent with the clinical diagnosis of HN. On the other hand, the diagnosis of HN in a young white patient is unusual, and these findings suggest an alternative diagnosis.

Imaging Studies

• An echocardiogram may be required to assess left ventricular size.
• Renal imaging with either an ultrasound or an intravenous pyelogram reveals that kidney size is usually symmetric and may be normal or modestly reduced.
• The renal calices and pelves are normal.
• Renal asymmetry or irregularities in the contour raise the possibility that hypertension could be secondary to renal artery stenosis or reflux nephropathy.

Other Tests

• ECG typically shows left ventricular hypertrophy; however, this may not be evident on the ECG tracings.

Procedures

• A definitive diagnosis of HN cannot be made without a renal biopsy, especially in the white patient population. In the absence of a renal biopsy, the diagnosis of HN is one of exclusion.

Histologic Findings

Upon gross pathologic examination, the kidneys are shrunken and scarred. According to Tracy and Ishii (2000), the descriptive pathologic abnormalities of benign nephrosclerosis seen on renal biopsy specimens include glomeruli obsolescence, interstitial fibrosis, arterial intimal fibroplasia, arteriolar hyalinization in arterioles (most notably afferent), and small arteries (arcuate and interlobular artery, see Media file 1).

Myointimal hypertrophy of the interlobular arteries, hyaline degeneration, and sclerosis of afferent arterioles are the most characteristic findings of HN. Interlobular arteries often show reduplication of the internal elastic lamina and medial hypertrophy. The arterial wall shows hyaline changes, appearing as eosinophilia, and distinctively periodic acid-Schiff–positive deposits (see Media file 2). The arteriolar lumen is narrowed.

Early in the disease process, the glomeruli are normal. With time, ischemic changes become visible, including wrinkling of the glomerular tuft and thickening of the Bowman capsule (see Media file 3). Occasionally, mild focal mesangial cell proliferation and matrix expansion occur. Eventually, complete glomerular hyalinosis and obsolescence ensue with the development of secondary tubular atrophy and interstitial fibrosis (see Media file 4). In contrast, the presence of enlarged glomeruli and the absence of collapse of the basement membrane suggest that the patient is most likely developing secondary FSGS superimposed on primary hypertensive disease.

With immunofluorescence, no specific pattern is noted, with the exception of an increased prevalence of immunoglobulin M deposits in the arterioles and mesangium. Fibrinoid necrosis and microinfarcts are features of malignant or accelerated hypertension, not nephrosclerosis. Of note, electromicroscopy examination of renal biopsy specimens may help to distinguish primary FSGS from secondary FSGS. In primary FSGS, foot process effacement is widespread; in secondary FSGS, it is more localized.

As noted by Fogo et al (1997), none of the above lesions is pathognomonic. Consider the diagnosis of HN only when the constellation of these changes is present in the absence of other lesions of primary glomerular disease.

TREATMENT

Section 6 of 11  

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Medical Care

BP control is closely linked to the decline in cardiovascular and cerebrovascular mortality rates over the last 3 decades. Recent epidemiologic studies underscore that even modest decrements of renal function, usually identified by a serum creatinine level of greater than 1.4 mg/dL or estimated GFR of less than 60 mL/min, magnify long-term cardiovascular risk. One interpretation of these findings is that nephrosclerosis is part of generalized vascular disease elsewhere. With regard to antihypertensive therapy and ACE inhibitor administration, patients with cardiovascular disease and impaired renal function benefit proportionately more than those with normal kidney function. The National Kidney Foundation has identified that a reduction in the cardiovascular risks associated with renal disease is a critical focus of the care of patients with renal disease.

Treatment of hypertension in patients with parenchymal renal disease is also effective in preserving renal function, particularly in proteinuric renal diseases such as diabetic nephropathy. Similarly, positive evidence suggests that antihypertensive treatment protects renal function in patients with malignant hypertension.

Remarkably, whether treating hypertension is effective to prevent ESRD attributed to HN is not clear. This is surprising because the percent of patients aware of their hypertension has increased from 51% to 84% over the last 20 years. At the same time, the percent of patients on medications increased from 36% to 73%. However, recent studies have shown that BP is adequately controlled (<140/90 mm Hg) in only 25-30% of patients taking antihypertensive medication.

Early data from large treatment surveys provide little information on the ability of antihypertensive treatment to prevent progressive renal deterioration in patients with essential hypertension. For example, Beevers and Lip (1996) analyzed the combined results of 9 major treatment trials of mild hypertension, which included 21,826 patients. According to their analysis, the number of patients randomized to active treatment who subsequently developed renal failure was the same (ie, 50) as those patients who were randomized to placebo treatment.

Similarly, among the 2125 cases of men with hypertension followed by Madhavan et al (1995), no evidence showed that controlling BP influenced renal function. Patients with hypertension who were treated for up to 5 years exhibited GFRs and renal plasma flow rates similar to those obtained in patients who were not treated. In the Hypertension Detection and Follow-up Program (HDFP), renal function was found to decline in some patients despite optimal antihypertensive treatment.

Zucchelli and Zuccalà (1998) followed the cases of 30 patients with essential hypertension for more than 20 years. In 15 of these patients, renal function was maintained, while the other 15 patients showed the onset of renal impairment. Both groups were matched for age, sex, and treatment duration. At the end of the study, BP profiles indicated similar or better pressure control in patients with progressive renal disease compared with patients with normal renal function.

Similarly, Rostand et al (1989) retrospectively reviewed the records of 181 patients with hypertension. In patients with a primary renal disease diagnosed based on either suggestive medical history or renal biopsy findings, those with urinary protein excretion greater than or equal to 1.5 g/d or a serum creatinine level greater than or equal to 1.5 mg/dL were excluded from the analysis. Ninety-four patients were considered as having essential hypertension. Fourteen patients (15%) had an increase in their serum creatinine level greater than 0.4 mg/dL from baseline. However, renal function declined and was independent of the degree of BP control. In addition, Whelton and Klag (1989) reviewed 6 large antihypertensive treatment trials and reported that the total number of renal events was small, with no statistical difference between the treated groups and the placebo groups.

Toto et al (1995) reported on a long-term, prospective, randomized trial of 87 patients with the clinical diagnosis of HN to determine whether strict versus conventional BP control was associated with a slower decline in renal function. In this trial, strict control of BP (ie, mean diastolic BP of 81 mm Hg ± 0.8) was not better than conventional BP control (ie, mean diastolic BP of 86.7 mm Hg ± 1.1) for preserving renal function; however, both groups experienced a slow decline in the GFR.

More recently, Hsu (2001) conducted a meta-analysis of 10 randomized controlled trials of antihypertensive drug therapy of more than 1 year's duration that reported renal dysfunction as an outcome. Trials enrolling only those patients with known renal insufficiency or established renal parenchymal disease were excluded. Totals included 26,521 individuals, 114,000 person-years, and 317 renal outcomes. This meta-analysis failed to demonstrate a difference between treated and untreated subjects regarding the development of ESRD. Notable limitations of this study were that the study (1) did not address how stricter or longer-term control of BP would affect the incidence of renal dysfunction and (2) was unable to evaluate the effects of newer classes of antihypertensive medications such as ACE inhibitors or angiotensin receptor blockers (ARBs).

Similarly, Ruilope et al (2001) reported on the renal function effect of intensive lowering of BP in hypertensive participants of the Hypertension Optimal Treatment (HOT) study. Baseline serum creatinine values were available in 18,597 patients. Among them, 470 subjects had a serum creatinine value higher than 1.5 mg/dL. Their conclusion was that in contrast to patients with normal renal function, the frequency of major cardiovascular events did not differ in the 3 groups of patients with mild renal insufficiency randomized to different diastolic BP targets. In most patients, no significant changes in serum creatinine values were noted at the end of the 3- to 9-year treatment period. However, a small group of patients (0.58% of the total study population) had deterioration of renal function (increase of >30% over baseline and final serum creatinine values > 2 mg/dL) despite a satisfactory reduction in diastolic BP.

A criticism to the study is that systolic BP remained more than 10 mm Hg (mean) above the goal of less than 130 mm Hg, which has been recommended for patients with high serum creatinine levels, and the attained BP differed by only 4 mm Hg among the lowest and highest target groups (139.7-143.7 mm Hg). Whether tighter systolic BP control could have had an impact in this population with progressive renal impairment cannot be addressed with the available data. In any case, the group of hypertensive patients in whom renal function progressively deteriorated was small.

Studies of black patients with hypertension have not consistently shown a benefit of BP control on the progression of renal disease. Determining whether more intense BP control may slow renal disease progression in black patients is the objective of the AASK trial, the results of which have recently been published.

The study involved 1094 black people aged 18-70 years with GFRs from 20-65 mL/min/1.73 m² and no other identified causes of renal insufficiency. Based on a 3 X 2 factorial design, participants were randomized equally to a usual mean arterial pressure goal of 102-107 mm Hg or to a lower goal of 94 mm Hg or lower and to treatment with 1 of 3 antihypertensive drugs (ie, beta-blocker, ACE inhibitor, calcium channel blocker). The primary analysis was based on the rate of change in GFR (GFR slope). Secondary outcome included confirmed reduction in GFR by 50% or by 25 mL/min/1.73 m² from the mean of the 2 baseline GFRs, ESRD, or death.

After randomization, BP decreased from 152/96 mm Hg to 128/78 mm Hg in the lower BP group and from 149/95 mm Hg to 141/85 mm Hg in the usual BP goal group. A mean separation of approximately 10 mm Hg mean arterial pressure was maintained throughout most of the follow-up period. However, the mean GFR decline did not differ significantly between the lower and the usual BP groups during the total follow-up period from baseline to 4 years. Similarly, the number of events (ie, rates/participant year) for the main clinical composite outcome (ie, declining GFR events, ESRD, death) was no different between the BP groups. As such, results of the AASK trial do not support additional BP reduction as a strategy to prevent progression of HN.

These results are in agreement with previous findings in the MDRD study, which showed no effect on GFR decline in patients assigned to rigorous BP control (goal mean arterial pressure <92 mm Hg in participants <60 y or <98 mm Hg in participants >60 y) compared with the usual BP goal (ie, <107 mm Hg in participants <60 y or <113 mm Hg in participants >60 y). However, further analysis showed a protective effect of tight BP control in patients with proteinuria at baseline.

Finally, the Systolic Hypertension in the Elderly Program (SHEP) prospectively studied the relationship between baseline BP and an incident decline in kidney function among 2182 participants older than 65 years with serum creatinine values less than 2 mg/dL enrolled in the placebo arm of the study. A decline in kidney function was defined as an increase in serum creatinine values of greater than or equal to 0.4 mg/dL. Over the 5 years of follow-up, 226 subjects experienced an increase in serum creatinine values of greater than or equal to 0.4 mg/dL. The incidence and relative risk of a decline in kidney function increased at higher levels of BP for all BP components (systolic, diastolic, pulse, and mean arterial pressure, independent of age, gender, ethnicity, smoking, diabetes, and history of cardiovascular disease). Systolic BP imparted the highest risk of decline in kidney function, with the risk tending to be greater in persons with diabetes and in black persons. Among the limitations of this work

isthe failure to identify the relative contribution of patients in these 2 categories to the total of the 226 persons who showed evidence of declining kidney function. In addition, the absence of a comparison group of subjects with normal systolic BP makes it difficult to fully estimate the effect of systolic BP on kidney function.

Taken together, in the universe of individuals with essential hypertension, a review of the evidence shows that (1) in patients with essential HN, the absolute risk of developing renal insufficiency that will lead to ESRD is low (as opposed to hypertension being a promoter of existing renal disease, which is a well established fact) and (2) the progression of renal disease is not clearly related to hypertension per se because recent therapeutical trials have failed to demonstrate that intensive antihypertensive therapy slows the progression of renal diseases attributed to HN.

The following outlines the indications, effects, and adverse effects of the most commonly used antihypertensive medications.

Diuretics

• Effects and indications
• • Induce natriuresis
  • Thiazide-induced vasodilation occurs
  • Reduce target organ morbidity and mortality in hypertension
  • Maximal BP-lowering effects achieved at low doses (12.5-25 mg/d)
  • Potentiate antihypertensive effects of all other blood pressure medications
  • Antihypertensive effect observed in all demographic groups
  • Thiazides superior to loop diuretics as antihypertensive agents.
• Adverse effects
  • Hypokalemia (dose dependent)
  • Hyperlipidemia (usually short-lived)
  • Glucose intolerance (dose dependent)
  • Hyperuricemia and gout (dose dependent)
  • Thiazides ineffective when GFR is less than 30 mL/min
  • Impotence
  • Hypochloremic metabolic alkalosis (dose dependent)

ACE inhibitors

• Effects and indications
  • Reduce proteinuria
  • Specific renal protective effect both in diabetic and nondiabetic renal impairment
  • Reduce morbidity and mortality rates in congestive heart failure
  • Monotherapy less effective in older patients (>50 y)
  • Larger doses required in black patients
  • Inhibit or blunt all adverse metabolic effects of thiazides
  • Dose reduction required in renal failure
  • Reduce left ventricular hypertrophy and thirst
• Adverse effects
  • Cough (approximately 10%)
  • Angioedema (rare)
  • Hyperkalemia (especially in renal tubular acidosis type IV)
  • GFR reduction in patients with impaired renal function
  • May precipitate acute renal failure in patients with renal artery stenosis
  • Interfere with breakdown of bradykinin
  • Contraindicated in pregnancy

Calcium channel blockers

• Effects and indications
  • Effective as monotherapy in black patients and elderly patients
  • Potentiate ACE inhibitor effects
  • Renal protection not proven
  • Reduce morbidity and mortality rates in congestive heart failure
  • Indicated in patients with diastolic dysfunction
  • No change in dose with renal failure
• Adverse effects
  • Possible increase in cardiovascular mortality rate with short-acting dihydropyridines
  • Edema
  • Constipation (verapamil)
  • Profound bradycardia possible when verapamil and diltiazem used in combination with a beta-blocker

Beta-blockers

• Effects and indications
  • Precise mechanism of antihypertensive action unknown
  • Suppress renin secretion
  • Reduce morbidity and mortality rates after myocardial infarction
  • Possible dose adjustment of some beta-blockers required in renal failure
  • Monotherapy less effective in black patients
• Adverse effects
  • Bradyarrhythmia
  • Hypoglycemia unawareness
  • Bronchospasm
  • May precipitate heart failure
  • Depression
  • Lowers high-density lipoprotein levels and increases triglyceride levels

Vasodilators

• Effects and indications
  • Arteriolar dilation by blocking arterial wall calcium uptake
  • Effective in severe hypertension (minoxidil is better than hydralazine)
  • Minoxidil most potent vasodilator available for oral use
  • No dose adjustment in renal failure
  • Best used in combination with a diuretic plus a beta-blocker
• Adverse effects
  • Reflex activation of sympathetic nervous system (headache, tachycardia)
  • Activation of renin-angiotensin system (sodium retention)
  • Loop diuretic possibly required to control edema
  • Hirsutism (minoxidil)
  • T-wave inversion in approximately 50% of patients on minoxidil

Angiotensin II receptor antagonists

• Effects and indications
  • Reduce proteinuria
  • Indicated in patients intolerant of ACE inhibitors
  • Can be used in combination with an ACE inhibitor
  • Do not cause cough
  • Reduce left-ventricular hypertrophy and thirst similarly to ACE inhibitors
  • Do not interfere with breakdown of bradykinin
• Adverse effects
  • Hyperkalemia
  • May reduce GFR in patients with impaired renal function
  • May precipitate acute renal failure in patient with renal artery stenosis
  • Angioedema (rare)
  • Data in black patients limited

Central-acting alpha-2 agonists

• Effects and indications
  • Methyldopa drug of choice in pregnancy
  • Hypertensive emergency (clonidine)
  • Clonidine useful when patient has migraine in association with hypertension
• Adverse effects
  • Sedation
  • Orthostatic hypotension
  • Dry mouth, skin irritation (clonidine patch)
  • Rebound hypertension upon abrupt discontinuation
  • Possible Coombs-positive hemolytic anemia with methyldopa

Alpha-1 antagonists

• Effects and indications
  • Improve insulin sensitivity
  • Improve urine flow in patients with benign prostatic hypertrophy
  • Reduce total cholesterol and triglyceride levels and increase high-density lipoprotein levels
• Adverse effects
  • Orthostatic hypotension
  • Caution when using in patients with autonomic neuropathy

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Antihypertensives

Several antihypertensive medications, including thiazide diuretics, beta-blockers, ACE inhibitors, ARBs, and calcium channel blockers, in principle, can be used as initial monotherapy in patients with hypertension. The Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure VII (JNC VII) has recommended the following for uncomplicated hypertension:

• Therapy begins with lifestyle modification.
• If the BP goal is not achieved, thiazide-type diuretics should be used as initial therapy for most patients, either alone or in combination with one of the other classes (ie, ACE inhibitors, ARBs, beta-blockers, calcium channel blockers) that have also been shown to reduce one or more hypertensive complications in randomized controlled outcome trials.
• Selection of one of these other agents as initial therapy is recommended when a diuretic cannot be used or when a compelling indication requires the use of a specific drug.
• More than two thirds of hypertensive individuals do not achieve adequate control on one drug and require 2 or more antihypertensive agents selected from different drug classes.
• The initiation of therapy with more than one drug increases the likelihood of achieving the BP goal faster. The use of multidrug combinations often produces greater BP reduction at lower doses of the component agents, resulting in fewer adverse effects.
• Hypertension may exist in association with other conditions with compelling indications for use of a particular treatment based on clinical trial data demonstrating benefits of such therapy on the natural history of the associated condition. Compelling indications for specific therapy involve high-risk conditions that can be direct sequelae of hypertension (eg, HF, ischemic heart disease, chronic kidney disease, recurrent stroke) or commonly associated with hypertension (eg, diabetes, high coronary disease risk). Therapeutic decisions in such individuals should be directed at both the compelling indication and lowering of BP.

Low-dose thiazides

Low-dose thiazides are now recognized as achieving maximal effects on BP with minimal adverse effects. Results from multiple treatment trials show the benefits of low-dose diuretics and alpha-blockers in preventing stroke, coronary events, congestive heart failure, and all-cause mortality.

ACE inhibitors

With the exception of ACE inhibitors in patients with diabetes, no data indicate the best way to treat patients with essential hypertension while preserving renal function. However, results obtained with the use of different antihypertensive treatment in patients with chronic renal failure and/or diabetes (in both animal and human studies) may be extrapolated to guide the treatment of patients with essential hypertension.

In animal models of chronic renal failure and diabetes, control of hypertension with the use of ACE inhibitors has been clearly demonstrated, and angiotensin II receptor antagonists can decrease proteinuria, reduce the severity of glomerulosclerosis and interstitial fibrosis, and slow the progression of renal disease.

Human studies show that ACE inhibitors are capable of slowing the progression of renal failure in all forms of nephropathy, except in patients with polycystic kidneys. Based on these and other results, ACE inhibitors have become the recommended initial therapy to treat hypertension in patients with diabetes.

This recommendation is also supported by the results of the Heart Outcomes Prevention Evaluation (HOPE) trial. According to this study, an ACE inhibitor administered once daily reduces cardiovascular events in patients without heart failure but with at least one cardiovascular risk factor, not including diabetes. Similarly, the Microalbuminuria, Cardiovascular, and Renal Outcomes (MICRO-HOPE) substudy of the HOPE trial randomized 3577 subjects with diabetes who had a prior cardiovascular event or at least one other cardiovascular risk factor and no clinical proteinuria to receive either ramipril (10 mg/d) or placebo. Treatment with ramipril resulted in a 24% risk reduction of overt nephropathy development after 4.5 years of follow-up care (independent of BP reduction).

The beneficial effect of ACE inhibitors is attributed, at least in part, to their ability to reduce or suppress proteinuria. This is particularly important for patients with diabetes because the development of microalbuminuria is associated with an increased prevalence of cardiovascular complications. A few studies have suggested that microalbuminuria is an early marker of renal damage in patients with hypertension, and patients with microalbuminuria experience a faster decline in renal function. Ruilope et al (1994) reported a faster decline in creatinine clearance in patients who are hypertensive with microalbuminuria compared with patients who are hypertensive with normal albumin excretion (11 mL/min vs 2 mL/min).

Similar findings were observed by Bianchi et al (1999). In a few studies, ACE inhibitors, but not calcium channel blockers, reduced microalbuminuria in patients with essential hypertension. Other studies have also confirmed the ability of ACE inhibitors to reduce proteinuria in these patients.

Whether a reduction in microalbuminuria results in a decreased prevalence of ESRD in patients with hypertension remains to be determined. While combining an ACE inhibitor with a calcium channel blocker has been shown to reduce cardiovascular events in clinical trials of hypertension, the renoprotective effects are less uniformly demonstrated. Recent studies, including the Fosinopril versus Amlodipine Cardiac Events Trial (FACET), the HOT study, and the Systolic Hypertension in Europe (Syst-Eur) trial, have reported conflicting results in terms of both cardiovascular and renal outcomes.

In the FACET, combination therapy with ACE inhibitors and calcium channel blockers resulted in significantly lower BPs compared with other groups. Moreover, combination therapy also showed the best results in reducing the mortality rate. To date, in patients with established renal failure (ie, serum creatinine >1.4 mg/dL), none of the dihydropyridine calcium channel blockers available in the United States has been shown to slow renal disease progression in the absence of an ACE inhibitor.

Alpha-blocker and ACE inhibitor combination

Alpha-adrenergic receptor blockers at low doses may be used as monotherapy in the treatment of hypertension. Alpha-adrenergic receptor blockers improve insulin sensitivity, improve urine flow, reduce total cholesterol and triglyceride levels, and increase high-density lipoprotein levels.

Combinations of alpha-blockers and ACE inhibitors have additive effects for lowering BP only in patients with a baseline pulse rate that is greater than 84 beats per minute. In terms of slowing renal disease progression in patients with diabetes or impaired renal function, alpha-blockers are of no additional benefit. Some patients may require an additional arteriolar vasodilator to control BP. Finally, angiotensin II receptor blockers, alone or in combination with other antihypertensive medications, offer a therapeutic alternative. Angiotensin II receptor blockers have a favorable adverse effect profile and appear to share the same beneficial effects of ACE inhibitors; however, no conclusive human data on renal disease progression are available for these agents.

Remember that only approximately 50% of patients with hypertension reach target BP control with antihypertensive monotherapy. Approximately 80-90% of patients require a second agent. The remainder of the patients require a combination of 3 or more agents in order to reach target BP control.

Drug Category: Diuretics

Induce natriuresis, reduce target organ morbidity and mortality rates in patients with hypertension, achieve maximal BP-lowering effects at low doses (12.5-25 mg/d), and potentiate antihypertensive effects of other BP medications. Antihypertensive effect of these agents is observed in all demographic groups. Thiazides induce vasodilation and are superior to loop diuretics as antihypertensive agents.

Drug Category: Angiotensin-converting enzyme inhibitors

Reduce proteinuria, have specific renal protective effects in both diabetic and nondiabetic renal impairment, and reduce morbidity and mortality rates in congestive heart failure. Less effective as monotherapy if patient >50 y. Black patients require increased doses. Inhibit or blunt all adverse metabolic effects of thiazides, and reduce left ventricular hypertrophy.

Drug Name	Ramipril (Altace)
Description	Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.
Adult Dose	10 mg PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; history of angioedema
Interactions	NSAIDs may reduce hypotensive effects; may increase digoxin, lithium, and allopurinol levels; rifampin decreases levels; probenecid may increase levels; hypotensive effects may be enhanced when administered concurrently with diuretics
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Category D in first trimester of pregnancy; caution in renal impairment, valvular stenosis, or severe CHF

Drug Category: Angiotensin II receptor antagonists

Indicated in patients intolerant of ACE inhibitors because they do not interfere with the breakdown of bradykinin or cause cough. Reduce left ventricular hypertrophy and thirst similarly to ACE inhibitors and reduce proteinuria.

Drug Name	Valsartan (Diovan)
Description	Prodrug that produces direct antagonism of angiotensin II receptors. Displaces angiotensin II from AT1 receptor and may lower BP by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. May induce more complete inhibition of renin-angiotensin system than ACE inhibitors, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors.
Adult Dose	80 mg/d PO qd; may increase to maximum 320 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe hepatic insufficiency; biliary cirrhosis or obstruction; primary hyperaldosteronism; bilateral renal artery stenosis
Interactions	Ketoconazole, troleandomycin, sulfaphenazole, and phenobarbital may decrease effects; cimetidine and monoxidine may increase effects
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in hyperkalemia, suspected bilateral renal artery stenosis, or solitary kidney with unilateral renal artery stenosis

Drug Category: Calcium channel blockers

Effective as monotherapy in black patients and elderly patients. Potentiate ACE inhibitor effects. Renal protection is not proven, but reduce morbidity and mortality rates in congestive heart failure. Indicated in patients with diastolic dysfunction.

Drug Name	Amlodipine (Norvasc)
Description	Relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery. Benefits nonpregnant patients with systolic dysfunction, hypertension, or arrhythmias. Can be used during pregnancy if clinically indicated.
Adult Dose	2.5-5 mg PO qd; not to exceed 10 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe CHF; sick sinus syndrome; second- or third-degree AV block; hypotension (<90 mm Hg systolic)
Interactions	May increase carbamazepine, digoxin, cyclosporine, and theophylline levels; coadministration with amiodarone may cause bradycardia and decrease in cardiac output; may increase cardiac depression when administered with beta-blockers
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Adjust dose in renal or hepatic impairment; may cause lower extremity edema; allergic hepatitis has occurred but is rare

Drug Name	Felodipine (Plendil)
Description	Relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery.
Adult Dose	5 mg PO qd; not to exceed 20 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe CHF; sick sinus syndrome; second- or third-degree AV block; hypotension (<90 mm Hg systolic)
Interactions	Bioavailability may be decreased with coadministration of barbiturates, carbamazepine, or hydantoins; effects may be increased with coadministration of erythromycin; may increase digoxin and cyclosporine levels; coadministration with amiodarone may cause bradycardia and decrease in cardiac output; may increase cardiac depression when administered with beta-blockers; with coadministration, theophylline levels may be slightly decreased
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Monitor BP closely during dosage adjustment; may cause greater hypotensive effect in elderly patients; adjust dose in renal or hepatic impairment; may cause lower extremity edema

Drug Category: Beta-adrenergic blocking agents

Suppress renin secretion. Monotherapy less effective in black patients. Reduce morbidity and mortality rates after myocardial infarction.

Drug Category: Vasodilators

Cause arteriolar dilation by blocking arterial wall calcium uptake. Effective in severe hypertension (minoxidil more effective than hydralazine). Best if used in combination with a diuretic plus a beta-blocker.

Drug Name	Hydralazine (Apresoline)
Description	Decreases systemic resistance through direct vasodilation of arterioles.
Adult Dose	10 mg PO qid; not to exceed 300 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; mitral valve rheumatic heart disease
Interactions	MAOIs and beta-blockers may increase toxicity; indomethacin may decrease pharmacologic effects
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Implicated in MI; caution in suspected coronary artery disease

Drug Category: Alpha-adrenergic agonists

Improve hemodynamic status by increasing myocardial contractility and heart rate, resulting in increased cardiac output. Also increase peripheral resistance by causing vasoconstriction. Increased cardiac output and increased peripheral resistance lead to increased BP.

Drug Name	Clonidine (Catapres)
Description	Stimulates alpha-2 adrenoreceptors in brain stem, activating an inhibitory neuron, which results in reduced sympathetic outflow. Decreases vasomotor tone and heart rates. Used in hypertensive emergency. Useful when patient has a migraine in association with hypertension.
Adult Dose	Initial: 0.1 mg PO bid Maintenance: 0.2-1.2 mg/d PO in 2-4 divided doses; not to exceed 2.4 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	TCAs inhibit hypotensive effects; coadministration with beta-blockers may potentiate bradycardia; TCAs may enhance hypertensive response associated with abrupt clonidine withdrawal; hypotensive effects enhanced by narcotic analgesics
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in cerebrovascular disease, coronary insufficiency, sinus node dysfunction, and renal impairment

Drug Name	Doxazosin (Cardura)
Description	Inhibits postsynaptic alpha-adrenergic receptors, resulting in vasodilation of veins and arterioles and decrease in total peripheral resistance and BP.
Adult Dose	1 mg PO hs; not to exceed 16 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Effects decrease with coadministration of NSAIDs; effects increase with coadministration of diuretics and antihypertensive medications
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Caution in renal impairment; may cause marked hypotension following first dose; may worsen CHF

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction