The term hypertensive nephrosclerosis 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 hypertensive nephrosclerosis 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 hypertensive nephrosclerosis.

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 hypertensive nephrosclerosis has been overestimated. The paradoxical results of increasing incidence of renal failure despite wider antihypertensive drug therapy and reduction in hypertensive target events, such as stroke and cardiovascular disease, raises questions about the causal role of hypertension in this disorder.

As reported by Zuccalà and Zucchelli (1996), part of the confusion in the classification of hypertensive nephrosclerosis stems from the use of the word nephrosclerosis.[1] Coined almost a century ago by Theodor Fahr, nephrosclerosis literally means "hardening of the kidney." In the United States and Europe, the terms hypertensive nephrosclerosis, benign nephrosclerosis, and nephroangiosclerosis are commonly used to describe the same clinical condition. These terms refer more to the renal pathologic changes attributed to the effects of hypertension than to the clinical disorder in question.[2] 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.

The histologic effects of nephrosclerosis are demonstrated in the images below.

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Nephrosclerosis. The glomerular tuft is shrunken, with wrinkling of the capillary walls (asterisk), global glomerular sclerosis (arrow), and complete ....

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Nephrosclerosis. Glomerulus with wrinkling of glomerular basement membranes accompanied by reduction of capillary lumen diameter (silver stain at 400X....

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Nephrosclerosis. Hyaline arteriosclerosis with hyaline deposits (arrows) (trichrome stain at 250X magnification).

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Nephrosclerosis. Fibrointimal proliferation of the arcuate artery (periodic acid-Schiff stain at 150X magnification).

In a 2015 review, Meyrier cites clinical and experimental evidence that nephrosclerosis, especially in blacks, can be explained by a genetic renovasculopathy that precedes the rise in blood pressure. He argues that  the use of the term nephrosclerosis to classify a patient with renal insufficiency leads to the possibility of an overlooked nephropathy complicated by hypertension and to the mistaken belief that drastic blood pressure control may retard progression to end-stage renal disease (ESRD).[3]

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 different studies. First, in 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 in 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 in 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.


Two pathophysiologic mechanisms have been proposed for the development of hypertensive nephrosclerosis. One mechanism suggests that glomerular ischemia causes hypertensive nephrosclerosis. 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 may occur 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.[4] Rather, nephrosclerosis appears to be multifactorial. It may be, in part, 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 hypertensive nephrosclerosis. The Dahl salt-sensitive rat develops proteinuria before hypertension and before a high-sodium diet is administered.

In patients with primary 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.

Wang et al investigated whether podocyte injury is an important factor in the pathogenesis of hypertensive nephrosclerosis. In a study involving 41 patients with biopsy-proven hypertensive nephrosclerosis, 10 cadaveric kidney donors, and 9 healthy subjects, the authors found that compared with controls, intrarenal messenger ribonucleic acid (mRNA) expression was lower, and urinary mRNA expression was higher, for the podocyte-associated molecules nephrin, podocin, and synaptopodin in patients with hypertensive nephrosclerosis. Moreover, patients with nephrosclerosis had a significantly lower density of glomerular podocytes than did kidney donors (545 +/- 237 vs 773 +/- 296 per glomeruli, respectively; P < .02).[5, 6]


A genetic link for hypertension and related renal failure is supported by studies demonstrating familial clustering of hypertensive nephrosclerosis in black people and, to some extent, in white people.

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 2008, 2 separate groups showed strong association between genomic variants within MYH9 (non–muscle myosin heavy chain 9) on 22q and nondiabetic ESRD in African Americans.[7, 8] The 2 other disease entities associated with MYH9 included HIV nephropathy and focal segmental glomerulosclerosis (FSGS) in African Americans.

In 2010, 2 other groups showed an even stronger association between the APOL1 gene and risk of ESRD in African Americans.[9, 10] APOL1, which encodes apolipoprotein L1, is also on 22q and is separated from the MYH9 gene by only 14’000 nucleotides. Two variants of APOL1 that have been associated with increased risk of nephropathy include nonsynonymous coding variants termed G1 (glycine-342 to methionine-384) and in-frame 6bp deletion termed G2. The ApoL1 protein protects against Trypanosoma infection. However, the wild-type ApoL1 protein can be neutralized by Trypanosoma brucei rhodesiense. These 2 gene variants restore immunity to Trypanosoma brucei rhodesiense. As a result, genomic evolution has led to positive selection for APOL1 risk variant.

More recent studies have further shown that nondiabetic carriers of 2 APOL1 variants have a 3-times higher rate of proteinuria and reduced renal function and carriers of 1 or 2 variants are significantly younger at the time of initiation of dialysis.

The African American Study of Kidney disease (AASK) trial evaluated the role of intensive versus standard BP control on progression of kidney disease in 1094 black patients with chronic kidney disease (GFR 20-65 mL/min/SA).[11] The study was done in a trial phase followed by a cohort phase. Overall, no difference was noted in the rate of disease progression in the 2 groups. In the subanalysis, in which patients were stratified based on the degree of proteinuria, patients who had initial urinary protein-to-creatinine ratios of less than 0.22 did not benefit from the intensive BP control, whereas those with urinary protein-to-creatinine ratio of greater than 0.22 benefited from the intensive therapy at the end of the cohort phase. APOL1 and MYH9 nephropathy risk variants have been associated with kidney disease in the AASK participants.[12]

This genetic predisposition may be the reason why tighter control of BP in this black population does not slow the progression of kidney disease. Some authors argue that hypertension in this setting is secondary to underlying renal injury.[13]

In different populations studied regarding 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 a modulator for the renal response to injury and the response to treatment in persons with hypertensive nephrosclerosis. Whether these data are also applicable to the black population remains to be determined.

Noting that hypertension-associated ESRD displays familial aggregation in the black population, Fung et al investigated possible links between genetic variations and GFR declines. In a study of 554 black patients, the investigators found evidence that such declines can be predicted by variations in the adrenergic beta-1 (ADRB1) receptor at the Ser49Gly position. The authors also found that GFR decline was significantly smaller in patients who were Gly(49)/Gly(49) (minor allele) homozygotes than in those who were Ser(49) carriers.[14]



United States

Over the last 2 decades, ESRD attributed to hypertensive nephrosclerosis has contributed significantly to the increase in new patients starting dialysis in the United States. According to the 2016 US Renal Data System (USRDS) data, the rate with ESRD due to hypertension plateaued in 2003 at approximately 100 cases per million and has been stable since then. Compared to whites, ESRD prevalence in 2014 was about 3.7 times greater in blacks. However the report cautions that although hypertension is an almost universal finding among all ESRD patients, the significantly higher rates among blacks could be due to ascertainment bias with nephrologists more likely to ascribe it as the causative factor for blacks than for whites.[15]


In Europe, according to the European Dialysis and Transplant Association registry, hypertensive nephrosclerosis is a less common cause of ESRD, accounting for 12% of new patients starting renal replacement therapy. However, the reported incidence varies among different countries, with France and Italy reporting hypertensive nephrosclerosis as being responsible for ESRD in 25% and 17% of patients starting dialysis, respectively. Whereas in United Kingdom (all countries included), it accounts for 6.1% of patients starting new on dialysis. 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.


According to the 2011 USRDS, the annual mortality rate for patients on hemodialysis in the United States is 23.3%. Hypertensive nephrosclerosis accounts for more than one third of patients on hemodialysis.


Marked differences exist in the stated prevalence of hypertensive nephrosclerosis among patients of different ethnic backgrounds. Although black people make up 12% of the US population, they account for 28.3% 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 hypertensive nephrosclerosis. In black people, hypertensive nephrosclerosis 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 rate of developing ESRD is 3.5 times higher than the rate found among whites. 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 because the rate of new ESRD cases has remained stable in African Americans, whereas it has grown 7.2% among white, and, in addition, the rates of stroke and cardiovascular mortality have decreased equally in both white and African American populations.

Results from the MRFIT trial indicated that effective BP control was associated with stable renal function in white people but not in black people. In the AASK trial, which specifically evaluated black populations, intensive control of BP in nonproteinuric patients did not decrease progression of kidney disease.

Several renal, hormonal, physiologic, and genetic factors have been proposed as explanations for the increased rate of hypertension and progression of chronic kidney disease in African Americans. These include increased BP sensitivity to high-salt diet, increased renal vascular resistance, decreased renal blood flow, increased tortuosity and occlusion in the interlobular and arcuate arteries based on renal angiograms in African Americans, and decreased nephron mass secondary to low birth weight (more common in African Americans). Lastly, the increased variant in APOL1 gene has been proposed as the cause of the increased rate of ESRD in African Americans.


The diagnosis of hypertensive nephrosclerosis 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 hypertensive nephrosclerosis in older patients is made clinically because of the reluctance to perform a renal biopsy in this elderly population.[16] 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.[17] 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.[18] 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.[18] If these predictions are correct, ischemic renal disease is likely the fourth most common cause of ESRD in patients older than 50 years.

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).[19] 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).


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 hypertensive nephrosclerosis are as follows:


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.


No specific causes for hypertensive nephrosclerosis are known.

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. It must be noted that the APOL1 gene variant can increase the risk of renal disease progression in African American hypertensive patients, but the mechanism by which it causes progression of renal disease is unknown and it is unclear whether the gene variant causes hypertension other than by causing renal disease first.

Correct identification of hypertensive nephrosclerosis susceptibility genes requires accurate hypertensive nephrosclerosis phenotyping. The major impediment to establishing a reliable hypertensive nephrosclerosis phenotype is the absence of strong clinical criteria to distinguish hypertensive nephrosclerosis from other renal diseases. Genetic approaches to hypertensive nephrosclerosis require careful scrutiny of clinical diagnoses before assigning phenotypes to study subjects.

See also Pathophysiology.

Laboratory Studies

Based on Joint National Commission (JNC VII) recommendations,[28]  evaluation of a hypertensive patient has the following three objectives:

  1. Identifying other cardiovascular risk factors
  2. Revealing identifiable causes of high blood pressure (BP,)
  3. Evaluating for evidence of end-organ damage.

Laboratory evaluation includes the following studies:

In a large series of patients, most had urine protein excretion of lower than 1 g/d; however, in some patients with biopsy-proven hypertensive nephrosclerosis, a 24-hour urinary protein excretion greater than 1 g/d has 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 hypertensive nephrosclerosis.[29] 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).[30] Freedman et al (1994) questioned these findings because many biopsy specimens showed segmental and diffuse glomerulosclerosis.[31] Harvey et al attributed these lesions to the effect of hypertension, but Freedman et al believed that these patients had idiopathic FSGS, not hypertensive nephrosclerosis.[30, 31]

The contrasting conclusions of Harvey et al and Freedman et al highlight the problems of distinguishing hypertensive nephrosclerosis 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 hypertensive nephrosclerosis. On the other hand, the diagnosis of hypertensive nephrosclerosis in a young white patient is unusual, and these findings suggest an alternative diagnosis.

Measurement of uric acid may also be valuable for providing prognostic information. A review of data from 45 patients diagnosed with arterial/arteriolar nephrosclerosis concluded that a baseline serum uric acid level of 8.0 mg/dL or higher was significantly associated with a ≥50% decline in eGFR or end-stage renal disease (ESRD).[32]

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

An electrocardiogram (ECG) typically shows left ventricular hypertrophy; however, this condition may not be evident on the ECG tracings. The sensitivity of ECG in helping to detect left ventricular hypertrophy may be as low as 22%. However, ECG is recommended as part of the initial evaluation of hypertensive patients (JNC VII).


A definitive diagnosis of hypertensive nephrosclerosis cannot be made without a renal biopsy, especially in the white patient population. In the absence of a renal biopsy, the diagnosis of hypertensive nephrosclerosis 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). (Histologic effects on the arcuate artery are seen in the image below.)[4]

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Nephrosclerosis. Fibrointimal proliferation of the arcuate artery (periodic acid-Schiff stain at 150X magnification).

Myointimal hypertrophy of the interlobular arteries, hyaline degeneration, and sclerosis of afferent arterioles are the most characteristic findings of hypertensive nephrosclerosis. 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. The arteriolar lumen is narrowed. The image below demonstrates hyaline arteriosclerosis.

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Nephrosclerosis. Hyaline arteriosclerosis with hyaline deposits (arrows) (trichrome stain at 250X magnification).

Early in the disease process, the glomeruli are normal. With time, ischemic changes become visible, including wrinkling of the glomerular tuft (seen in the image below) and thickening of the Bowman capsule. 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. 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.

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Nephrosclerosis. The glomerular tuft is shrunken, with wrinkling of the capillary walls (asterisk), global glomerular sclerosis (arrow), and complete ....

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.[33] Consider the diagnosis of hypertensive nephrosclerosis only when the constellation of these changes is present in the absence of other lesions of primary glomerular disease.

Medical Care

Improvements in blood pressure (BP) control are closely linked to the decline in cardiovascular and cerebrovascular mortality rates over the last 3 decades. 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 glomerular filtration rate (eGFR) 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. 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 end-stage renal disease (ESRD) attributed to hypertensive nephrosclerosis is not clear. This is surprising because the percentage of patients aware of their hypertension has increased from 51% to 84% over the last 20 years. At the same time, the percentage of patients on antihypertensive medications increased from 36% to 73%. However, 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.[34] 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.[35] 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.[36] 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.[37] 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.[38]

Toto et al (1995) reported on a long-term, prospective, randomized trial of 87 patients with the clinical diagnosis of hypertensive nephrosclerosis to determine whether strict versus conventional BP control was associated with a slower decline in renal function.[39] 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.

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.[40] 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 (1) the study did not address how stricter or longer-term control of BP would affect the incidence of renal dysfunction, and (2) the study 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.[41] 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 was the objective of the AASK trial. 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 mmHg or to a lower goal of 94 mmHg 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 hypertensive nephrosclerosis.

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.

The combination of hypertension and diabetes can result in more rapid progression of renal disease. The UK Prospective Diabetes Study (UKPDS) and few more recent studies have shown that adequate control of BP decreases microvascular complications, including nephropathy. The JNC VII guideline recommends a goal BP of less than 130/80 mm Hg for diabetic patients with hypertension. However, whether lowering systolic BP to less than 130 mm Hg would improve microvascular and macrovascular complications has remained in question.

The Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD-BP) trial was designed to answer this question.[42] A subset of patients (4733) from the ACCORD trial were enrolled in the ACCORD-BP trial and were randomized to intensive (systolic <120 mm Hg) or standard (systolic <140 mm Hg) therapies. The participants had type 2 diabetes with cardiovascular risk factors and were an average age of 62.2 years. They were followed for a median of 5 years.

At the end of the study, no difference was noted between the 2 groups in the primary outcome defined as the first occurrence of a major cardiovascular event (composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). The mean estimated GFR was lower in the group receiving intensive therapy, with more patients with an estimated GFR of less than 30 mL/min/SA compared with the standard-therapy group. The rate of macroalbuminuria was lower in the intensive-therapy group, but no difference in the frequency of ESRD or need for dialysis was reported. It should be emphasized patients with creatinine values greater than 1.5 mg/dL were excluded from this study. The rate of total and nonfatal stroke was higher in the standard-therapy group.

The authors concluded that no additional benefit was gained from more intensive therapy (systolic < 120 mm Hg) in diabetic patients. Even though it may be true that additional reduction in the systolic BP in diabetic patients may not further reduce the risk of coronary disease events, further reduction in systolic BP does seem to reduce the risk of stroke. Based on the ACCORD-BP trial, there does not appear to be any additional benefit from reducing the systolic BP in controlling the rate of renal disease progression in diabetic patients with creatinine values less than 1.5 mg/dL. At this point, the question of what goal BP is optimal in diabetic patients remains unanswered.

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  0.4 mg/dL or more.

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, sex, 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 is the 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.

Finally, the Hypertension in the Very Elderly Trial (HYVET) evaluated whether treatment of hypertension in patients aged 80 years or older is of any benefit.[43] Close to 4000 patients were enrolled in the study and were divided into active treatment (indapamide +/- perindopril) versus placebo for a goal BP of less than 150/80 mm Hg and were followed for median of 1.8 years. The mean BP difference at 2 years between the 2 groups was 15/6 mm Hg. At the end of the study, patients undergoing active treatment had a lower rate of both fatal and nonfatal stroke and a reduction in overall rate of death. There was no difference in the creatinine values between the 2 groups. Those patients with creatinine values greater than 1.7 mg/dL were excluded. This study highlights the importance of treating BP in very elderly persons.

Taken together, in the universe of individuals with essential hypertension, a review of the evidence shows that (1) in patients with essential hypertensive nephrosclerosis, 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 well established), and (2) the progression of renal disease is not clearly related to hypertension per se because therapeutical trials have failed to demonstrate that intensive antihypertensive therapy slows the progression of renal diseases attributed to hypertensive nephrosclerosis.

The indications, effects, and adverse effects of the most commonly used antihypertensive medications are outlined below.


Effects and indications are as follows:

Adverse effects are as follows:

ACE inhibitors

Effects and indications are as follows:

Adverse effects are as follows:

Angiotensin II receptor antagonists

Effects and indications are as follows:

Adverse effects are as follows:

Renin inhibitors

See the list below:

Adverse effects are as follows:

Calcium channel blockers

Effects and indications are as follows:

Adverse effects are as follows:


Effects and indications are as follows:

Adverse effects are as follows:

Direct vasodilators

Effects and indications are as follows:

Adverse effects are as follows:

Central-acting alpha-2 agonists

Effects and indications are as follows:

Adverse effects are as follows:

Alpha-1 antagonists

Effects and indications are as follows:

Adverse effects are as follows:

Medication Summary


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. However, controversy regarding which drug to use as a first-line therapy continues partly due to the belief that antihypertensive medications have benefits beyond BP-lowering effects. It is important to point out that regardless of which medication is chosen as the initial therapy, in the majority of patients monotherapy does not achieve adequate BP control. As shown in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), more than 60% of patients required 2 or more therapies for BP control. Similar numbers were noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA), in which more than 50% of patients required combination therapy.

The Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure VII (JNC VII) has recommended the following for uncomplicated hypertension:

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 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).[45]

Similar findings were observed by Bianchi et al (1999).[46] 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.

ACE inhibitor and calcium channel blockers

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. Different 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.

ACE inhibitor and ARB combination therapy

Data regarding the benefit of adding an ARB to an ACE inhibitor are controversial, and no consensus has been reached. Results from the single trial, the Combination Treatment of Angiotensin Receptor Blocker and Angiotensin Converting Enzyme Inhibitor in Nondiabetic Renal Disease (COOPERATE) trial, suggested combined therapy with losartan and trandolapril preserved renal function better than monotherapy with either drug. These patients had nondiabetic proteinuric chronic kidney disease. However, since the publication of this trial, serious concerns about the quality of the data have been raised by Kunz et al. A meta-analysis by Kunz et al showed better reductions in proteinuria with combined therapy, although safety data were sparse.[47]

In 2008, Mann et al evaluated the effects of ACE inhibitors versus ARB versus combination therapy on renal outcomes in patients at high vascular risk from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET).[48] More than 25,000 patients were enrolled in this study and were followed for more than 5 years. The primary goal was to evaluate whether combination therapy would result in better cardiovascular protection compared with ACE inhibitors. The primary renal outcome was the composite outcome of death, ESRD, and doubling of serum creatinine.

Even though the rate of microalbuminuria and macroalbuminuria was lower with the combination therapy, the rate of decline in estimated GFR (-6.1 mL/min/SA) was greater compared with the ACE inhibitor group (-2.8 mL/min/SA), which was statistically significant. In addition, the rate of acute dialysis was greater in the group receiving combination therapy. Note that the patients included in the ONTARGET were at low renal risk and cannot be generalized to include patients with overt nephropathy.

Because of the lack of conclusive data regarding the benefits of combined therapy and because of the ongoing concerns for increased adverse effects, dual ACE inhibitor-ARB therapy should be prescribed with caution.

ACE inhibitor and alpha-blocker 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.

Calcium channel blockers

Dihydropyridines are effective BP medications that can be used as monotherapy for BP control. More recently, however, their effects in combination with ACE inhibitors has been evaluated.

The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) compared the effect of a calcium channel blockers (amlodipine) with an ACE inhibitor (perindopril) added as needed to a beta-blocker (atenolol) with thiazide (bendroflumethiazide) added as needed in preventing nonfatal myocardial infarction and fatal coronary heart disease.[49] The study was conducted in British and Scandinavian countries and enrolled more than 19,000 patients with hypertension and at least 3 cardiovascular risk factors (type 2 diabetes mellitus, left ventricular hypertrophy, peripheral vascular disease, microalbuminuria, prior stroke or transient ischemic attack) and followed them for more than 5 years.

Even though the primary outcome (nonfatal myocardial infarction and fatal coronary heart disease) did not reach significance when comparing the 2 groups, the calcium channel blockers plus ACE inhibitors was found to be superior to beta-blockers plus thiazide in preventing fatal and nonfatal strokes, all-cause mortality, and total cardiovascular events and in lowering the rate of renal impairment and diabetes.

The lack of reaching statistical significance in primary outcome has been attributed to the premature termination of trial, which was done because of significant overall mortality reduction in the group receiving calcium channel blocker plus ACE inhibitor therapy. Note, however, that the group receiving combination therapy with a calcium channel blocker plus an ACE inhibitor had lower BP (2.7/1.9 mm Hg) compared with the group receiving a beta-blocker plus thiazide, and the benefits noted from the combination therapy with a calcium channel blocker plus an ACE inhibitor may be partly related to the differential BP control.

More recently, the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial compared a calcium channel blocker (amlodipine) combined with an ACE inhibitor (benazepril) to hydrochlorothiazide combined with benazepril.[50] The ACCOMPLISH trail was a multicenter trial in 5 countries, including the United States, that enrolled patients with hypertension and high cardiovascular disease risk (history of coronary artery disease, myocardial infarction, revascularization, stroke, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, and diabetes mellitus). More than 11,000 patients were enrolled and followed for a median of 36 months.

The study was terminated early as the difference between the 2 groups exceeded the boundary of the prespecified stopping rule. The primary endpoint was the time to the first event defined as the composite of a cardiovascular event and death from cardiovascular causes. By the end of the study, 9.6% in the calcium channel blocker plus ACE inhibitor group, compared with 11.8% in the diuretic plus ACE inhibitor group, had a primary outcome event. Individuals receiving calcium channel blockers plus ACE inhibitors also had fewer fatal and nonfatal myocardial infarctions and fewer coronary revascularizations. These results suggest that the combination of a calcium channel blocker with an ACE inhibitor may be a great choice for treatment of patients with hypertension and cardiovascular risk factors.

Hydrochlorothiazide (Esidrix, HydroDIURIL)

Clinical Context:  Inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium, water, potassium, and hydrogen ions.

Class Summary

Induce natriuresis, reduce target organ damage 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.

Fosinopril (Monopril)

Clinical Context:  Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.

Ramipril (Altace)

Clinical Context:  Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.

Class Summary

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.

Losartan (Cozaar)

Clinical Context:  Blocks vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce a 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.

Angiotensin II receptor blockers reduce BP and proteinuria, protecting renal function and delaying onset of ESRD.

Valsartan (Diovan)

Clinical Context:  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.

Class Summary

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.

Aliskiren (Tekturna)

Clinical Context:  Aliskiren directly inhibits renin, which results in a reduction in plasma renin activity and thereby a decrease in the conversion of angiotensinogen to angiotensin I.

Class Summary

This is a new class of renin-angiotensin-aldosterone system (RAAS) inhibitors that works by inhibiting renin activity. They are long-acting and can be used for treatment of hypertension with once daily dosing.

Verapamil (Calan, Covera, Verelan)

Clinical Context:  During depolarization, inhibits calcium ion from entering slow channels or voltage-sensitive areas of vascular smooth muscle and myocardium.

Amlodipine (Norvasc)

Clinical Context:  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.

Felodipine (Plendil)

Clinical Context:  Relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery.

Class Summary

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.

Labetalol (Normodyne, Trandate)

Clinical Context:  Blocks beta1-, alpha-, and beta2-adrenergic receptor sites, decreasing BP.

Class Summary

Suppress renin secretion. Monotherapy less effective in black patients. Reduce morbidity and mortality rates after myocardial infarction. Not considered a first-line therapy in the absence of a compelling indication (eg, coronary artery disease).[44]

Minoxidil (Loniten)

Clinical Context:  Most potent vasodilator available for oral use.

Relaxes arteriolar smooth muscle, causing vasodilation, which, in turn, may reduce BP.

Hydralazine (Apresoline)

Clinical Context:  Decreases systemic resistance through direct vasodilation of arterioles.

Class Summary

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.

Methyldopa (Aldomet)

Clinical Context:  DOC in pregnancy. Mechanism of action is likely due to drug's metabolism to alpha-methyl norepinephrine, which lowers arterial pressure by stimulating central inhibitory alpha-adrenergic receptors, false neurotransmission, or reducing plasma renin activity.

Clonidine (Catapres)

Clinical Context:  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.

Doxazosin (Cardura)

Clinical Context:  Inhibits postsynaptic alpha-adrenergic receptors, resulting in vasodilation of veins and arterioles and decrease in total peripheral resistance and BP.

Class Summary

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.


For hypertension complicating primary renal disease, considerations for prevention include the following:


See the list below:


With regard to the target BP, the Working Group Report on Hypertension and Diabetes recommended a BP goal of less than 130/80 mm Hg to preserve renal function and to reduce cardiovascular events in patients with hypertension and diabetes. Lower BPs are recommended for patients with proteinuria greater than 1 g/d and renal insufficiency, regardless of etiology. The optimal BP goal to slow the progression of renal failure in patients with hypertensive nephrosclerosis currently is unknown.

Hypertensive nephrosclerosis remains a poorly defined entity. Researchers continue to search for a clear definition, a pathophysiologic mechanism, and optimal treatment for patients with this condition. As suggested by Meyrier (1996), hypertensive nephrosclerosis may conceivably be a primary microvascular nephropathy.[59]

Uncontrolled hypertension can accelerate the decline of renal function in patients with primary renal disease; however, whether mild-to-moderate essential hypertension can cause ESRD in white people is uncertain. The available data do not support the hypothesis that high BP is the only factor determining ESRD in these patients.

Medical treatment is indicated in patients younger than 80 years with BP higher than 140/90 mm Hg. In these patients, antihypertensive treatment has proven to reduce the risk of stroke and cardiovascular mortality. Data from HYVET showed decreased strokes, heart failure, and all-cause mortality from the treatment of patients older than 80 years with BP less than 160 mm Hg. However, the effect of treatment on renal function was not assessed, and patients with a creatinine value of greater than 1.7 mg/dL were excluded from the trial.

Evidence for the beneficial effect of hypertension treatment on patients with hypertensive nephrosclerosis is lacking, and many questions regarding the ability of these drugs to protect renal function in the long term remain unanswered.

Patient Education

For patient education resources, see the Diabetes Center and Cholesterol Center, as well as Acute Kidney Failure, High Cholesterol, and Cholesterol FAQs.


Fernando C Fervenza, MD, PhD, Professor of Medicine, Mayo Graduate School of Medicine; Consulting Staff, Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic

Disclosure: Nothing to disclose.


David Rosenthal, MD, Staff Nephrologist, Department of Nephrology, Kaiser Permanente

Disclosure: Nothing to disclose.

Ladan Zand, MD, Fellow in Nephrology, Department of Internal Medicine, Division of Nephrology, Mayo Medical School

Disclosure: Nothing to disclose.

Stephen C Textor, MD,

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Eleanor Lederer, MD, FASN, Professor of Medicine, Chief, Nephrology Division, Director, Nephrology Training Program, Director, Metabolic Stone Clinic, Kidney Disease Program, University of Louisville School of Medicine; Consulting Staff, Louisville Veterans Affairs Hospital

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Society of Nephrology<br/>Received income in an amount equal to or greater than $250 from: Healthcare Quality Strategies, Inc<br/>Received grant/research funds from Dept of Veterans Affairs for research; Received salary from American Society of Nephrology for asn council position; Received salary from University of Louisville for employment; Received salary from University of Louisville Physicians for employment; Received contract payment from American Physician Institute for Advanced Professional Studies, LLC for independent contractor; Received contract payment from Healthcare Quality Strategies, Inc for independent cont.

Chief Editor

Vecihi Batuman, MD, FASN, Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System

Disclosure: Nothing to disclose.

Additional Contributors

Chike Magnus Nzerue, MD, FACP, Professor of Medicine, Associate Dean for Clinical Affairs, Meharry Medical College

Disclosure: Nothing to disclose.


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Nephrosclerosis. The glomerular tuft is shrunken, with wrinkling of the capillary walls (asterisk), global glomerular sclerosis (arrow), and complete obliteration of the capillary loops and glomerular ischemia (periodic acid-Schiff stain at 250X magnification).

Nephrosclerosis. Glomerulus with wrinkling of glomerular basement membranes accompanied by reduction of capillary lumen diameter (silver stain at 400X magnification).

Nephrosclerosis. Hyaline arteriosclerosis with hyaline deposits (arrows) (trichrome stain at 250X magnification).

Nephrosclerosis. Fibrointimal proliferation of the arcuate artery (periodic acid-Schiff stain at 150X magnification).

Nephrosclerosis. Fibrointimal proliferation of the arcuate artery (periodic acid-Schiff stain at 150X magnification).

Nephrosclerosis. Hyaline arteriosclerosis with hyaline deposits (arrows) (trichrome stain at 250X magnification).

Nephrosclerosis. The glomerular tuft is shrunken, with wrinkling of the capillary walls (asterisk), global glomerular sclerosis (arrow), and complete obliteration of the capillary loops and glomerular ischemia (periodic acid-Schiff stain at 250X magnification).

Nephrosclerosis. The glomerular tuft is shrunken, with wrinkling of the capillary walls (asterisk), global glomerular sclerosis (arrow), and complete obliteration of the capillary loops and glomerular ischemia (periodic acid-Schiff stain at 250X magnification).

Nephrosclerosis. Glomerulus with wrinkling of glomerular basement membranes accompanied by reduction of capillary lumen diameter (silver stain at 400X magnification).

Nephrosclerosis. Hyaline arteriosclerosis with hyaline deposits (arrows) (trichrome stain at 250X magnification).

Nephrosclerosis. Fibrointimal proliferation of the arcuate artery (periodic acid-Schiff stain at 150X magnification).