eMedicine Specialties > Nephrology > Hypertension and the Kidney

Nephrosclerosis: Treatment & Medication

Author: Fernando C Fervenza, MD, PhD, Professor of Medicine, Mayo Graduate School of Medicine; Consulting Staff, Department of Internal Medicine, Division of Nephrology, Mayo Clinic
Coauthor(s): Stephen C Textor, MD, Professor of Medicine, Mayo Clinical College of Medicine; Consultant, Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic; Participating Author, Joint National Commission Guidelines VI; David Rosenthal, MD, Staff Nephrologist, Department of Nephrology, Kaiser Permanente
Contributor Information and Disclosures

Updated: Oct 20, 2008

Treatment

Medical Care

BP control is 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 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 hypertensive nephrosclerosis 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, 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.17 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.18 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.19 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.20 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.21

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.22 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.23 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.24 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 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 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.

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 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.

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.

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 

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)
    • Contraindicated in pregnancy
    • Data in black patients limited

Renin inhibitors

  • Effects and indications
    • New class of renin-angiotensin-aldosterone system (RAAS) blocker
    • Long half-life, effective 24-hour BP reduction with once-daily dosing
    • Reduce proteinuria in patients with diabetes
    • No data documenting renoprotection
    • Additive BP reduction with ACE or ARB
  • Adverse effects
    • More hyperkalemia with dual (ie, ACE, ARB) therapy
    • Less (ie, one half to one third the rate) cough than with ACE inhibitors
    • No bradykinin inhibition, rare angioedema (0.06%)
    • 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

Direct 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 

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

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).25

Similar findings were observed by Bianchi et al (1999).26 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. 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-ARB combination therapy

Data regarding the benefit of adding an ARB to an ACE inhibitor are mixed, and no consensus has been reached. In the Combination Treatment of Angiotensin Receptor Blocker and Angiotensin Converting Enzyme Inhibitor in Nondiabetic Renal Disease (COOPERATE) trial, 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 recent meta-analysis by Kunz et al showed better reductions in proteinuria with combined therapy, although safety data were sparse.27 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 cautiously.

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. Other patients require a combination of 3 or more agents in order to reach target BP.

Diuretics

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.


Hydrochlorothiazide (Esidrix, HydroDIURIL)

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

Adult

12.5-25 mg/d PO

Pediatric

Not established

May decrease effects of anticoagulants, antigout agents, and sulfonylureas; may increase toxicity of allopurinol, anesthetics, antineoplastics, calcium salts, loop diuretics, lithium, diazoxide, digitalis, amphotericin B, and nondepolarizing muscle relaxants

Documented hypersensitivity; anuria; renal decompensation

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 renal or hepatic disease, gout, diabetes mellitus, and erythematosus

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.


Fosinopril (Monopril)

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

Adult

10 mg/d PO initially; may increase to 20-40 mg/d PO

Pediatric

Not established

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

Documented hypersensitivity; history of angioedema

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

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Category D in second and third trimester of pregnancy; caution in renal impairment, valvular stenosis, or severe CHF


Ramipril (Altace)

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

Adult

10 mg PO qd

Pediatric

Not established

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

Documented hypersensitivity; history of angioedema

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

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Category D in second and third trimester of pregnancy; caution in renal impairment, valvular stenosis, or severe CHF

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.


Losartan (Cozaar)

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.

Adult

50 mg PO qd initially; not to exceed 100 mg/d

Pediatric

Not established

Ketoconazole, sulfaphenazole, and phenobarbital may decrease effects; cimetidine 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

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Category D in second and third trimester of pregnancy; caution in patients with unilateral or bilateral renal artery stenosis


Valsartan (Diovan)

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

80 mg/d PO qd; may increase to maximum 320 mg/d

Pediatric

Not established

Ketoconazole, troleandomycin, sulfaphenazole, and phenobarbital may decrease effects; cimetidine and monoxidine may increase effects

Documented hypersensitivity; severe hepatic insufficiency; biliary cirrhosis or obstruction; primary hyperaldosteronism; bilateral renal artery stenosis

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

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Category D in second and third trimester of pregnancy; caution in hyperkalemia, suspected bilateral renal artery stenosis, or solitary kidney with unilateral renal artery stenosis

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.


Verapamil (Calan, Covera, Verelan)

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

Adult

240-480 mg/d PO divided tid/qid

Pediatric

Not established

May increase carbamazepine, digoxin, and cyclosporine levels; coadministration with amiodarone can cause bradycardia and a decrease in cardiac output; may increase cardiac depression when administered concurrently with beta-blockers; cimetidine may increase levels; may increase theophylline levels

Documented hypersensitivity; severe CHF; sick sinus syndrome or second- or third-degree AV block; hypotension (<90 mm Hg systolic)

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Hepatocellular injury may occur; transient elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have occurred (elevations have been transient and may disappear with continued treatment); periodically monitor liver function; may cause constipation


Amlodipine (Norvasc)

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

2.5-5 mg PO qd; not to exceed 10 mg/d

Pediatric

Not established

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

Documented hypersensitivity; severe CHF; sick sinus syndrome; second- or third-degree AV block; hypotension (<90 mm Hg systolic)

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


Felodipine (Plendil)

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

Adult

5 mg PO qd; not to exceed 20 mg/d

Pediatric

Not established

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

Documented hypersensitivity; severe CHF; sick sinus syndrome; second- or third-degree AV block; hypotension (<90 mm Hg systolic)

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

Beta-adrenergic blocking agents

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).


Labetalol (Normodyne, Trandate)

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

Adult

100 mg PO bid initially; not to exceed 2400 mg/d

Pediatric

Not established

Decreases effect of diuretics and increases toxicity of methotrexate, lithium, and salicylates; may diminish reflex tachycardia resulting from nitroglycerin use without interfering with hypotensive effects; cimetidine may increase blood levels; glutethimide may decrease effects by inducing microsomal enzymes

Documented hypersensitivity; cardiogenic shock; pulmonary edema; bradycardia; AV block; uncompensated congestive heart failure; reactive airway disease

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 impaired hepatic function; discontinue therapy if signs of liver dysfunction are present; in elderly patients, a lower response rate and higher incidence of toxicity may be observed

Direct 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.


Minoxidil (Loniten)

Most potent vasodilator available for oral use.
Relaxes arteriolar smooth muscle, causing vasodilation, which, in turn, may reduce BP.

Adult

2.5-5 mg PO qd initially; increase gradually to maximum 100 mg/d

Pediatric

Not established

Concurrent use with guanethidine, diuretics, or hypotensive agents may result in additive hypotension

Documented hypersensitivity; pheochromocytoma

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

May cause hirsutism, use cautiously in women; may exacerbate angina pectoris; caution in pulmonary hypertension, CHF, coronary artery disease, and significant renal failure


Hydralazine (Apresoline)

Decreases systemic resistance through direct vasodilation of arterioles.

Adult

10 mg PO qid; not to exceed 300 mg/d

Pediatric

Not established

MAOIs and beta-blockers may increase toxicity; indomethacin may decrease pharmacologic effects

Documented hypersensitivity; mitral valve rheumatic heart disease

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

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.


Methyldopa (Aldomet)

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.

Adult

250 mg PO bid/tid; increase q2d prn; not to exceed 3 g/d

Pediatric

Not established

Coadministration with nonselective beta-blockers may cause paradoxical hypertension; may potentiate antipsychotic effects of haloperidol or produce psychosis; effects of lowering BP with methyldopa may be potentiated by levodopa; central effects of levodopa in Parkinson disease may be potentiated by methyldopa; may need reduced doses of anesthetics; coadministration with lithium may cause lithium toxicity; concurrent use with MAOIs leads to excessive sympathetic stimulation; coadministration with phenothiazines may cause serious BP elevation; may potentiate pressor effects of sympathomimetics; tolbutamide metabolism may be impaired, resulting in enhanced hypoglycemic effects; barbiturates and TCAs may reduce effects

Documented hypersensitivity; active hepatic disease; coadministration with MAOIs

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Perform periodic LFTs (particularly during first 6-12 wk); notify physician of unexplained prolonged tiredness, fever, or jaundice; urine may darken when exposed to air after voiding


Clonidine (Catapres)

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

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

Not established

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


Doxazosin (Cardura)

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

Adult

1 mg PO hs; not to exceed 16 mg/d

Pediatric

Not established

Effects decrease with coadministration of NSAIDs; effects increase with coadministration of diuretics and antihypertensive medications

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 renal impairment; may cause marked hypotension following first dose; may worsen CHF

More on Nephrosclerosis

Overview: Nephrosclerosis
Differential Diagnoses & Workup: Nephrosclerosis
Treatment & Medication: Nephrosclerosis
Follow-up: Nephrosclerosis
Multimedia: Nephrosclerosis
References
[ CLOSE WINDOW ]

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Further Reading

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Keywords

nephrosclerosis, hypertension, hypertensive nephrosclerosis, hypertensive nephropathy, nephroangiosclerosis, end-stage renal disease, ESRD, end stage renal disease, end-stage kidney disease, end stage kidney disease, hypertensive retinopathy, left ventricular hypertrophy, minimal proteinuria, progressive renal insufficiency, benign nephrosclerosis, nephroangiosclerosis, blood pressure control, BP control, HN

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Contributor Information and Disclosures

Author

Fernando C Fervenza, MD, PhD, Professor of Medicine, Mayo Graduate School of Medicine; Consulting Staff, Department of Internal Medicine, Division of Nephrology, Mayo Clinic
Fernando C Fervenza, MD, PhD is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, and National Kidney Foundation
Disclosure: Nothing to disclose.

Coauthor(s)

Stephen C Textor, MD, Professor of Medicine, Mayo Clinical College of Medicine; Consultant, Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic; Participating Author, Joint National Commission Guidelines VI
Stephen C Textor, MD is a member of the following medical societies: American Association for the Advancement of Science, American Heart Association, American Society of Hypertension, American Society of Nephrology, and International Society of Nephrology
Disclosure: Nothing to disclose.

David Rosenthal, MD, Staff Nephrologist, Department of Nephrology, Kaiser Permanente
David Rosenthal, MD is a member of the following medical societies: American Society of Hypertension
Disclosure: Nothing to disclose.

Medical Editor

Chike Magnus Nzerue, MD, Associate Dean for Clinical Affairs, Meharry Medical College
Chike Magnus Nzerue, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Society of Nephrology, and National Kidney Foundation
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Eleanor Lederer, MD, Consulting Staff, Louisville VA Hospital; Professor of Medicine; Interim Chief of Nephrology; Director of Nephrology Training Program; Director, Metabolic Stone Clinic; Director of Outpatient Clinics, Kidney Disease Program, University of Louisville School of Medicine
Eleanor Lederer, MD is a member of the following medical societies: American Association for the Advancement of Science, American Federation for Medical Research, American Society for Biochemistry and Molecular Biology, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Transplantation, International Society of Nephrology, Kentucky Medical Association, National Kidney Foundation, and Phi Beta Kappa
Disclosure: Nothing to disclose.

CME Editor

Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine
Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association
Disclosure: Abbott Grant/research funds Speaking and teaching; Genzyme Honoraria Consulting; Amgen Honoraria Speaking and teaching; Ortho Biotech Honoraria Speaking and teaching

Chief Editor

Vecihi Batuman, MD, FACP, FASN, Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System
Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, and International Society of Nephrology
Disclosure: Nothing to disclose.

 
 
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