Renovascular Hypertension Treatment & Management

Antihypertensive drug therapy is indicated. Optimal blood pressure control plays an essential role in the therapeutic management of renovascular hypertension (RVHT), with renin-angiotensin-aldosterone system (RAAS) blockers (ie, angiotensin-converting enzyme inhibitors [ACEi], angiotensin receptor blockers [ARBs]) considered the first-line drugs in this setting. ^[42]

Aggressive control of other risk factors for atherosclerosis is also crucial. Cessation of smoking is important for its positive impact on the cardiovascular risk profile in patients with hypertension. Similarly, antidyslipidemic therapy for those patients with hyperlipidemia likely provides benefit in atherosclerotic RVHT. In patients with fibromuscular dysplasia, antiplatelet therapy (typically, aspirin 75–100 mg daily), if not contraindicated, is reasonable to prevent thrombotic and thromboembolic complications. ^[43]

Progression of atherosclerotic stenosis may occur in as many as one third of patients, and the sequelae of ongoing ischemia to the stenotic kidney are a theoretical concern. Furthermore, normalization of blood pressure may be associated with reduced renal perfusion pressures, and kidney function may deteriorate despite good blood pressure control.

Definitive therapy for the underlying cause must be considered in order to avoid the development of ischemic nephropathy. ^[11] Intervention to treat hemodynamically significant stenoses has been presumed to offer clinical benefit; however, trials comparing renal artery revascularization with medical management do not unequivocally favor surgical over medical intervention, suggesting the need for research to identify patients most likely to benefit from intervention. ^{[18, 44]} A Kidney Disease: Improving Global Outcomes (KDIGO) consensus statement lists the following as definite indications for revascularization in patients with atherosclerotic renovascular disease ^[42] :

• Acute pulmonary edema or acute decompensations of heart failure in a patient with high-grade renal artery stenosis (RAS)
• Progressive chronic kidney disease (CKD) in a patient with high-grade (> 75%) RAS (bilateral or solitary kidney)
• Acute kidney injury (AKI) due to acute renal artery occlusion or high-grade RAS
• ACEi or ARB intolerance in a patient with high-grade RAS
• RAS (symptomatic or asymptomatic) in a kidney transplant recipient

Possible indications for revascularization, according to KDIGO, are as follows ^[42] :

• Chronic heart failure and high-grade RAS
• Coexistence of progressive CKD and uncontrolled hypertension
• Asymptomatic high-grade RAS (bilateral or supplying a solitary kidney) with viable renal parenchyma (to prevent atrophy)
• Nonfunctioning but possibly viable kidney in a patient who has been receiving dialysis for less than 3 months

The invasive and surgical options for treatment of renovascular hypertension include the following ^[45] :

• Percutaneous transluminal angioplasty (PTA)
• Surgical revascularization
• Nephrectomy

Catheter-based radiofrequency denervation of the renal arteries has entered clinical use in many countries as a treatment for resistant hypertension. The SYMPLICITY HTN-3 trial randomized 535 patients with severe resistant hypertension and found that catheter-based radiofrequency denervation of the renal arteries was safe but did not result in a significant reduction of systolic blood pressure 6 months post-procedure, as compared with a sham control. ^[46] Subsequent reviews, however, have shown that renal denervation was not effectively or consistently achieved in the trial. ^[47]

The patient should be transferred to a tertiary care medical facility whenever the need for invasive or surgical treatments has been established and the current treating facility is not equipped for such procedures.

Inpatient care usually is necessary for the management of hypertensive urgencies or emergencies associated with RVHT. Timely diagnosis of RVHT and early intervention are required to prevent further ischemic end-organ damage to the kidney and other organs.

Hypertensive patients should receive antihypertensive medication. In children with severe hypertension, it may be necessary to initiate medical treatment before a definitive diagnosis is obtained.

RVHT is often refractory to medical treatment. Because current approaches to renal artery dilation and surgical revascularization yield excellent results, these procedures are generally considered the treatments of choice in preference to life-long antihypertensive medication that does not achieve optimal blood pressure control. However, attempts to control the patient’s blood pressure in preparation for surgical intervention should always be made. In particular, it is advisable to defer surgery until manifestations of malignant hypertension are relieved.

All classes of antihypertensive medications are used to treat RVHT, and multiple drugs may be used initially. However, the most effective therapy is with ACEi, which minimize the ischemia-induced rise in angiotensin production. There has been less clinical experience with ARBs, but these agents appear to be as effective as ACEi.

Most patients with RVHT tolerate RAAS blockers well. However, in individuals with marginal renal perfusion pressure, sodium depletion, or both, glomerular filtration depends on the action of angiotensin II, and in that setting, ACEi and ARBs may markedly decrease renal blood flow, with an ensuing deterioration in kidney function. However, in patients with high-grade RAS, therapy with any antihypertensive drug may result in further reductions in renal blood flow and loss of kidney function. ^[42]

Certainly, any patients with RVHT who are treated with an ACEi or ARB should have their serum creatinine levels monitored, and therapy should be discontinued if their creatinine levels rise significantly. In patients without hemodynamically significant RAS, a serum creatinine increase of up to 35% above baseline with an ACEi or an ARB is considered acceptable and is not a reason to withhold treatment unless hyperkalemia develops.

Both beta blockers and diuretics also are used, the latter often in conjunction with ACEi. Diuretics enhance sodium and water diuresis, thereby eliminating the volume-mediated component of RVHT. Calcium channel blockers may provide equally good control of hypertension while presumably causing less impairment of the function of the ischemic kidney than ACEi do. Nitroprusside and phenoxybenzamine are useful in the short-term management of malignant hypertension before surgery.

The selective aldosterone inhibitor eplerenone is also available for the treatment of hypertension. This agent selectively blocks aldosterone at the mineralocorticoid receptors in both epithelial tissues (eg, kidney) and nonepithelial tissues (eg, heart, blood vessels, and brain), thereby decreasing blood pressure and sodium reabsorption. The adult dosage is 50 mg/day orally, which may be increased after 4 weeks to a dosage not exceeding 100 mg/day. Contraindications include the following:

• Documented hypersensitivity
• Hyperkalemia
• Coadministration with drugs causing increased serum potassium levels
• Moderate-to-severe reduction in renal function (ie, creatinine clearance less than 30 mL/min)

Because eplerenone is a cytochrome P-450 (CYP450) 3A4 substrate, potent CYP3A4 inhibitors (eg, ketoconazole) increase serum levels of the drug about 5-fold, whereas less potent CYP3A4 inhibitors (eg, erythromycin, saquinavir, verapamil, and fluconazole) increase serum levels about 2-fold. Grapefruit juice increases serum eplerenone levels by about 25%.

Coadministration of eplerenone with potassium supplements, salt substitutes, or drugs known to increase serum potassium (eg, amiloride, spironolactone, triamterene, ACEi, and ARBs) and increases the risk of hyperkalemia. Eplerenone may cause hyperkalemia, headache, or dizziness. Caution is advised in patients with hepatic insufficiency.

PTA is a therapeutic nonsurgical procedure using pressure expansion of a small balloon on a special vascular catheter to dilate narrow areas in a blood vessel. PTA is less expensive and less invasive than surgical revascularization and can be performed at the time of angiography. If the stenosis is refractory to treatment or if restenosis develops, surgical revascularization can still be performed.

In patients with RVHT, PTA is performed to open stenotic renal arteries (percutaneous transluminal renal angioplasty [PTRA]), the most amenable lesions being those without total occlusion. PTRA is most effective against midvessel stenosis. Lesions involving segmental arteries or the ostia of renal arteries and lesions in patients with neurofibromatosis are especially refractory to balloon angioplasty.

Outcomes appear to be significantly better in patients with fibromuscular dysplasia (FMD) than in those with atherosclerotic stenosis. A systematic review and meta-analysis found that after PTRA, hypertension was cured in 37% of patients with FMD and improved in 80%, although rates varied highly across studies. ^[48] Restenosis necessitating repeat angioplasty has been reported in fewer than 10% of patients with FMD and in 8-30% of those with atherosclerotic stenosis. ^[49]

A Swedish study of 105 patients treated with PTRA reported a 5-year survival rate of 83% for patients with arteriosclerotic renovascular disease. ^[50] The rate for patients with fibromuscular vascular disease was even higher, reaching 100%.

PTRA has yielded mixed results in children. Long-term maintenance of blood pressure improvement ranges from 38% to 90%. Guzzetta et al ^[51] and Tyagi et al ^[13] found that approximately 25% of patients treated with PTRA developed restenosis. Casalini et al, evaluating PTRA in a selected group of 36 children with RVHT, found that 34 (94%) of the patients were normotensive 2 years after the procedure. ^[52]

The results of PTRA in patients with bilateral renal artery disease have been relatively poor, suggesting that surgical intervention should be a strong consideration in this setting. In patients with diffuse atherosclerosis, the complication rate is relatively high with either surgery or angioplasty; medical therapy may be preferred in this setting.

Renal stents

Placement of intravascular stents during angioplasty (see the images below) may be helpful in preventing restenosis and managing RVHT. Data suggest that stenting may prove useful in patients with ostial disease, those who develop restenosis after PTRA, or those with complications resulting from PTRA (eg, dissection). Primary renal artery stenting in patients with atherosclerotic RAS has a high rate of technical success and a low rate of complications. ^{[53, 54, 55]}

Angiogram showing bilateral renal artery stenosis. Courtesy of Department of Radiology, Henry Ford Hospital.

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After percutaneous transluminal angioplasty (right renal artery). Courtesy of Department of Radiology, Henry Ford Hospital.

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After percutaneous transluminal angioplasty and stent placement (left renal artery). Courtesy of Department of Radiology, Henry Ford Hospital.

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The Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trial—a randomized, unblinded trial in 806 patients with atherosclerotic renovascular disease that compared revascularization (PTRA with or without stenting) plus medical therapy with medical therapy alone—found substantial risks but no evidence of a worthwhile clinical benefit from revascularization. Over a 5-year period, the two patient groups showed no statistically significant difference in systolic blood pressure or in the rate of progression of renal impairment, renal or major cardiovascular events, or death. ^[56]

Similarly, the addition of renal artery stenting to comprehensive medical therapy provided no significant clinical benefit in the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study, which included 947 patients with atherosclerotic renal artery stenosis and hypertension or chronic kidney disease. Despite a consistent modest difference in systolic blood pressure favoring the stent group (-2.3 mm Hg), there was no significant difference in adverse cardiovascular and renal events or all-cause mortality. ^[57]

Saad and colleagues have offered a partial explanation for the limited clinical benefit of renal stenting. These researchers reported that severe renovascular disease is associated with tissue hypoxia and increased levels of renal venous markers of inflammatory cytokines and tissue injury. In their study, revascularization reduced hypoxia and partially restored blood flow, but failed to alter markers of inflammation, suggesting that additional measures may be needed to reverse the process of kidney injury. ^[58]

Other authors have proposed that stenting may be beneficial in carefully selected patient subgroups. Noory et al suggest that patients with hemodynamically significant RAS who have progressive renal insufficiency and/or deteriorating arterial hypertension may derive clinical benefit from stent revascularization. ^[59]

According to a consensus statement from the Society for Cardiovascular Angiography and Interventions (SCAI), the strongest evidence supporting renal artery stenting for RAS is in patients with a cardiac disturbance syndrome or flash pulmonary edema. In addition, carefully selected patients with severe bilateral RAS or stenosis to a solitary functioning kidney may experience clinical improvement with renal artery stenting. ^[23]

Other cases in which renal artery stenting generally represents appropriate care after a trial of optimal medical therapy, according to the SCAI, include the following ^[23] :

• Patients with accelerated or resistant hypertension (failure of ≥3 maximally tolerated medications including the use of a diuretic)
• Global renal ischemia (bilateral RAS or severe RAS in a solitary functioning kidney)
• Hypertension with medication intolerance

Sustained benefit of renal artery stenting was shown in a retrospective study of 26 patients with ≥70% stenosis and uncontrolled systolic hypertension despite three or more antihypertensive drugs. On m ^[43] edian follow-up of 5.1 years, blood pressure reduction was sustained (135/70 ± 18/11 mmHg) compared with initial reduction at 6 months and from baseline (162/80 ± 24/18 mmHg). The patients were also taking fewer antihypertensive drugs than at baseline (2.7 ± 2.1, down from 4.1 ± 1.0). ^[60]

In patients with FMD, however, kinking and fracture of renal artery stents have been reported. Consequently, PTRA alone is the revascularization approach of choice, with the use of stents reserved for the treatment of procedural complications (eg, flow-limiting dissection, arterial rupture). ^[43]

Complications

The rate at which complications of PTRA develop varies among physicians, but potential adverse consequences are known to include thrombosis, vascular or renal perforation, and tearing or dissection of the vessel wall. Restenosis appears to occur in approximately 25% of cases.

The goal of surgical revascularization is correction of RVHT with preservation of kidney function. However, in older patients with widespread atherosclerotic disease, surgical revascularization poses considerable morbidity and mortality risk; complications include the release of cholesterol emboli during the operation. Consequently, it is reserved primarily for individuals with associated aortic surgical disease and/or failed endovascular repair. ^[61]  In patients with FMD, the cure rate is as high as 80%, and morbidity is low; however, these results are not significantly better than what can be achieved by means of PTRA with less morbidity, mortality, cost, and inconvenience. ^[62]

Pharmacologic treatment of RVHT should be provided before the operation in an effort to control blood pressure. Routine chest radiography, electrocardiography (ECG), and, perhaps, echocardiography are important in evaluating the patient’s cardiovascular stability under the stress of hypertension. Abdominal aortography and arteriography are necessary, not only to help establish a diagnosis but also to determine the extent of disease and the approach to surgical intervention.

Postoperative care involves blood pressure monitoring; postoperative medical therapy may be necessary. Postoperative renal scanning or arteriography is also important to identify possible thrombosis, stricture, or any failures in the graft or anastomosis.

Most authors have reported little or no short-term mortality after surgical revascularization. ^{[63, 64, 65]} Failure or complications of the procedure may lead to another operation in approximately 27% of cases; usually, the second operation is curative. Date from larger series indicate that graft stenosis may occur about 5% of the time and that thromboses may occur in about 10% of revascularization operations. The various graft materials that may be used are all associated with their own specific complications.

As noted, the goal of therapy for RVHT is to resolve systemic hypertension without compromising renal function. Nephrectomy should be considered a last resort in the treatment of RVHT.

Because renovascular disease is often bilateral, with the contralateral renal system occasionally not affected until years later, it is always best to keep both kidneys functioning whenever possible. However, in cases of severe renal hypoplasia that reduces functional capacity to less than 10% of total renal function, removal of the kidney is the best form of treatment. ^[66]

Nephrectomy may be necessary if complications arise during surgical revascularization or if the disease is too widespread (especially in segmental arteries) to be effectively bypassed. Children whose hypertension is refractory to the previously mentioned forms of treatment may also need nephrectomy to correct their high blood pressure. ^{[64, 67]}

Placing all patients who are hypertensive on a low-salt diet is recommended. In patients with RVHT, this is unlikely to correct the systemic hypertension, but it may assist in managing the hypertension until more definitive therapy can be performed. It certainly does not hurt patients.

In addition, efforts should be made to keep patients well hydrated; dehydration may lead to decreased renal perfusion or increased renin release.

Atherosclerotic RAS is now recognized as an important and fast-growing cause of end-stage renal disease. Because this form of renal failure can be prevented by performing an operation or angioplasty, it is important to identify patients who may be at risk for renal ischemia as a result of atherosclerosis. Even when renal function is impaired, relief of the stenosis, if achieved early enough, may result in dramatic improvement.

Factors that should prompt evaluation for renal artery disease include the following ^{[1, 2]} :

• Onset of hypertension before age 30 years
• Accelerated, resistant, or malignant hypertension
• Elevation in serum creatinine of more than 30% after starting an angiotensin- converting enzyme inhibitor or angiotensin-receptor blocker
• New onset of hypertension after 50 years of age (suggests atherosclerotic renal artery stenosis)
• Asymmetric kidneys with more than 1.5 cm of difference in the size and otherwise unexplained loss of kidney function
• Sudden unexplained pulmonary edema
• Abdominal bruit on physical examination

Deterioration of kidney function in the setting of diffuse atherosclerosis without proteinuria or known renal parenchymal disease, even in the absence of hypertension, is highly suggestive of renovascular disease.

The need for consultation depends on the potential for, development and degree of end-organ damage.  Heart failure likely warrants referral to a cardiologist should be considered; similarly, neurologic symptoms likely warrant referral to a neurologist.

Once a diagnosis of RVHT is made, prompt treatment of the disease is the best protection against further end-organ damage.

In addition to diagnosis and treatment of hypertension, kidney function must be assessed and followed so that any dysfunction can be recognized at an early stage, allowing definitive intervention (when appropriate) to be initiated promptly.