Hypertension (HTN) affects one in every four men and one in every five women worldwide. HTN can be classified as either primary/essential or secondary. Secondary HTN is defined as that which occurs secon dary to identifiable causes and constitutes approximately 5%—10% of all patients with HTN. Renal causes constitute the majority of all causes of secondary HTN, with renal artery stenosis (RAS) being the most common. Renovascular HTN (RVH) is an outcome of low renal perfusion secondary to luminal stenosis. RAS is defined as the narrowing of the lumen to an extent that disrupts the laminar flow of blood within the renal artery. Stenosis secondary to atherosclerotic renal artery is the most common cause. Fibromuscular dysplasia, arteritis of the renal artery, renal artery dissection or infarction, extrinsic compression of the renal artery, and extrarenal emboli are other causes of RAS. In this article, we will review the epidemiology, patient presentation, diagnostic, and management modalities of atherosclerotic RAS.
The prevalence of RAS was 24.2% in a population of patients with resistant HTN. Atherosclerotic RAS (ARAS) is often observed in elderly patients with other risk factors, such as diabetes, HTN, and smoking, which are all risk factors for the development of atheroma. As patients with RAS are often asymptomatic or without severe HTN, the true prevalence is not known, as cases may go undetected. Within the United States Medicare population, Duplex identified ARAS in 1%-7% of individuals. RAS due to fibromuscular dysplasia fluctuates between <1% and 6% and is typically observed in younger women.
RAS occurs due to many causes, including atherosclerotic changes, which eventually lead to kidney hypoperfusion. Such changes activate the renin-angiotensin-aldosterone system (RAAS) and stimulate sympathetic activities, prostaglandin synthesis intrarenally, nitric oxide, and aldosterone secretion. This decreases sodium excretion and causes global vasoconstriction. Compromised renal perfusion causes microvascular dysfunction and interstitial fibrosis. In addition to fluid retention and activation of the RAAS due to unilateral ARAS, the normal contralateral kidney counteracts a phenomenon defined as pressure natriuresis. The occurrence of kidney and heart failure along with fluid retention is due to the absence of compensatory sodium excretion, which is the outcome of bilateral RAS. Consequently, chronic kidney disease (CKD), accompanied by a lack of filtration capacity, is either caused by hypoperfusion or recurrent microembolism.
Given the insidious onset of RAS, clinicians struggle to diagnose and treat it for three reasons. First, HTN is a highly prevalent condition and is asymptomatic. Second, it is usually overlooked due to the presence of one or more other common clinical conditions that may lead to CKD. Third, accurate RAS diagnosis requires extensive and, occasionally, invasive measures. Features indicating HTN secondary to RAS include the onset of HTN in either <30 or >50 years, unresponsive and uncontrolled HTN, “flash” pulmonary edema, acute rise of 30% or more in serum creatinine (Cr) after initiating angiotensin-converting enzyme inhibitors (ACEI), unexplained progression of renal failure, unilateral kidney atrophy, abdominal vascular bruit, and an unknown cause of hypokalemia. Coronary artery disease is the only independent predictor of RAS according toYorgun et al.
This is an effective radiological method that can functionally assess the renal arteries as well as their anatomic information. Duplex results obtained by an experienced sonographer revealed comparable outcomes with invasively measured renal trans-stenotic hemodynamic parameters. Duplex conveys hemodynamic data from the extra-parenchymal part of the renal artery, which are considered direct signs, in addition to indirect sonographic signs through the parenchymal vasculature pattern.
Duplex demonstrated a sensitivity of 89%, specificity of 69%, and negative predictive value of 95% for spotting a significant RAS. Duplex has several advantages, including noninvasiveness, affordability, and the ability to assess the progression of the disease and post-revascularization surveillance without exposing the patient to potential harm secondary to the iodine contrast or ionizing radiation, which is required in computed tomography angiography (CTA) and magnetic resonance angiography (MRA). A major disadvantage is that it requires a well-trained sonographer and is a time-consuming procedure. Furthermore, it requires patient preparation to avoid superimposition of bowel gas and is difficult in obese patients. Table 1 shows the diagnostic criteria for ARAS via Duplex.
Computed tomography angiography
CTA is an invasive method with high-resolution cross-sectional imaging, which can be subsequently used to reconstruct 3-dimensional angiographic images of the renal and visceral arteries and aorta. CT can accurately reveal the anatomical details of the renal arteries and their branches (Figure 3). It detects significant RAS with a sensitivity and specificity of 59%-96% and 82%-99%, respectively, compared to standard digital subtraction angiography (DSA). Furthermore, CTA delineates the surrounding tissues and organs, which makes it an extremely useful preoperative modality. Despite its advantages, as mentioned above, it exposes the patient to contrast-induced nephrotoxicity, the allergic effect of the contrast, and the hazard of radiation. CTA is an extremely useful modality for observing patients with stents and for patency follow-ups after bypass surgeries.
Magnetic resonance angiogram
This investigation can localize and enumerate the lesions of the renal arteries and characterize the stenosis. It has a sensitivity and specificity of 92%-97% and 73%-93%, respectively, when compared to selective angiography. A serious drawback is the need for gadolinium contrast, which is a risk for nephrogenic systemic fibrosis in impaired kidneys [estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2]. Furthermore, considerable artifacts may occur; hence, it is not an appropriate test for patients with preceding renal stenting. A major limitation of MRA is the inability to assess the intraparenchymal branches of the renal artery. Patients who are claustrophobic or those with implanted ferromagnetic medical devices (e.g., artificial joints and permanent pacemakers) cannot be evaluated using MRA.
Noncontrast MRA provides high-quality diagnostic images of the visceral arteries in 87.8%-90.2% of cases. Furthermore, in cases of assessment of stenosis, noncontrast MRA had a sensitivity of 100%, a positive predictive value of 50%, and a negative predictive value of 100%.
Blood oxygen level-dependent MR is a noncontrast imaging technique that provides functional information related to renal tissue oxygenation in various pathophysiological conditions. It may provide important opportunities to better assess renal function longitudinally in these patients. MR imaging is a versatile modality with growing clinical applications, and further assessment of these techniques in clinical studies is warranted.
DSA (Figure 4) is the gold standard for characterizing these lesions and is usually combined with endovascular procedures, including dilation and stent placement. However, given the occurrence of stenotic lesions in tortuous arteries, it is difficult to ascertain the precise severity of the lesion. Stenotic lesions vary in size, and subtotal lesions can be readily identified. The most common lesion is mild-to-moderate stenosis, whose hemodynamic severity is unknown. The severity of stenotic lesions has been determined objectively by experts using conventional angiography. It was concluded that severe ARAS is >70% in diameter and moderately severe when the stenotic diameter ranges from 50% to 70%. Severe lesions do not require any further testing, unlike moderately severe lesions, in cases where confirmation of hemodynamic severity is recommended preceding an intervention.
Hemodynamic severity was confirmed by obtaining a resting or hyperemic trans-lesion systolic gradient of ≥20 mm Hg, a resting or hyperemic mean trans-lesional gradient of ≥10 mm Hg, or a renal fractional flow reserve (RFFR) <0.8. False impressions from a semi-occlusive catheter can be avoided while attaining trans-lesional pressure gradients using a nonobstructive catheter or a 0.014-inch pressure wire. A dose of 40 mg of papaverine administered as an intra-arterial bolus or dopamine 50 µg/kg may provoke hyperemia. Researchers have compared conventional angiography to RFFR as well as the trans-lesion pressure gradients determining ARAS severity; a poor association was demonstrated with stenosis in the angiogram and RFFR (r = —0.18; P = 0.54). However, an excellent correlation (r = 0.76; P = 0.0016) was observed between the RFFR and the resting trans-lesional pressure gradient.
Conventional angiography and CTA are identical in terms of limitations, which involve the use of iodinated contrast as well as radiation exposure. This provokes a potential decline in renal function, especially in patients with concurrent renal insufficiency. CO2 angiography may be a better alternative modality for patients who are incapable of receiving iodinated contrast. It should be noted that CO2 is a negative contrast agent. Hence, motion artifacts and bowel gas can disturb image quality.
Management and Prognosis
Reducing the morbidity and mortality rates that are linked to elevated blood pressure (BP) is the main aim of treating RVH secondary to ARAS. The secondary objective was to protect blood circulation and kidney function, which may be directly or indirectly affected. Treatment of patients with asymptomatic RAS lacks evidence.
ARAS is a common and unpleasant medical condition, in which the treatment remains a research target, especially in those who have transplanted kidneys, a single kidney, severe bilateral disease, flash pulmonary edema episodes, or resistant/malignant/accelerated HTN. Moreover, its importance has escalated in those with a recent decline in kidney function and worsening GFR.
The current options to treat ARAS-related HTN are either medical therapy alone or the same as revascularization (which may be an endovascular or open approach). This is despite the fact that in three large randomized controlled trials (RCTs), endovascular revascularization was compared to pharmacotherapy, but it failed to demonstrate any clinical benefits. However, conflicting responses to stents have been demonstrated in several other studies. Some studies reported an improvement in kidney function, some reported it as unchanged, and others reported of deteriorating kidney function. The incidence of deterioration in kidney function poststenting varies between 20% and 40% due to contrast nephropathy and atheroembolism.
HTN in patients with RAS can be controlled by pharmacological therapy alone in almost 90% of cases. It includes managing patients with optimal medical therapy (OMT), which comprises anti-platelet agents, potent statins, antihypertensive drugs, blood glucose management in case of diabetes, and lifestyle modification, such as abstaining from tobacco products, dietary modifications, and physical activity. Concerns regarding the medical options are the worsening of the stenosed lesion and the injurious impact of lowering BP on the diseased kidney.
The Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial exemplifies an ideal standard for patients with RAS receiving OMT combined with a long-acting angiotensin receptor blocker (candesartan), a long-acting calcium channel antagonist (amlodipine), and a statin (atorvastatin). If further adjustment of BP is required, hydrochlorothiazide is added. However, other studies have proposed different antihypertensive agents, such as a thiazide diuretic (chlorthalidone or indapamide), a long-acting calcium channel blocker, a mineralocorticoid receptor antagonist, or a beta-blocker. The angiotensin II receptor blocker (ARB), candesartan, has anti-inflammatory effects that are mediated by the suppression of activated nuclear factor kappa-light-chain-enhancer of activated B-cells and chemokine expression, which play a role in renal protection. However, the CORAL trial did not include patients with resistant or refractory HTN.
Although there were concerns regarding the role of RAAS antagonists in deteriorating kidney function, patients who received it in several observational studies showed better outcomes. This is possibly due to the interruption of various pathophysiological routes as described above. RAAS antagonists were found to affect 53% of patients with renovascular diseases in a subsequent observational study that enrolled 3,750 patients, and this category of patients had a significantly lower risk of primary outcomes (stroke, myocardial infarction, or death) [hazard ratio 0.70; 95% confidence interval (CI) 0.53-0.90]. However, selection bias was a limitation of this observational data. Altogether, patients who receive RAAS antagonists have less severe disease and may have better results.
Notably, therapy with ACEI or ARB is often avoided in cases of ARAS due to a concern of worsening renal function. Hypothetically, RAAS inhibitors can decrease the glomerular capillary hydrostatic pressure enough to trigger a transient decrease in the GFR and an increase in the serum Cr level; therefore, attention and close follow-up are required. However, these drugs reduce mortality and morbidity in patients with ARAS, as proven by large observational studies, especially in those with decreased eGFR. However, these findings could be secondary to selection bias because patients who could not tolerate the pharmacological approach tend to have more widespread disease and possibly benefit more from revascularization. However, candesartan in the CORAL trial was well tolerated.
Patients with RVH routinely receive statins, as atherosclerosis is a systemic disease that can be found in any artery. Moreover, experiments have demonstrated that statins are capable of modifying the kidney’s micro-vascular milieu, limiting fibrosis and other inflammatory damage. Patients treated with statins, in whom nephrectomy was indicated for nonsalvageable ischemic nephropathy, showed a lower level of activated transforming growth factor-beta, which may aid in slowing the progression of fibrosis.
In an established retrospective study, lipid-lowering agents were associated with a lower morbidity rate secondary to progressive renal insufficiency (7.4% vs. 38.9%) and a significantly lower mortality rate (5.9% vs. 36.1%), with a P <0.001 for both. The mean follow-up period was 11 years. This finding highlights the need for prospective randomized controlled studies to investigate the potential effects of statins in patients with renovascular disease.
Pharmacological intervention is the cornerstone of the ARAS treatment. However, the major risks of available medical interventions include the acceleration of diminishing kidney function. If a critical decline (over 30%) in GFR is observed (or an upsurge in serum Cr level over 0.5 mg/dL), then revascularization may be inevitable.
Percutaneous trans renal arterial stenting (PTRAS) is a modality of revascularization in patients whose RAS is hemodynamically significant (>70% of the diameter of the stenosed renal artery on angiography or a meaningful trans-lesion gradient of >10 mm Hg). Failure of OMT is often a crucial factor in deciding on revascularization. Nonetheless, patients who are unlikely to benefit from PTRAS include those with controlled HTN and stable renal function with low-dose antihypertensive agents. In addition, patients with stage 5 CKD and those receiving hemodialysis therapy for ≥3 months or a poleto-pole kidney size <7.0 cm are categorized as having severely declined renal function, and PTRA may have no role. Endovascular intervention is still controversial and case-based, and the American Heart Association guidelines and the European Society of Cardiology guidelines are presented in (Table 2).
In a randomized trial, 85 patients with HTN (BP >160/95 mm Hg, mean 186/103 mm Hg) who had ostial ARAS (unilateral in 51% of patients) underwent either percutaneous balloon angioplasty alone or percutaneous balloon angioplasty with stenting. The trial used the degree of stenosis and serum Cr level as selection parameters, and the patients were allocated randomly to one of these interventions. According to the results, PTRA plus stenting displayed a higher long-term success compared to PTRA alone. Stenting has a higher primary success rate, defined as a remnant stenosis of less than 50% (88% versus 57%), superior patency rate (75% versus 29%), and reduced restenosis rate (14% versus 48%). Moreover, 12 patients who were distributed to only PTRA were eventually stented after six months because of treatment failure. Furthermore, other studies have agreed with the stated trial. In elderly patients with ARAS, the efficacy of revascularization that requires stenting is limited, and it may not decrease the requirements for antihypertensive drug therapy.
A fundamental part of the intervention is to determine the patient who can have a successful response rate and better clinical results after PTRAS.
The current European Society of Cardiology guidelines on the management of atherosclerotic lesions, direct that if a patient is planned for angioplasty, stenting is advocated for ostial ARAS (Class I, level of evidence B). In all other clinical settings reviewed within the guidelines, the level of recommendation was Class IIb. Angioplasty alone may be considered in more than 60% of symptomatic ARAS cases. In individuals with compromised kidney function due to RAS, an endovascular approach may be considered. Therefore, the treatment of RAS using balloon angioplasty with or without stenting may be considered in designated patients with inexplicable recurrent congestive heart failure or abrupt pulmonary edema. PTRA without stent placement is seldom performed unless the anatomy impedes stenting.
The incidence of restenosis after endovascular techniques reach up to 10%-20%, which is significant. As a result, long-term patient follow-up is the key to success in such procedures. Generally, surveillance of the stented renal artery is performed using a duplex scan to distinguish lesions that require re-intervention.
Open surgical treatment
Surgical interventions in the form of nephrectomy, open surgical correction, and bypass are the main interventional modalities in certain circumstances. Complex anatomic lesions, such as multiple small renal arteries, early primary branching of the main renal artery, and aortic reconstruction near the renal arteries for other indications, such as aneurysmal repair, are anatomical challenges that favor the open approach. In the open approach, severe preoperative HTN, bilateral atherosclerotic disease due to high-grade stenosis or renal artery occlusion, and rapidly deteriorating renal function before intervention are the main factors favoring the recovery of renal function following the operation. Preoperative segmental renal artery Duplex spectral analysis along with high renin assays are predictors of poor improvement in renal function or HTN. In the case of bilateral RAS, ischemic nephropathy, and severe HTN, open renal reconstruction is indicated. Based on a population-based study, most experts do not favor prophylactic intervention for asymptomatic renovascular disease in elderly patients. Moreover, all substantial renal artery disease stenoses should be corrected in a single operation, with the exception of the disease requiring bilateral ex vivo reconstructions, which must be staged. Complete nephrectomy should be performed for a patient with a nonfunctioning kidney and severely distorted renal artery disease.
This approach could be either direct anatomical or indirect anatomical surgical correction. Direct correction included thrombo-endarterectomy. In cases of ostial lesions involving the origin of both renal arteries, this could be the preferred procedure. Renal endarterectomy may be transaortic or transrenal. Aortorenal bypass is another direct anatomical approach that can be fashioned as either end-to-side or end-to-end anastomoses. The saphenous vein is usually the conduit of choice; however, if the vein is small (<4 mm in diameter) or sclerotic, the hypogastric artery or a synthetic graft may be used. Vein enlargement can be anticipated in virtually all young adults, but structural immaturity has been reported. Renal artery translocation and reimplantation are indicated in the case of oral stenosis and redundant arteries.
Indirect surgical techniques, including splanchnic-renal bypass, hepatorenal bypass, and splenorenal bypass, are well described in the literature. Renal function must be protected when renal artery reconstruction requires more than 40 min of warm renal ischemia, and ex vivo reconstruction may be the procedure of choice.
In patients who underwent renal artery reconstruction, 58% demonstrated improved renal function three weeks after the repair. Approximately 85% of surgical survivors were cured or had improved conditions, and 15% had no changes in BP. However, surgery-associated bleeding, urinary tract infection, and pseudomembranous colitis were observed among the surgical candidates.
A meta-analysis of 47 studies compared the results of surgical revascularization and endovascular techniques. An identical success rate was observed for both methods. Furthermore, it demonstrated better long-term control of BP and renal function but higher perioperative mortality after surgery. Therefore, open surgery is predominantly performed for stenotic lesions coupled with complex aneurysms, complex lesions (arterial bifurcation or branches), or endovascular therapy failure.
Recent Randomized Controlled Trials
Many RCTs have been published to unify this approach with a better understanding of atherosclerotic renal artery diseases.
The CORAL study is the most recent multicenter randomized trial designed to determine the reliability of whether OMT alone or OMT with renal artery angioplasty will have improved renal function and different outcomes. OMT consisted of medications that control BP, blood glucose, and lipid levels, in accordance with recent guidelines. It was conducted in 2014 with 947 patients who were hypertensive on antihypertensive medication(s), who had renal dysfunction, and who had RAS detected by angiography, Duplex, CTA, or MRA. Exclusion criteria included patients who had recent major medical events and had a kidney size <7 cm and Cr level >4 mg.
The primary clinical endpoint was to assess the incidence of mortality secondary to major cardiovascular events, such as myocardial infarction, stroke, and renal causes due to a decline in renal function or the need for permanent renal replacement therapy. The secondary clinical endpoint was the improvement in BP. The trial showed that the difference in systolic BP (SBP) was statistically significant in contrast to the GFR and Cr, which were not significant. Therefore, at the end of the trial, both groups had lower SBP, whereas OMT plus stenting had an average SBP lower by 2.3 mm Hg. However, OMT plus stenting is not superior to OMT alone in terms of clinical outcomes.
The Herculink Elite Renal Stent to Treat Renal Artery Stenosis (HERCULES) trial is a prospective multicenter trial that took place between August 2007 and September 2009 to assess the efficacy of the RX Herculink Elite Renal Stent System (Abbott Vascular, Santa Clara, CA) in 202 patients who were known to either have significant ARAS or uncontrolled HTN (SBP 140 mm Hg or diastolic BP 90 mm Hg) despite the maximal dosage of two or more antihypertensive agents.
Patients who underwent successful primary renal artery stent deployment, successful percutaneous transluminal angioplasty, and ARAS of a solitary functioning kidney or transplant RAS, and had a serum Cr level >2.5 mg/dL, impaired left ventricular ejection fraction (25%), myocardial infarction, stroke, or transient cerebral ischemia were not enrolled in this trial.
The primary endpoint was evaluated (under the hypothesis of the superiority of the 9-month binary restenosis rate) using duplex ultrasound or angiography. The secondary endpoints were all-cause mortality, kidney damage due to embolization, ipsilateral nephrectomy at 30 days, changes in renal function between baseline and nine months, BP, and anti-hypertensive agents used. As the trial ended, it proved that the correlation between the reduction of SBP and baseline brain natriuretic peptide (BNP) or BNP reduction was lacking. Furthermore, it was statistically and clinically significant that patients with severe forms of HTN demonstrated a perceptible reduction in BP, which was not experienced with OMT.
The Angioplasty and Stenting for Renal Atherosclerotic Lesions (ASTRAL) multicenter trial was conduc-ted in 2009 to determine the ideal method for treating candidates with ARAS using either OMT alone or revascularization plus OMT, and to attribute these findings to lower morbidity and mortality. The trial enrolled 806 candidates with confirmed ARAS >50% and those whose physicians were uncertain whether revascularization would undoubtedly improve the patients’ outcomes. The trial excluded candidates eligible for surgical revascularization or those with a high likelihood of requiring revascularization within six months, those with nonatheromatous cardiovascular disease, and those who previously experienced RAS stenting.
The major endpoint of GFR was measured by measuring the mean reciprocal slope of serum Cr over time (Cl/Cr). The secondary endpoints were the change in BP, time to first major renal event (such as the occurrence of new AKI and initiation of dialysis), time to first major cardiovascular event (such as stroke or myocardial infarction), and mortality.
The trial documented that there was no clinical benefit in revascularizing patients with ARAS, as it did not statistically or clinically lower any substantial risk with respect to kidney function, renal or cardiovascular outcomes, death, or changes in BP.
This multicenter trial was conducted in 2009 and enrolled 140 patients to compare medical therapy with medical therapy plus stenting. The Stent Placement in Patients with Atherosclerotic Renal Artery Stenosis and Impaired Renal Function (STAR) trial protocol defined that patients with a known Cr clearance <80 mL/min, ostial ARAS per nonDuplex imaging, and a stabilized BP were eligible to be included in the trial. Furthermore, those with renal size <8 cm, renal artery diameter <4 mm, estimated Cr clearance <15 mL/min, diabetes mellitus with proteinuria >3 g/day, and malignant HTN were excluded.
Renal artery diseases, including ARAS, are common causes of secondary HTN. Changes in kidney perfusion activate the RAAS and stimulate sympathetic activities, intrarenal prostaglandin synthesis, nitric oxide, and aldosterone secretion, which eventually leads to systemic vasoconstriction and HTN. These patients usually present with resistant HTN (typically three or more antihypertensives). They are usually below the age of 30 or above 50 years of age.
Duplex is the best screening modality in almost all patients when performed by an experienced radiographer. It has many limitations, including patient cooperation, body habitus, and the presence of bowel gases. CTA is an excellent investigative modality for diagnosis and preoperative planning. It delineates the surrounding structures. Both CTA and MRA have nephrotoxic effects and the risk of allergic reactions. DSA is the gold standard for characterizing these lesions and can be combined with endovascular intervention, including dilation and stent placement. However, iodinated contrast and radiation exposure could potentially provoke a decline in renal function and lead to cancer in the long term.
Managing RAS is a challenging process aimed at reducing morbidity and mortality rates, in addition to improving kidney function. Medical management of RAS alone is effective in almost 90% of cases. Evidence is lacking in terms of renal artery revascularization in patients with resistant HTN despite medical management, acutely deteriorating kidney function, critical lesions in functioning solitary kidneys, and patients with flash pulmonary edema due to heart failure. Revascularization may be performed using endovascular techniques or open surgery. However, the incidence of restenosis after the endovascular technique is 10%-20%. Open surgical interventions area valid option for complex anatomic lesions.
Conflict of interest: None declared.
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