Current Concepts in the Treatment of Renovascular Hypertension

Abstract

Renovascular disease (RVD) remains a major cause of secondary and treatment-resistant hypertension. Most cases are related either to fibromuscular or atherosclerotic lesions, but a variety of other causes including arterial dissection, stent occlusion, and embolic disease can produce the same syndrome. Recent studies emphasize the kidney’s tolerance to moderate flow reduction during antihypertensive drug therapy and the relative safety of medical therapy to control blood pressure. Several prospective trials in moderate RVD fail to identify major benefits from endovascular revascularization for moderate atherosclerotic disease. However, high-risk and progressive renovascular syndromes are recognized to be relatively refractory to medical therapy only and respond better to combining renal revascularization with ongoing medical therapy. Clinicians caring for complex hypertension should be familiar with pathogenic pathways, imaging techniques, and a rational approach to managing renovascular hypertension in the current era.

Studies linking renovascular occlusion and blood pressure (BP) regulation early in the 20^th century remain among the seminal observations in clinical hypertension.^1,2 They established the major hemodynamic role of the kidney and the potential for identifying a reversible cause of systemic BP elevation that translated directly into clinical cases of renovascular hypertension (RVH). Renal revascularization either with surgical or endovascular techniques subsequently established a record of success for a subset of patients, albeit with associated costs and risks. Restoring vessel patency and blood flow to compromised kidneys not only promised benefits regarding BP control but also had obvious value in protecting the viability of the organ. As Western populations have been aging over the last few decades, the prevalence of renovascular disease (RVD) due to atherosclerosis has increased. RVH remains among the most common causes of secondary and treatment-resistant hypertension.

Remarkable changes have accompanied widespread application of effective antihypertensive drug therapy, statins, and other measures to manage vascular disease. Treatment options for RVH broadened well beyond surgical or endovascular therapy alone. Attempts to define the role of optimized medical therapy alone vs. combining it with revascularization with randomized, prospective trials have been complicated by major differences between patients enrolled in these trials and those encountered in practice with refractory hypertension and/or renal injury. Hence, management of RVD continues to be controversial. It behooves hypertension specialists to have a firm grasp of the pathophysiology and major syndromes associated with RVH for the benefit of their patients.

EPIDEMIOLOGY OF RVD

Many vascular obstructive lesions can lead to the syndromes of RVH. These lesions account for 1% to 2% of all cases of hypertension in the general population and their prevalence may reach up to 6.8% in the population with >65 years of age and 5.8% in cases of secondary hypertension in young adults.^3–5 Atherosclerotic renal artery stenosis (ARAS) and fibromuscular dysplasias (FMD) account for the large majority, but clinicians must be alert to other potential causes as summarized in Table 1. These can include iatrogenic forms of renal artery disease, such as those from endovascular aortic stent grafts that migrate to obstruct renal artery segments or branch vessel occlusions from renal artery stents placed across the mouth of a branch vessel.

Table 1:

Causes of renovascular hypertension

Causes of renovascular hypertension
Atherosclerotic renal artery stenosis
Fibromuscular disease
Medial fibroplasia
Perimedial fibroplasia
Intimal fibroplasia
Medial hyperplasia
Extrinsic fibrous band
Renal trauma
Arterial dissection
Segmental renal infarction
Page kidney (perirenal fibrosis)
Aortic dissection
Arterial embolus
Aortic endograft occluding the renal artery
Miscellaneous:
Hypercoagulable state with renal infarction (e.g., Lupus anticoagulate)
Autoimmune diseases (e.g., Takayasu’s arteritis, Polyarteritis nodosa))
Malignancy encircling the renal artery (e.g., Renal cell carcinoma, pheochromocytoma)

Various forms of FMD are now recognized to be common. These are noninflammatory, nonatherosclerotic arteriopathies most commonly seen in the renal and cerebrovascular territories in young adults between 15 and 55 years. Asymptomatic FMD may be identified in between of 2% and 4% of normotensive kidney donors with no identifiable renal functional abnormalities.⁶ Clinical manifestations leading to hypertension are more common in women (nearly 90%) with a mean age of 43 years and appear to be linked to smoking. Recent reviews emphasize that FMD represents an array of congenital vascular disorders that can affect cerebral and coronary vessels leading to dissection syndromes.⁷ These lesions are located commonly in the midportion of the vessel and are sometimes associated with aneurysms in the renal hilum. The most common form is medial fibroplasia with characteristic “string-of-beads” appearance consistent with alternating ridges within the vessel wall.

Atherosclerotic disease commonly develops at the origin of the renal artery, sometimes linked to areas of flow turbulence. These lesions commonly develop beyond the fifth decade and are linked to atherosclerotic risk factors, including tobacco use, dyslipidemias, diabetes, and hypertension. Imaging studies of “at risk” populations demonstrate rising prevalence by decade of age and associations with other vascular disease, including coronary, cerebral, and peripheral vascular disease. Population-based studies using duplex ultrasound indicate that more than 6.8% of individuals over age 65 have RVD of more than 60% occlusion. Doppler studies indicate progressively higher prevalence rates for older subjects with 25% of individuals above age 70.⁸

It must be emphasized that the above prevalence estimates for RVD reflect detection based on imaging, not necessarily based on clinical or hemodynamic significance. Clinical manifestations of RVD are remarkably heterogeneous, as illustrated in Figure 1. Many lesions produce only minimal hemodynamic effects and are clinically silent until they progress to a “critical” level associated with activation of pressor mechanisms and/or triggering inflammatory or ischemic injury.

Figure 1.

Clinical manifestations of renovascular disease. Abbreviation: CV, cardiovascular disease.

PATHOPHYSIOLOGY OF RVH

Occlusive RVD leading to reduced renal perfusion pressures were shown to raise systemic BP, largely attributed to studies by Goldblatt and Loesch in the 1930s. Studies of this phenomenon led to identification of the renin–angiotensin–aldosterone system (RAAS) that activates multiple pressor pathways (Figure 2), including peripheral vasoconstriction, sodium retention, vascular remodeling, activation of additional pressor mechanisms including endothelin and sympatho-adrenergic pathways, and inflammation.^9,10 These effects develop over varying time intervals and can be transient. A full discussion of these pathways is beyond the scope of this review and can be obtained elsewhere. Syndromes associated with unilateral RVD commonly assume a normal contralateral kidney (designated 1-clip-2-kidney RVH) that can offset rising systemic BP with pressure natriuresis and make hypertension angiotensin-dependent. When no contralateral kidney is present or able to induce natriuresis (designated 1-clip-1-kidney RVH), circulating levels of plasma renin activity fall and the BP exhibits more “sodium sensitive” characteristics and is less angiotensin dependent. In clinical practice, the contralateral kidney is rarely normal and most patients exhibit overlap features of these 2 formulations. However, a few elements warrant particular emphasis. First, studies in humans suggest that sufficient vascular obstruction to induce renin release requires lowering post-stenotic renal perfusion pressures by at least 10–20 mm Hg (or 20% as compared to aortic pressures) as measured by translesional gradients.¹¹ Achieving such pressure reductions generally requires cross-sectional luminal obstruction well beyond 70%. An important corollary of this observation is that failure to detect a pressure gradient across a stenotic lesion makes it unlikely that RVH is present. Second, despite reductions in post-stenotic pressures and 30–40% of renal blood flow, tissue oxygenation and renal parenchyma can be well preserved as demonstrated in clinical studies.¹² This reflects the high levels of blood flow normally delivered to the kidney related to its filtration function. These levels of blood flow normally far exceed the oxygen requirements for metabolic process within the kidney. Hence, applying medical therapy to reduce systemic BP and thereby further reduce renal artery pressures and flow usually can be tolerated for many patients without progressive kidney damage.¹³ As a result, many patients with RVH remain undetected and are treated simply with antihypertensive medications, particularly if only one kidney is affected. Third, the function and viability of the kidney ultimately requires adequate oxygenated blood. When reduced perfusion exceeds the tolerance of the post-stenotic kidney, overt tissue hypoxia develops¹⁴ activating oxidative and inflammatory injury pathways within the kidney as illustrated in Figure 3.^15,16

Figure 2.

Pathogenic pathways in renovascular hypertension. Abbreviations: ACE, angiotensin-converting enzyme; LV, left ventricle.

Figure 3.

Pathways of kidney injury in atherosclerotic renovascular disease. Abbreviations: GFR, glomerular filtration rate; IL, interleukin; MCP, monocyte chemoattractant protein; RAAS, renin–angiotensin–aldosterone system; TGF, tissue growth factor.

Furthermore, it is important to highlight that while the post-stenotic kidney has reduced perfusion, the contralateral kidney undergoes hyperperfusion and glomerular hyperfiltration associated with RAAS activation from the stenotic kidney. In these patients, exposure to prolonged hypertension is associated with development of arteriolosclerotic lesions and parenchymal injury of the contralateral kidney. This process can lead to proteinuria sometimes observed in the patient with RVH, and its persistence results in pathological change from secondary focal segmental glomerulosclerosis of the contralateral kidney.^17,18 Indeed, previous reports indicate that proteinuria observed in unilateral RVH is derived from the contralateral kidney.¹⁹ Thus, contralateral kidney is involved in the pathophysiology of RVH and progressive renal injury. In light of these observations, RAAS inhibition by angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) is desirable for to reduce hyperfiltration in the contralateral kidney and to decrease proteinuria in RVH. Remarkably, parenchymal fibrosis rarely develops in patients with FMD, unless complicated by dissection and/or thrombus formation leading to renal infarction. These observations suggest that remodeling mechanisms and injury in the post-stenotic kidney are related partly to the atherosclerotic milieu itself.

CLINICAL MANIFESTATIONS AND DIAGNOSIS OF RVD

RVD is associated with a spectrum of clinical manifestations as illustrated in Figure 1. Recognizing these manifestations and their progression within individual patients forms the framework for treating RVD. Symptoms may range from mild-to-severe hypertension to circulatory congestion and kidney failure. Many patients with atherosclerotic RVD present with incidental disease identified during vascular imaging for different reasons.^16,20,21 Such patients often remain effectively treated with medical therapy alone. With more severely reduced kidney perfusion, activation of additional pressor mechanisms can produce severe, sometimes, rapid BP elevations leading to accelerated target-organ injury superimposed upon pre-existing essential hypertension.^22,23 Sodium and water retention contribute to circulatory congestion and pulmonary edema in patients with left-ventricular dysfunction, particularly when both kidneys are affected and loss of renal mass are present. Chronic activation of the RAAS is implicated in the development of abnormal left-ventricular remodeling leading to cardiac dysfunction. These processes reinforce a feedback cycle that contributes over time to accelerated progression of renal and myocardial damage.²⁴ Ultimately, prolonged reduction of blood flow with tissue hypoxia produces irreversible kidney damage and fibrosis, often designated “ischemic nephropathy”.

Imaging

Identification of RVD hinges upon demonstration of large vessel occlusive disorders and is therefore dependent upon imaging. The precise advantages and characteristics of various vascular imaging methods are beyond the scope of this review. Digital subtraction angiography is the gold standard for characterizing these lesions, but is an invasive and expensive procedure, usually combined with endovascular procedures including dilation and stent placement. Major advances in noninvasive vascular imaging allow more frequent detection and precise diagnostic assessment with use of Doppler ultrasonography, computed tomography angiography, and magnetic resonance (MR). Duplex Doppler renal ultrasonography is an excellent initial imaging tool and can provide both functional and structural assessment. These studies are relatively inexpensive and suitable for serial studies to determine progression and/or restenosis within affected kidneys. We suggest that renal artery duplex ultrasound should be routinely conducted for patients with significant hypertension and otherwise unexplained azotemia. As a practical matter, limitations of this technique include dependence upon operator skills and patient body habitus that may vary widely between institutions. In some cases, additional computed tomography and/or MR angiographic studies may be warranted to better define vascular anatomy, renal functional characteristics and anomalies before proceeding with intra-arterial angiography. The main limitations of these imaging studies include the concern for contrast nephropathy with computed tomography angiography and risk of developing nephrogenic systemic fibrosis in patients with significant renal insufficiency [glomerular filtration rate (GFR) <30 ml/min/1.73 m²] receiving gadolinium with MR.^25,26 Consideration for additional imaging, including intra-arterial angiography, may vary widely depending upon specific clinical goals for each patient. The actual requirements for an individual subject likely will reflect the degree of commitment to act on the information to be obtained, namely the level of commitment to pursue revascularization procedures. Another modality not yet widely utilized in the clinical practice for functional evaluation of ARAS is blood oxygen level-dependent MR imaging. This is a noninvasive technique for evaluating renal tissue oxygenation that requires no contrast exposure. blood oxygen level-dependent MR imaging is based on paramagnetic properties of deoxyhemoglobin, whereas oxyhemoglobin is diamagnetic. The presence of deoxyhemoglobin affects the T2* relaxation time of neighboring water molecules and in turn influences the MR imaging signal of T2*-weighted (gradient echo) images. The rate of spin dephasing R2* (R2:1/T2) thereby is closely related to the tissue content of deoxyhemoglobin. As the capillary blood pO2 is normally in equilibrium with the surrounding tissue, changes in R2* levels represent changes in tissue pO2. blood oxygen level-dependent MR imaging can provide critical insights into changes in renal function prior to the onset of irreversible renal injury and may identify patients most likely to gain from measures to reverse or repair disorders of tissue oxygenation.²⁷

Treatment of RVH

As with all forms of hypertension, the overall goal of managing RVH is to reduce the morbidity and mortality associated with elevated BP. A second goal is to protect the circulation and function of the kidneys. As noted above, many of the pressor pathways, including activation of the RAAS, are activated at reductions of post-stenotic pressures and blood flows that are well tolerated by the kidney itself. As a result, antihypertensive drug therapy often can be implemented with effective BP reduction and minimal adverse effects upon the post-stenotic kidney(s).

Patient selection.

Achieving BP control should be obtained both by integrating medical and revascularization maneuvers. For younger subjects with FMD, many of whom will require lifelong therapy, attempting renal artery revascularization with percutaneous renal artery angioplasty alone may limit the need for ongoing medical therapy with low risk.²⁸ For older subjects with ARAS, the efficacy of revascularization routinely requires stenting, is more limited and likely will not reduce antihypertensive drug therapy requirements much. Several prospective, randomized trials have failed to show major clinical benefits from angioplasty with stenting in atherosclerotic patients, albeit with limited generalizability.²⁵ As a result, many would argue that optimizing medical therapy should be the initial step for nearly all patients. The response, or lack thereof, to optimizing medical therapy is often an important element in deciding on interventional maneuvers Figure 4.

Figure 4.

Management of renovascular hypertension and ischemic nephropathy. Abbreviations: ACE, angiotensin-converting enzyme; eGFR, estimated glomerular filtration rate; RAS, renal artery stenosis.

Medical management of RVH.

Prior to the introduction of agents that block the RAAS, drug therapy for RVH was limited and often poorly tolerated. Reports of accelerated hypertension and malignant-phase hypertension, progressive encephalopathy, and/or circulatory congestion included patients with RVH, occasionally leading to therapeutic nephrectomy as a life-saving measure.²⁹ Beginning with the introduction of ACE inhibitors, and later ARBs, effective BP control became more practical in the 1990s. Combining these agents with calcium channel blocking agents, diuretics, and other classes has led to effective BP control with drug therapy alone for the majority of uncomplicated RVH patients. For many patients with moderate RVH (sometimes undiagnosed), medical therapy achieves satisfactory BP control that needs no further diagnostic study or intervention.

Should ACE/ARB therapy be included for all patients with RVH? Because of the pivotal role of RAAS activation in the development of RVH, it seems intuitive that these agents should be preferred therapy. Several prospective, randomized trials utilizing ACE/ARB therapy for patients with atherosclerotic disease elsewhere indicate a mortality benefit during long-term therapy, particularly for those with reduced estimated GFR (eGFR).^30,31 Registry data from Canada and elsewhere suggest that patients with identified RVD treated with ACE/ARB rx have reduced mortality.^32,33 Enthusiasm for RAAS blockade is tempered somewhat by the realization that removal of angiotensin effect from the efferent arteriole can be associated with reduced glomerular filtration pressures, particularly under conditions of limited arterial inflow to the kidney. Hence, some clinicians are wary of including ACE/ARB therapy in patients with “unexplained” creatinine elevations. Some of the early prospective antihypertensive trials comparing medical vs. revascularization therapy excluded ACE inhibitors from the drug regimen. Examination of the pretrial use of ACE/ARB therapy in subjects enrolled in the CORAL trial revealed wide variation in their use.³⁴ Diabetic and proteinuric patients were more likely to be treated with these agents, whereas pre-existing azotemia was associated with less use. This was particularly relevant for the CORAL trial, as all 947 enrolled subjects were required to be treated with ACE/ARB therapy. Withdrawal of RAAS blockade in CORAL was infrequent. Registry data from the United Kingdom demonstrate that most patients with clinically verified RVH tolerated RAAS blockade, even with bilateral disease.³⁵ Some subjects who developed an abrupt rise in creatinine were re-challenged successfully after revascularization. Taken together, authorities experienced in treating RVH tend to favor RAAS blockade as part of the medical regimen, particularly with unilateral RVD. If and when unexplained loss of GFR develops, particularly under conditions of volume depletion, it is prudent to withdraw RAAS blockade, at least temporarily.³⁶ Recovery of GFR under these conditions is an important clue that the degree of renovascular compromise has reached critical levels and may warrant consideration of renal revascularization.

Because atherosclerotic disease is a systemic disorder, RVH patients should routinely be treated with statin therapy and lifestyle measures including withholding tobacco products. Statins have been shown experimentally to modify the microvascular milieu with the kidney and limit fibrosis and inflammatory damage. Statin-treated patients subjected to nephrectomy of completely occluded kidneys demonstrate reduced activation of transforming growth factor-beta and interstitial fibrosis as compared to those not treated with statins.³⁷ Hence, this routinely should be part of medical therapy of patients with ARAS.

Goals of therapy for RVH are similar to those of treating all patients with hypertension and cardiovascular risk. Many of these patients have associated atherosclerotic disease, diabetes, and reduced eGFR (e.g., stage 3 chronic kidney disease (CKD)). Recent data from SPRINT and ACCORD address the potential benefits and risks of lowering BP goals in patients with essential hypertension with and without diabetes.^38,39 Although some controversies remain about the relative risks and benefits of lower goals, mortality and stroke events were reduced in SPRINT and possibly would have been in ACCORD with larger numbers.^40,41 These trials excluded subjects with known RVH, but some were likely included. The CORAL trial effectively utilized target BP ranges below 130/80 mm Hg for subjects with diabetes and/or stage 3 chronic kidney disease.

A major element of management for RVH concerns the risk for progressive vascular disease during long-term therapy. Prospective trials of ARAS using high-accuracy duplex ultrasound during the 1990s indicated a meaningful progression in 30–50% of subjects over 3–5 years.^42,43 These were defined by a rise in ultrasound peak systolic velocities of more than 100 cm/s. Remarkably, rates of identifiable change in serum creatinine were considerably lower, consistent with compensation by the remaining kidney to mask loss of post-stenotic kidney function. Some patients with RVH lose function in the post-stenotic kidney completely, manifest by complete occlusion on arteriography in 14% of subjects treated medically in one of the hypertension trials.⁴⁴ The single largest component of trial endpoint in both CORAL and ASTRAL was a loss of eGFR, which occurred both in medically treated and revascularized subjects. Meaningful loss of eGFR (defined as more than 30% reduction from baseline) in CORAL ranged between 16% and 18% of enrolled patients.⁴⁵ Similar decrements in eGFR were observed in patients subjected to renal revascularization (see below).

Renal revascularization in the Management of RVH.

Soon after the early recognition of RVH as a clinical syndrome, removal of the affected “pressor” kidney was occasionally effective at reversing hypertension, providing confirmation of the role of the kidney. This was infrequent, however, and associated with obvious loss of kidney function. Surgical restoration of renal blood flow became practical in the 1960s and led to wide experience with surgical renal revascularization in major centers. While sometimes dramatically effective both for reversal of RVH and salvage of kidney function, surgical approaches in older patients with widespread atherosclerotic disease poses considerable morbidity and mortality risk.^46,47 It is now reserved primarily for individuals with associated aortic surgical disease and/or failed endovascular repair.

The development of endovascular interventional techniques has been a major advance in managing vascular disease. It is now possible to restore vessel patency in the large majority of patients with high-grade ARAS and FMD.⁴⁸ Stent placement is warranted for ARAS and is associated with greater long-term patency than angioplasty alone. With low-profile systems and technical advances to minimize endovascular trauma, complication rates from atheroembolic disease have fallen to low levels, as we have reviewed. The use of endovascular procedures for renal artery revascularization rose exponentially during the 1996–2005 decade.^49,50

When should revascularization be applied for RVH? This question has been central to multiple small trials regarding BP control and several larger trials addressing the additive benefits of revascularization regarding renal function and cardiovascular outcomes. Numerous observational series report improved BP control and occasional dramatic recovery of kidney function in patients with both FMD and ARAS as the basis for RVH.⁵¹ However, prospective randomized trials reported between 1998 and 2015 fail to identify additional benefits from endovascular stent revascularization for ARAS when added to medical therapy. These have been systematically reviewed at the request of the Agency for Health Care Quality Research (AHCQR).⁵² These trials suffered from limited recruitment, partly due to reluctance from clinicians to randomize patients with severe disease that are known to benefit from treatment in some cases. As the authors note, nonrandomized series of complex patients report improved BP outcomes and recovery of kidney function as well as resolution of congestive cardiac failure after endovascular stent therapy Table 2. As a result, patients selected for randomization overrepresent “mild disease” with easily achieved BP control, relatively preserved renal function and absence of circulatory congestion. These trials all have been underpowered to detect differences in mortality over limited time periods.

Table 2:

Widespread blood pressure variation after PTRAS in randomized and non-randomized studies

Study	Date enrollment	Intervention	N	Baseline SBP/DBP [MAP], mean, mm Hg	Blood pressssure ∆SBP/DBP mm Hg	Comments
Ziakka et al.,200865 (RCT)	NA	PTRAS	36	178/88	Cured: 11% Improved 67%	Mean stenosis 74% ARAS Enrolled 82 patients who had ARAS demonstrated by an angiogram
Scarpioni et al.,200566 (NITER-RCT)	NA	PTRAS	24	148/79	Cured: 0%	Stenosis ≥70%, renal failure, HTN on ≤5 medications
Bax et al.,200967 (STAR-RCT)	2000–2005	PTRAS	64	160/83	∆ –9/–6	>50% ostial ARAS with CKD CrCl<80 mL/min per 1.73 m2 according to the Cockcroft and Gault formula
Wheatley et al.,200913 (ASTRAL-RCT)	2000–2007	PTRAS	403	149/76	∆ –8/–3	% Stenosis(no data) with substantial ARAS with uncontrolled HTN or unexplained CKD
Marcantoni et al.,201268 (RASCAD-RCT)	2006–2009	PTRAS	43	133/73	∆ –6/–2	50% and ≤80% ARAS with CKD ≤4 mg/dL and incident HD, but without AMI. ARAS >80% were excluded because at the time the study was design
Cooper et al.,201445 (CORAL-RCT)	1995–2007	PTRAS	459	150/NA	∆ –17/NA	≥60% ARAS with uncontrolled HTN (SBP≥155 mm Hg while receiving two or more antihypertensive medications) and CKD eGFR<60. However, recruitment and intervention protocols changed over time allowing patients W or WO hypertension
Hanzel et al.,200569 (NCP)	NA	PTRAS	26	162/82	∆ –15/–8	≥70% ostial ARAS with non−proteinuric CKD scr ≤2.0 mg/dL. Excluded patients with known parenchymal renal disease
Arthurs et al.,200770 (NCR)	2001–2005	PTRAS	22	162/75	∆ 4/5	≥60% ostial ARAS with >6 mo HTN >140/90 and scr ≥1.5.4/18 in the medical arm had previous angioplasty
Ditchel et al.,201071 (NCR)	1999–2007	PTRAS	47	145/75	∆ –3/–1	>75% stenosis by MRA or aortic ratio on duplex US >3.5 with CKD (defined as eGFR 15−60 mL/ min/1.73m–2)
Kalra et al.,201054(NCP)	1995–2007	PTRAS (Germany) PTRAS (UK)	472 89	144/78 157/81	∆ –10/–4 ∆ –13/–9	>50% ARAS with a subset with decompensation. UK: after enrolment into the ASTRAL trial. Germany, no ARAS excluded
Kane et al.,201072 (NCPR)	NA	PTRAS	50	154/NA	∆ –28/NA	70% stenosis and uncontrolled (accelerated or resistant) HTN or CKD 3–5(non-dialysis)
Cianci et al.,201173 (NCP)	2004–2009	PTRAS	53	160/NA	∆ –5/–2	≥70% stenosis ARAS and without diabetes mellitus
Sofroniadou et al.,201274 (NCP)	1997–2003	PTRAS	26	177/90	∆ –28/–13	>70% unilateral ARAS and/or FPE, AKI, and refractory HTN:eligible for PTRAS >50% unilateral ARAS w/wo HTN and wo AKI or FPE: medical therapy
Ritchie et al.,201422 (NCP)	1995–2011	PTRAS PTRAS (RDKF & RHTN) PTRAS (RHTN)	127 11 33	163/83 177/86 175/87	NA ∆–45/–16 ∆–20/–8	>50% unilateral ARAS wo occlusion. Exclusion: unilateral occlusion and insignificant contralateral stenosis
Rocha−Singh, 201175 (NOR)	NA	PTRAS	286	179/83	∆ –25/–6	≥70% de novo or restenotic ARAS with uncontrolled HTN and CKD (≤3.0 mg/dL)

Abbreviations: AKI, acute kidney injury; AMI, acute miocardial infarction; ARAS, atherosclerotic renal artery stenosis; CKD, chronic kidney disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; ESRD, end stage of renal disease; FPE, flash pulmonary edema; HD, hemodialysis; HTN, hypertension; N, number of participants; NA, not available; PTRAS, percutaneous transluminal renal angioplasty with stent; RCT, randomized clinical trial; RRT, renal replacement therapy; SBP, systolic blood pressure; scr, serum creatinine; UK, United Kingdom; W, with; WO, without; ∆:change.

Notably, some investigators associated with the prospective trials independently report subsets with distinct mortality benefits associated with renal revascularization. The half-cohort of CORAL patients with low urinary protein excretion rates, for example, had reduced cardiovascular events and mortality over a 4-year period.⁵³ Participants from ASTRAL were combined with subjects treated in Germany and experienced substantial improvements in mortality and progressive disease.⁵⁴ Registry data from the United Kingdom suggest that specific “high-risk” clinical syndromes, including episodes of pulmonary edema and/or rapidly deteriorating GFR with hypertension, have ominous prognoses and benefit considerably from revascularization procedures despite medical therapy.²² It is clear that selected patients with progressive vascular occlusive disease benefit substantially from restoring renal blood flow. It is incumbent on clinical hypertension specialists to recognize and threat these individuals.

Recurrent disease and follow-up after Stenting.

Despite restoring main vessel patency, restenosis can develop in up to 14–18% of subjects followed for a year.⁵⁵ Recommendations for follow-up include surveillance ultrasound as well as BP and renal function. Some institutions favor antiplatelet agents such as clopidogrel for several months after stenting, although data are limited to support this. Reports of angiographic estimates for restenosis suggest that ultrasound measurements of peak systolic velocities rise after stenting, making the thresholds for identifying “high-grade” stenosis approximately 100 cm/s higher than without having a stent in place.⁵⁶

When is the likelihood of benefit from revascularization past? This question is at the center of the debate about endovascular therapy. The approach to the care or complex renal patients must be individualized and include close review of the time-course of kidney disease progression, imaging studies, and association with the manifest clinical syndromes. Patients with nearly or completely occluded vessels, ultrasound evidence of high resistance indices ≥0.8, marked renal atrophy (size <7 cm), absent function measured by split nuclear scan, and/or significant albuminuria are believed to have worse outcomes after revascularization.^53,57,58 Predictors of benefit regarding both improvement in BP and recovery of kidney function depend strongly on the duration of the abnormality.⁵⁹ In general, the more recent the development of accelerated hypertension, the more likely the patient is to benefit from restoring vessel patency with stenting.⁶⁰ This tenet underscores the multiplicity of factors triggered by reduced renal perfusion that increase systemic BP, only some of which are reversible. Similarly, declining kidney function may be partially a functional loss that can be recovered, but eventually is associated with activation of injury and inflammation within the kidney that persists—and may progress—despite restoring kidney perfusion. Follow-up data from more than a thousand ARAS patients undergoing renal revascularization demonstrate a definite relationship between the level of pretreatment eGFR and the degree of proteinuria as predictors of both progressive renal disease and death.⁶¹ Hence, there is a point beyond which recovery of kidney function and/or BP benefit is reduced. For individuals with diabetes, chronic kidney disease 3b or higher and/or substantial proteinuria, the likelihood of benefit from renal artery stenting procedures is limited.

An integrated approach and future directions in the management of RVH.

Recent developments in the field confirm the remarkable tolerance of the renal circulation to moderate reductions in blood flow. Sampling of the renal vein effluents indicate cytokine profiles that are proinflammatory and may be partially protective against repetitive episodes of hypoperfusion, suggestive of “ischemic preconditioning”.^62,63 Experimental studies along with preliminary clinical studies suggest that administration of mitochondrial protective agents may mitigate oxidative stress injury at the time of revascularization.⁶⁴ Additional studies suggest a role for mesenchymal stem cell therapy to stimulate angiogenesis and restore tissue oxygenation in experimental and human ARAS, offering the potential to boost intrinsic repair of kidneys beyond high-grade stenotic lesions.^65,66 These areas are promising areas of ongoing research.

As a practical matter, clinicians are routinely presented with challenging, sometimes resistant, hypertension in patients with reduced kidney function. We follow the general guidelines for management of such patients outlined in Figure 4. When reduced GFR or high vascular risk are present, it seems prudent to examine the renal circulation and anatomy with either renal artery duplex or computed tomography angiography to establish the presence or absence of RVD, its severity, whether bilateral or unilateral, and the relative size and functional characteristics of the kidney. Antihypertensive drug therapy should be managed progressively as needed to achieve goal BPs for the individual. This normally should include agents that block the RAAS and is undertaken as part of the decision as to whether further consideration need be given to diagnostic and interventional procedures for RVH. If goal BP can be achieved and renal function remains stable and adequate, little is likely to be gained from further studies. The clinician nonetheless has an obligation to recognize and follow this individual for progressive disease. If adequate BP cannot be readily achieved and/or conditions develop defining “high-risk” clinical syndromes with refractory hypertension, progressive renal dysfunction and/or episodes of circulatory congestion, we strongly recommend moving forward with further characterization and restoration of the renovascular supply. More than ever before, clinicians focused on managing complex hypertension will be called upon to balance potential benefits and risks in the management of RVH.

DISCLOSURE

The authors declared no conflict of interest.