How to manage renovascular hypertension

Introduction

A suspected case of renal hypertension's holds relative simplicity in theoretical terms yet it masks a rather complicated situation in clinical practice. In theory, renal artery stenosis results in increased blood pressure values and declined renal function; as a consequence, removal of the obstruction (the stenosis) should allow proper hypertension (HTN) control and good restoration of renal function.
In clinical practice, however, the physician must make difficult decisions, personalised for each patient. Questions are:

• When must we suspect RVH? 
• What is the standard protocol to manage such a patient?
• Can we consider we have found the cause for the HTN and treat it once renal artery stenosis is diagnosed?
• Are these two coexisting clinical entities that share no causal link, and simply influence on each other? 
• Should we, or not, turn to revascularisation therapy? 
• If so, which is the best technique – surgery or angioplasty? 
• Where does pharmacologic therapy stand? 

This paper aims to answer some of these questions, as an update to diagnostic and therapeutic challenges in this field. 

Background

Renovascular hypertension (RVH) is the most frequent form of secondary hypertension. It is most often diagnosed among elderly patients and has significant effects on prognosis and patient outcomes. An increased risk of cardiovascular (CV) events and death (16% per year, six times more than end-stage renal disease) in patients 67 years of age and older with a new diagnosis of RVH was revealed on examination of Medicare records (1). 
Renal artery stenosis causes clinical syndromes that go from asymptomatic obstruction (incidental renal artery stenosis) to RVH and ischemic nephropathy. In turn, thes syndromes are often complicated by accelerated CV disease - congestive heart failure, stroke and secondary aldosteronism.
Strictly speaking though, renovascular hypertension can only be diagnosed in retrospect, based on the reaction of blood pressure (BP) values to a given therapeutic intervention - to remove the stenosis. Thus, RVH is correctly and properly diagnosed 6 to 12 weeks after an intervention, when BP is lower than it was prior to the intervention, with the patient taking the same or fewer antihypertensive medications. 

Stenosis

In contrast to the pathophysiology-based definition of RVH seen above, the diagnosis of renal artery stenosis (RAS) takes into account several anatomical criteria; classically, RAS is diagnosed when a >75% narrowing of the diameter of a main renal artery, or >50% luminal narrowing with a poststenotic dilatation are found (2). The distinction between RVH and RAS is important. There are patients with advanced RAS in whom BP values are normal, and RVH patients who due to ischemic nephropathy presumably, necessitate surgical small kidney removal yet who do not reach normalisation of BP values - only 25% of these patients do. Atherosclerotic disease of renal arteries may progress to complete arterial occlusion. When the entire renal parenchyma is affected (i.e., in bilateral stenosis or stenosis to a solitary kidney), renal artery stenosis may cause severe deterioration of renal function, often referred to as ischemic nephropathy. This represents an important consequence of atherosclerotic renovascular HTN, which, in many cases, may remain undetected. It is a frequent cause of end-stage renal disease and is associated with a poor prognosis even after initiation of renal replacement therapy. 

Etiology

Causes for renovascular HTN are:

• Atherosclerosis and fibromuscular dysplasia.
• Less frequent causes which may lead to or accelerate development of RVH include systemic vasculitis, renal arterial aneurysm, arteriovenous fistula, systemic emboli generated during endovascular manipulation, aortic dissection, renin-secreting renal tumor, extrinsic compression of either kidney or renal artery due to tumors or metastases and subcapsular intrarenal hematoma (3).

Atherosclerotic RAS is the predominant lesion detected in patients over 50 years of age; it frequently affects the ostium and the proximal one-third of the renal artery's main branch. Atherosclerosis accounts for nearly 90% of renovascular hypertension. Many individuals with atherosclerotic renal artery lesions have years of preexisting essential hypertension, active smoking history, and coexisting diabetes mellitus.
The true prevalence of atherosclerotic renal artery disease in the general population is unknown. In selected populations displaying atherosclerotic disease of other vascular territories, prevalence is around 10-30% (4). One must note that even among those in whom RAS is documented, only in some of these patients does the stenosis have pathophysiological significance, thus explaining the highly heterogeneous outcomes of studies investigating benefits of renal revascularisation. 
Fibromuscular dysplasia (FMD) is a noninflammatory, nonatherosclerotic vascular disease that preferentially affects small - to medium - sized arteries. Most FMD lesions are caused by medial fibroplasia, consisting of banded lesions in the mid portion of the renal arteries. Fibromuscular dysplasia may generally occur in any vascular territory, including the coronary bed, but usually affects the renal arteries. Most frequently fibromuscular dysplasia is located in the distal two-thirds of the renal arteries, their secondary or distal branches. Screening angiography in potential kidney donors indicates that such lesions can be asymptomatic and may be detected in up to 3% to 6% of normotensive individuals (5). When they reach sufficient hemodynamic severity to produce renovascular hypertension, they most commonly affect women between 15 and 50 years of age. Screening angiography of a population with resistant HTN showed a FMD prevalence of 16% (6).
Revascularisation, in most cases, restores blood pressure values, and thus cures HTN. Fibromuscular dysplasia occurring as an isolated disease does usually not associate with renal failure. 

Pathophysiology

To make a renovascular hypertension diagnosis, RAS evaluation is required but not sufficient. When stenosis is severe enough (i.e., when it causes at least 75% reduction in diameter), renal hypoperfusion and functional changes in the affected kidney may ensue, leading to activation of the renin-angiotensin-aldosterone system, which plays a central role in the development of RVH. When the stenosis is due to atherosclerosis, however, it is sometimes difficult or impossible to establish whether it is the stenosis that is causing the hypertension, or whether the hypertension is preexisting essential hypertension. Under these circumstances, it may be difficult to predict whether the revascularisation procedure will lower blood pressure.
The mechanism is different in unilateral or bilateral renal artery stenosis:

• In significant unilateral stenosis the plasma renin activity increases as a result of ischemia in the affected kidney. The activation of the renin-angiotensin-aldosterone system (RASS), leads to excessive secretion of angiotensin II, with secondary vasoconstriction and aldosterone, resulting in water and sodium retention. The mechanism was described in 1971 and has been referred to since as "angiotensin-dependent hypertension” (7). The reaction in the contralateral kidney, the pressure diuresis, is however insufficient to counterbalance the increase in BP values. 
• In the case of bilateral renal artery stenosis, the increase in angiotensin II and aldosterone levels results in water and sodium retention; in the absence of a healthy kidney to balance it, volume-dependent HTN develops and suppresses renin secretion. This hypertension can be converted back to angiotensin II dependency by sodium and volume depletion. For example, excessive diuretic therapy may reduce volemia, but restores renin secretion, activates the RASS, which further inhibits sodium excretion, thus leading to resistance to diuretic therapy. 

Clinical clues

Clinical settings in which RVH should be considered in the differential diagnosis:

• Significant atherosclerosis in other vascular territories (is associated with atherosclerotic RAS);
• Onset of HTN before the age of 30 (consider FMD) or after 55 years old (especially if there is no family history of hypertension);
• Abdominal bruit (especially diastolic component); 
• Worsening of previously controlled hypertension;
• History of “accelerated/malignant hypertension” or refractory hypertension to an appropriate three-drug regimen;
• Unilateral small kidney; difference of >1.5 cm in length between the two kidneys (renal ultrasound);
• Rapid deterioration in renal function (spontaneous or in response to ACE inhibitor or ARB);
• Recurrent congestive heart failure or flash pulmonary edema in a hypertensive patient, especially when left ventricle ejection fraction is preserved;
• Keith-Wegener-Barker grade III or IV fundi;
• Angina without significant coronary artery disease in hypertensive patients. 

Diagnostic testing 

The screening tools developed for diagnosis of renovascular HTN are either based on physiological parameters (e.g. renin activity or blood flow to each kidney), or on anatomic parameters (CT angiography and MR angiography), while others combine some of each (Doppler ultrasound, captopril scintigraphy). Useful noninvasive tools frequently used in clinical practice are: duplex ultrasonography (DUS), CT angiography (CTA) and MR angiography (MRA). Arteriography remains the gold standard to RAS diagnosis, however with a degree of invasiveness which prevents it from becoming a screening tool. 

• Duplex ultrasonography 

It has high sensitivity (82%) and high specificity (90%), and is relatively inexpensive. It also has its limits – the operator dependent variability and the technical difficulties in the case of obese patients or in those with overlying bowel gas. There are significant renal artery stenoses of accessory renal arteries which may lead to renovascular hypertension and are difficult to identify in ultrasound studies. Furthermore, it may be negative in patients with FMD, making other imaging modalities mandatory. It is often difficult to differentiate using Doppler studies between a 50-70% vs a >70% stenosis, and thus the majority of ultrasonographers use a cut-off value of 50% for “significant stenoses”. In general however, DUS is a reasonable screening solution for patients in whom there is a clinical suspicion of atherosclerotic RAS. Significant RAS stenosis is diagnosed in the presence of a velocity ratio between the renal artery and aorta larger than 3.5. The resistivity index can be used to appreciate the benefit of possible future renal revascularisation therapy: an index over 0.8 suggests renal parenchymal disease, which will not improve with revascularisation. Furthermore, patients with kidneys 8 cm or less in length have a low probability to benefit from revascularisation therapy. A more recent study concluded that the resistivity index (and not post-procedural HTN) represents an independent predictor of renal function and all-cause mortality in patients with RVH (8). 
According to European Guidelines, DUS is recommended as the first-line imaging test to establish the diagnosis of RAS (class I, LOE B) (9). 

• Computed tomographic angiography

This is a very efficient imaging modality to investigate RAS, allowing for simultaneous evaluation of both the anatomic presence of a stenosis and also its physiologic effect on the kidney (Figure 1). CTA has nonetheless its limitations: excess radiation, iodine contrast (with the risk of inducing contrast nephropathy and limiting its use in patients without renal impairment), and incorrect evaluation of severity in patients with significant artery calcification. The time to reconstruct and interpret images is longer than for other screening tests. In the presence of renal artery stents, CTA is the preferred noninvasive investigation technique. It is not widely used for screening purposes and thus CTA has not been correlated with BP-lowering outcomes after intervention (10).
CTA (in patients with creatinine clearance over 60 mL/min) is recommended to establish the diagnosis of RAS according to the European Guidelines on the management of peripheral artery disease (PAD) (class I, LOE B). 

• Magnetic resonance angiography 

The method has the advantage of obtaining images similar to those acquired through aortography. MRA can be useful to appreciate renal perfusion, even though this is not part of routine evaluation. It has good specificity and sensibility – 88% for both. Moreover, MRA does not imply use of iodine contrast, which makes it useful in patients with impaired renal function. However, in patients with significant decline in glomerular filtration rate one must be cautious, as gadolinium administration has been associated with nephrogenic systemic fibrosis, a rare but untreatable fibrosing condition that primarily affects the skin, but may affect also other organs (11). MRA has a series of limitations: the evaluation of RAS is difficult in those with pre-existing stents; there is a tendency to overestimate moderate stenoses (40-69%); it has reduced accuracy in small, branch, and distal renal arteries; it cannot be carried out in claustrophobic patients or in those with metallic prostheses, cardiac pacemakers; the high cost may also represent a limitation. 
Magnetic Resonance Angiography is recommended by the European Guidelines for the management of PAD (in patients with creatinine clearance >30 mL/min) to establish the diagnosis of RAS (Class I, LOE B).

Figure 1. Computed tomography angiography – atherosclerotic left renal artery stenosis. 

A hypertensive, diabetic insulin-dependent female patient with coronary heart disease – 70% stenosis on first segment of left anterior descending coronary, with uncontrolled hypertension. 
CTA reveals an abdominal aorta with severe parietal calcifications. Main right renal artery – ostial and juxtaostial calcification, without significant stenosis. Left renal artery presents a 3 mm in length severe stenosis, 9 mm from its emergence from the aorta, with a 75% obstruction on CT evaluation, with mild post-stenotic dilatation. (Images from authors' personal collection)

Figure 2. Digital substraction renal angiograms from the same patient as Fig. 1.
A – Before angioplasty. B – After left renal angioplasty.
(Images from authors' personal collection)

• Angiography 

Renal angiography is the “gold standard” for renal artery imaging. Nearly all authorities also agree that, presuming all other criteria are met, individuals who have a very high absolute risk of renal artery stenosis or renovascular hypertension should proceed directly to renal angiography, rather than undergo an imperfect screening test. The limitations come from the degree of invasiveness, which prevents it from becoming a screening tool, and the use of iodine contrast which have the risk of inducing renal failure and anaphylaxis. 
When the clinical index of suspicion is high and the results of non-invasive tests are inconclusive, digital subtraction angiography is recommended as a diagnostic test (prepared for intervention) to establish the diagnosis of RAS (class I, LOE C).

Other diagnostic tools 

The intravenous pyelogram was one of the first diagnostic tests used for evaluation of RAS and is no longer recommended because of its poor sensitivity and high false-positive rate. 
Plasma renin activity has a low predictive value; its specificity increases with the administration of an angiotensin-converting enzyme inhibitor (conventionally, captopril is used), but with poor results in case of bilateral RAS. Furthermore, the test is limited by the need to previously stop administration of many of the main classes of antihypertensive drugs in order to obtain unbiased results. 
Captopril scintigraphy (CS) is useful for the diagnosis of unilateral RAS in patients with normal renal function; it, too, requires interruption of antihypertensive medication. A few retrospective analyses have suggested that CS results might predict BP outcomes after angioplasty/surgery. Nevertheless, the 2005 American College of Cardiology/ American Heart Association Guidelines do not recommend CS as a screening test for renovascular hypertension (12).
Renal scintigraphy without captopril avoids intravenous contrast, but only has about a 74% sensitivity and 77% specificity. It is now usually performed only after a captopril scan has been interpreted as abnormal.
According to the latest ESC Guidelines on the management of PAD, Captopril renal scintigraphy, selective renal vein renin measurements, plasma renin activity, and the captopril test are not recommended as useful screening tests to establish the diagnosis of RAS (class III, LOE B).
In all, we cannot recommend any single, ideal noninvasive test. Rather, the choice of an initial screening test should incorporate the availability and expertise at any given institution. In addition, patient related factors such as body size, concomitant medication use, and underlying renal function should be considered. However, the value of testing depends on the pretest probability of disease.

Treatment

The purpose of therapy in patients with renal artery disease is to control blood pressure and preserve renal function. Currently, there is ongoing controversy regarding therapeutic management of patients with RAS, both regarding the method used for revascularisation and its actual benefit in practice. If HTN control cannot be achieved or a decline in renal function is evident, revascularisation should be more strongly considered. The table below shows the clues that may help with this decision, personalised according to characteristics of each patient. 

Table 1. Factors influencing patient selection for revascularisation (2)

Medical management

Publication of results from most recent clinical trials indicate the intensification of antihypertensive therapy and the control of additional risk factors (smoking cessation, glycemic control, pharmacologic therapy using aspirin, statins) (13). All patients with atherosclerotic RAS should be treated according to the European Guidelines on Cardiovascular Disease Prevention (14). 
Medical therapy remains the cornerstone of treatment for renal-artery stenosis (15). ACE inhibitors, angiotensin II receptor blockers and calcium channel blockers are effective in the treatment of hypertension in the presence of unilateral RAS and may lead to slowing of the progression of renal disease (class I, level B). 
The major risk of current pharmacologic therapy resides in the decline of renal function, a clinical situation often encountered when introducing an ACE inhibitor or ARB. These drugs are efficient antihypertensives in 86-92% of RVH patients, usually in combination with a calcium antagonist and a diuretic. ACEIs and ARBs are generally well tolerated, with only 5% of cases requiring cessation during the first three months. A significant (over 30%) fall in GFR (or an over 0.5 mg/dL rise in serum creatinine) may be an indication to consider renal revascularisation. 
ACE inhibitors and ARBs are contraindicated in the case of bilateral RAS and when this lesion affects a single functional kidney.
There is evidence that thiazides, hydralazine, and beta-blockers are also effective in achieving target blood pressure in individuals with RAS (16).

Surgical revascularisation

Currently, surgical revascularisation is seldom practiced as the number of angioplasty procedures has been increasing. By-pass procedures from nonaortic donor sites (splenic, celiac, mesenteric, or hepatic artery) are more agreeable than the traditional aortic-renal by-pass and the renal endarterectomy (for technical and anatomic reasons). These procedures limit aortic manipulation and minimize atherosclerotic emboli formation, with the disadvantage of an increased perioperatory mortality rate (2-6%) mainly secondary to graft failures or other complications of widespread atherosclerotic vascular disease. 
Surgical revascularisation may be considered for patients undergoing surgical repair of the aorta, patients with complex anatomy of the renal arteries, or after a failed endovascular procedure (class IIb, level C). 
A metaanalysis of 47 retrospective or nonrandomized studies compared the outcomes in patients subjected to surgical revascularisation vs patients subjected to endovascular procedures. The results showed similar technical success rates, better long-term BP control and renal function, but slightly higher perioperative mortality (attributed to concomitant aortic surgery) (17). 

Angioplasty 

The renal percutaneous transluminal angioplasty (RPTA) is an accepted and durable treatment strategy when the etiology of RVH is fibromuscular dysplasia. The rate of restenosis varies in the range of 5 to 11% after one year (18).
In atherosclerotic renal artery disease the role of interventional therapy is a subject of controversy, as trials so far have not proven significant clinical benefits. Angioplasty for an ostial lesion, for sequential stenoses of a single artery, or for stenoses in multiple renal arteries on the same side, are all associated with an even poorer response. 
Expert opinion, especially from the fields of Cardiology and Interventional Radiology, argue that revascularisation offers the potential to improve or reverse renovascular hypertension, to salvage or preserve the renal circulation and renal function, and to improve the management of patients with refractory forms of congestive heart failure (19). Many nephrologists however argue that renal revascularisation does not offer major benefits in the control of HTN and that the periprocedural risk for complications is larger, including the less frequent renal function decline secondary to atherosclerotic embolization. In observational series, technical failures (~19%), restenosis (~13%), and persistently elevated BP (~35%) were more common. 
Angioplasty plus stenting would, in theory, have more advantages, especially when carried out in locations at high risk for restenosis. The largest experience published to date comes from Durros et al. In this study, after a 4 years follow-up, patients treated with a specific, early renal artery stent, registered a significant decrease in blood pressure values, a small decrease in number of antihypertensive drugs needed for HTN control, with an overall mortality rate of 26%. Restenosis rate varied from 10% to 30%, depending on the type of stenosis and length of follow-up (20).  
According to the current ESC Guidelines on the management of PAD, in the case of indication for angioplasty, stenting is recommended in ostial atherosclerotic RAS (Class I, LOE B). In all other clinical situations discussed within the Guidelines the level of recommendation is Class IIb:  angioplasty, preferably with stenting, may be considered in the case of >60% symptomatic RAS secondary to atherosclerosis; endovascular treatment of RAS may be considered in patients with impaired renal function. Treatment of RAS, by balloon angioplasty with or without stenting, may be considered for patients with RAS and unexplained recurrent congestive heart failure or sudden pulmonary edema and preserved systolic left ventricular function.

Clinical trials

Three studies have compared initial angioplasty without stenting with medical therapy: EMMA (Essai Multicentrique Medicaments vs Angioplastie) (21), the Scottish and Newcastle Renal Artery Stenosis trial (22) and DRASTIC (the Dutch Renal Artery Stenosis Intervention Cooperative) (23). After combining the results of these trials, patients subjected to angioplasty had a small decrease in BP values (6.3/3.3 mmHg, p 0.02/0.03) when compared to those receiving pharmacologic treatment, with a less than significant change in serum creatinine (p 0.06) (24).  
Since 2009, results have been published from new trials comparing best medical therapy versus angioplasty with stenting. However, no significant benefits were seen in revascularisation therapy of RAS. 
The ASTRAL (Angioplasty and Stenting for Renal Artery Lesions) trial, published in 2009, was based on the hypotheses that interventional therapy delays the decline in renal function. Thus, 806 patients were randomised to either receive best medical treatment plus revascularisation, or best medical therapy alone (25). Study results were negative. However, it should be noted that the study did not include patients with flash pulmonary edema, critical RAS and very severe or uncontrolled hypertension; intervention in these subsets of patients is not supported by a high level of evidence but is often performed in clinical practice. Moreover, the primary goal of this trial was to follow-up on the decline rate of renal function and not HTN control after the intervention. 
The STAR (Stent Placement in Patients With Atherosclerotic Renal Artery Stenosis and Impaired Renal Function) trial conducted on a significantly smaller number of patients (140) offered similar results (26). 
The most recently published trial on this topic, the CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) trial included 947 patients with RAS and significant HTN (on two or more antihypertensive drugs) who were then randomised to receive either medical therapy alone or medical therapy plus renal stenting (27). Even though CORAL included only patients with a significant renal artery stenosis of at least 60% of the diameter (as opposed to the 40% cut-off value used in the ASTRAL and STAR trials), no clinical benefit was proven for stenting. This trial concludes that implanting stents for moderately severe obstructive renovascular disease is no better than medical therapy alone in preventing the primary end point of death from cardiovascular or renal causes, myocardial infarction, stroke, hospitaliation for heart failure, progression of renal failure, or the need for renal-replacement therapy.
In canine models, only stenoses ³ 75% of diameter determine HTN and only those ³ 80% are associated with a decline in renal function (28). The degree of stenosis that causes a switch from aerobic to anaerobic metabolism in renal tubular cells and results in the commonly discussed, but poorly defined, condition of “ischemic nephropathy” has not been determined.
In clinical practice, results after intervention vary significantly from a slight improvement to a lack of response or even worsening of the condition. When interpreting these results, one must consider the causality between atherosclerotic renal artery disease and hypertension or renal failure (or even both). 
In summary, in the care of atherosclerotic RAS patients with refractory HTN, recurrent or refractory congestive heart failure, or worsening renal function, renal revascularisation may be considered, keeping in mind all uncertainties above mentioned. Until new treatments are found to be safe and effective, patients in everyday practice who have moderately severe atherosclerotic renovascular disease and either hypertension or stage 3 chronic kidney disease, should receive medical therapy to control blood pressure and prevent the progression of atherosclerosis. 

Conclusions 

Renal artery stenosis must be considered in any patient with a history of severe or resistant HTN, especially in those associating a decline in renal function or significant atherosclerosis in other vascular territories. Initial work-up must include renal function evaluation and lipid profile, followed by a DUS evaluation. If high-quality duplex imaging is not available, then CTA or MRA may be appropriate. From a therapeutic standpoint, patients with FMD benefit from angioplasty. Intensive medical therapy, including tight control of BP with a regimen that includes a blocker of the renin–angiotensin–aldosterone system, is appropriate. Serum creatinine and serum potassium must be closely monitored especially at drug therapy initiation and at drug dosage increments. Furthermore, patients with RAS must receive maximal medical treatment, including an antiplatelet agent and a statin, with care given to the treatment of diabetes, if present. The role of revascularisation in the treatment of atherosclerotic renal-artery stenosis is still controversial. Recently published trials did not prove superiority of interventional therapy, but most authors recommend angioplasty with or without stenting when HTN control cannot be achieved, if renal function is declining and in patients with “flash pulmonary oedema”.