Renal Artery Stenosis

In patients with atherosclerosis, the initiator of endothelial injury is not clear. However, dyslipidemia, hypertension, cigarette smoking, diabetes mellitus, viral infection, immune injury, and increased homocysteine levels may contribute to endothelial injury. 

The formation of atherosclerotic lesions involves increased permeability of endothelium to plasma macromolecules (eg, low-density lipoprotein [LDL]), increased turnover of endothelial cells and smooth muscle cells, and increased numbers of intimal macrophages. When atherogenic lipoproteins exceed certain critical levels, the mechanical forces may enhance lipoprotein insudation in these regions, leading to early atheromatous lesions.

Renal blood flow is 3- to 5-fold greater than the perfusion to other organs because it drives glomerular capillary filtration. Both glomerular capillary hydrostatic pressure and renal blood flow are important determinants of the glomerular filtration rate (GFR).[9]

In patients with renal artery stenosis, the chronic ischemia produced by the obstruction of renal blood flow leads to adaptive changes in the kidney that are more pronounced in the tubular tissue. These changes include atrophy with the following:

• Decreased tubular cell size
• Patchy inflammation and fibrosis
• Tubulosclerosis
• Atrophy of the glomerular capillary tuft
• Thickening and duplication of the Bowman capsule
• Intrarenal arterial medial thickening

In patients with renal artery stenosis, the GFR is dependent on angiotensin II and other modulators that maintain the autoregulation system between the afferent and efferent arteries and can fail to maintain the GFR when renal perfusion pressure drops below 70-85 mm Hg. Significant functional impairment of autoregulation, leading to a decrease in the GFR, is not likely to be observed until arterial luminal narrowing exceeds 50%.

The degree of renal artery stenosis that would justify any attempt at either surgical intervention or radiologic intervention is not known. One study found that when the pressure distal to renal artery stenosis was less than 90% of aortic pressure, renin release from the affected kidney was significantly elevated (renin being measured in the ipsilateral renal vein). This might be useful as a functional measurement of significant renovascular stenosis leading to hypertension and, thus, a marker of greater likelihood of benefit from angioplasty and stenting.[10, 11]

Risk factors associated with ischemic renal disease (IRD) are as follows:

• Hypertension: Of patients with IRD, 35% can be normotensive
• Advanced age: Numerous cases occur in persons aged 60-69 years; incidence increases in persons older than 70 years
• Kidney insufficiency
• Extrarenal atherosclerosis
• Diabetes mellitus
• Smoking

In young adults, fibromuscular dysplasia is a common cause of bilateral renal artery stenosis.[5]

In patients with mild hypertension, the prevalence of renal artery stenosis is probably less than 1%, while in those with acute as high as 10 % to 40% in patients with acute, severe, or refractory hypertension, the prevalence may be as high as 10-40%.[12]  Studies suggest that ischemic nephropathy may be responsible for 5-22% of advanced kidney disease in all patients older than 50 years.

A review of a random sample of Medicare claims data (patients 67 years of age and older) found that the incidence of atherosclerotic renovascular disease was 3.7 per 1000 patient-years. The prevalence decreased with advancing age; the adjusted odds ratio (OR) was 0.86 for patients age 75 to 84 years and 0.44 for those age ≥85 years, compared with those age 67 to 74 years. The prevalence was highest in whites (adjusted OR for Blacks, 0.66).[13]

RVD is less common in blacks than in whites. The incidence rate in two studies of patients with severe hypertension was 27-45% in whites versus 8-19% in blacks.[14]

Although the incidence of atherosclerotic RVD is independent of sex, Crowley et al showed that female sex (as well as older age, elevated serum creatinine level, coronary artery disease, peripheral vascular disease, hypertension, and cerebrovascular disease) is an independent predictor of RVD progression.[15]

In 1964, Holley et al reported data from 295 consecutive autopsies performed in their institution during a 10-month period.[16]  The mean age at death was 61 years. The prevalence rate of renal artery stenosis was 27% of 256 cases identified as having history of hypertension, while 56% showed significant stenosis (>50% luminal narrowing). In normotensive patients, 17% had severe renal artery stenosis (> 80% luminal narrowing). In those older than 70 years, 62% had severe renal artery stenosis.

Another similar autopsy study reported similar results, with 5% of patients older than 64 years showing severe stenosis; this figure increased to 18% for patients aged 65-74 years and 42% for patients older than 75 years.

Renal artery stenosis develops in 1%-12% of transplanted kidneys and is the principal vascular complication of kidney transplantation.[17, 18] Risk factors include older age in donors and recipients and expanded donor criteria. These cases most often occur 3-6 months after kidney transplantation.[17]

The consequences of renal artery stenosis are hypertension, which may be particularly difficult to control or may require multiple antihypertensive agents (with increased adverse effects), and progressive loss of renal function (ischemic nephropathy).

In addition, the discovery of atherosclerotic renal vascular disease (RVD) frequently occurs in the setting of generalized vascular disease (ie, cerebral, cardiac, peripheral), with the co-morbidity associated with disease in those vascular beds. Thus, any therapeutic intervention for renal artery stenosis should logically take into account the underlying prognosis associated with these co-morbidities.

Researchers have studied the natural history of atherosclerotic renal artery stenosis by obtaining images from sequential abdominal aortographs or duplex ultrasound scans in patients with documented renal artery lesions who have been treated medically. Most studies show that progressive arterial obstruction occurs in 42-53% of patients with atherosclerotic renal artery stenosis, often within the first 2 years of radiographic follow-up. The incidence rate of progression to complete renal artery occlusion in these studies ranges from 9-16%; this often occurs in patients with a high-degree stenosis. In a study of 85 patients at the Cleveland Clinic who were followed for 3-172 months, patients with mild-to-moderate stenosis remained unchanged upon follow-up, and 39% of patients with greater than 75% lesions progressed to total occlusion.[19]

Patients with ischemic renal vascular disease (RVD) present with one or more of the following clinical, historical, or diagnostic scenarios.

Because of the strong association of RVD with generalized atherosclerosis, many patients with RVD will have evidence of cerebrovascular, cardiovascular, or peripheral vascular disease  (eg, carotid bruits, history of transient ischemic attack or stroke).  Abdominal bruits are highly specific for RVD when heard over the flank and are back-and-forth in nature (ie, present during both systole and diastole).

Sudden worsening of hypertension or kidney function may occur.  Acute kidney injury or decreased kidney function may occur after initiation of antihypertensive therapy, especially with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs); an increase in serum creatinine levels of more than 15% in this setting is strongly suggestive of RVD. 

Unexplained kidney insufficiency may develop in elderly patients.

Congestive heart failure may occur with poor control of hypertension and renal insufficiency in the absence of a significant decrease in ejection fraction (so-called flash pulmonary edema).  Although flash pulmonary edema has been reported in patients with unilateral renal stenosis, it occurs more commonly in patients with bilateral renal stenosis.[6]

Obtain serum creatinine levels to assess the level of renal dysfunction. Serum levels can be used to calculate an estimated creatinine clearance based on the Cockcroft-Gault equation or the Modification of Diet in Renal Disease (MDRD) formula.[20]

Perform a 24-hour urine collection, or obtain a protein-creatinine ratio on a random void urine specimen, to more accurately assess the level of renal dysfunction and to measure the degree of proteinuria. Vascular renal disease is more often associated with minimal-to-moderate degrees of proteinuria; levels rarely reach the nephrotic range.

Perform urinalysis to ensure that red blood cells or red blood cell casts (a hallmark of glomerulonephritis) are absent.

Perform serologic tests for systemic lupus erythematosus or vasculitis if these conditions are suggested (eg, antinuclear antibodies, C3, C4, antinuclear cytoplasmic antibodies).

Studies designed to assess the renin-angiotensin system are of little diagnostic utility in patients with atherosclerotic renovascular disease (RVD).

Peripheral renin activity reflects volume status in healthy individuals. It may be elevated in patients with renovascular causes of hypertension and in those with essential hypertension. It is equally nondiscriminatory in patients with atherosclerotic RVD with ischemic nephropathy.

Ultrasonography

Renal ultrasonography scanning is performed frequently in patients with renal dysfunction. Ultrasonography scanning is an anatomic, not a functional, test. The only contribution to the entity of renal artery stenosis is a suggestion of the diagnosis when examination results indicate significant asymmetry of kidney size (ie, size discrepancy of >1.5 cm). Additionally, ultrasonography may be useful in detecting the presence of a solitary kidney, in which case, renal artery stenosis of that solitary kidney takes on more significant prognostic and therapeutic importance.

Duplex ultrasonographic scanning combines a B-mode ultrasonographic image with a pulse Doppler unit to obtain flow velocity data. The technique is noninvasive, relatively inexpensive, and can be used in patients with any level of renal function. The test is very sensitive and specific (98%); however, it is very labor intensive and technician-dependent. Thus, duplex ultrasonographic scanning may not be available in many medical centers.

Radermacher et al reported that the renal resistance index, calculated through the use of color Doppler ultrasonography, can be used to predict the outcome of invasive therapy  for renal artery stenosis.Patients with a resistance index (calculated as [1 - end-diastolic velocity divided by maximal systolic velocity] x 100) greater than 80, indicating small vessel and large vessel disease, were likely to have a poor response to angioplasty or surgery with respect to improvement in hypertension, renal function, or kidney survival.[21]

Radionuclide scanning

Use of radionuclide scanning, particularly following a single dose of captopril, is more useful in patients with normal renal function, in whom fibromuscular disease is suspected. See the image below.

Stratigis et al reported that captopril renal scintigraphy was highly accurate in predicting the  clinical outcome of percutaneous renal revascularization with stenting in patients with atherosclerotic renal artery stenosis who have a high coronary artery disease burden. In their study of 64 consecutive patients referred after coronary angiography, scintigraphy had sensitivity and specificity of 100% for both a hypertension and renal benefit from renal revascularization in patients with atherosclerotic renal artery stenosis of ≥ 70%.[22]

Patients with possible ischemic nephropathy (ie, serum creatinine values >2 mg/dL) frequently have associated parenchymal disease or bilateral vascular disease, in which case, the results obtained with scanning are unable to distinguish between parenchymal renal disease and renal artery stenosis/ischemic nephropathy.

Spiral CT angiography

This technique involves the use of an intravenous injection of a relatively large dose of iodinated contrast material and allows 3-dimensional reconstruction images of the renal arteries.

In 1995, Olbricht et al compared renal CT angiography with arterial digital subtraction angiography for detecting renal artery narrowing of more than 50%.[23] The CT technique showed positive and negative predictive values of 91%.

Spiral CT angiography is a useful technique that avoids arterial catheterization and produces accurate images of renal artery anatomy. This technique requires iodinated contrast material and significant time to perform the computer-based reconstruction. This technique avoids arterial puncture and, thus, the risk of atheroemboli, but it can be associated with contrast associated nephropathy, particularly in patients with preexisting chronic kidney disease.

Magnetic resonance imaging

Magnetic resonance angiography (MRA) is a noninvasive technique capable of demonstrating the renal vascular anatomy and revealing physiological information about kidney function (see the image below). This technique is capable of direct visualization of renal artery lesions without iodinated contrast material and provides a measurement of the absolute blood flow rate, GFR, and renal perfusion rate. Furthermore, MRA can provide accurate serial renal size and volume measurement. The limitations of MRA are its expense and its contraindication in patients with metallic clips, pacemakers, intraocular metallic devices, or other implants.

Concern regarding the association of gadolinium use with the development of nephrogenic systemic fibrosis (NSF) in patients with moderate to severe renal insufficiency significantly limits the use of this agent and, therefore, this modality, for the recognition of anatomic renal artery stenosis. In one study, for example, Broome et al reported an odds ratio of 22.3 for the development of NSF in dialysis patients who underwent enhanced imaging with the gadolinium-based contrast agent gadodiamide (vs patients in the study who underwent unenhanced imaging).[24]

However, all of the patients in the Broome study who developed NSF received 0.2 mmol/kg of gadodiamide; no cases of NSF were found among members of the cohort who received 0.1 mmol/kg of the agent. In a subsequent study, Garovic et al found no reported cases of NSF among 335 patients who underwent contrast-enhanced MRA, using 0.1 mmol/kg gadodiamide, for suspected or known renal artery stenosis.[25]

MRA has been validated only for the stenosis situated in the proximal 3-3.5 cm of renal arteries. Distal renal artery stenosis and segmental renal artery stenosis were generally not analyzed. The sensitivity of MRA was 90% for proximal renal artery stenosis, 82% for main renal artery stenosis, and 0% for segmental stenosis. In a follow-up study, Loubeyre and colleagues examined 46 patients with clinical renal artery stenosis.[26] Using a combination of techniques, they determined a sensitivity of 100%, a specificity of 90%, a positive predictive value of 58%, and a negative predictive value of 100% for detecting stenosis of the main, but not accessory or distal, renal artery. These data were obtained with fast-scanning machines using gadolinium enhancement and a breath-holding technique.[27]

An additional study compared the accuracy of CT angiography and MRA to digital subtraction angiography and concluded that digital subtraction angiography remains the method of choice to establish a diagnosis.

However, in the above-mentioned study by Garovic et al, the diagnostic efficacy of contrast-enhanced MRA (using 0.1 mmol/kg gadodiamide) was compared with that of intra-arterial digital subtraction angiography, using a cohort of 335 patients with known or suspected renal artery stenosis. The authors concluded, based on image analyses by multiple readers, that the sensitivity and specificity of the 2 modalities were equivalent in the evaluation of renal artery stenosis.[25]

Blood oxygen level–dependent MRI

Blood oxygen level–dependent (BOLD) MRI is a noninvasive technique for evaluating kidney tissue oxygenation that requires no contrast exposure and has the potential to allow functional assessment for patients with atherosclerotic renal artery stenosis. Although a decrease in renal blood flow does not invariably lead to renal hypoxia, severe vascular occlusion can overwhelm the kidney's capacity to adapt to reduced blood flow, and BOLD MRI has demonstrated renal cortical hypoxia in patients with severe renal artery stenosis.[28]

Conventional arteriography

This technique remains the criterion standard for the confirmation and identification of renal artery occlusion in persons with IRD. Specialists can perform renal arteriography by conventional aortography, intravenous subtraction angiography, intra-arterial subtraction angiography, or carbon dioxide angiography. See the images below.

Conventional aortography produces excellent radiographic images of the renal artery, but it requires an arterial puncture, carries the risk of cholesterol emboli, and uses a moderate amount of contrast material with the risk of contrast-induced acute tubular necrosis (ATN). Low osmolar contrast material can limit the risk of this complication. Complication rates for renal angiography are 6-10% in most series.

Intravenous subtraction angiography is sensitive for identifying stenosis of the main renal artery but does not demonstrate accessory or branch renal arteries sufficiently. Solitary stenosis of a branch of the renal artery is a common source of renovascular hypertension in pediatric patients, among the fraction in whom the disorder does not result from syndromes such as neurofibromatosis.[29] However, intravenous subtraction angiography avoids the use of a high volume of contrast and the risk of artery puncture and arterial atherosclerotic emboli.

Intra-arterial digital subtraction angiography has a high diagnostic accuracy compared to conventional angiography and is associated with fewer complications, lower doses of contrast, and smaller catheter size.

Carbon dioxide angiography is an alternative angiographic contrast agent used in combination with digital subtraction angiography to avoid the risk of conventional nephrotoxic contrast agents in patients with severe renal insufficiency. The images obtained are similar in quality to intra-arterial digital subtraction angiography; however, the technique requires an experienced investigator and a dedicated person to inject the carbon dioxide. Discomfort and inadequate images are potential complications of the procedure.

Contrast nephrotoxicity

Patients with progressive ischemic nephropathy (ie, underlying chronic renal failure) are at risk for contrast nephrotoxicity and should be informed of this risk prior to any contrast procedure.

Contrast nephropathy typically manifests as a brief rise in the serum creatinine level 3-6 days after exposure to radiocontrast and is reported in up to 40% of patients with underlying renal failure.

Most patients with contrast nephropathy ultimately recover renal function. Porter reviewed results from nearly 300 patients with contrast nephropathy and concluded that fewer than 10% of these patients required dialysis permanently.

Selection of diagnostic tests

Once patients are identified as being at high risk for renal artery stenosis, the choice of the best test for diagnosis is controversial.

Accurate identification of patients with correctable renovascular hypertension can be difficult with use of standard noninvasive techniques (eg, sonography) because they provide only indirect evidence of the presence of renal artery lesions.

On the other hand, invasive techniques with more accurate diagnostic potential can produce a worsening of renal function because of contrast toxicity and complications related to the procedures themselves (eg, arterial puncture, catheter-induced atheroembolism).

Gilfeather et al performed a study evaluating conventional angiography versus gadolinium-enhanced MRA in 54 patients and 107 kidneys.[30] The study showed that in 70 kidneys (65%), the average degree of stenosis reported by readers of both modalities differed by 10% or less. In 22 cases (21%), MRA overestimated the degree of stenosis by more than 10% relative to the results of conventional angiography; in 15 cases (14%), MRA underestimated the stenosis by more than 10%.

The obvious advantages of conventional angiography are its ability to determine the clinical importance of suggestive lesions and the ability to concurrently perform endovascular therapy. In addition, measurement of the pressure gradient across a stenotic lesion may be helpful in determining the clinical significance of a lesion.[31] However, specialists should weigh these advantages against the higher cost and greater morbidity of conventional angiography. The slightly inferior variability of MRA in diagnostic interpretation further supports the use of this technique as potentially the most appropriate tool for screening patients strongly suggested to have atherosclerotic RVD.

See Imaging in Renal Artery Stenosis/Renovascular Hypertension for a complete discussion of this topic.

Incidental atherosclerotic renovascular disease is often discovered in patients at the time of cardiac angiography. The impact of this finding on a patient’s outcome and, therefore, on the need to dilate and stent the renal vessel, the so-called "drive-by" percutaneous transluminal renal angioplasty with stenting (PTRAS), is the subject of intense debate.[32, 33, 34]

All patients with significant (> 80%) bilateral stenosis or stenosis in a solitary functioning kidney are candidates for revascularization, regardless of whether they have kidney insufficiency. When kidney insufficiency is present, patients with unilateral stenosis are also possible candidates for revascularization. The criteria are slightly different depending on the presence or absence of kidney insufficiency.

When kidney function is normal or nearly normal, specialists recommend revascularization for prevention of kidney insufficiency if the patient meets the following criteria:

• The degree of stenosis is more than 80-85%.
• The degree of stenosis is 50-80%, and captopril-enhanced scintigraphy demonstrates an activation of intrarenal renal artery stenosis.

Conversely, physicians can choose observation instead of revascularization (serial control every 6 mo with duplex scanning, accurate correction of dyslipidemia, use of drugs that block platelet aggregation) when the patient meets the following criteria:

• Stenosis is 50-80% and scintigraphy findings are negative.
• The degree of stenosis is less than 50%.

When kidney insufficiency is present and the objective is recovery of kidney function together with prevention of further kidney function impairment, the prerequisites for revascularization are as follows:

• The serum creatinine level is lower than 4 mg/dL, or
• The serum creatinine level is higher than 4 mg/dL but with a possible recent renal artery thrombosis.

When either of those conditions is satisfied, the authors propose revascularization if the following apply:

• The degree of stenosis is more than 80%.
• The serum creatinine level rises after administration of angiotensin-converting enzyme (ACE) inhibitors.
• The degree of stenosis is 50-80% and scintigraphy findings are positive.

Restrict conservative treatment in patients with an established diagnosis of ischemic renal disease to those with absolute contraindications to surgery or angioplasty or to patients who are likely to succumb to other comorbid conditions before advancing to end-stage renal disease because of ischemic renal disease. Clinicians must rely on pharmacologic agents (eg, combination of calcium channel blockers to control blood pressure and optimize renal perfusion), accepting the high probability of deterioration in kidney function and shortened survival.

In 1962, Morris et al compiled the first report on a surgical treatment for occlusion of the renal arteries.[35] They described eight patients with kidney failure who underwent revascularization. Six of these patients returned to essentially normal kidney function.

Reports from retrospective studies clearly document that surgical revascularization can improve renal function in patients with ischemic nephropathy. In 1993, Rimmer and Gennari reported postoperative improvement (ie, 20% decrease in serum creatinine concentration) in more than half the patients in nine studies.[36]  A long-term study (median follow-up, 10.6 years) of open surgical renal artery reconstruction that included 31 patients with stenosis reported low mortality, fairly low morbidity, and excellent durability and recommended that open surgery remain an option for patients with complex renal artery disease.[37]

Bypass procedures include aortorenal, hepatorenal, splenorenal, and ileorenal conduits constructed with autologous saphenous veins, autologous arteries, or prosthetic material. For atherosclerotic disease, surgeons can also perform atherectomy to improve renal blood flow. In persons with nonatheromatous renal artery disease, surgeons can reconstruct the renal arteries ex vivo and then can reimplant the revascularized kidney. Reilly and coworkers reported an operative mortality rate of only 6% and immediate improvement in the serum creatinine level of 32% of surgical bypass procedures in 35 patients with solitary kidneys.[38]

Subsequent studies reported more consistent success. The largest series suggests that the glomerular filtration rate (GFR) improved postoperatively in 49-80% of patients with underlying kidney failure.  

Guidelines from the American Heart Association/American College of Cardiology and the European Society of Cardiology include recommendations for the use of peripheral revascularization and surgical revascularization. See Guidelines.

Revascularization

One unresolved issue is how to determine whether revascularization will salvage kidney function when the renal artery is totally occluded. Features that may predict successful restoration of kidney function include the following:

• Collateral circulation and nephrogram on angiography findings
• Kidney length longer than 9 cm
• Lateralization of renin secretion
• Differential concentration of urine on split-function study results
• Spontaneous back-bleeding findings after arteriotomy during surgery
• Viable nephrons on biopsy tissue examination

Specialists suggest nephrectomy as a modality of treatment in persons with unilateral renovascular disease. However, in one study that involved 95 hypertensive patients and 100 kidneys with chronic atherosclerotic renal artery occlusion, nephrectomy versus revascularization provided equivalent estimated survival and blood pressure benefits, but in patients treated for unilateral disease, improvement in kidney function was observed only after revascularization. Moreover, improved kidney function was significantly and independently associated with improved survival. Those authors reserved nephrectomy for a surgically unreconstructible renal artery to a poorly functioning kidney.[39]

Angioplasty and stenting

Angioplasty is effective for treating renovascular hypertension associated with atheromatous lesions. Indicative of this is the decreased rate of referrals for surgical renovascularization of atheromatous renovascular hypertensive nephropathy by the early 1980s (from 41% to 26%). In practical terms, angioplasty can usually limit hospitalization, avoid general anesthesia, and minimize tissue trauma.

In 1987, Ziegelbaum et al compared the outcomes of angioplasty and surgical bypass.[40] The researchers studied 70 elderly patients with atheromatous disease and found that angioplasty caused major complications, including two deaths. Kidney function improved (ie, > 20% decrease in serum creatinine level) in 57.5% of surgery patients but in only 15.8% of angioplasty patients. After 48 months of follow-up, the unassisted patency rate was only 69% in the angioplasty group compared with 100% in the surgical group.

Erdoes et al examined the results of 58 surgical and 18 percutaneous revascularizations in nonrandomized patients.[41] These two approaches showed similar operation risk (mortality rate 4.8-5.3%); however, functional improvement (ie, blood pressure, serum creatinine level) and patency of the renal artery were dramatically better in the surgical group than in the revascularization group after nearly 4 years of follow-up.

van Jaarsveld et al reported the results of a multicenter trial designed to evaluate the relative benefit of angioplasty versus medical therapy for hypertension associated with renovascular disease.[42] They found that both groups had similar decreases in blood pressure, although the patients who underwent angioplasty used one fewer hypertensive medication. While kidney function was improved at 3 months in those undergoing angioplasty, the function at 12 months was similar. They concluded that restricting angioplasty to those with atherosclerotic renovascular hypertension persisting despite use of three or more antihypertensive medications was prudent. Note that the patients in this trial did not undergo angioplasty with stent placement. In addition, 9% of patients in the medical therapy–only group demonstrated total occlusion of the affected renal artery on 12-month follow-up angiography.

A randomized study by van de Ven et al that compared percutaneous transluminal angioplasty (PTA) with PTA plus stenting (PTAS) for ostial atherosclerotic renal artery stenosis showed that PTAS is better than PTA for achieving vessel patency in these patients.[43] The primary success rate was 88% for PTAS compared with 57% for PTA. The restenosis rate after a successful primary procedure was 14% for PTAS versus 48% for PTA. In the last few years, the use of PTAS in patients with ostial stenosis or early restenosis has led to a considerable reduction in the restenosis rate.

However, controversy still surrounds the best approach to patients with atherosclerotic renovascular disease.[44, 45, 46, 47] A study  by Bax et al found that renal artery stenting had no clear effect on kidney function impairment in patients with atherosclerotic renal artery stenosis, and led to significant complications in some of them.[48] The multicenter trial included 140 patients with creatinine clearance of less than 80 mL/min per 1.73 m2 and renal artery stenosis of 50% or greater. All patients received medical treatment with antihypertensive agents, a statin, and aspirin. Although 64 patients were randomized to stent placement, only 46 had the procedure; in many patients, assessment of renal artery stenosis by noninvasive imaging was inaccurate and stenting was in fact not indicated.

In the study, progression of kidney dysfunction, as indicated by a decrease in creatinine clearance of 20% or greater, occurred in 16% of patients in the stent placement group and in 22% of patients in the medication group (hazard ratio, 0.73 [95% confidence interval [CI], 0.33-1.61]). Serious complications in the stent group included two procedure-related deaths.[48]

The 2009 ASTRAL trial "found substantial risks but no evidence of a worthwhile clinical benefit from revascularization in patients with atherosclerotic renovascular disease". ASTRAL included 806 patients with at least one stenotic renal artery and an estimated GFR of approximately 40 mL/min who were randomized to revascularization (ie, interventional radiology) or medical therapy. No difference was observed in the primary outcome, decline of kidney function, between the two groups.[49] Although the ASTRAL trial, like the study by Bax et al, had some design flaws, the results suggest that medical therapy is appropriate for patients with a single stenotic renal artery. Two review articles, one by Simon and another by Lao et al, discuss this subject in significant detail.[50, 51]

A multicenter review reported that the frequency of PTA for renal artery stenosis decreased in the years following the publication of the ASTRAL trial, indicating a higher threshold for invasive treatment of these patients. However, 4 years mean clinical follow-up suggested that most patients being treated with PTA benefited from the procedure, with reduced blood pressure, reduced need for anti-hypertensive medication, and stabilization of kidney function.[52]

The Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study demonstrated no added benefit from the addition of stenting to medical therapy for renal artery stenosis. In CORAL, 947 participants with atherosclerotic renal-artery stenosis and either systolic hypertension or chronic kidney disease were randomized to medical therapy plus renal artery stenting or medical therapy alone. The resulting rate of adverse cardiovascular and renal events (ie, death, myocardial infarction, stroke, hospitalization for heart failure, progressive kidney insufficiency, or the need for renal replacement therapy) showed no significant differences (35.1% and 35.8%, respectively; hazard ratio with stenting, 0.94; 95% CI, 0.76 to 1.17; P = 0.58).[53]

However, a post hoc analysis of CORAL by Murphy et al found that in patients whose baseline urine albumin/creatinine ratio was at or below the median (22.5 mg/g), renal artery stenting was associated with significantly better outcome, including event-free survival, cardiovascular disease–related death, progressive kidney insufficiency, and overall survival. The authors suggest that low albuminuria may identify a potentially large subgroup of renal artery stenosis patients who would benefit from stent placement plus medical therapy.[54]

A meta-analysis of revascularization versus medical therapy for the treatment of renal artery stenosis found no clear benefit from percutaneous transluminal angioplasty with or without stenting over medical management. In the final analysis, which included 540 studies and seven randomized controlled trials and 2,139 patients, angioplasty with or without stenting was not superior to medical therapy with respect to any outcome. The incidence of nonfatal myocardial infarction was 6.74% in both the stenting and medical therapy group (odds ratio 0.998, 95% CI 0.698 to 1.427, P = 0.992), and the incidence of renal events with stenting population was 19.58% versus 20.53% with medical therapy (odds ratio 0.945, 95% CI 0.755 to 1.182, P = 0.620).[55]

Revascularization may not result in restoration of kidney function because of damage sustained during the period of reduced blood flow.[8] Hypoxia can result in functional loss of microcirculation (rarefaction) and recruitment of inflammatory cellular elements (as indicated by elevation of inflammatory biomarkers[56] ) that ultimately produce fibrosis.[45]

However, there is also evidence that percutaneous revascularization may benefit some patients in high-risk subgroups. In a retrospective analysis of a single-center prospective cohort study of 467 patients, Ritchie and colleagues reported that those individuals presenting with flash pulmonary edema, rapidly declining kidney function, or refractory hypertension who received revascularization had a significantly reduced risk for death and cardiovascular events compared with those who received medical management.[57]

In a single-center, case-control study that included 188 patients with renal artery stenosis, Meredith and colleagues identified previous myocardial infarction, left ventricular ejection fraction (LVEF) ≤35%, and GFR ≤45 mL/min/1.73 m2 as risk factors. Renal artery stenting was associated with a 43% reduction in mortality in patients with none or one of those risk factors, but stenting had no effect on mortality in patients with two or three risk factors.[58]

Use of renal artery revascularization has been declining in recent years, mainly because trials to date have failed to demonstrate major advantages from the procedure. However, in a 2013 review, Textor et al note that trials of revascularization “have been small, conducted over short intervals, and have been ferociously criticized on methodologic grounds”.[59] These authors observe that endovascular repair is most likely to succeed when it is performed in patients with a recent deterioration in kidney function, which argues for careful identification and selection of patients for revascularization before loss of GFR becomes far advanced.

In some institutions, PTAS is the first-step approach in patients with ischemic renal disease, and practitioners reserve surgery for the technical failure of percutaneous maneuvers. However, surgery remains the first choice of treatment under certain conditions, including the following:

• Simultaneous abdominal aortic aneurysm
• Renal artery aneurysm
• Renal artery occlusion (with unsuccessful thrombolysis)
• Renal artery rupture
• Renal artery stenosis secondary to kinking
• Peripheral multifocal stenosis
• Unsuccessful angioplasty

A small, retrospective review of 20 patients older than 55 years with chronic kidney disease and proximal renal artery stenosis who underwent a revascularization procedure (ie, surgery, PTA, PTAS) revealed a high complication rate (increased serum creatinine concentration in 25%, eosinophilia in 5%, atheroemboli in 15%, renal artery dissection in 5%) and improved serum creatinine values in only 25%.[60] Fifty percent of patients had stable azotemia. The authors conclude that a prospective, randomized trial of medical management with or without PTAS is warranted for this complex clinical problem.

Renal artery fibromuscular dysplasia

PTA is the treatment of choice for renal artery fibromuscular dysplasia. A retrospective analysis by Yang et al of 76 PTA procedures in 64 patients reported that in the majority of cases (79.7%) the patient experienced immediate clinical benefit, with cure of hypertension in 35.9% and improvement in hypertension and a lower requirement for antihypertensive medications in 43.8%. In the long term (mean, 47.5 months), the survival rate was 96.9%, freedom from restenosis was 84.4%, and 76.6% of patients showed a sustained clinical benefit (cure rate 40.6%, improvement rate 35.9%).[61]

Patients with restenosis showed good response to repeat PTA. Eight patients were treated with a second procedure and two had a third procedure, resulting in improvement in hypertension in half of those patients.[61]

Kidney transplant recipients

In kidney transplant recipients, PTA and PTAS are the standard of care for renal artery stenosis.[62, 63, 64] However, good long-term outcomes with medical management have been reported in transplant recipients with less than 50% stenosis.[65] A comparison of PTA (n=34)  with PTAS (n=31) in kidney transplant recipients reported that freedom from graft failure or renal artery restenosis was significantly higher for PTAS at 1 year, but similar for PTA and PTAS at 10 years.[64]

The optimal approach to therapeutic interventions should be developed in consultation with an interventional radiologist and vascular surgeon. The relative expertise of these subspecialists at the individual medical center will determine the best course of action for the patient.

In view of the natural history of RVD, patients require serial determinations of serum creatinine levels. Adequate blood pressure control is required, with monitoring of serum potassium levels as necessary. Duplex ultrasound, if available, allows regular follow-up of radiologic progression.

The following organizations have released guidelines for the management of renal artery stenosis (RAS):

• American College of Cardiology (ACC)/American Heart Association (AHA)
• European Society of Cardiology (ESC)
• Society for Cardiovascular Angiography and Interventions (SCAI)

Diagnosis

The 2013 ACC/AHA and 2017 ESC guidelines recommend performing diagnostic studies to identify RAS in patients with any of the following[66, 67] :

• Onset of hypertension before the age of 30
• Onset of severe hypertension after the age of 55
• Accelerated hypertension (sudden and persistent worsening of previously controlled hypertension)
• Resistant hypertension
• Malignant hypertension (hypertension with coexistent end-organ damage;  ie, acute kidney injury, flash pulmonary edema, hypertensive left ventricular failure, aortic dissection, new visual or neurological disturbance, and/or advanced retinopathy)
• New azotemia or worsening renal function after the administration of an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB)
• Unexplained atrophic kidney or size discrepancy of greater than 1.5 cm between the kidneys
• Unexplained renal failure
• Flash pulmonary edema

The ACC/AHA guidelines define resistant hypertension as failure of blood-pressure control despite full doses of an appropriate three-drug regimen including a diuretic.[66] The ESC defines it as failure to achieve target blood pressure despite use of four drug classes, including a diuretic and a mineralocorticoid receptor antagonist in appropriate doses, in cases where another form of secondary hypertension is unlikely.[67]

The ESC also lists the combination of hypertension and abdominal bruit as a possible indication of RAS.[67]

In its 2014 SCAI Expert Consensus Statement for Renal Artery Stenting Appropriate Use, the SCAI utilized the ACC/AHA recommendations.[68]

Class I recommendations for establishing a diagnosis of RAS generally concur and include the following[66, 67] :

• Duplex ultrasonography (DUS) is the first-line test
• Computed tomography angiography in patients with creatinine clearance >60 mL/min
• Magnetic resonance angiography in patients with creatinine clearance >30 mL/min

When the clinical index of suspicion is high and the results of noninvasive tests are inconclusive, ACC/AHA recommends catheter angiography,[66] while ESC recommends digital subtraction angiography.[67]

Both guidelines are in agreement that captopril renal scintigraphy, selective renal vein renin measurements, plasma renin activity, and the captopril test are not recommended as useful screening tests for RAS (class III).[66, 67]

SCAI recommends renal angiography as the gold standard for invasive assessment of hemodynamically significant RAS and categorizes stenosis severity as follows[68] :

• Mild: < 50%
• Moderate: 50–70%
• Severe: >70%

Severe angiographic stenosis is considered hemodynamically significant. Moderate angiographic stenosis is considered hemodynamically significant only when the patient also has a resting mean pressure gradient >10 mm Hg or systolic hyperemic pressure gradient >20 mm Hg or renal fractional flow reserve (FFR) ≤0.8. Mild and moderate stenosis that is not hemodynamically significant should only rarely be considered for revascularization.[68]

Medical Therapy

ACC/AHA, ESC and SCAI all prefer medical therapy as the first-line treatment for RAS.[66, 67, 68] ACC/AHA and ESC recommend ACE inhibitors, ARBs, and calcium channel blockers for unilateral RAS,[66, 67] but ESC advises that patients with bilateral severe RAS or RAS in a single functional kidney require very careful monitoring when started on ACE inhibitors or ARBs.[67]

The ACC/AHA also recommends beta-blockers for treatment of hypertension associated with RAS.[66] The ESC considers the use of antiplatelet agents to be part of best medical therapy.[67]

Revascularization

The ACC/AHA guidelines recommend percutaneous revascularization in patients with hemodynamically significant RAS and any of the following[66] :

• Recurrent congestive heart failure or sudden unexplained pulmonary edema (class I)
• Unstable angina (class IIa)
• Accelerated, resistant, or malignant hypertension or hypertension with unexplained unilateral small kidney and intolerance to medication (class IIa)
• Asymptomatic bilateral or single functioning kidney; however, this treatment is clinically unproven in asymptomatic unilateral hemodynamically significant RAS in a viable kidney (class IIb)

In addition, percutaneous revascularization is reasonable for patients with progressive chronic kidney disease (CKD) and bilateral RAS or a RAS to a single functioning kidney and can be considered for unilateral RAS with chronic renal insufficiency.[66] The ESC also recommends revascularization in patients with symptomatic fibromuscular dysplasia who have signs of organ ischemia.[67]

ACC/AHA and ESC recommend renal stent placement for ostial atherosclerotic RAS (class I).[66]

ACC/AHA  gives a class I recommendation for balloon angioplasty with bailout stent placement if necessary for fibromuscular dysplasia lesions;[66] whereas ESC recommends considering balloon angioplasty with or without stenting for patients with RAS and recurrent congestive heart failure or sudden pulmonary edema and preserved systolic left ventricular function (class IIb).{ref55)

Based on an expert panel review of scientific data, the SCAI concluded that patients with the following are most likely to benefit from renal artery stenting[68] :

• Cardiac disturbance syndromes (flash pulmonary edema or acute coronary syndrome)
• Hypertension that has not been controlled by three or more medications at maximal tolerated doses
• Blockages in both kidneys or severe blockages in a single functioning kidney where blood pressure or renal dysfunction cannot be managed medically

The SCAI concluded that patients with any of the following are typically not good candidates for renal artery stenting[68] :

• Mild or moderate blockages (less than 70%)
• Long-standing loss of blood flow
• Complete blockage of the renal artery

ACC/AHA gives class I recommendations to surgical revascularization for the following indications:[66]

• Fibromuscular dysplasia, especially in those exhibiting complex disease or macroaneurysms
• Atherosclerotic RAS and multiple small renal arteries or early primary branching of the main renal artery
• Atherosclerotic RAS in combination with pararenal aortic reconstruction

ESC gives a class IIb recommendation to consider surgical revascularization in patients undergoing repair of the aorta or with complex anatomy of renal arteries or after failure of endovascular treatment.[67]

The general approach to therapy of ischemic nephropathy involves control of hypertension, preferably with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Unfortunately, these two classes of drugs may lead to increased serum creatinine levels and hyperkalemia, limiting their utility. In this case, calcium channel blockers are likely the most useful and best-tolerated agents.

Initiate strict control of serum cholesterol, which usually requires the use of statins, as with all conditions associated with atherosclerosis. A study by Bianchi et al suggested that statins, in addition to ACE inhibitors and ARBs, may reduce proteinuria and slow the progression of kidney disease.[69]

Class Summary

These agents decrease aldosterone secretion.

Captopril (Capoten)

Parent compound of this class of medications. Sulfhydryl group associated with proteinuria and neutropenia when used at high doses. Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.

Enalapril (Vasotec)

One example of this class of compounds. Similar precautions to captopril with respect to potential increase in potassium and creatinine. Major adverse effect is dry cough. Newer and, occasionally, better tolerated than parent compound. Many variations that allow for once-daily dosing and better tissue ACE inhibition.

Class Summary

Useful for hypertension and heart failure in patients who are intolerant of ACE inhibitors. Many alternative compounds exist with few significant clinical differences.

Losartan (Cozaar)

Initial compound in class to gain approval. Useful for treatment of hypertension and heart failure in patients who are intolerant of ACE inhibitors. Many alternative compounds exist with few significant clinical differences. Nonpeptide angiotensin II receptor antagonist that blocks the vasoconstricting and aldosterone-secreting effects of angiotensin II. May induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors, does not affect the response to bradykinin, and is less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors.

Class Summary

Adjunct to diet to reduce total and LDL cholesterol in patients with hypercholesterolemia. Also lower triglycerides.

Atorvastatin (Lipitor)

One of many compounds with comparable efficacy and adverse effect profiles. Inhibits HMG-CoA reductase, which, in turn, inhibits cholesterol synthesis and increases cholesterol metabolism.