Renal artery stenosis medical therapy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Shivam Singla, M.D.[2]
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Overview
Patients with Renal artery stenosis require the widespread use of intensive medical therapy. The drugs responsible for the management of renal artery stenosis are ACE inhibitors or ARB's. These drugs inhibit the sympathetic and renin-angiotensin system resulting in controlling hypertension. In patients with bilateral renal artery stenosis, there is an associated decrease in renal function after using the ACE inhibitors and ARB, but it is neither a sensitive nor specific finding. Aggressive statin use, optimal glycemic regulation, and therapy for smoking abstinence are of vital significance. Other modalities used are renal artery revascularization, Percutaneous transluminal renal angioplasty, Renal artery stenting, brachytherapy and cutting balloon atherotomy, and surgery in complicated and nonresponding cases. Although morbidity and mortality are high in surgery vs stenting.
Treatment
Medical Therapy
The patients with Renal artery stenosis requires the wide spread use of intensive medical therapy. The drugs responsible for the management of renal artery stenosis are ACE inhibitors or ARB's. These drugs inhibit the sympathetic and renin-angiotensin system resulting in controlling the hypertension. In patients with bilateral renal artery stenosis there is associated decrease in the renal function after using the ACE inhibitors and ARB, but it is neither sensitive nor specific finding. Aggressive statin use, optimal glycemic regulation, and therapy for smoking abstinence are of vital significance.
Aggressive use of statins, optimal glycemic control, and smoking cessation counseling are of paramount importance. The results of various medical regimens on the treatment of ARAS-related hypertension were not analyzed in a randomized clinical trial because such patients frequently have refractory hypertension and need multiple antihypertensive medicines. Medical therapy is preferred to revascularization in patients with ARAS and progressive renal disease (i.e. chronic renal dysfunction, proteinuria[>1 g/d]), diffuse intrarenal vascular disease, and renal atrophy.
Renal Artery Revascularization
It is less obvious and much more contentious whether patients with ARAS and hypertension would undergo surgical revascularization. According to studies patients with extreme ostial renal artery stenosis who have been successfully revascularized percutaneously do not necessarily have therapeutic benefits.
The ACC/AHA description of RAS is as follows:
(1) visually approximate stenosis of 50 percent to 70 percent diameter with a translational peak gradient of at least 20 mm Hg or a mean gradient of at least 10 mm Hg
(2) angiographic stenosis of at least 70 percent diameter
(3) greater than 70% stenosis according to the measurement by intravascular ultrasounds.
Present ACC/AHA recommendations do not however, include these steps and prescribe revascularization of ARAS only when it is associated with certain medical conditions mentioned as follows:
1) Asymptomatic stenosis: Percutaneous revascularization can be considered for the treatment of:
- An asymptomatic bilateral
- Solitary viable kidney with hemodynamically significant ARAS (class Jib, degree of proof II.OF.I C),.
- The efficacy of percutaneous or asymptomatic unilateral hemodynamically significant ARAS in a viable kidney is not well known and clinically unrecognized (class 11b, LOE C)
2) Hypertension
- Percutaneous revascularization is used for the patients with
- Hemodynamically significant renal artery stenosis along with accelerated hypertension
- Malignant hypertension
- Resistant hypertension
- In cases with hypertension and associated unilateral small kidney.
3) Preservation of renal function
- Percutaneous revascularization is helpful in patients with ARAS + Chronic progressive kidney disease with bilateral renal artery stenosis or solitary functioning kidney. (Class IIa, LOE B)
- Also considered significant in patients with RAS and chronic renal insufficiency with unilateral renal artery stenosis. (Class IIb, LOE C)
4) Effects of renal artery stenosis on Congestive heart failure and unstable angina: Percutaneous revascularization is considered in patients with
- RAS + Recurrent congestive heart failure or sudden unexplained pulmonary edema. (Class I, LOE B)
- Patients with hemodynamically significant RAS along with unstable angina (Class IIa, LOE B)
Percutaneous Transluminal Renal Angioplasty
The largest randomized trial that compared drug treatment and PTRA was the Dutch Renal Artery Stenosis Intervention Cooperative (DRASTIC) study.66 In that study, 106 patients were randomly assigned to PTRA or medical therapy. The study design was such that patients in the drug treatment group whose condition was refractory to medical therapy were allowed to undergo balloon angioplasty if their blood pressure control was inadequate. Major limitations of that study included enrollment of patients with insignificant ARAS, a 44% crossover from medical therapy to PTRA, and low use of stents (20%). Despite the authors' assertion that PTRA in addition to drug therapy provided “little benefit,” patients in the PTRA group were less likely to have deterioration of their blood pressure control or renal artery occlusion during 12 months of follow-up.
Renal Artery Stenting
Results from observational studies have demonstrated that renal stenting is safe and effective in reducing blood pressure.67,68 The problem of elastic recoil is alleviated by using stents, which provide mechanical scaffolding. In a meta-analysis of 1322 patients, stent placement had a significantly higher technical success rate and lower restenosis rate than did PTRA (98% vs 77% and 17% vs 26%, respectively) and higher cure rates for hypertension.69
A randomized trial demonstrated the superiority of renal stenting vs PTRA for immediate procedural success (88% vs 57%, respectively) and lower restenosis rates (14% vs 48%, respectively).70 The limitation of that study appears to be the complication rates, although no significant differences in complications were noted between either study arm. The authors identified bleeding as a complication in 19% of patients in both arms (although the definition of bleeding was unclear) and cholesterol embolism as a complication in 10% of both arms. Other studies have demonstrated improvement or stabilization of renal function after unilateral or bilateral renal stenting in patients with ARAS and progressive renal insufficiency.71,72 In patients with ARAS and hypertension (blood pressure >140/90 mm Hg) despite treatment with at least 2 antihypertensive medications, renal stenting resulted in systolic blood pressure reduction of 20 mm Hg and use of 1 less antihypertensive medication.73
Two important randomized trials of renal artery stenting vs medical therapy have recently been reported. In the Stent Placement in Patients with Atherosclerotic Renal Artery Stenosis and Impaired Renal Function (STAR) trial,74 140 patients with a creatinine clearance of less than 80 mL/min/m2, RAS greater than 50%, and well-controlled hypertension were randomized to either renal artery stenting plus medical therapy or medical therapy alone. The primary end point was a 20% or greater decrease in creatinine clearance, and secondary end points included safety and cardiovascular morbidity and mortality. The authors concluded that stent placement with medical treatment did not clearly affect progression of impaired renal function but led to a few serious procedure-related complications.75 However, this study had a number of important limitations. Foremost, as noted by the editors of Annals of Internal Medicine, the study was “underpowered to provide a definitive estimate of efficacy.”75 Several patients were incorrectly identified as having ARAS greater than 50% by noninvasive imaging and did not require stenting, yet they were analyzed by intention to treat in the stent group. Also, 33% of the study participants had only mild RAS (50%-70%), and more than half of the patients had unilateral disease. Because the primary end point was a change in renal function, it is not surprising that patients with unilateral disease and stenosis of less than 70% had no benefit from revascularization.
In the Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trial, 806 patients with ARAS were randomized to undergo stent-based renal revascularization plus medical therapy or medical therapy alone. The primary outcome was renal function, as measured by the reciprocal of the serum creatinine level, and secondary outcomes were blood pressure, time to renal and major cardiovascular events, and mortality. After a median follow-up of 34 months, the authors found “substantial risks but no evidence of a worthwhile clinical benefit from revascularization in patients with ARAS.”74 This study had a number of limitations that might affect interpretation of the results. By limiting study participation to patients in whom the treating physicians had to be undecided about the appropriate treatment strategy (ie, patients were excluded if physicians were sure stenting was necessary), selection bias was introduced into the trial design. Of course, this selection bias is also reflective of clinical practice because many physicians will often refer patients for renal revascularization if they are unsure of the appropriate course of management. In addition, 25% of patients had normal renal function, a significant number had unilateral disease, and 41% had a stenosis of less than 70%. A subgroup analysis of the cohort with bilateral disease also failed to show clinical benefit, downplaying the notion that the negative results were largely affected by the high enrollment of patients with unilateral disease who would benefit less from renal revascularization. Importantly, there was no core laboratory to adjudicate the imaging studies and ensure their accurate and unbiased interpretation. During the 7 years of recruitment, more than half of the centers enrolled fewer than 1 patient per year, perhaps explaining the high adverse event rate. In summary, as the authors of the trial have stated, the results of ASTRAL appear to indicate that renal stenting does not provide a significant net clinical benefit for patients with RAS and may inflict harm because 2 deaths and 3 amputations were attributed to complications of the procedure.
Importantly, in both the ASTRAL and the STAR trials, creatinine clearance equations used to estimate glomerular filtration rate have not been validated in patients with ARAS. Patients with advanced nephropathy (who would be less likely to benefit from revascularization) were included in both trials, and neither trial used an adjunctive measurement of renal ischemia, such as translesional pressure gradients, which adds variability to the assessment of lesion severity.
The CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) study is a large randomized, prospective multicenter trial funded by the National Institutes of Health that is comparing the effects of angioplasty with stenting and optimal medical therapy to medical therapy alone on a composite of adverse cardiovascular and renal events.76 Enrollment ended on January 31, 2010, and study data will not be available for several years. The CORAL investigators realized that previous trials of ARAS have lacked rigorous medical treatment that could prevent the progression of cardiovascular and renal disease pervasive in this population. Thus, this trial focuses on strict antihypertensive therapy, smoking cessation, aggressive treatment of dyslipidemia and diabetes, administration of an antiplatelet agent, and complications of renal insufficiency. The CORAL treatment algorithm is based on current evidence-based practice guidelines even though the effect of these medical interventions on outcomes has not yet been well defined in this population.
In the CORAL trial, randomization to the revascularization or medical treatment arm was performed at the time of the invasive assessment. Patients in the stent therapy arm underwent implantation of a Genesis stent (Cordis, Warren, NJ). The study was designed to have more than 80% power to detect a threshold effect size of 25% with a sample of 1080 randomized patients. This is the pivotal study of stent therapy for ARAS, on par with large randomized clinical trials of carotid artery or coronary artery bypass surgery (NASCET [North American Symptomatic Carotid Endarterectomy Trial] and CASS [Coronary Artery Surgery Study], respectively).
We anticipate that the CORAL study will greatly clarify the controversy regarding renal artery stenting. However, the strict crossover requirements may have led some centers to avoid enrolling patients in whom the indication to treat was weak.
Additional Interventional Procedures
Although brachytherapy and cutting balloon atherotomy have been used successfully for renal artery in-stent restenosis,77,78 long-term outcomes are unknown. Use of coronary drug-eluting stents has also been described for small renal arteries,79 but well-designed studies to determine the adequate dosing of the eluting drug for this vessel are lacking. The largest drug-eluting stent is only 3.5 mm in diameter, an inadequate size for stenting of a renal artery (with a normal diameter of 4-7 mm). Distal embolic protection devices have also been used to capture atherosclerotic debris and prevent it from distal embolization during renal stenting,80 which may help preserve renal function.
Surgery
Surgical revascularization is effective for treating ARAS; however, morbidity and mortality are higher with surgery vs stenting.59 In one of the few studies that compared surgical to percutaneous revascularization for ostial ARAS, Balzer et al81 found no significant difference in long-term morbidity or mortality, a significant improvement in durability of the result in the surgical arm, and no significant difference in blood pressure reduction (although blood pressure improved significantly from baseline in both study arms). These results suggest that surgical revascularization may be at least equivalent to PTRA for ostial ARAS.
Medical Therapy
The following are the list of medications indicated for patients with unilateral renal artery stenosis (RAS) with their corresponding level of evidence, based on 2013 ACC/AHA Guidelines for the Management of PAD[1]
Medication Class | Level of Evidence |
ACE-Inhibitors | A |
Calcium Channel Blockers | A |
Beta-Blockers | A |
ARB | B |
- The recommended initial pharmacologic therapy in patients with RAS is either an Angiotensin converting enzyme inhibitor (ACE-I) or a calcium channel blocker (CCB), both of which have been proven effective not only for lowering blood pressure values, but also for delaying the progression of renal disease.[2][3][4][5][6] Other well-established therapies for lowering blood pressures in patients with RAS include beta-blockers,chlorothiazides, and hydrazine.[6] ARBs can also be used to treat hypertension associated with unilateral RAS.[1] These recommendations for management of hypertension are based upon guidelines from the JNC in 2004[7] and/or ESH/ESC guidelines in 2013[8].
- Diuretics can also be administered to treat the hypertension associated with renal artery stenosis.
- Co-morbidities like diabetes, heart disease, or hardening of the arteries should be treated as well.
- Lifestyle changes are important and they include:
- Healthy diet
- Regular exercise
- Smoking cessation
- Limiting alcohol intake: 1 drink a day for women, 2 a day for men
- Limited sodium (salt) intake less than 1,500 mg per day. Check with your doctor about how much potassium you should be eating.
- Stress reduction
- Maintain a healthy body weight
Complications of ACE and ARB therapy
There is ongoing debate as to whether ACE inhibitors and ARBs offer a net benefit when hypertensive control and renal perfusion are both considered. Careful monitoring of the creatinine in these patients is critical to assure that the patient does not reach a tipping point where renal perfusion is so reduced that they develop ischemic atrophy.
Unilateral or bilateral renal artery stenosis reduce renal perfusion which in turn activates the renin-angiotensin-aldosterone system (RAAS). Activation of the RAAS system in turn reduces Na excretion and expands intravascular volume. ACE inhibition and diuretics are therefore well suited to blocking this pathophysiologic response to a stenosis.
As the blood pressure is lowered with antihypertensive treatment, this may further reduce renal perfusion, and at a certain point may further lower the glomerular filtration rate (GFR) causing the creatinine to go up. Both ACE inhibitors and ARB block the usual autoregulatory response to compensate for reduced renal perfusion which would be to increase the postcapillary resistance. There is concern that sustained reductions in renal perfusion may lead to ischemic atrophy of the kidney.
The rise in creatinine (Cr) with the use of ACE inhibtors and ARBS is not a contraindication to their use since the decline in glomerular filtration rate with their use is generally small with only 5-10% of patients having a 30% or greater rise in creatinine. Nonetheless, the creatinine should be carefully monitored. If the creatinine does rise to near 30%, then either the diuretic or the ACE inhibitor or the ARB can be discontinued.
In those patients who develop a significant rise in Cr after ACE inhibition, the reduction in blood pressure may not allow maintenance of renal perfusion, and these patients should be considered candidates for percuatenous or surgical revascularization.
Management of Patients With Peripheral Artery Disease (Compilation of 2005 and 2011 ACCF/AHA Guideline Recommendations) : A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines[9]
Class I |
"1. Angiotensin-converting enzyme inhibitors are effective medications for treatment of hypertension associated with unilateral RAS. (Level of Evidence: A)" |
"2. Angiotensin receptor blockers are effective medications for treatment of hypertension associated with unilateral RAS. (Level of Evidence: B)" |
"3. Calcium-channel blockers are effective medications for treatment of hypertension associated with unilateral RAS. (Level of Evidence: A)" |
"4. Beta-blockers are effective medications for treatment of hypertension associated with RAS. (Level of Evidence: A)" |
References
- ↑ 1.0 1.1 Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH; et al. (2013). "Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines". Circulation. 127 (13): 1425–43. doi:10.1161/CIR.0b013e31828b82aa. PMID 23457117.
- ↑ Plouin PF (2003). "Stable patients with atherosclerotic renal artery stenosis should be treated first with medical management". Am J Kidney Dis. 42 (5): 851–7. PMID 14582030.
- ↑ Nordmann AJ, Woo K, Parkes R, Logan AG (2003). "Balloon angioplasty or medical therapy for hypertensive patients with atherosclerotic renal artery stenosis? A meta-analysis of randomized controlled trials". Am J Med. 114 (1): 44–50. PMID 12557864.
- ↑ Webster J, Marshall F, Abdalla M, Dominiczak A, Edwards R, Isles CG; et al. (1998). "Randomised comparison of percutaneous angioplasty vs continued medical therapy for hypertensive patients with atheromatous renal artery stenosis. Scottish and Newcastle Renal Artery Stenosis Collaborative Group". J Hum Hypertens. 12 (5): 329–35. PMID 9655655.
- ↑ Plouin PF, Chatellier G, Darné B, Raynaud A (1998). "Blood pressure outcome of angioplasty in atherosclerotic renal artery stenosis: a randomized trial. Essai Multicentrique Medicaments vs Angioplastie (EMMA) Study Group". Hypertension. 31 (3): 823–9. PMID 9495267.
- ↑ 6.0 6.1 Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, Hiratzka LF, Murphy WR, Olin JW, Puschett JB, Rosenfield KA, Sacks D, Stanley JC, Taylor LM, White CJ, White J, White RA, Antman EM, Smith SC, Adams CD, Anderson JL, Faxon DP, Fuster V, Gibbons RJ, Hunt SA, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B (2006). "ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation". Circulation. 113 (11): e463–654. doi:10.1161/CIRCULATIONAHA.106.174526. PMID 16549646. Retrieved 2012-10-09. Unknown parameter
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ignored (help) - ↑ Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL; et al. (2003). "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report". JAMA. 289 (19): 2560–72. doi:10.1001/jama.289.19.2560. PMID 12748199.
- ↑ Mancia G, Fagard R, Narkiewicz K, Redán J, Zanchetti A, Böhm M; et al. (2013). "2013 Practice guidelines for the management of arterial hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC): ESH/ESC Task Force for the Management of Arterial Hypertension". J Hypertens. 31 (10): 1925–38. doi:10.1097/HJH.0b013e328364ca4c. PMID 24107724.
- ↑ Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA, Findeiss L; et al. (2013). "Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA Guideline Recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines". J Am Coll Cardiol. 61 (14): 1555–70. doi:10.1016/j.jacc.2013.01.004. PMC 4492473. PMID 23473760.