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2. Atherosclerosis accounts for about 90% of cases of renal artery stenosis in people over age 40 Fibromuscular dysplasia - the other major cause

3. Percutaneous intervention has become very popular for treating atherosclerotic renal artery stenosis use of stents has boosted the rate of technical success more cases are being discovered incidentally during angiography of other arteries

4. Number of angioplasty-stenting procedures performed every year is on the rise Yet there is no overwhelming evidence that intervention yields clinical benefits—ie, better blood pressure control or renal function— than does medical therapy

5. Renal angioplasty began replacing surgical revascularization in the 1990s Less-invasive, more readily available, similar clinical outcomes Last decade, stent placement during angioplasty has become standard - improving the rates of technical success

6. Prevalence of RAS depends on the definition used and the population screened. More common in older patients who have risk factors for other vascular diseases than in the general population Affect between 1% and 5% of patients with hypertension Derkx FH, Schalekamp MA. Renal artery stenosis and hypertension. Lancet. 1994; 344: 237–239 Renal artery stenosis is found in 11% to 28% of patients undergoing diagnostic cardiac catheterization White CJ, Olin JW.Diagnosis and management of atherosclerotic renal artery stenosis: improving patient selection and outcomes. Nat Clin Pract Cardiovasc Med 2009; 6:176–190.

7. No studies of the prevalence of renal artery stenosis have been performed in the general population Holley et al in an autopsy series, found renal artery stenosis of greater than 50% in 27% of patients over age 50 and in 56.4% of hypertensive patients Prevalence was 10% in normotensive patients

8. Renal Doppler ultrasonography can detect stenosis only if the artery is narrowed by more than 60% Hansen et al used ultrasonography to screen 870 people over age 65 and found a lesion (a narrowing of more than 60%) in 6.8%. Angiography can detect less-severe stenosis define RAS as a narrowing > 50% severe disease - narrowing > 70% Unilateral stenosis needs to be more than 70% to pose a risk to the kidney Cohen MG, et al. A simple prediction rule for significant renal artery stenosis in patients undergoing cardiac catheterization. Am Heart J 2005; 150:1204–1211

9. Factors associated with a higher risk of finding RAS on a radiographic study Older age, Female sex Hypertension, Three-vessel CAD Peripheral artery disease Chronic kidney disease Diabetes, Tobacco use Low HDL Cohen MG, et al. A simple prediction rule for significant renal artery stenosis in patients undergoing cardiac catheterization. Am Heart J 2005; 150:1204–1211

10. In studies that used duplex ultrasonography, roughly half of lesions smaller than 60% grew to greater than 60% over 3 years Risk of total occlusion of an artery was relatively low and depended on the severity of stenosis: 0.7% if the baseline stenosis was less than 60% and 2.3% to 7% if it was greater Caps MT, Perissinotto C, Zierler RE, et al. Prospective study of atherosclerotic disease progression in the renal artery. Circulation 1998; 98:2866–2872

11. Schreiber and colleagues _ compared serial angiograms obtained a mean of 52 months apart in 85 patients who did not undergo intervention Stenosis had progressed in 37 (44%), and to the point of total occlusion in 14 (16%) Schreiber MJ, Pohl MA, Novick AC.The natural history of atherosclerotic and fibrous renal artery disease 1998 study found progression in 11.1% over 2.6 years Crowley JJ, et al.Progression of renal artery stenosis in patients undergoing cardiac catheterization

12. Rates of progression differed because – Indications for screening were different (clinical suspicion vs routine screening during CAG) Severity of stenosis at the time of diagnosis- different Fewer people were taking statins.

13. Clinically silent stenosis Renovascular hypertension Ischemic nephropathy Recurrent “flash” pulmonary edema

14. Less common presentation Occurring in patients with critical bilateral renal artery stenosis or unilateral stenosis in an artery supplying a solitary functioning kidney Most have severe hypertension (average systolic blood pressure 174–207 mm Hg) and poor renal function

15. Association between pulmonary edema and bilateral renal artery stenosis was first noted in 1998 by Pickering et al Several case series showed that 82% to 92% of patients with recurrent pulmonary edema and renal artery stenosis had bilateral stenosis Pickering TG, et al. Recurrent pulmonary oedema in hypertension due to bilateral renal artery stenosis: treatment by angioplasty or surgical revascularisation. Lancet 1988; 2:551–552 Later case series corroborated this finding: 85% to 100% of patients with renal artery stenosis and pulmonary edema had bilateral stenosis Messina LM, Zelenock GB, Yao KA, Stanley JC. Renal revascularization for recurrent pulmonary edema in patients with poorly controlled hypertension and renal insufficiency: a distinct subgroup of patients with arteriosclerotic renal artery occlusive disease. J Vasc Surg 1992; 15:73–80 Gray BH, et al. Clinical benefit of renal artery angioplasty with stenting for the control of recurrent and refractory congestive heart failure. Vasc Med 2002; 7:275–279.

16. Stenting has become standard in the endovascular treatment of renal artery stenosis Most atherosclerotic renal artery lesions are located in the ostium and many are extensions of calcified aortic plaque Textor SC. Ischemic nephropathy: where are we now? J Am Soc Nephrol 2004; 15:1974–1982 These hard lesions tend to rebound to their original shape more often with balloon angioplasty alone Stenting provides the additional force needed to permanently disrupt the lesion- longer-lasting result

17. Rates of technical success are higher with stents than without them (98% vs 46%– 77%) Beutler JJ, et al. Long-term effects of arterial stenting on kidney function for patients with ostial atherosclerotic renal artery stenosis and renal insufficiency. J Am Soc Nephrol 2001; 12:1475–1481 If the lesion is ostial, this difference is even more impressive (75% vs 29%) Restenosis rates at 6 months are lower with stents (14% vs 26%–48%) Van de Ven PJ, et al. Arterial stenting and balloon angioplasty in ostial atherosclerotic renovascular disease: a randomized trial. Lancet 1999; 353:282–286

18. Endovascular procedures pose some risk to the patient - critical to intervene only in patients most likely to respond clinically In renovascular HTN - improve blood pressure control In ischemic nephropathy- slow the decline in renal function or to improve it

19. INDICATIONSUPPORT IN THE LITERATURE Hypertension resistant to three drugs, including a diuretic Subgroup analysis of a randomized controlled trial Recurrent flash pulmonary edemaRetrospective Acute kidney injury after introduction of a renin-angiotensin system inhibitor Retrospective Rapidly declining renal function Not supported by subgroup analysis from randomized controlled trials New onset or worsening control of hypertension in older patients Retrospective

21. Coincidental RAS in a patient with unrelated CKD is very hard to differentiate from true ischemic nephropathy Most patients with ischemic nephropathy do not benefit from revascularization, making it challenging to identify those few whose renal function may respond

22. In a prospective cohort study in 304 patients with CKD & RAS who underwent surgical revascularization, Textor reported that serum creatinine improved - in 28% worsened in 19.7% remained unchanged in 160 - 52.6% Textor SC. Revascularization in atherosclerotic renal artery disease. Kidney Int 1998; 53:799–811

23. Davies et al found that 20% of patients who underwent renal stenting had a persistent increase in serum creatinine of 0.5 mg/dL or more Nearly three times more likely (19% vs 7%) to eventually require dialysis Lower 5-year survival rate (41% vs 71%) Davies MG, et al. Implications of acute functional injury following percutaneous renal artery intervention. Ann Vasc Surg 2008; 22:783–789

24. Zeller et al found that renal function improved slightly in 52% of patients who received stents Mean decrease in serum creatinine in this group was 0.22 mg/Dl However, the other 48% had a mean increase in serum creatinine of 1.1 mg/dL.Zeller T, et al. Predictors of improved renal function after percutaneous stent-supported angioplasty of severe atherosclerotic ostial renal artery stenosis. Circulation 2003; 108;2244–2249.

25. In several case series, patients whose renal function had been declining before intervention had impressive rates of better renal function afterward In a prospective cohort study by Muray et al a rise in serum creatinine of more than 0.1 mg/mL/month before intervention seemed to predict an improvement in renal function afterward

26. Acute pulmonary edema in the setting of bilateral RAS - improvement in clinical status can be expected in most patients after intervention Blood pressure improves in 94% to 100% Messina LM, Zelenock GB, Yao KA, Stanley JC. Renal revascularization for recurrent pulmonary edema in patients with poorly controlled hypertension and renal insufficiency: a distinct subgroup of patients with arteriosclerotic renal artery occlusive disease. J Vasc Surg 1992; 15:73–80 Renal function either improves or stabilizes in 77% to 91% Pulmonary edema resolves without recurrence in 77% to 100% Gray BH, et al. Clinical benefit of renal artery angioplasty with stenting for the control of recurrent and refractory congestive heart failure. Vasc Med 2002; 7:275–279.

27. Scottish and Newcastle Renal Artery Stenosis Collaborative Group Essai Multicentrique Medicaments vs Angioplastie (EMMA) Study Group Dutch Renal Artery Stenosis Intervention Cooperative (DRASTIC) study STAR TRIAL ASTRAL TRIAL CORAL TRIAL

28. Before stents came into use, several randomized controlled trials found that blood pressure was no better controlled after angioplasty except in cases of bilateral stenosis This may be because stenosis tended to recur after angioplasty without stents

29. Randomised comparison of percutaneous angioplasty vs continued medical therapy for hypertensive patients with atheromatous renal artery stenosis Methods Out of 135 eligible patients 55 (44%) were randomised Eligible patients had sustained hypertension, with a minimum diastolic BP of 95 mm Hg on at least two anti- hypertensive drugs RAS was defined by renal angiography as at least 50% stenosis in the affected vessel

30. Results: BP fell in angioplasty and medical groups Bilateral RAS - a statistically significant (P < 0.05) fall in bp Mean fall in bp - 26/10 mm hg In unilateral RAS, no statistically significant differences in outcome were observed No significant differences or trends in serum creatinine were observed between the two groups Major outcome events (death, MI, heart failure, stroke, dialysis) were similar Scottish and Newcastle Renal Artery Stenosis Collaborative Group

31. Conclusions In hypertensive patients with atheromatous RAS percutaneous renal angioplasty results in a modest improvement in systolic BP compared with medical therapy alone This benefit was confined to patients with bilateral disease. No patient was 'cured', renal function did not improve, and intervention was accompanied by a significant complication rate. J Webster, F Marshall, M Abdalla, A Dominiczak, R Edwards, C G Isles, H Loose, J Main, P Padfield, I T Russell, B Walker, M Watson and R Wilkinson on behalf of the Scottish and Newcastle Renal Artery Stenosis Collaborative Group J Hum Hypertens 1998; 12:329– 335

32. Aim - document the efficacy and safety of angioplasty for lowering BP in patients with atherosclerotic RAS Randomly assigned to antihypertensive drug treatment (control group, n=26) or angioplasty (n=23) Primary end point - 24 hour ambulatory BP - measured at baseline and at termination(6 months after randomization) Secondary end points were the incidence of complications

33. Early termination was required for refractory hypertension in 7 patients in the control group. Antihypertensive treatment was resumed in 17 patients in the angioplasty group Mean ambulatory BP at termination did not differ between control (141±15/84±11 mm Hg) and angioplasty (140±15/81±9 mm Hg) groups Two patients in the control group and 6 in the angioplasty group suffered procedural complications (RR 3.4; 95% confidence interval, 0.8 to 15.1)

34. Angioplasty allowed easier BP control than medication alone Antihypertensive agents - required at termination for all control patients but not for 6 of the 23 allocated to angioplasty (26%) Moreover, 7 of 25 patients in the control group (28%) developed refractory hypertension leading to secondary angioplasty within 6 Months

35. Angioplasty madeBP control easier in the short term but was more frequently associated with complications than conservative management in patients with unilateral atherosclerotic RAS Plouin PF, Chatellier G, Darne B, Raynaud A Blood pressure outcome of angioplasty in atherosclerotic renal artery stenosis: a randomized trial. Essai Multicentrique Medicaments vs Angioplastie (EMMA) Study Group. Hypertension 1998; 31:823–829.

36. Only unilateral renal artery disease was enrolled Groups were not well balanced - 23 patients for angioplasty and 26 for control Cross-over - seven of the control-group crossed over to intervention group High complication rate in angioplasty group which was about (6 of 23, or 26%)

37. Examined the effect of angioplasty on BP control in RAS Overall, intervention (balloon angioplasty without stents in 54 of 56 patients, with stents in the other 2) carried no benefit However, in subgroup analysis, the patients who crossed over because of resistant hypertension were more likely to benefit from angioplasty van Jaarsveld BC, et al.The effect of balloon angioplasty on hypertension in atherosclerotic renal-artery stenosis. Dutch Renal Artery Stenosis Intervention Cooperative Study Group. N Engl J Med 2000; 342:1007–1014

38. Randomly assigned 106 patients with HTN who had atherosclerotic RAS (luminal diameter < 50 %) and a serum creatinine 2.3 mg/dl or less to undergo PTRA or to receive drug therapy Also had to have a diastolic BP > 95 mm Hg or higher despite treatment with two antihypertensive drugs Blood pressure, doses of antihypertensive drugs, and renal function were assessed at 3 and 12 months, and patency of the renal artery was assessed at 12 months

39. No significant differences between the angioplasty and drug-therapy groups in systolic and diastolic blood pressures, daily drug doses, or renal function In the treatment of patients with hypertension and renal- artery stenosis, angioplasty has little advantage over antihypertensive-drug therapy

40. Sample size was not sufficient to detect a significant difference between treatment groups Renal artery stenosis was defined as greater than 50% stenosis High rate of cross over - Twenty-two of 50 patients randomized to medical therapy crossed over to the angioplasty group

41. 50 patients (female 18, male 32, mean age 64.4 years) with RAOOD of at least 70% stenosis in one or both renal arteries Randomized to either OSRP (n = 25 patients, 49 arteries) or PTRA + stent (n = 25 patients, 28 arteries)

42. Patients were followed on a regular basis for 4 years and longer Endpoints were re-occurrence of RAOOD and impairment of either kidney function or RVH

43. Results Directly procedure-related morbidity was 13% in the interventional group and 4% in the surgical group Four-year follow-up mortality was 18% vs 25% Both groups showed significant improvement of RVH (P <.001) as well as improvement or stabilization of renal function Both treatment modalities showed good early results concerning RVH, kidney function, and renal perfusion

44. Single center Groups were not well balanced (PTRA+ stent group number= 22, Surgical group = 27) Power calculation was not mentioned

45. NEW RANDOMIZED TRIALS

46. Despite the lack of evidence supporting revascularization of renal artery stenosis, many interventionalists practice under the assumption that the radiographic finding of renal artery stenosis alone is an indication for renal revascularization Only three randomized controlled trials in the modern era attempt to examine this hypothesis: STAR, ASTRAL, and CORAL

47. Randomized trial - medical treatment of renal artery stenosis was compared with medical treatment plus stenting 140 Patients with RAS and renal insufficiency were randomized to revascularization with stenting (n = 64) versus continued medical management (n = 76) Renal artery stenosis >50% luminal narrowing Renal insufficiency - creatinine clearance <80 ml/min/1.73 m 2 Patients could crossover from medical therapy to stent placement if necessary for refractory HTN

48. Patients Screened: 185 Patients Enrolled: 140 Mean Follow Up: 2 years Mean Patient Age: 66 years Female: 33%

49. From: Stent Placement in Patients With Atherosclerotic Renal Artery Stenosis and Impaired Renal Function :

50. Hypertension was treated to <140/90 mm Hg with the use of diuretics, CCB, beta blockers All patients received atorvastatin 10 mg & aspirin 75- 100 mg daily

51. No difference in baseline characteristics between the groups Stent group – Mean age was 66 years 33% were women mean creatinine was 1.7 mg/dl mean systolic blood pressure was 160 mm Hg, mean number of antihypertensive drugs was 2.8, >90% stenosis was present in 34%.

52. Participant Characteristics at Baseline – STAR TRIAL

53. Primary Endpoint 20% or more decrease in creatinine clearance Secondary Endpoints: Procedural complications Hypertension Mortality

54. Primary outcome - occurred in 16% of the stent group versus 22% of the medical therapy group (p = NS) Unilateral stenoses - 9% versus 20% (p = NS) With only bilateral stenoses, 22% vs 23% (p = NS).

55. All-cause mortality was 8% vs 8% and cardiovascular mortality was 3% vs 5% 3/5 deaths in the stent group were due to procedure- related deaths and one late death was due to infected hematoma

57. With RAS and renal insufficiency strategy of revascularization with stenting was not superior to continued medical therapy Renal artery stenting was not able to preserve creatinine clearance at 2 years of follow-up No difference based on the presence of unilateral or bilateral stenoses

58. Stent placement with medical treatment had no clear effect on progression of impaired renal function but led to a small number of significant procedure-related complications

59. Study was under-powered Moreover, four patients lost in follow up and 3% drop out Included patients with mild RAS 33% of the patients - RAS 50%-70% 12 (19%) intervention group RAS < 50%

60. Not all “stent” group patients received stents Only 46 (72%) of the 64 patients subjected to stenting infact received a stent, while 18 (28%) did not More than half of the patients had unilateral disease Complication rates were high

61. Aim - To evaluate percutaneous renal artery revascularization compared with medical therapy in patients with significant renal artery stenosis Hypothesis - Percutaneous revascularization of stenotic renal arteries would be more effective at decreasing the rate of decline in renal function

62. Patients Enrolled: 806 Mean Follow Up: 27 months Mean Patient Age: 70 years Female: 37

63. Primary Endpoint Change in renal function Secondary Endpoints: Blood pressure control Time to first renal event Time to first cardiovascular event Mortality

64. Clinical suspicion for atherosclerotic renal disease, with substantial anatomical atherosclerotic stenosis in at least one renal artery

65. Need for surgical revascularization High likelihood of needing revascularization within 6 months Nonatheromatous cardiovascular disease History of prior revascularization for renal artery stenosis

66. Patients with significant RAS were randomized to PTRA (angioplasty and/or stenting) plus medical therapy (n = 403) or medical therapy alone (n = 403).

67. Serum creatinine - 2.02 mg/dl Estimated GFR - 40 ml/min Mean stenosis - 76% Mean number of antihypertensive - 2.8 per patient BP - 151/76 mm Hg 53% ex-smokers, 30% diabetics, and 41% PVD 6% of the medically treated patients crossed over to revascularization 82% of the revascularization group that were successfully revascularized (95% of revascularized patients ) received a stent

68. Overall mortality - 25.6% in the revascularization group 26.3% in the medical groups (p = 0.46) Cardiovascular mortality - 7.4% of the revascularization gp 8.2% of medically treated gp (p=NS) Any CV event - 35% in revascularization gp 36% in the medically treated group (p = 0.96) Hospitalization for fluid overload or heart failure 12% of the revascularization group 14% of the medically treated group (p = NS) No difference in serum creatinine, SBP, time to first renal event, or overall vascular event during follow-up (p = NS for all outcomes).

69. Currently - no evidence of benefit for renal artery revascularization Renal revascularization did not improve serum creatinine, SBP, renal events mortality, or overall vascular events

70. It remains to be determined if renal revascularization would benefit certain subgroups – Acute renal failure with a critical RAS Flash pulmonary edema

71. Normal renal function at baseline - 25% of patients in each group had normal renal function (eGFR > 50 ml/min/1.73 m2) at the entry of the trial No core laboratory were found - some patients in the 50%– 70% stenosis group actually had a stenosis of < 50%

72. Possible selection bias - physicians were aware that which patients would benefit from either revascularization or medications High complication rate - major complication rate in first 24 hrs - 9% Measurement of GFR - by the Cockcroft–Gault not MDRD Non-blinding - observer and selection bias - high Rate of cross-over - 6% from medication to intervention gp

74. Ongoing multicenter randomized controlled trial Contrasting optimum medical therapy alone to stenting with optimum medical therapy Composite cardiovascular and renal end point: o Cardiovascular or renal death o MI & hospitalization for CHF o Stroke o Doubling of serum creatinine o need for renal replacement therapy.

75. Secondary end points - evaluate effectiveness of revascularization in important subgroups o All-cause mortality o Kidney function o Renal artery patency o Microvascular renal function o Blood pressure control

76. CORAL is using a standardized medical protocol to control blood pressure Use of embolic protection devices during stenting is encouraged Randomization will occur in 1080 subjects

77. 1. An atherosclerotic renal stenosis of > or = 60% with a 20 mm Hg systolic pressure gradient or > or = 80% with no gradient necessary 2. Systolic hypertension of > or = 155 mm Hg on > or = 2 antihypertensive medications

78. CORAL represents a unique opportunity to determine the incremental value of stent revascularization, for the treatment of atherosclerotic RAS Hopefully, the large size and inclusion of patients with more marked HTN will address the utility of intervention in higher-risk populations with RAS

79. Renal stenting carries an increasingly common risk to kidney function: atheroembolism Stent crushes the plaque against vessel wall Leads to obstruction of the renal microvasculature, increasing the risk of irreversible damage to renal function Embolic protection devices - inserted downstream of the lesion before stenting Catch any debris that may break loos

80. Holden et al prospectively studied 63 patients with renal artery stenosis and deteriorating renal function who underwent stenting with an embolic protection device At 6 months renal function had either improved or stabilized in 97% of patients Suggesting that many of the deleterious effects of stenting are related to atheroembolism

81. Prospective Randomized Study Comparing Renal Artery Stenting With or Without Distal Protection In patients with mild renal dysfunction and GFR was not declining (average estimated GFR 59.3 mL/min), found contrary results

82. Recommendations for intervention in renal artery stenosis Intervention is not recommended: In patients whose renal function has remained stable over the past 6 to 12 months and whose hypertension can be controlled medically Intervention should be considered: In patients with recurrent episodes of congestive heart failure without an obvious cardiac cause and with bilateral renal artery stenosis or stenosis to a single functioning kidney In patients whose renal function has been rapidly declining over the past 3 to 6 months with bilateral renal artery stenosis or stenosis to a single functioning kidney, without another obvious cause In patients in whom it is impossible to control hypertension with intense medical management (at least three maximally dosed antihypertensive medications, one of which is a diuretic)

83. Attention should now be focusing on clinical, rather than radiographic, indications for intervening on renal artery stenosis Multidisciplinary approach - includes the input of a nephrologist well versed in renal artery stenosis

84. Two large randomized trials of intervention vs medical therapy showed negative results for intervention. A third trial is under way Intervention is not recommended if renal function has remained stable over the past 6 to 12 months and if hypertension can be controlled medically The best evidence supporting intervention is for bilateral stenosis with flash pulmonary edema, but the evidence is from retrospective studies Stenosis by itself, even if bilateral, is not an indication for renal artery stenting

85. Results of STAR and ASTRAL confirm the growing suspicion that the surge seen in the last decade in renal artery stenting should be coming to an end Results either from CORAL or possibly a post hoc analysis of ASTRAL might identify potential high-risk groups that will benefit from renal intervention

86. As embolic protection devices become more agile and suitable to different renal lesions, there remains the possibility that, due to lower rates of unidentified atheroembolic kidney disease, CORAL may demonstrate improved renal outcomes after stenting

87. If not, the search for the best means to predict who should have renal intervention will continue The clinical problem is too intriguing, and too profitable, to die altogether

88. Thank you

89. Evaluate short and long-term outcomes of PTRA renal artery stenosis due to RAFMD Technical success was 100% Short-term outcomes Majority (69%) had an immediate clinical benefit for hypertension 6% were cured without BP medications, and 63% improved with less than or equal to preoperative BP medications. For the entire cohort, renal function (mean eGFR) significantly increased from 71.9 mL/minute to 80.8 mL/minute (P =.007

90. Long-term outcomes: freedom from recurrent or worsening hypertension (>140 systolic blood pressure [SBP] and >90 diastolic blood pressure [DBP]) was (93%, 75%, and 41%) freedom from reduced renal function (eGFR <30 mL/minute) was (100%, 95%, and 64%) at 1, 5, and 8 years, respectively Renal angioplasty is a safe and durable modality for treating RAFMD with favorable short and long-term clinical outcomes