renovascular.doc

Treatment ofRenovascular Disease

Resident Grand RoundsDepartment of Internal Medicine

Wake Forest University School of Medicine

W. Cody McClatchey, M.D.

September 21, 1999

Case Presentation

In July 1999, a 74 year old white female with a history of hypertension, coronary artery disease, congestive heart failure, chronic renal insufficiency, and smoking returned to the Medicine OPD for further evaluation of hypertension which had been difficult to control. She was without any new complaints and had been compliant with her medications. Recently, her captopril had been discontinued because of worsening renal function (serum creatinine 2.1).

Additional medical history: emphysema, seronegative rheumatoid arthritis, status post non-Q wave myocardial infarction 1997, status post recent hip fracture after fall which was managed nonsurgically

Social history: Recently quit smoking, but has 50 pack-year history

Current medications: methotrexate 15mg per week, prednisone 7mg qd (tapering), amlodipine 10mg qd, furosemide 40mg bid, hydralazine 50mg qid, lanoxin 0.125mg qd, aspirin 325mg qd, albuterol MDI prn

Blood pressure 140/60, pulse 88, weight 191lbs.

Physical exam: alert and fully oriented obese femaleHEENT: WNL, no JVDLungs: clearC/V: regular, no murmurs, normal S1 and S2Abd: NT, normal BS, no bruitsExtr: bilateral nonpitting LE edema,

decreased peripheral pulses

Labs: CBC normal, Sodium 136, potassium 4.0, chloride 93, bicarbonate 30,BUN 32, creatinine 1.3 (baseline 1.2 for several years) (GFR 55),Glucose 107, urine clear and without protein or casts

Echocardiogram 1998: EF 35%, LVH

EKG July 1999: NSR, LVH

Renal duplex sonography June 1999:Critical right renal artery stenosis (> 60% stenosis)Probable left renal artery occlusion

Definition

Adult renovascular disease (RVD) is an acquired anatomic narrowing or obstruction of one or more renal arteries that may lead to hypertension (renovascular hypertension) and/or reduction in glomerular filtration rate (ischemic nephropathy).

Causes of Renovascular Disease

Atherosclerosis of renal artery (70%)Usually at or near ostiumLeft more common than right

Fibromuscular dysplasia of renal artery (25%)Females > males

Thromboembolic diseaseAtheroembolic diseaseNeurofibromatosis of renal artery

Irradiation of renal arteryRenal artery traumaTakayasu’s arteritisRenal artery aneurysmArteriovenous fistulasSpontaneous dissection of renal arteryStenosis of renal artery of transplanted kidney

Epidemiology

The prevalence of renovascular disease (RVD) has not been obtained from a population based cohort, but is estimated at between 2 and 5 percent of the U.S. hypertensive population. Atherosclerotic RVD is rarely found in young patients, and Fibromuscular dysplasia (FMD) is typically found in young females. Appel, Freedman, and Hansen compiled the following retrospective data:1

Prevalence of RVDN Study type/selection Subgroups >50% RAS

154 unselected autopsy Age < 55 yrs 7%

Age > 55 yrs 12-36%

295 unselected autopsy Age < 60 yrs 14%

Age >60 yrs 29%

100 consecutive angiograms for PVD normotensive 17.50%

hypertensive 28%

346 consecutive angiograms for PVD or AAA PVD 28%

AAA 29%

100 consecutive angiograms for PVD renal function normal 36%

renal function abnormal 50%

127 consecutive angiograms for PVD 28%

1235 consecutive angiograms for CAD w/CAD 19%

w/o CAD 9%

w/CHF 25%

w/o CHF 13%

RAS, renal artery stenosis; PVD, peripheral vascular disease; AAA, abdominal aortic aneurysm;

CAD, coronary artery disease; CHF, congestive heart failure

Pathophysiology

The pathology of arterial atherosclerosis is well understood. It is hypothesized that the risk factors for progression of atherosclerotic coronary heart disease apply to atherosclerotic renovascular disease, but has not been shown in prospective data. Atherosclerotic RVD most often involves the proximal renal artery and/or ostium. The mechanism that leads to severe hypertension is thought to be increased secretion of renin by juxtaglomerular cells in the afferent arteriole of the glomerulus, stimulated by decreased renal perfusion. However, hypertension has been shown not to be renin-dependent in a minority of patients with atherosclerotic RVD and hypertension2. These patients saw improvement in hypertension following renal artery reperfusion therapy (bypass surgery), despite “nonlateralizing” renal vein renin assays.

The term ischemic nephropathy is used in the literature to define renal insufficiency presumed secondary to decreased renal perfusion.

Fibromuscular dysplasia (FMD) is a class of abnormal pathology of the intima and/or media of stenotic renal arteries with distinct angiographic appearance. This is typically a lesion of the distal 2/3 of the renal artery and is usually seen as microaneurysms (“string of beads”) on angiogram.

Diagnosis

History:Many historical clues and risk factors should lead physicians to consider RVD. Smokers have been shown retrospectively to be at increased risk for atherosclerotic RVD. Renovascular hypertension may be suspected in the setting of worsening blood pressure despite addition of multiple antihypertensives, and/or worsening renal function not attributable to other causes. Acute renal insufficiency associated with the use of ACE inhibitors and or other antihypertensives should lead one to suspect RVD. Prevalence of renovascular hypertension (RVH) is four to sixfold if age of onset of HTN is after 60 years3

Physical signs:Abdominal bruit (odds ratio 11.5)4

Two to threefold increased prevalence when diastolic blood pressure > 110mm Hg5

Laboratory:1. Serum potassium less than 3.4 mEq/L associated with four to sixfold risk for RVH6

2. Renal insufficiency may be present3. Renal duplex sonography (RDS) has been found to be 93% sensitive and 98%

specific for renal artery stenosis (RAS) with experienced technicians.7

4. Magnetic resonance angiography, although more expensive than sonography, has sensitivity and specificity greater than 90% in recent studies.

5. Captopril renal scanning is another screening test for RAS that compares a baseline radionuclide renogram to a post-captopril radionuclide renogram. RAS is suggested by an increase in time to peak activity to more than 11 minutes, or by glomerular filtration ratio between left and right kidneys greater than 1.5:1. Sensitivity ranges from 73% to 91% and specificity ranges from 72% to 89%.8 However, sensitivity and specificity in setting of bilateral disease and/or decreased renal function are reduced, and anatomic information is not revealed.

6. Renal-vein renin assays may be used in the setting of unilateral and non-solitary RAS to evaluate functional significance. Separate right and left renal vein samples are obtained by central venous catheter. “Lateralizing” refers to the finding of increased renin in the side of the stenotic artery. Although results of this study have not demonstrated good specificity for functional significance in most clinical settings, nephrectomy may be indicated by a positive study in the setting of unilateral and non-solitary disease to an atrophic kidney not amenable to revascularization.

Treatment

Renovascular disease has been shown to be a progressive disease that may result in hypertension and/or renal failure. There has not been a prospective, randomized clinical trial that compares treatment of any manifestation of RVD with currently available antihypertensives versus surgical or percutaneous transluminal interventions. It has been

shown in clinical trials that treatment of hypertension lowers mortality, and that end-stage renal disease (ESRD) is associated with very high mortality. It is hypothesized that controlling blood pressure and preventing ESRD in patients with RVD will lower mortality. To date, normotension has not been associated with stable renal function in patients with RVD.

Zierler et al prospectively demonstrated progression of atherosclerotic renal artery stenosis by serial renal duplex sonography in a cohort of 80 patients referred to the University of Washington for hypertension or renal failure over a mean interval of 13 months.9 The inclusion criterion was having at least one “abnormal” renal artery not considered eligible for surgery or percutaneous transluminal angioplasty (PTA). Baseline characteristics of patients included mean age 65, mean serum creatinine (Cr) 1.4, mean BP 168/85, 45% men, and 42% had previous MI or CABG. At baseline, 26% of arteries were normal, 25% had less than 60% stenosis, 45% had greater than 60% stenosis, and 4% were occluded.

Prospective study of percutaneous renal angioplasty for treatment of RVH

A prospective study by Sos, et al10, published in 1983, followed 89 patients for a mean interval of 16 months after percutaneous renal angioplasty (PRA), with intention to treat analysis. 51 patients had atherosclerotic RVD, 31 patients had fibromuscular dysplasia (FMD), and 7 patients had other miscellaneous diseases of the renal artery. Inclusion criteria were arteriographically documented RAS (>=75%), abnormal renal-vein renin values, and hypertension. Patients did not receive anticoagulation therapy during PRA, but “most” were maintained on aspirin 350mg qd following PRA. There were no operative deaths.

Baseline characteristics of the atherosclerotic RVD cohort included mean Cr 2.0, mean age 57, 63% male, mean BP 200/108. 21 patients had bilateral RAS. Of those with

unilateral RAS, 5 were occluded, 5 were ostial, and 20 were non-occluded and non-ostial. Complications of PRA included four dissections and three puncture site traumas.

Good results:87% of unilateral, non-occluded, and non-ostial interventions resulted in cure or improvement of BPPoor results:100% of unilateral ostial interventions failed to lower BP86% of bilateral interventions failed to lower BP80% of occluded interventions failed to lower BP

Baseline characteristics of the FMD cohort included mean Cr 1.0, mean age 31, 87% female, mean BP 171/100. Complications of PRA included two dissections. 93% of patients had improvement or cure in hypertension.

This study suggests PRA is efficacious for the treatment of renovascular hypertension in patients with FMD and unilateral, non-occluded, non-ostial atherosclerotic RVD.

Prospective study of renal angioplasty with stents for treatment of ostial renovascular disease

A prospective study by Blum, et al11, published in 1997, followed 75 patients with non-occlusive ostial atherosclerotic RVD (6 bilateral) for a mean interval of 27 months after PRA. 68 patients adjunctively received short endoprostheses (Palmaz stent by Johnson and Johnson) because of primary technical failure. The inclusion criterion was >50% ostial stenosis within 5mm of the renal artery lumen. Patients received heparin 5000 IU bolus iv during the intervention, followed by 2 days of PTT> 60. Additionally, all patients were maintained on aspirin 100mg or ticlopidine 250mg per day following intervention. Baseline patient characteristics included mean age 60, mean BP 188/105, and mean creatinine 1.2. There were no major operative complications, and the average hospital stay was 4.5 days. 78% of patients with stents placed had improvement or cure in hypertension, creatinine levels remained unchanged, and only 12% had angiographic restenosis at the site of the stent over the followup period. A secondary patency rate of 92% was obtained at 60 months.

This study suggests PRA with adjunctive stent placement and antiplatelet therapy is efficacious and safe for the treatment of renovascular hypertension in patients with non-occlusive, ostial RVD. PRA may slow the progression of ischemic nephropathy in such patients.

Retrospective case series of surgical treatment of renovascular disease

K. Hansen, J. Burkart, G. Plonk, and R. Dean published a retrospective case series of patients who underwent surgical therapy for RVD (> 60% stenosis) at Bowman Gray School of Medicine between 1987 and 1991.12 157 patients with atherosclerotic RVD (80 men, 77 women) were followed for a mean period of 24 months. Baseline patient characteristics included mean age 62, mean BP 212/114, 82% smoked cigarettes, 75% had Cr> 1.3, 15% had Cr> 3.0, and 36 % had “extreme disease” (more than one extrarenal manifestation of atherosclerosis plus either EF< 30%, clinical CHF, or Cr 3.0). The types of RVD were 36% unilateral (18 occluded, 37 ostial, and 2 nonostial lesions), 59% bilateral (37occlusions, 140 ostial, and 7 nonostial lesions), and 5% a solitary kidney. Operative mortality was 3.2% and 90% of patients experienced improvement or cure of hypertension. No patients experienced renal failure in the immediate postoperative period. Low preoperative glomerular filtration rate (GFR) was most highly associated with operative mortality. Although patients with severe renal insufficiency (mean GFR 15mL/min) and unilateral renal artery repair did not experience significant improvement in GFR postoperatively, such patients with bilateral or solitary repairs did experience a significant early improvement in GFR (p = 0.0007).

This study suggests surgical therapy is efficacious and reasonably safe for treatment of renovascular hypertension secondary to atherosclerotic RVD. It also suggests efficacy and safety in the treatment of ischemic nephropathy from bilateral or solitary atherosclerotic RVD.

Prospective, non-randomized study of surgery versus medical therapy for treatment of renovascular disease

In 1973, Hunt and Strong13 published a prospective, non-randomized comparison of surgical versus medical therapy for RVD over a minimum of seven years. Inclusion criteria included angiographic RVD, “severe” hypertension, male Cr< 2.5, female Cr< 2.0, no more than one previous MI or stroke, and age “not much greater than 60.” 81 patients with atherosclerotic RVD entered the study and received operative intervention only if hypertension or renal function worsened significantly within the first three months. Medical therapy consisted of low sodium diet and HCTZ +/- spironolactone. Methyldopa was “usually added.” Guanethidine was substituted for methyldopa if diastolic blood pressure persisted above 110mm Hg. Surgical therapy consisted of renal artery repair, bypass, or nephrectomy (12). Baseline patient characteristics included 65% male, mean age 53, mean BP 212/124, and 36% with abdominal bruits. Mean age was three years older in the medical therapy cohort. Of the 37 patients in the surgical therapy cohort: there was no operative mortality, 78% survived five years, and 70% survived 7 years. Of the 44 patients in the medical therapy cohort: 64% survived five years and 39% survived 7 years. A weakness of this study is that it is unknown how well blood pressure was controlled in patients in the medical therapy arm.

This study suggests surgical therapy for atherosclerotic RVD results in improved mortality compared to 1973 medical therapy alone, in good surgical candidates with severe hypertension.

Prospective, randomized study of angioplasty versus surgery for treatment of unilateral atherosclerotic renovascular disease

A prospective, randomized comparison of percutaneous transluminal renal angioplasty (PTRA) versus operation for treatment of unilateral atherosclerotic RVD was published by Weibull, et al in 199314. Inclusion criteria consisted of age < 70, untreated BP > 160/100, unilateral atherosclerotic stenosis within one cm of the aorta, and Cr < 3.4. Baseline patient characteristics were mean age 57 and mean Cr 1.2. Primary endpoints were restenosis, death, or 24 months. 58 patients were randomly assigned to either surgery or PTRA. Patients undergoing PTRA were not anticoagulated and were not instructed to take antiplatelet agents. There was no significant difference in major complications between the two treatment groups. PTRA primary patency was 62% and secondary patency was 90%, compared to 96% patency rate for surgery (mostly endarterectomy) at end of followup. 69% of patients treated with PTRA had improved or cured hypertension at end of followup compared to 90% of surgical patients. 79% of patients treated with PTRA had stable or improved GFR at end of followup compared to 72% of surgical patients.

This study suggests the efficacy and safety of surgery and PTRA for treatment of renovascular hypertension and ischemic nephropathy in patients with unilateral atherosclerotic RVD is comparable.

Conclusions

Evidence-based decisions pertaining to optimal therapy for renovascular disease remain controversial in most patients, and should involve the patients themselves. Long-term, prospective, randomized studies with statistical power and significance are lacking. Consideration of local expertise in renovascular surgery and percutaneous interventions is warranted. Neither interventional nor surgical management has been shown to significantly improve mortality compared to current medical therapy alone in prospective, randomized trials. PRA has been shown to be safe and effective treatment for renovascular hypertension secondary to fibromuscular dysplasia, and is currently accepted as the treatment of choice.

The techniques and technology involved in PRA remain primitive. The use of antiplatelet agents and stents revolutionized the efficacy of percutaneous coronary interventions, and have brought into question current indications for coronary artery bypass grafting, but have not been rigorously studied in the setting of PRA. Evidence supports PRA with adjunctive stents and antiplatelet agents as therapy of choice for renovascular hypertension refractory to medical therapy and/or ischemic nephropathy secondary to non-occlusive, unilateral atherosclerotic renovascular disease causing greater than 60% stenosis. Evidence supports surgery as therapy of choice for renovascular hypertension refractory to medical therapy and/or ischemic nephropathy

secondary to bilateral (including solitary), non-ostial atherosclerotic renovascular disease causing greater than 60% stenosis.

1 Appel RG, Freedman BI, and Hansen KJ: Renovascular disease and progressive renal insufficiency. Seminars in Dialysis 8: 285-293, 1995.2 Hansen JH, et al: Contemporary surgical management of renovascular disease. Journal of Vascular Surgery 16: 319-331, 1992.3 Anderson GH, Blakeman N, and Streeten D.H.P.: Prediction of renovascular hypertension. American Journal of Hypertension 1:301-304, 1988.4 Svetkey LP, et al: Clinical characteristics useful in screening for renovascular disease. Southern Medical Journal 83: 743-747, 1990.5 Anderson GH, Blakeman N, and Streeten D.H.P.: Prediction of renovascular hypertension. American Journal of Hypertension 1:301-304, 1988.6 Ibid.7 Hansen KJ, et al: Renal duplex sonography: Evaluation of clinic utility. Journal of Vascular Surgery 12: 227-236, 1990.8 Canzanello VJ, Textor SC. Noninvasive diagnosis of renovascular disease. Mayo Clinic Proceedings 69: 1172-1181, 1994.9 Zierler RE, et al: Natural history of atherosclerotic renal artery stenosis: A prospective study with duplex ultrasonography. Journal of Vascular Surgery 19: 250-258, 1994.10 Sos TA, et al: Percutaneous transluminal renal angioplasty in renovascular hyperension due to atheroma or fibromuscular dysplasia. The New England Journal of Medicine 309: 274-279, 1983.11 Blum U, et al: Treatment of ostial renal-artery stenoses with vascular endoprostheses after unsuccessful balloon angioplasty. The New England Journal of Medicine 336: 459-535, 1997.12 Hansen KJ, et al: Contemporary surgical management of renovascular disease. Journal of Vascular Surgery 16: 319-331, 1992.13 Hunt JC and Strong CG: Renovascular hypertension. The American Journal of Cardiology 32: 562-574, 1973.14 Weibull, et al: Percutaneous transluminal renal angioplasty versus surgical reconstruction of atherosclerotic renal artery stenosis: A prospective randomized study. Journal of Vascular Surgery 18: 841-852, 1993.