Treatment ofRenovascular Disease Resident Grand Rounds Department of Internal Medicine Wake Forest University School of Medicine W. Cody McClatchey, M.D. September 21, 1999
Case PresentationIn July 1999, a 74 year old white female with a history of hypertension, coronary arterydisease, congestive heart failure, chronic renal insufficiency, and smoking returned to theMedicine 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 postnon-Q wave myocardial infarction 1997, status post recent hip fracture after fall whichwas managed nonsurgicallySocial history: Recently quit smoking, but has 50 pack-year historyCurrent 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 prnBlood pressure 140/60, pulse 88, weight 191lbs.Physical exam: alert and fully oriented obese female HEENT: WNL, no JVD Lungs: clear C/V: regular, no murmurs, normal S1 and S2 Abd: NT, normal BS, no bruits Extr: bilateral nonpitting LE edema, decreased peripheral pulsesLabs: 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
DefinitionAdult renovascular disease (RVD) is an acquired anatomic narrowing or obstruction ofone or more renal arteries that may lead to hypertension (renovascular hypertension) and/or reduction in glomerular filtration rate (ischemic nephropathy).Causes of Renovascular DiseaseAtherosclerosis of renal artery (70%) Irradiation of renal artery Usually at or near ostium Renal artery trauma Left more common than right Takayasu’s arteritisFibromuscular dysplasia of renal artery (25%) Renal artery aneurysm Females > males Arteriovenous fistulasThromboembolic disease Spontaneous dissection of renal arteryAtheroembolic disease Stenosis of renal artery of transplanted kidneyNeurofibromatosis of renal arteryEpidemiologyThe prevalence of renovascular disease (RVD) has not been obtained from a populationbased cohort, but is estimated at between 2 and 5 percent of the U.S. hypertensivepopulation. Atherosclerotic RVD is rarely found in young patients, and Fibromusculardysplasia (FMD) is typically found in young females. Appel, Freedman, and Hansencompiled the following retrospective data:1 Prevalence of RVD N 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
PathophysiologyThe pathology of arterial atherosclerosis is well understood. It is hypothesized that therisk factors for progression of atherosclerotic coronary heart disease apply toatherosclerotic renovascular disease, but has not been shown in prospective data.Atherosclerotic RVD most often involves the proximal renal artery and/or ostium. Themechanism that leads to severe hypertension is thought to be increased secretion of reninby juxtaglomerular cells in the afferent arteriole of the glomerulus, stimulated bydecreased renal perfusion. However, hypertension has been shown not to be renin-dependent in a minority of patients with atherosclerotic RVD and hypertension2. Thesepatients 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 insufficiencypresumed secondary to decreased renal perfusion.Fibromuscular dysplasia (FMD) is a class of abnormal pathology of the intima and/ormedia of stenotic renal arteries with distinct angiographic appearance. This is typically alesion of the distal 2/3 of the renal artery and is usually seen as microaneurysms (“stringof beads”) on angiogram.
DiagnosisHistory:Many historical clues and risk factors should lead physicians to consider RVD. Smokershave been shown retrospectively to be at increased risk for atherosclerotic RVD.Renovascular hypertension may be suspected in the setting of worsening blood pressuredespite addition of multiple antihypertensives, and/or worsening renal function notattributable to other causes. Acute renal insufficiency associated with the use of ACEinhibitors and or other antihypertensives should lead one to suspect RVD. Prevalence ofrenovascular hypertension (RVH) is four to sixfold if age of onset of HTN is after 60years3Physical signs:Abdominal bruit (odds ratio 11.5)4Two to threefold increased prevalence when diastolic blood pressure > 110mm Hg5Laboratory:1. Serum potassium less than 3.4 mEq/L associated with four to sixfold risk for RVH62. 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.74. 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.TreatmentRenovascular disease has been shown to be a progressive disease that may result inhypertension and/or renal failure. There has not been a prospective, randomized clinicaltrial that compares treatment of any manifestation of RVD with currently availableantihypertensives versus surgical or percutaneous transluminal interventions. It has been
shown in clinical trials that treatment of hypertension lowers mortality, and that end-stagerenal disease (ESRD) is associated with very high mortality. It is hypothesized thatcontrolling blood pressure and preventing ESRD in patients with RVD will lowermortality. To date, normotension has not been associated with stable renal function inpatients with RVD.Zierler et al prospectively demonstrated progression of atherosclerotic renal arterystenosis by serial renal duplex sonography in a cohort of 80 patients referred to theUniversity of Washington for hypertension or renal failure over a mean interval of 13months.9 The inclusion criterion was having at least one “abnormal” renal artery notconsidered eligible for surgery or percutaneous transluminal angioplasty (PTA). Baselinecharacteristics of patients included mean age 65, mean serum creatinine (Cr) 1.4, meanBP 168/85, 45% men, and 42% had previous MI or CABG. At baseline, 26% of arterieswere normal, 25% had less than 60% stenosis, 45% had greater than 60% stenosis, and4% were occluded. 50 Cumulative Incidence (%) 40 Normal <60% 30 >=60% 20 10 0 0 months 6 months 12 months 18 months 24 months Follow-up Interval Prospective study of percutaneous renal angioplasty for treatment of RVHA prospective study by Sos, et al10, published in 1983, followed 89 patients for a meaninterval of 16 months after percutaneous renal angioplasty (PRA), with intention to treatanalysis. 51 patients had atherosclerotic RVD, 31 patients had fibromuscular dysplasia(FMD), and 7 patients had other miscellaneous diseases of the renal artery. Inclusioncriteria were arteriographically documented RAS (>=75%), abnormal renal-vein reninvalues, and hypertension. Patients did not receive anticoagulation therapy during PRA,but “most” were maintained on aspirin 350mg qd following PRA. There were nooperative deaths.Baseline characteristics of the atherosclerotic RVD cohort included mean Cr 2.0, meanage 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 orimprovement 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 BPBaseline 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% ofpatients had improvement or cure in hypertension. 100 80 Improved BP (%) 60 40 20 0 Ostial Bilateral Occluded UNONOThis study suggests PRA is efficacious for the treatment of renovascular hypertension inpatients 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 afterPRA. 68 patients adjunctively received short endoprostheses (Palmaz stent by Johnsonand Johnson) because of primary technical failure. The inclusion criterion was >50%ostial stenosis within 5mm of the renal artery lumen. Patients received heparin 5000 IUbolus iv during the intervention, followed by 2 days of PTT> 60. Additionally, allpatients were maintained on aspirin 100mg or ticlopidine 250mg per day followingintervention. Baseline patient characteristics included mean age 60, mean BP 188/105,and mean creatinine 1.2. There were no major operative complications, and the averagehospital stay was 4.5 days. 78% of patients with stents placed had improvement or curein hypertension, creatinine levels remained unchanged, and only 12% had angiographicrestenosis at the site of the stent over the followup period. A secondary patency rate of92% was obtained at 60 months.This study suggests PRA with adjunctive stent placement and antiplatelet therapy isefficacious and safe for the treatment of renovascular hypertension in patients with non-occlusive, ostial RVD. PRA may slow the progression of ischemic nephropathy in suchpatients. Retrospective case series of surgical treatment of renovascular diseaseK. Hansen, J. Burkart, G. Plonk, and R. Dean published a retrospective case series ofpatients who underwent surgical therapy for RVD (> 60% stenosis) at Bowman GraySchool of Medicine between 1987 and 1991.12 157 patients with atherosclerotic RVD (80men, 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 oneextrarenal 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 solitarykidney. Operative mortality was 3.2% and 90% of patients experienced improvement orcure of hypertension. No patients experienced renal failure in the immediatepostoperative period. Low preoperative glomerular filtration rate (GFR) was most highlyassociated with operative mortality. Although patients with severe renal insufficiency(mean GFR 15mL/min) and unilateral renal artery repair did not experience significantimprovement in GFR postoperatively, such patients with bilateral or solitary repairs didexperience a significant early improvement in GFR (p = 0.0007).This study suggests surgical therapy is efficacious and reasonably safe for treatment ofrenovascular hypertension secondary to atherosclerotic RVD. It also suggests efficacyand safety in the treatment of ischemic nephropathy from bilateral or solitaryatherosclerotic RVD. Prospective, non-randomized study of surgery versus medical therapy for treatment of renovascular diseaseIn 1973, Hunt and Strong13 published a prospective, non-randomized comparison ofsurgical versus medical therapy for RVD over a minimum of seven years. Inclusioncriteria 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.” 81patients with atherosclerotic RVD entered the study and received operative interventiononly if hypertension or renal function worsened significantly within the first threemonths. Medical therapy consisted of low sodium diet and HCTZ +/- spironolactone.Methyldopa was “usually added.” Guanethidine was substituted for methyldopa ifdiastolic blood pressure persisted above 110mm Hg. Surgical therapy consisted of renalartery 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 wasthree years older in the medical therapy cohort. Of the 37 patients in the surgical therapycohort: there was no operative mortality, 78% survived five years, and 70% survived 7years. 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 pressurewas controlled in patients in the medical therapy arm. 90 80 70 survival (%) 60 50 Medical 40 Surgical 30 20 10 0 5 years 7 years
This study suggests surgical therapy for atherosclerotic RVD results in improvedmortality compared to 1973 medical therapy alone, in good surgical candidates withsevere hypertension.
Prospective, randomized study of angioplasty versus surgery for treatment of unilateral atherosclerotic renovascular diseaseA prospective, randomized comparison of percutaneous transluminal renal angioplasty(PTRA) versus operation for treatment of unilateral atherosclerotic RVD was publishedby 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 endpointswere restenosis, death, or 24 months. 58 patients were randomly assigned to eithersurgery or PTRA. Patients undergoing PTRA were not anticoagulated and were notinstructed to take antiplatelet agents. There was no significant difference in majorcomplications between the two treatment groups. PTRA primary patency was 62% andsecondary patency was 90%, compared to 96% patency rate for surgery (mostlyendarterectomy) at end of followup. 69% of patients treated with PTRA had improved orcured hypertension at end of followup compared to 90% of surgical patients. 79% ofpatients treated with PTRA had stable or improved GFR at end of followup compared to72% of surgical patients.This study suggests the efficacy and safety of surgery and PTRA for treatment ofrenovascular hypertension and ischemic nephropathy in patients with unilateralatherosclerotic RVD is comparable.ConclusionsEvidence-based decisions pertaining to optimal therapy for renovascular disease remaincontroversial 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 iswarranted. Neither interventional nor surgical management has been shown tosignificantly improve mortality compared to current medical therapy alone inprospective, randomized trials. PRA has been shown to be safe and effective treatmentfor renovascular hypertension secondary to fibromuscular dysplasia, and is currentlyaccepted as the treatment of choice.The techniques and technology involved in PRA remain primitive. The use ofantiplatelet agents and stents revolutionized the efficacy of percutaneous coronaryinterventions, and have brought into question current indications for coronary arterybypass grafting, but have not been rigorously studied in the setting of PRA. Evidencesupports PRA with adjunctive stents and antiplatelet agents as therapy of choice forrenovascular hypertension refractory to medical therapy and/or ischemic nephropathysecondary to non-occlusive, unilateral atherosclerotic renovascular disease causinggreater than 60% stenosis. Evidence supports surgery as therapy of choice forrenovascular hypertension refractory to medical therapy and/or ischemic nephropathy
secondary to bilateral (including solitary), non-ostial atherosclerotic renovascular diseasecausing greater than 60% stenosis.
1 Appel RG, Freedman BI, and Hansen KJ: Renovascular disease and progressive renal insufficiency. Seminars in Dialysis8: 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 ofHypertension 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 ofHypertension 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 fibromusculardysplasia. 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 balloonangioplasty. 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 arterystenosis: A prospective randomized study. Journal of Vascular Surgery 18: 841-852, 1993.