Renovascular DiseaseMichael Shomaker, MDJanuary 7, 2003

GoalsDefine those at risk for RAS and who should be screenedReview the pathophysiology, clinical features, and natural history of RAS and how this effects therapeutic decisionsProvide a brief overview of the different diagnostic tests and their performance profilesCritically review the literature as it pertains to the different treatment optionsProvide house staff with an evidence-based, practical algorithm for the evaluation and treatment of RAS at Wake ForestAttempt to persuade Al Hadley from inundating the housestaff with Duke basketball scores each day at morning report

EtiologyAtherosclerosis (ARAS) 70-90% of casesUsually involves the ostium and/or proximal third of the main renal artery, with non-ostial lesions comprising only 15-20% of cases Fibromuscular dysplasia (FMD) 10-20%Renal thromboembolic diseaseRenal atheroembolic diseaseAortorenal dissectionVasculitis involving the renal artery (i.e. PAN)AVMs involving the renal arteryNephroangiosclerosis (hypertensive injury)TraumaIrradiation of the renal arteryScleroderma

Prevalance of ARASAn overlooked clinical entity?Hansen et al in September 2002 published the first population based study estimating the prevalence of RAS:834 patients consecutive patients who were participants in the Forsyth county cohort of the Cardiovascular Health Study underwent RAD. The Cardiovascular Health Study is a longitudinal cohort study of cardiovascular disease risk factors among adults >65 y/o.The overall prevalence rate of RVD (>60% stenosis) was 6.8%, which would represent 2.4 million affected individuals in the U.S.Those variables independently associated with the presence of RVD were increasing age (OR 1.87), increasing systolic blood pressure (OR 1.44) and HDL

Natural HistoryMajor PointsARAS is a progressive diseaseARAS has been shown to be associated with renal insufficiencyPatients with IRD that progress to ESRD has a dismal prognosis

Natural HistoryCrowley et alLargest cohort of patients evaluating the progression of ARAS (1,189).Mean follow up was 2.6 yrsThe incidence of significant stenosis (>50%) at baseline was 6.3%

Natural HistoryCrowley et al. cont.Disease progression was associated with a decline in renal function.patients in whom stenosis progressed from normal to >75% showed a significant rise in serum creatinine compared with those with less significant progression.

Follow up serum creatinine level in patients with normal renal function at baseline, categorized according to progression of arterial stenosis

Natural HistoryIt is clear that anatomical ARAS is progressive in a proportion of patients; however, it has likely been overstated.The variable most predictive of anatomic progression is the degree of initial stenosis:Patients with bilateral ARAS with one occluded renal artery are 3 times as likely to progress to ESRD within 2 years than those with bilateral disease without occlusion (50% vs. 18%)The rate of loss of functional renal tissue (implied by ultrasound evidence of renal atrophy) is 3 times higher in patients with bilateral disease than for those with unilateral disease (43% vs. 13%).

PrognosisPatients with IRD who do reach ESRD do poorly:Highest mortality rate among all etiologies of ESRD.2, 5 and 10 year survival rates are 56%, 18% and 5% respectively Median survival is 25 monthsMortality linked to CAD/CHFHowever, the recent prospective cohort by Hansen et al showed that ARAS had a strong independent effect on mortality (Hazard Ratio 3.0)UnadjustedAdjusted

PrognosisGiven these patients dismal prognosis once reaching dialysis, should we be aggressively treating these patients?

PathophysiologyOverviewThe pathogenesis of arterial atherosclerosis is well understood and rat studies have shown ARAS follows a similar pattern.However, it is important to review the mechanisms by which renovascular hypertension and IRD develop.

PathophysiologyOverviewIntraglomerular pressure remains constant during wide swings in systemic blood pressure by alterations in afferent and efferent glomerular vascular resistance secondary to renal autoregulation.Renal autoregulation fails to maintain GFR when renal perfusion pressure dips below 70-85mmHg, generally correlating with a greater than 70% renal artery stenosis.It has been hypothesized that this critical reduction in perfusion pressure is required in order to set off the cascade of events that lead to renovascular hypertension and/or ischemic renal disease.

PathophysiologyRenovascular Hypertension

PathophysiologyRenovascular Hypertension Unilateral RASHigh renin, low volumeHigh/normal renin, elevated plasma volume Irreversible parenchymal HTNThere seems to be three phases of hypertension seen in patients with unilateral RAS:

PathophysiologyRenovascular Hypertension Unilateral RAS

Irreversible parenchymal HTN:Prolonged exposure to high BP and high levels of ATII causes widespread arteriolar damage and glomerulosclerosis in the contralateral kidney.This is likely why RVH secondary to ARAS does not resolve after revascularization.Hughes et al showed that corrective surgery for unilateral RVH was successful in 78% of those with HTN of less than 5 years duration but in only 25% of those with HTN of a longer duration.

PathophysiologyRenovascular Hypertension Bilateral RASMuch less is known about the mechanisms of RVH in bilateral RAS.The overall picture is a mixed one, with both renin and volume factors playing a role.Evidence suggests there is an increase in effective circulating blood volume owed to elevated aldosterone levels and a blunted pressure naturesis effect.

PathophysiologyIschemic Renal DiseaseSeveral reversible, adaptive changes occur in response to chronic renal ischemia:Structural renal atrophyDiminished cortical blood flow Reduction in GFR in order to decrease oxygen demandHypertrophy of the contralateral kidney Hyperfiltration occurs in the functional nephrons of the non-effective kidney, which leads to glomerulosclerosis.

PathophysiologyIschemic Renal DiseaseIt is very difficult to reliably delineate to what degree renal insufficiency is due to adaptive changes vs. irreversible parenchymal disease

Clinical FeaturesOverviewThese patients do not exhibit specific clinical findings, and it is therefore particularly important to identify high-risk groups in which suspicion of this condition should be heightened.There are two important ischemic renal syndromes to consider:ARF after the institution of an ACEIUnexplained chronic and/or progressive azotemia in the elderly with evidence of other vascular disease Most of these patients have a bland urine sediment with minimal or no proteinuria and atrophic kidneys on US

Clinical FeaturesThe following clinical features should raise the suspicion of renovascular disease:Young hypertensive pts with no family history or new onset HTN in pts >50y/oAbrupt onset of HTNSevere or Resistant HTNDeteriorating BP control in long-standing, compliant hypertensive patientsDeterioration in renal function with ACEIEvidence of secondary hyperaldosteronism (low plasma potassium, high renin)Recurrent flash pulmonary edema and hypertensive urgency (more common with bilateral RAS)Elderly patients with PVDAbdominal bruit (OR 11.5)Unexplained renal azotemia>1.5 cm difference in kidney size on US (70% of atrophic kidneys in the elderly are associated with ARAS)

Clinical FeaturesIschemic Renal DiseaseIt is important to search for evidence of underlying irreversible parenchymal renal disease, as this subgroup will not likely benefit from therapy.Moderate to severe protenuriaSevere renal atrophy distal to obstruction Unilateral RAS with renal insufficiency

DiagnosisOverviewThere are two groups of diagnostic studies used to evaluate RAS: Anatomic studies:Renal angiography the gold standardDoppler ultrasonographySpiral CT angiographyMR angiographyFunction studies:Renal-vein-renin measurementNuclear imaging with I125iothalamate or DTPA to determine GFRConventional renographyACEI renography

DiagnosisRenovascular HTNCaptopril Renography is a nuclear study which takes advantage of the fact that ACEI can abruptly reduce renal function in an ischemic kidney.Patients are given radio-labeled agents that are either exclusively filtered (Tc99-DTPA), thus estimating GFR, or agents that are filtered and secreted (Tc99-MAG or I131-hippurate), thus estimating RBF.A baseline study is done on day 1 and 50mg of captopril is given 1 hr prior to the second study on day 2.The difference between the left and right kidney with regard to uptake, excretion, kidney size and asymmetry can be determined by this study.Either a slowing of the excretion of Tc99-DTPA or a reduction of the uptake of the Tc99-MAG can be used to identify the effect of the ACEI in removing the protective actions of high levels of ATII on the autoregulation of GFR and on the maintenance of renal blood flow.

DiagnosisCaptopril Renography

Diagnosis

DiagnosisFunctional studies

DiagnosisAnatomic StudiesIf youre searching for a lesion, look at the vessel.

DiagnosisConventional Angiography of ARASMRA of ARASCT angiography of ARASConventional angiography of FMD

DiagnosisRecommendationsThe diagnostic work up of RVH or IHD should proceed as follows: Evaluation of RVH:If the patient has normal renal function, the first test should be ACEI renography or Doppler US, based on the local experience and equipment.If this test is positive, an anatomic study should be performed to confirm the diagnosis, if intervention is being considered.Evaluation of IRD:Doppler US is the test of choice if local expertise adequate followed by a more definitive study to delineate the anatomy if intervention is being considered.If not: CTA/conventional angiography should be performed if RI is mildMRA if RI is moderate/severe or due to diabetic nephropathy

TreatmentOverviewTo date, there has been no large randomized, clinical controlled trial comparing medical therapy to newer stenting procedures or surgery.In addition, most of the reported data as to therapy have been non-experimental reports. As result, no improvements in survival, freedom from dialysis, or protection from adverse cardiovascular disease events have been demonstrated relative to an equivalent non-interventional comparison group.Thus, I will present a summary of the major experimental reports on PTRA/S and surgery

TherapyRenovascular HTNThe Effect of Balloon Angioplasty on Hypertension in Atherosclerotic Renal-Artery Stenosis. Van Jaarsveld, et al. NEJM, Apr. 2000Objective The long-term effects of renal artery angioplasty on RVH are not well understood. This study was conducted to define the efficacy of angioplasty on RVH.Methods106 patients randomized to medical therapy or angioplastyFollow up at 3 and 12 mo. Primary outcome measures was BPSecondary outcome measures were number and defined daily doses of ant-HTN meds, Pcr, Clcl, and results of ACEI renographyThe pts. in the drug- therapy group underwent rescue balloon angioplasty if, after 3 months, their diastolic BP was > target despite 3 or more anti-HTN meds or if the creatinine had risen by more than 0.2 mg/dl.Intention-to-treat analysis was performed

TherapyRVH - van Jaarsveld, et al

TherapyRVH - van Jaarsveld et al.RESULTS:There was no difference in mean BP between the groups at 3 and 12 monthsThe dose of anti-HTN drugs used by patients in the angioplasty group were significantly lower than those used in the control group at 3 months, but this difference was no longer significant at 12 months.HTN was considered cured (goal BP on no anti-HTN meds) in only 7% of the angioplasty group

TherapyRVH van Jaarsveld et al.RESULTS cont:Median serum creatinine levels and creatinine clearance did not significantly change in either group; however the follow up period was short.In the 22 patients randomized to the control group who crossed over and underwent rescue angioplasty, statistically significant improved blood pressure control was seen post-angioplasty.In the treatment group, the presence of an abnormal ACEI renogram did not predict blood pressure control after angioplasty.

TherapyRVH van Jaarseveld et alStrengths:Largest study to dateCareful validation of the radiographic diagnosis of ARASAdherence to a strict treatment protocolWell defined population who would likely benefit from intervention (mostly unilateral disease (78%), normal-mild renal insufficiency, evidence of renin-mediated HTN with abnormal ACEI renogram).Weaknesses:Almost 50% of the control group crossed overcritical ARAS was defined as >50%Short follow up period with no long term outcomes such as death or ESRDStents not used

TherapyRVH van Jaarsveld et al.Conclusions:The results of this study are difficult to evaluate given the large amount of crossover; however, the data is consistent with other smaller randomized studies.For patients who have RVH secondary to ARAS with normal or mildly impaired renal function, primary angioplasty was not more effective than antihypertensive drugs alone for reducing blood pressure.Rescue angioplasty for difficult to control RVH was efficacious. As for the use of PTRA in limiting progression of IRD, this question can not be ascertained from this study given the short follow up period.ACEI renogram has little use in the management of RVH as it does not predict who will respond to therapy.

TherapyAlthough the data is not entirely clear, it appears PTRA is likely not the initial treatment of choice for RVH secondary to ARAS.Thus, attention has turned to assessing how best to slow the progression of ischemic renal disease.Over the next few slides, I will review the best of the abundant non-experimental reports on stenting procedures and surgery for IRD.

TherapyPTRA and PTRASStent placement for Renal Artery Stenosis: Where Do We Stand? A Meta-analysis. Leertouwer et al. Radiology; Jan. 2000Largest review to date evaluating the efficacy of PTRA and PTRASMethods:All studies dealing with PTRA (10 articles; 644 patients) and PTRAS (14 articles; 678 patients) between 1991-1998 were selectedThe patient population in the majority of studies were similar: (mild to moderate renal insufficiency, age 60-75 y/o, renal insufficiency as indication for therapy)Criteria for RAS did varied amongst studies (>40 to >70%)Most criteria for renal improvement was Pcr decrease by >20%Primary outcome measures were similar (change in renal function, change in HTN control, angiographic patency)Patient follow up in most studies was adequate

TherapyPTRA and PTRAS Meta-analysis

TherapyPTRA and PTRAS Meta-analysisFollow up ranged from 6 48 monthsThe criteria used in most studies to describe BP improvement was poor:Most studies considered a10mmHg reduction in SBP or DBP as significant and many patients who were cured were still on BP meds. BP meds were not actively followed in the majority of studies. Harm: 7% in the stent group had severe complications (ARF 5%, renal infarction 1.3%, and perinephric hematoma 1.3% were the most common). Studies using Palmaz stents had a significantly lower complication rate (7% vs. 25%)Overall mortality rate was 1%

TherapyPTRA and PTRAS Meta-analysisConclusions:PTRAS appears to be a better technical therapy than PTRA given the higher initial success rate and lower restenosis rate. This is consistent with the CV literature and is likely related to the fact that most ARAS lesions are ostial in nature.Stent placement was associated with a significantly lower percentage of patients with improved renal function. However, this is likely due to the fact that the baseline Pcr was higher in the PTRAS studies.These studies suggest that 65-70% of patients do have stable or improved renal function after PTRA/S.

TherapySurgeryCherr et al (J Vasc Surg 2002) recently reviewed the clinical outcomes of 626 patients who underwent operative repair at Wake Forest between 1987-1999.Largest review to date of the surgical management of ARASPatient population had a high burden of vascular disease: criteria for ARAS was stenosis >80%63% of patients had bilateral ARAS164 RAO were present in 155 patients41% underwent aortic or mesenteric reconstruction in addition to RA revascularizationThe vast majority of patients had severe, treatment-resistant HTN, and this was considered one of the indications for surgery (avg BP 200+/-35/104+/-21)Preoperative mean Pcr was 2.3 with a mean EGFR of 40.5+/-23.2

TherapySurgeryRESULTS:Renovascular HTN -> HTN was considered cured in 12% and improved in 73% Ischemic Renal Disease -> 43% had improvement in EGFR (defined as >20% increase) and 47% had unchanged renal function. Only 10% did not respond.28 patients were removed from dialysis dependence following surgery!However, on follow up, patients with renal function unchanged by surgery continued to have a progressive decline of renal function unchanged from before the operation.

TherapySurgeryPerioperative mortality rate was 4.5%Complications occurred in 16% (HAP, arrhythmia, ARF, and MI)Significant independent predictors of perioperative death included:Hazard RatioAdvanced age (>70) 3.23Clinical CHF 3.05Advanced RI 2.35Diabetes 2.14Severe aortic disease 1.69

TherapySurgeryConclusions:This non-experimental report suggest that 45% of patients have a slowing of the progression of their IRD.RVH - Surgery does seem to improve RVH to a greater degree than PTRA/S, but it is not clear whether this difference is clinically significant.IRD - it does appear that surgery is more efficacious than PTRA/S; but there are no large randomized trials to confirm this.Given the high perioperative mortality rate, the surgical risk is needless for the 55% who did not respond to revascularization.

TherapySo this begs the question -> Are there reliable clinical predictors of who will respond to therapy?

TherapyIRD - Who will respond to therapy?Rapid Decline in Renal Function Reflects Reversibility and Predicits the Outcome After Angioplasty in RAS. Muray et al, AJKD, 1/2002Purpose To identify factors influencing clinical success after PTRAMethods73 patients with IRD (Crcl 60%The rate of renal failure was assessed by the slope of the regression line of serum creatinine versus time. Response was assessed by comparison of the slope before and after PTRA.42.5% had bilateral RAS, and 21.9% had unilateral RAS with contralateral RAOMean follow up was 627+/-284 days

TherapyIRD Who will respond to therapy?Muray et al. AJKD, 2002A: pts w/ slope 0.00013Cr = -0.001 mg/dl/mo

TherapyIRD Who will respond to therapy?RESULTS:58% of patients had improvement in renal function, including 3 out of 6 who became dialysis independentOnly the slope of 1/Cr was significantly associated with a favorable decline in renal failure progression (p=0.004)Subacute and rapidly progressive renal failure is associated with a favorable response after PTRA, as they are likely to have less parenchymal disease

TherapyIRD Who will respond to therapy?Use of Doppler Ultrasonography to Predict the Outcome of Therapy for RAS. Radermacher et al. NEJM, 2/2001Purpose To evaluate whether a high level of resistance to flow in segmental renal arteries can be used prospectively to select appropriate patients for treatment.Methods138 patients who had either bilateral (47pts.) or unilateral RAS (91pts.) underwent PTRA/S or surgery.Clcr and BP were measured before the intervention and 3,6 and 12 months and then yearly after the intervention.Patients were grouped by a segmental artery RI of >80 (35pts) or

TherapyIRD Who will respond to therapy?* indicates p < 0.05

TherapyIRD Who will respond to therapy?RESULTS:For patients with RI < 80 and a Crcl < 40 ml/min, RI has a 95% sensitivity and 85% specificity for predicting an improvement in renal function.RI >80 (p

TherapyIRD Who will respond to therapy?Thus, it appears clear that a fast rate of renal decline (>0.1mg/dl/mo) and RI

ConclusionsNatural History and PathophysiologyARAS is clearly a progressive diseaseThe initial degree of stenosis/burden of vascular disease is most predictive of IRD progression.Once patients with IRD are dialysis dependent, their prognosis is extremely poor.The pathogenesis of IRD is multifactorial, and predicting the degree of reversible vs. irreversible disease in a particular patient is challenging.High RI, slow progression of IRD, significant proteinuria and advanced age seem to be predictors of irreversible diseaseNormal RI, minimal proteinuria, and fast progression of renal insufficiency seem to be predictors of reversible disease

ConclusionsDiagnosisThe diagnosis of IRD secondary to ARAS should be based on anatomical studies.Functional studies such as ACEI renography and renal-vein-renin sampling are insensitive in detecting significant stenosis in patients with renal insufficiency.Functional studies do not reliably predict who will respond to therapy

ConclusionsTherapyGiven the paucity of controlled, randomized data, it is difficult to make any level I recommendations for the treatment of RVH or IRD due to ARAS.However, the following statements are reasonable based on the above data:PTRA/S is not the initial treatment of choice in patients with RVH secondary to ARAS.Surgery appears to be more efficacious than PTRA/S for both RVH and IRD, but is also associated with a much higher morbidity/mortality rate.Surgery appears to be appropriate for patients with a high burden of disease (bilateral or effective bilateral ARAS) who have minimal preoperative risks factors for perioperative death.Rate of renal decline and underlying parenchymal damage affect the likelihood of renal improvement with therapy.

ConclusionsAt first, do no harm.As mentioned above, without randomized, controlled comparisons with matched controls to show mortality benefit or freedom from dialysis, it is difficult to recommend aggressive treatment which has such a high burden of harm:Surgery has a 4.5% mortality rate and 16% morbidity ratePTRA/S has a 1% mortality rate and 11% complication rate

Progression of RF or uncontrolled HTNYesNoUncontrolled HTNLow preoperative RiskHigh vasc. disease burdenPoor surgical candidatePredictors of operative mortalityAge >70Unstable CHFAdvanced RIDiabetes

Medical ManagementStrict BP controlAntiplatelet angentsGoal LDL < 100Screening for progression of ARAS

FutureASTRAL (angioplasty and stent for renal artery lesions)A British randomized, controlled trial comparing surgery, PTRAS and medical therapy in 1000 pts with ARAS.New stenting procedures/technology

Who cares about Duke?Number of Internal Medicine Residents 93Number of Residents with ACC school ties 25Number of residents from Duke - 2

Thank you!Dr. Edwards Vascular Surgery FellowDr. Regan Interventional RadiologyDr Satko - NephrologyBob PreliAl HadleyChristian Sinclair the AV guruLeslie Shomaker