1、Renovascular Disease,Michael Shomaker, MD January 7, 2003,Goals,Define those at risk for RAS and who should be screened Review the pathophysiology, clinical features, and natural history of RAS and how this effects therapeutic decisions Provide a brief overview of the different diagnostic tests and
2、their performance profiles Critically review the literature as it pertains to the different treatment options Provide house staff with an evidence-based, practical algorithm for the evaluation and treatment of RAS at Wake Forest Attempt to persuade Al Hadley from inundating the housestaff with Duke
3、basketball scores each day at morning report,Etiology,Atherosclerosis (ARAS) 70-90% of cases Usually 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 disease Renal ath
4、eroembolic disease Aortorenal dissection Vasculitis involving the renal artery (i.e. PAN) AVMs involving the renal artery Nephroangiosclerosis (hypertensive injury) Trauma Irradiation of the renal artery Scleroderma,Prevalance of ARAS An overlooked clinical entity?,Hansen et al in September 2002 pub
5、lished 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 ri
6、sk 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)
7、 and HDL 40 (OR 2.63).,Natural History Major Points,ARAS is a progressive disease ARAS has been shown to be associated with renal insufficiency Patients with IRD that progress to ESRD has a dismal prognosis,Natural History Crowley et al,Largest cohort of patients evaluating the progression of ARAS (
8、1,189). Mean follow up was 2.6 yrs The incidence of significant stenosis (50%) at baseline was 6.3%,Natural History Crowley 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 cre
9、atinine 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 History,It is clear that anatomical ARAS is progressive in a proportion of patients; h
10、owever, 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%
11、 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%).,Prognosis,Patients with IRD who do reach ESRD do poorly: Highest mortality rate among all
12、 etiologies of ESRD. 2, 5 and 10 year survival rates are 56%, 18% and 5% respectively Median survival is 25 months Mortality linked to CAD/CHF However, the recent prospective cohort by Hansen et al showed that ARAS had a strong independent effect on mortality (Hazard Ratio 3.0),Unadjusted,Adjusted,P
13、rognosis,Given these patients dismal prognosis once reaching dialysis, should we be aggressively treating these patients?,Pathophysiology Overview,The pathogenesis of arterial atherosclerosis is well understood and rat studies have shown ARAS follows a similar pattern. However, it is important to re
14、view the mechanisms by which renovascular hypertension and IRD develop.,Pathophysiology Overview,Intraglomerular pressure remains constant during wide swings in systemic blood pressure by alterations in afferent and efferent glomerular vascular resistance secondary to renal autoregulation. Renal aut
15、oregulation 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 re
16、novascular hypertension and/or ischemic renal disease.,Pathophysiology Renovascular Hypertension,Pathophysiology Renovascular Hypertension Unilateral RAS,High renin, low volume High/normal renin, elevated plasma volume Irreversible parenchymal HTN,There seems to be three phases of hypertension seen
17、in patients with unilateral RAS:,Pathophysiology Renovascular 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 AR
18、AS 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.,Pathophysiology Renovascular Hypertension Bilateral RAS,Much less
19、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.,Path
20、ophysiology Ischemic Renal Disease,Several reversible, adaptive changes occur in response to chronic renal ischemia: Structural renal atrophy Diminished cortical blood flow Reduction in GFR in order to decrease oxygen demand Hypertrophy of the contralateral kidney Hyperfiltration occurs in the funct
21、ional nephrons of the non-effective kidney, which leads to glomerulosclerosis.,Pathophysiology Ischemic Renal Disease,It is very difficult to reliably delineate to what degree renal insufficiency is due to adaptive changes vs. irreversible parenchymal disease,Clinical Features Overview,These patient
22、s 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 ACEI Unexplained chronic and/o
23、r 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 Features,The following clinical features should raise the suspicion of renovascular disease: Young hyper
24、tensive pts with no family history or new onset HTN in pts 50y/o Abrupt onset of HTN Severe or Resistant HTN Deteriorating BP control in long-standing, compliant hypertensive patients Deterioration in renal function with ACEI Evidence of secondary hyperaldosteronism (low plasma potassium, high renin
25、) Recurrent “flash” pulmonary edema and hypertensive urgency (more common with bilateral RAS) Elderly patients with PVD Abdominal 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 Features Isch
26、emic Renal Disease,It is important to search for evidence of underlying irreversible parenchymal renal disease, as this subgroup will not likely benefit from therapy. Moderate to severe protenuria Severe renal atrophy distal to obstruction Unilateral RAS with renal insufficiency,Diagnosis Overview,T
27、here are two groups of diagnostic studies used to evaluate RAS: Anatomic studies: Renal angiography the gold standard Doppler ultrasonography Spiral CT angiography MR angiographyFunction studies: Renal-vein-renin measurement Nuclear imaging with I125iothalamate or DTPA to determine GFR Conventional
28、renography ACEI renography,Diagnosis Renovascular HTN,Captopril 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 estimatin
29、g 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
30、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 r
31、enal blood flow.,Diagnosis Captopril Renography,Diagnosis,Diagnosis Functional studies,Diagnosis Anatomic Studies “If youre searching for a lesion, look at the vessel.”,Diagnosis,Conventional Angiography of ARAS,MRA of ARAS,CT angiography of ARAS,Conventional angiography of FMD,Diagnosis Recommendat
32、ions,The 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 co
33、nfirm 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 i
34、s mild MRA if RI is moderate/severe or due to diabetic nephropathy,Treatment Overview,To 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-experimen
35、tal 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 su
36、rgery,Therapy Renovascular HTN,The Effect of Balloon Angioplasty on Hypertension in Atherosclerotic Renal-Artery Stenosis. Van Jaarsveld, et al. NEJM, Apr. 2000 Objective The long-term effects of renal artery angioplasty on RVH are not well understood. This study was conducted to define the efficacy
37、 of angioplasty on RVH. Methods 106 patients randomized to medical therapy or angioplasty Follow up at 3 and 12 mo. Primary outcome measures was BP Secondary outcome measures were number and defined daily doses of ant-HTN meds, Pcr, Clcl, and results of ACEI renography The pts. in the drug- therapy
38、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,Therapy RVH - van Jaarsveld, et al,Therapy RVH - van Jaarsveld et al.,RESULT
39、S: There was no difference in mean BP between the groups at 3 and 12 months The 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 “
40、cured” (goal BP on no anti-HTN meds) in only 7% of the angioplasty group,Therapy RVH 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 c
41、ontrol 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.,Therapy RVH van Jaarsevel
42、d et al,Strengths: Largest study to date Careful validation of the radiographic diagnosis of ARAS Adherence to a strict treatment protocol Well defined population who would likely benefit from intervention (mostly unilateral disease (78%), normal-mild renal insufficiency, evidence of renin-mediated
43、HTN with abnormal ACEI renogram). Weaknesses: Almost 50% of the control group crossed over “critical” ARAS was defined as 50% Short follow up period with no long term outcomes such as death or ESRD Stents not used,Therapy RVH van Jaarsveld et al.,Conclusions: The results of this study are difficult
44、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
45、 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 predi
46、ct who will respond to therapy.,Therapy,Although 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 wi
47、ll review the best of the abundant non-experimental reports on stenting procedures and surgery for IRD.,Therapy PTRA and PTRAS,Stent placement for Renal Artery Stenosis: Where Do We Stand? A Meta-analysis. Leertouwer et al. Radiology; Jan. 2000 Largest review to date evaluating the efficacy of PTRA
48、and PTRAS Methods: All studies dealing with PTRA (10 articles; 644 patients) and PTRAS (14 articles; 678 patients) between 1991-1998 were selected The patient population in the majority of studies were similar: (mild to moderate renal insufficiency, age 60-75 y/o, renal insufficiency as indication f
49、or 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,Therapy PTRA an
50、d PTRAS Meta-analysis,Therapy PTRA and PTRAS Meta-analysis,Follow up ranged from 6 48 months The 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
51、 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%,
