Renovascular Disease Michael Shomaker, MDPresentation Transcript
Renovascular Disease Michael Shomaker, MD January 7, 2003
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 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 basketball scores each day at morning report
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 atheroembolic disease
Vasculitis involving the renal artery (i.e. PAN)
AVMs involving the renal artery
Nephroangiosclerosis (hypertensive injury)
Irradiation of the renal artery
Prevalance of ARAS An 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 <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 (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 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
It 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%).
Patients 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 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)
Given these patients’ dismal prognosis once reaching dialysis, should we be aggressively treating these patients?
The 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.
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 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.
Much 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.
Pathophysiology 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 functional 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 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 ACEI
Unexplained 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
The following clinical features should raise the suspicion of renovascular disease:
Young hypertensive 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)
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 Ischemic 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
There are two groups of diagnostic studies used to evaluate RAS: Anatomic studies:
Renal angiography – the gold standard
Spiral CT angiography
Nuclear imaging with I 125 iothalamate or DTPA to determine GFR
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 (Tc 99 -DTPA), thus estimating GFR, or agents that are filtered and secreted (Tc 99 -MAG or I 131 -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 Tc 99 -DTPA or a reduction of the uptake of the Tc 99- 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.
Reduced sens/spec in patients with renal insufficiency (P cr >2.0)
Test of choice for the diagnosis of RVH in many centers
Lower sens/spec compared to ACEI renography
Useful as both a screening test and functional study
Difficult to differentiate reversible from intrinsic disease
Allows calculation of single kidney GFR and/or RBF
Nuclear Imaging with Tc 99 -MAG or Tc 99 -DTPA to estimate fractional flow to each kidney
Nonlateralization not predictive of the failure of HTN to improve with therapy
Useful in confirming the functional significance of a lesion demonstrated by anatomical studies – particularly if bilateral disease is present
Renal Vein Renin Measurements Cons Pros Diagnostic Study
Diagnosis Anatomic Studies “If you’re searching for a lesion, look at the vessel.”
Prior stents produce artifacts
Blood flow turbulence can exaggerate measured stenosis
Provides excellent images
Non-nephrotoxic, thus useful in patients with renal insufficiency
Less reliable for visualizing distal segments and small accessory arteries
Excellent visualization of the vessel in 3D
Extremely operator dependent
Does not evaluate accessory vessels well
Bowel gas patterns/Obesity interfere
Inexpensive; widely available
Direct contrast load to kidneys
Sometimes difficult to distinguish between critical and non-critical lesions
Can visualize accessory vessels and intrarenal branches well
Renal Arteriography Cons Pros Diagnostic Study
Diagnosis Conventional Angiography of ARAS MRA of ARAS CT angiography of ARAS Conventional angiography of FMD
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 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.
CTA/conventional angiography should be performed if RI is mild
MRA if RI is moderate/severe or due to diabetic nephropathy
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-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
Therapy Renovascular HTN
The Effect of Balloon Angioplasty on Hypertension in Atherosclerotic Renal-Artery Stenosis. Van Jaarsveld, et al. NEJM, Apr. 2000
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 .
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, P cr , Cl cl , and results of ACEI renography
The 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
Therapy RVH - van Jaarsveld, et al
Therapy RVH - van Jaarsveld et al.
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 “cured” (goal BP on no anti-HTN meds) in only 7% of the angioplasty group
Therapy RVH – van Jaarsveld et al.
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.
Therapy RVH – van Jaarseveld et al
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 HTN with abnormal ACEI renogram).
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.
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.
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 will 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 and PTRAS
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 for therapy)
Criteria for RAS did varied amongst studies (>40 to >70%)
Most criteria for renal improvement was P cr decrease by >20%
Primary outcome measures were similar (change in renal function, change in HTN control, angiographic patency)
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 were not actively followed in the majority of studies.
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%
Therapy PTRA and PTRAS – Meta-analysis
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 P cr was higher in the PTRAS studies.
These studies suggest that 65-70% of patients do have stable or improved renal function after PTRA/S.
Cherr 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 ARAS
Patient population had a high burden of vascular disease:
criteria for ARAS was stenosis >80%
63% of patients had bilateral ARAS
164 RAO were present in 155 patients
41% underwent aortic or mesenteric reconstruction in addition to RA revascularization
The 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 P cr was 2.3 with a mean EGFR of 40.5+/-23.2
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.
Perioperative mortality rate was 4.5%
Complications occurred in 16% (HAP, arrhythmia, ARF, and MI)
Significant independent predictors of perioperative death included: Hazard Ratio
Advanced age (>70) 3.23
Clinical CHF 3.05
Advanced RI 2.35
Severe aortic disease 1.69
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.
So this begs the question -> Are there reliable clinical predictors of who will respond to therapy?
Therapy IRD - Who will respond to therapy?
Rapid Decline in Renal Function Reflects Reversibility and Predicits the Outcome After Angioplasty in RAS. Muray et al, AJKD, 1/2002
Purpose – To identify factors influencing clinical success after PTRA
73 patients with IRD (Crcl <50ml/min) underwent PTRA for critical ARAS defined as >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 RAO
Mean follow up was 627+/-284 days
Therapy IRD – Who will respond to therapy? Muray et al. AJKD, 2002 A: pts w/ slope <-0.00021 Cr ∆ = 0.1mg/dl/mo B: pts w/ slope >0.00013 Cr ∆ = -0.001 mg/dl/mo
Therapy IRD – Who will respond to therapy?
58% of patients had improvement in renal function, including 3 out of 6 who became dialysis independent
Only 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
Therapy IRD – Who will respond to therapy?
Use of Doppler Ultrasonography to Predict the Outcome of Therapy for RAS. Radermacher et al. NEJM, 2/2001
Purpose – To evaluate whether a high level of resistance to flow in segmental renal arteries can be used prospectively to select appropriate patients for treatment.
138 patients who had either bilateral (47pts.) or unilateral RAS (91pts.) underwent PTRA/S or surgery.
Cl cr 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 <80 (96pts)
Mean follow up was 32+/-21 months
Therapy IRD – Who will respond to therapy? * indicates p < 0.05
Therapy IRD – Who will respond to therapy?
For patients with RI < 80 and a Cr cl < 40 ml/min, RI has a 95% sensitivity and 85% specificity for predicting an improvement in renal function.
RI >80 (p<0.001), Cr cl <40 ml/min (p=0.01), and male sex (p=0.05) are independently associated with a higher risk of a decline in renal function after revascularization.
The mean rate of ESRD at 2 years: 50% for RI >80 and 5% for a RI<80.
Therapy IRD – Who will respond to therapy?
Thus, it appears clear that a fast rate of renal decline (>0.1mg/dl/mo) and RI <80 are reasonable clinical predictors of who will benefit from revascularization.
Conclusions Natural History and Pathophysiology
ARAS is clearly a progressive disease
The 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 disease
Normal RI, minimal proteinuria, and fast progression of renal insufficiency seem to be predictors of reversible disease
The 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
Given 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.
At 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 rate
PTRA/S has a 1% mortality rate and 11% complication rate
Progression of RF or uncontrolled HTN Yes No Uncontrolled HTN Low preoperative Risk High vasc. disease burden Poor surgical candidate Predictors of operative mortality Age >70 Unstable CHF Advanced RI Diabetes Medical Management Strict BP control Antiplatelet angents Goal LDL < 100 Screening for progression of ARAS Clinical findings of ARAS Diagnostic Evaluation Unilateral ARAS Bilateral ARAS Medical Management Medical Management Evidence of Irreversible disease? Invasive Treatment PTRAS Medical Management Surgery Evidence of Irreversible Disease RI >80 Slow prog. RI Proteinuria Severe atrophy
ASTRAL (angioplasty and stent for renal artery lesions)
A British randomized, controlled trial comparing surgery, PTRAS and medical therapy in 1000 pts with ARAS.