Medical therapy is best for atherosclerotic renal artery stenosis: Arguments for.

Atherosclerotic renal artery stenosis (ARAS) is a common condition that causes hypertension and reduction in the glomerular filtration rate and is an independent risk factor for death. Despite high technical success, the clinical benefit of renal artery (RA) angioplasty with stenting in ARAS remains doubtful. The published randomized clinical trials provide no support for the notion that renal angioplasty with stenting significantly improves blood pressure, preserves renal function, or reduces episodes of congestive heart failure in patients with ARAS. RA stenting is associated with procedure-related morbidity and mortality. Agents to block the renin-angiotensin-aldosterone system improve outcome and should be a part of a multifaceted medical regimen in ARAS. Medical therapy effectively controls atherosclerotic renovascular disease at all levels of vasculature and hence is the best therapy for ARAS.

Introduction

Atherosclerotic renal artery stenosis (ARAS) is a common clinical condition that can cause hypertension and reduction in the glomerular filtration rate (GFR). ARAS is associated with a high annual death rate of 16%, mainly due to cardiovascular causes[1] and is an independent predictor of death.[2] Technological advances in endovascular revascularization for ARAS in recent years have been spectacular, with a technical success of over 98% and as such there has been a 4-fold increase in the number of these procedures done in the United States between 1996 and 2005.[3] However, despite their widespread use, considerable controversy exists regarding the clinical benefits of these procedures. This lack of consensus is largely the result of a paucity of high-quality clinical trial evidence and the inherent complexity of the condition.

Burden of ARAS in India

Atherosclerotic renal artery stenosis is more common than we think. Coronary artery disease is prevalent in about 10% of the urban Indian population[4] and 8% of patients undergoing coronary angiography have significant ARAS (>70%).[5] Based on this, it could be estimated that 0.8% of adult urban population in India has significant ARAS. Indeed, Kalra et al. estimated that 0.5% of the population under Medicare in the United States has ARAS.[1] However, the prevalence of ARAS as a cause of advanced chronic kidney disease (CKD) or end stage renal disease (ESRD) is low in India and is estimated at 0.3% of the CKD and ESRD population.[6] This indicates that despite high prevalence, very few patients of ARAS actually present as advanced CKD. The possible reason for this discordance is that most of ARAS may not progress to ESRD or very many patients with ARAS die before they develop advanced CKD. Indeed, Leertouwer et al.[7] reported that none out of 126 patients with ARAS over 10 years and Conlon et al.[2] reported that only one out of 188 over 4 years developed ESRD.

Progression of ARAS

Caps et al. assessed the progression of ARAS in 295 kidneys in 170 patients over a mean period of 33 months.[8] They defined renal artery disease progression as either an increase in the renal artery peak systolic velocity (RAPSV) of >100 cm/sec compared with the baseline examination or complete renal artery (RA) occlusion. A 3-year cumulative incidence of disease progression stratified by baseline disease classification was 18%, 28%, and 49% for RA initially classified as normal, <60% stenosis, and >60% stenosis, respectively (P=0.03). However, on follow up of these patients, complete occlusion was very rare even in ARAS >60% at the baseline. The same group also studied the risk of renal atrophy, which was defined as a reduction in the length of the kidney by >1 cm.[9] The cumulative incidence of renal atrophy was significantly higher in ARAS >60% compared to normal or ARAS <60%, at the baseline. Multivariate regression analysis showed that increase in RAPSV predicted renal atrophy, but not systolic blood pressure or renal cortical end diastolic velocity. In this study, serum creatinine in patients who developed atrophy of both kidneys increased by a mere 0.33 mg/dl per year when compared to those who had no atrophy in both kidneys. These observations indicate that progression of ARAS is not necessarily associated with decline in GFR.

Filtration function does not correlate well with degree of ARAS

Leertouwer et al. showed that unilateral ARAS when prospectively observed over 8 years did not appear to differ significantly from the control population with respect to serum creatinine.[7] Suresh et al. found no correlation between residual proximal RA patency and creatinine clearance.[10] Cheung et al. studied 142 patients of ARAS with occlusion of one artery and variable contralateral RA luminal patency.[11] This single kidney model provided an opportunity to study the relationship of atherosclerotic renovascular disease (ARVD) and renal filtration function. Interestingly, they found that baseline serum creatinine was similar in groups who had normal renal arteries, insignificant ARAS (<50%), and significant ARAS (>50%). At a mean follow up of 80 months, they found that dialysis-free survival was similar in those with contralateral normal RA and significant ARAS. Multivariate analysis showed insignificant ARAS (OR=3.6) and baseline GFR <25 ml/min (OR=4.4) were the independent risk factors for the endpoint of mortality or the need for dialysis. Significant ARAS had a similar risk of this endpoint as normal RA (OR=0.95). These observations clearly indicate that GFR in ARAS appears to be dissociated from the degree of stenosis of RA.

Randomized trials of revascularization versus medical therapy in ARAS

The options for revascularization of ARAS are surgical renal auto-transplantation, angioplasty, and angioplasty followed by stenting. Surgical revascularization is associated with significant perioperative morbidity and mortality and is no longer preferred. RA stenting has a better short-term and long-term luminal patency compared to angioplasty alone and is the preferred method of revascularization worldwide. There are three randomized trials comparing medical management with angioplasty[12-14] and two recently published trials with RA stenting.[1516] Metanalysis of three angioplasty trials showed that angioplasty was not superior to medical therapy in blood pressure control, but had a significant drug-saving effect.[17] These trials were not designed to study the effect of intervention on GFR. Two large recent trials showed that RA stenting had no benefit over medical therapy in outcomes of blood pressure, renal function preservation, and mortality.[1516] Moreover, in the angioplasty and stenting for renal artery lesions (ASTRAL) trial that included 804 patients, a subgroup analysis was done based on baseline GFR, degree of stenosis, and renal size and no difference in outcome was found between the groups.[16] Similar results were seen in a subgroup of patients who had bilateral ARAS >70% or a single kidney with ARAS >70%, which is considered a standard indication for stenting.[16] Indeed, that revascularization reduces the incidence of ESRD in patients with ARAS has never been shown in any clinical trial. Gray et al.[18] reported that 39 patients who underwent RA stenting for recurrent episodes of congestive heart failure (CHF) showed significant decrease in hospitalizations for CHF in the year after stenting, and improvement in New York Heart Association functional class. In this trial, the number of patients receiving angiotensin-converting enzyme inhibitors also increased from 15% to 50%, however, which may have contributed to the improved outcome. At present, there are no prospective randomized data demonstrating that RA stenting reduces admissions for severe congestive heart failure, or any other cardiovascular event, compared with medical therapy alone.

Optimal medical therapy

Since no clinical trials comparing different modes of medical interventions in ARAS are available, the results of medical therapy in atherosclerotic coronary artery disease could be extrapolated to treatment of ARAS. A multifaceted medical approach is a powerful tool for preventing adverse cardiovascular events.[19] Tight blood pressure control to <130/80 mm Hg (<120/75, if significant proteinuria is present), tight glycemic control in diabetics (Hemoglobin A1c <7%), control of hyperlipidemia (LDL cholesterol <70 mg/dl), antiplatelet agents and life style modifications such as normalization of body weight and avoidance tobacco should be the integral part of the medical regimen in ARAS. Recent nonrandomized trials in ARAS show that renin angiotensin aldosterone system (RAAS) blockade offers significant benefit in terms of renal function preservation, as well as survival.[2021] Concern of acute kidney injury (AKI) in ARAS with impaired GFR has been a barrier to the use of these agents. Though this concern is real,[21] it can be easily detected early and reversed by meticulous monitoring while adjusting the dose of the drug. Since the benefits appear to be significant, an RAAS blocking agent, if tolerated, should be a part of the medical regimen in ARAS. There has been much criticism of the design of the randomized studies in ARAS, especially from the proponents of RA stenting.[22] However, it is often overlooked that less attention was paid to the medical regimens that patients received in these trials, especially the RAAS blockade and no targets for optimal medical therapy were defined. This deficiency in medical management is addressed effectively in the ongoing cardiovascular outcomes in renal atherosclerotic lesions (CORAL) trial, a large, multicenter, randomized, prospective trial comparing the effects of RA stenting, and optimal medical therapy to medical therapy alone on a composite of adverse cardiovascular and renal events.

Why does RA stenting not work in ARAS?

Despite a sound physiologic basis for revascularization, stenting fails to improve outcomes in ARAS. There are a few reasons for this. First, ARVD is a complex disease involving not only the main RA, but often also intrarenal arteries, arterioles, and peritubular capillaries. Stenting of the RA will have no effect on intrarenal ARVD. The pathophysiology of intrarenal damage in ARVD involves complex interactions of multiple pathways leading to inflammation and oxidative stress causing vascular injury.[2324] Activation of the intrarenal RAAS, oxidized low-density lipoprotein (LDL) cholesterol and hypertension appear to be the major initiators of this damage, all of which could be modified with appropriate medical intervention. Second, ARAS may protect the intrarenal vasculature from ill effects of high blood pressure since this pressure would not be transmitted beyond the stenosis. Revascularization in this situation may actually accelerate intrarenal vascular damage by exposing it to the ill effects of hypertension. Third, stenting can cause distal atheroembolism, dissection of RA and cholesterol embolism that accelerate renal damage.[25] In addition, stenting is associated with significant periprocedure morbidity of up to 7% (limb ischemia, complications associated with femoral artery puncture) and mortality of 0.5–3%.[12-15] In the final risk benefit analysis, the advantage of taking three as opposed to four blood pressure medications must be weighed against these risks. Fourth, there may be such a large burden of atherosclerotic disease by the time patients present that it is too late for an intervention in a single vascular bed to significantly alter outcomes.

Does anyone benefits from RA stenting in ARAS?

While most patients do not benefit from RA stenting in ARAS, a few individual patients appear to benefit from the procedure. Identifying them is a challenge in clinical practice and an area of intense clinical research. It appears that patients with significant ARAS (>70%) and recurrent flash pulmonary edema, rapidly declining GFR and severe hypertension not controlled despite optimal medical therapy are likely to benefit from stenting.[26] Again, even in these who are most likely to benefit from RA stenting, the key to success is the identification of significant distal intrarenal AVRD and prevention of atheroembolism following stenting.

Conclusions

In summary, published randomized clinical trials provide no support for the notion that renal angioplasty with stenting significantly improves blood pressure, preserves renal function, or reduces episodes of congestive heart failure in patients with ARAS. RA stenting is associated with procedure-related morbidity and mortality. Agents that block the RAAS improve outcomes and should be a part of the medical regimen in ARAS. Medical therapy effectively controls ARVD at all levels of the vasculature and hence is the best therapy for ARAS.