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| REVIEW ARTICLE |
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| Year : 2013 | Volume
: 59
| Issue : 4 | Page : 289-299 |
Renal angioplasty for atherosclerotic renal artery stenosis: Cardiologist's perspective
AS Gulati1, AN Patnaik1, R Barik1, R Kumari1, S Srinivas2
1 Department of Cardiology, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad, Andhra Pradesh, India
2 Department of Nephrology, Artemis Hospital, Gurgaon, Haryana, India
| Date of Submission | 16-Jun-2013 |
| Date of Decision | 26-Feb-2013 |
| Date of Acceptance | 06-Sep-2013 |
| Date of Web Publication | 17-Dec-2013 |
Correspondence Address:
A S Gulati
Department of Cardiology, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad, Andhra Pradesh
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0022-3859.123157
Atherosclerotic renal artery stenosis (ARAS) is frequently associated with concomitant coronary and peripheral arterial disease with a significant impact on cardiovascular morbidity and mortality. Renal angioplasty of ARAS is more challenging because of increased incidence of technical failures, complications, and restenosis; while there is barely perceptible control of hypertension and only marginal improvement in renal function. This is because most of the patient population in recent randomized trials had unmanifested or clinically silent renovascular disease. Manifestations of RAS should be looked for and incorporated in the management plan particularly before deciding for revascularization. In the absence of clinical manifestation like renovascular hypertension, ischemic nephropathy, left ventricular failure, or unstable coronary syndromes; mere presence of RAS is analogous to presence of concomitant peripheral arterial disease which increases risk of adverse coronary events. Dormant-RAS in the absence of any manifestations can be managed with masterly inactivity. Chronological sequence of events and clinical condition of the patient help in decision making by identifying progressive renovascular disease. Selecting patients for renal artery stenting who actually will benefit from revascularization shall also decrease the unnecessary complications inherent with any interventional procedure. The present review is an attempt to analyze the current view on the diagnostic and management issues more specifically about the need and rationale behind angioplasty.
Keywords: Atherosclerotic renovascular disease, ischemic nephropathy, renal artery stenosis, renal artery stenting, renovascular hypertension, randomized trials
How to cite this article:
Gulati A S, Patnaik A N, Barik R, Kumari R, Srinivas S. Renal angioplasty for atherosclerotic renal artery stenosis: Cardiologist's perspective. J Postgrad Med 2013;59:289-99 |
How to cite this URL:
Gulati A S, Patnaik A N, Barik R, Kumari R, Srinivas S. Renal angioplasty for atherosclerotic renal artery stenosis: Cardiologist's perspective. J Postgrad Med [serial online] 2013 [cited 2023 Oct 2];59:289-99. Available from: https://www.jpgmonline.com/text.asp?2013/59/4/289/123157 |
| :: Introduction | |  |
Atherosclerosis, fibromuscular dysplasia, and arteritis remain the three most important causes of renal artery stenosis (RAS) with the former two far more common than the arteritis. Approximately 90% of all the renovascular stenotic lesions are due to atherosclerosis. [1] As a group renal angioplasty of atherosclerotic RAS (ARAS) is more challenging because of increased incidence of technical failures, complications, and restenosis; while there is less cure rate particularly for hypertension. [2] Though the non-ARAS are dealt with prompt revascularization, the management of ARAS is controversial especially when to use angiotensinogen converting enzyme inhibitors (ACEIs) and when to intervene. The results of recent randomized trials have questioned the rationale to perform such a procedure and hence have made the decision making more difficult.
| :: Epidemiology and Natural History | | |
Prevalence studies have demonstrated significant RAS in 11-30% of patients with coronary artery disease
(CAD) [3],[4] and in 22-59% of patients with peripheral arterial disease (PAD). [5],[6],[7],[8] ARAS is a progressive disease. When the RAS was greater than 75% at the time of diagnosis total occlusion occurred in 39% of cases over a 12-60 month follow-up period. [9] Clinically, it may manifest as increase in serum creatinine (46%), decline in glomerular filtration rate (GFR; 29%) or decrease in kidney size by more than 10% (37%) as seen in a 28 month follow-up study. [10] The progression of renal failure and overall cardiovascular risk is more in patients with already set in renal dysfunction when compared to patients with normal GFR. [11] The presence of severe RAS is independently associated with mortality (4 year survival rate 57% compared with 89% in those without RAS) and the higher risk persisted even in those individuals who had undergone revascularization for CAD. [12]
| :: Pathophysiology and Manifestations of Renal Artery Stenosis | | |
Estimated GFR significantly decreases with age and has no association with the presence or absence of baseline renovascular disease (RVD). The inevitable deterioration of renal function and kidney size among hypertensive patients should no longer be a reason sufficient enough to recommend revascularization for mere presence of anatomic RAS. Control of resistant hypertension and prevention of ischemic nephropathy appear to be the major targets for treatment of RVD. Enhanced sodium reabsorption can lead to rapidly developing circulatory congestion ("flash pulmonary edema") or when combined with left ventricular heart dysfunction contributes to refractory congestive failure. Unilateral RAS may contribute to the development of unstable coronary syndromes by causing sudden increases in myocardial oxygen demand in patients with CAD secondary to peripheral vasoconstriction; together these two are the most noncontroversial indications for percutaneous transluminal renal angioplasty (PTRA).
Reno vascular hypertension (RVH) accounts for an estimated 0.5-4% of cases in unselected hypertensive patients. [13],[14],[15],[16] It is defined as hypertension that results from renal ischemia. Hypertension develops in patients with RVD from a complex set of pressor signals, including activation of the renin-angiotensin system, recruitment of oxidative stress pathways, and sympathoadrenergic activation. Mere radiographic identification of a vascular occlusive lesion alone does not establish its physiologic role and can be identified in 3-5% of normotensive subjects. [17] In true sense the definitive diagnosis of RVH can be established only after documentation of regression of hypertension after treatment of RAS. Patients with ARAS commonly have disturbed day-night blood pressures (BP) with loss of nocturnal BP fall, increased sympathetic nerve traffic as measured in efferent nerve fibers, more severe left ventricular hypertrophy, and lower GFR as compared to essential hypertension with similar clinic BPs. [18],[19] As a result, high rates of target organ injury are associated with RVH when compared to similar levels of "essential hypertension", [20] all the more reason to cure or at least treat RVH.
Ischemic renal disease (IRD) is defined as a clinically important reduction in GFR or loss of renal parenchyma caused by hemodynamically significant RAS and accounts for 11-14% of End stage renal disease (ESRD). [21] Sustained reduction in renal perfusion leads to disturbed microvascular function, vascular rarefaction, and ultimately development of interstitial fibrosis. Many patients with a presumed diagnosis of hypertensive nephrosclerosis actually have undiagnosed ischemic nephropathy as the etiology of their ESRD and hence a potentially reversible cause. A decrease in GFR sufficient to cause an elevation of the serum creatinine concentration usually requires injury to both kidneys or to a solitary functioning kidney. Common clinical settings for IRD can be: Acute renal failure precipitated by ACEI's in a known hypertensive; progressive azotemia in a patient with known RVH/refractory or severe hypertension; acute pulmonary edema in a poorly controlled hypertensive with renal failure; and progressive unexplained azotemia in an elderly patient with evidence of atherosclerotic disease. Progressive deterioration of renal function is a prerequisite for diagnosing IRD. Regression of serum creatinine after the treatment for RAS helps confirming the diagnosis of ischemic nephropathy. In unilateral RAS Leertouwer and coworkers [22] demonstrated, that the GFR in the revascularized kidney improved significantly over 1 year, but the overall GFR from both kidneys did not change. Treating unilateral RAS though not increasing the overall GFR may decrease the ongoing hyperfilteration in the contralateral normal kidney, decreasing proteinuria, and thus delaying the fibrotic changes. [23]
| :: Diagnostic Dilemmas | | |
The cutoff point beyond which revascularization is advised has been a matter of concern and not even conventional angiography (gold standard) is able to accurately help decision making regarding revascularization. In general more than 50% luminal narrowing is taken significant stenosis warranting treatment in recent randomized trials, [24] but some investigators consider stenosis to be hemodynamically important only if the diameter is reduced by more than 60% [25],[26] or by more than 70%. [27],[28] No correlation is found between the BP response to treatment and the severity of RAS at base line. [24] Reduction of renal blood flow sufficient to reduce kidney size and stimulate renin release may develop despite preserving normal overall levels of both cortical and medullary tissue oxygenation. [29] This is because kidney overall receives more blood than needed strictly for its metabolic activity. Anatomically and physiologically significant RAS is defined as >70-80% of cross-sectional area stenosis of either renal arteries and >15-25 mmHg gradient across the lesion, respectively measured with a less than or equal to 5 Fr catheter or pressure wire. [30] An important corollary of this observation is that vascular lesions that fail to generate such a gradient are unlikely to participate in RVH and do not benefit from measures to open the vessel. The visual assessment of the degree of stenosis on angiography is not accurate and almost always overestimates the degree of stenosis. [31],[32] In the STAR trial, 28% of stenotic lesions were not subjected to intervention despite assignment to this therapy, primarily due to identifying only clinically trivial disease after closer scrutiny during angiography. [33]
The long list of investigations to confirm/screen RAS have boiled down to just imaging modalities. Captopril renal scintigraphy is not recommended as a screening test to establish the diagnosis of RAS (level of evidence: C) [34] nor does it help in predicting response to therapy or in deciding the time to intervention. [24] In the DRASTIC trial, [24] the percentage of abnormal scintigrams was lower in the angioplasty group than in the drug therapy group at both 3 and 12 months though there was no difference in serum creatinine levels and in creatinine clearance. In patients with azotemia, bilateral RAS, or RAS of a solitary functioning kidney; the sensitivity and specificity of captopril renography is further decreased. Duplex ultrasound, computed tomographic angiography, magnetic resonance angiography, and catheter angiography continue to be recommended as class I recommendation to establish the diagnosis of significant RAS. [34] Renal artery resistive index on duplex ultrasound to predict individual patient response to revascularization remains to be controversial with lots of empty lacunae. [35],[36] A recent observational study did show that uricemia, proteinuria, and renal resistive index were higher at baseline in patients who worsened their renal function after revascularization. [37]
Lateralization of the renal vein renin ratio of more than 1.4:1 and duration of hypertension less than 5 years, predicts 95% cure rate of hypertension after revascularization. [38] Jenson et al., [39] had also shown 95% sensitivity and 75% specificity of renal vein renin investigation for the prediction of the clinical outcome after angioplasty. However, need for invasive catheterization and cumbersome procedure requiring preprocedural hospitalization, stoppage of all renin increasing medication, fixed low sodium intake prior to procedure, and high false positive rates has decreased clinical utility of this test. It remains to be class III indication as a screening test to detect RAS. [34] However, since renin is released in proportion to the reduction in renal blood flow, [40] it is entirely plausible that the ischemic kidneys exposed to the highest concentration of angiotensin II are also those more suitable to increase the GFR when the renal blood flow is restored by a successful PTRA. Thus peripheral plasma renin activity though not helpful in diagnosis may predict functional recovery of the kidney. The imaging modalities which are now recommended class I indication to diagnose anatomic RAS cannot decide the physiological significance of such stenosis. It is here that chronological sequence of events, the level of progression of anatomic stenosis, and the clinical manifestations of RAS will help decide the need for revascularization. In near future, PET shall also offer a promising, quantitative, low risk, and noninvasive assessment of renal perfusion in ARVD patients. [41]
| :: Restenosis and Complications | | |
Compared to coronary circulation, renal artery is bigger, having more flow, predominant systolic flow, more often ostial lesion, and less turbulent flow; hence less shear stress. With the use of stents though the rate of technical success is now close to 100%, [42] but restenosis continues. The restenosis rates after renal artery angioplasty vary from as low as 6% to as high as 48% [Table 1]. Factors determining the rate of restenosis are the etiology, the type as well as the sight of plaque, use of stents, as well as the medical treatment used to prevent it. [46] Restenosis is less with fibromuscular dysplasia, with nonostial lesions, and with the use of stents. Restenosis after stent implantation is usually caused by myointimal hyperplasia as seen in coronary circulation. In addition, flow separation and higher shear rates resulting from unfavorable volume-surface relations of the blood circulating through the stent is also responsible, [47] particularly because of the angle of departure of renal artery from the aorta. Most important factors promoting long-term patency is the short length of the endoprosthesis, complete covering of the orifice of the renal artery, and some over-dilation of the diameter of the original vessel. [44] | Table 1: Technical success and restenosis rates with and without use of stents
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All interventional procedures are associated with inherent complications and PTRA is no exception. In the era of borderline beneficial effects of renal artery stenting it is very important to keep a track of these complications. In the 1990's, 13.5% patients may have experienced a complication (including the need for dialysis) as a result of stenting and over one-third of these required some form of intervention ranging from blood transfusion to surgical bypass procedure. [48] Procedural complications occurred in six patients of a recent randomized trial with a relative risk of 3.4 (95% confidence interval, 0.8-15.1), including one case of dissection with segmental renal infarction. [49] In the largest randomized trial, the rate of these periprocedural complications was as high as 9%. [50] Local vascular complications predominate most of these adverse events with incidence as much as 20%. [33],[51] In the recent STAR trial, there were two procedure-related deaths related to renal artery perforation (3%), one late death secondary to an infected hematoma, and one patient who required dialysis secondary to cholesterol embolism. [33] Renal embolizations, renal arterial occlusions, renal-artery perforations, and peripheral artery cholesterol embolisms are the few serious complications with significant mortality. Their incidence can be significantly decreased with increased operator experience. Use of distal protection devices though seems logical, but has insufficient evidence of benefit to recommend widespread use. [52]
| :: Issues in Management of Renovascular Hypertension | | |
Four questions needs to be addressed regarding treatment for RVH. Firstly, is renal hypoperfusion causing increased renin and its adverse effects? Secondly, after improving renal hypoperfusion does renin and angiotensin II levels come back to normal? Thirdly, if so, what is the subgroup where this reversal is seen? Lastly, does this reversal in renin status correspond to decrease or cure of hypertension? In other words overlap with essential hypertension and other secondary causes must be ruled out before deciding on renal revascularization. Similarly, late stages of hypertensive nephrosclerosis must be ruled out avoiding revascularization of small nonfunctional kidney. So far there has been a mixed response from the published observational and randomized trials when it comes to cure of hypertension adding to the prevalent confusion over treatment of RAS. Comparison of studies addressing the effects of PTRA on BP is hampered by the different criteria of selection of patients, as well as by the differences in the definition of improvement in BP, in the duration and modalities of follow-up, and in medical treatment. Renal artery stents though have increased the patency rates, but cure rate of RVH is not affected significantly. Admittedly, several factors other than renal artery patency may influence the BP outcome after PTRA as discussed below.
Plouin et al., [49] did not find any difference in mean ambulatory BP between control (141±15/84±11 mm Hg) and angioplasty (140±15/81±9 mmHg) groups of ARAS patients, though it was easily controlled with lesser drugs in the angioplasty group. Similarly in patients with unilateral RAS, no statistically significant or clinically important differences in outcome were observed between angioplasty and medical management group by Webster et al. [51] Though in patients with bilateral RAS randomized to angioplasty, a statistically significant (P=0.05) though modest, fall in BP was observed at latest follow-up (range 3-54 months). The Dutch RAS intervention cooperative study group [24] also compared balloon angioplasty of the renal artery (without stent placement) to antihypertensive drug therapy after randomization. Inclusion criteria were either uncontrolled hypertension on two antihypertensives or rise in serum creatinine concentration on the second or third visit by at least 0.2 mg/dL (20 μmol/L) during treatment with an ACEI. Overall, both approaches resulted in similar decreases in BP, with the angioplasty group having reduced the need for one additional antihypertensive drug given in its usual daily dose.
It can be said that the patient population in the trials matched the actual population treated regularly based on anatomical diagnosis of significant RAS. The negative results of these trials may be due to the inherent flaws in the trial designs [Table 2]. The needed patients who were to benefit the most from PTRA were either excluded or did crossover underestimating the overall result. The medical management group was able to compete with the PTRA despite the fact that drugs like ACEI which inhibit increased functional renin system were either not used or used last in the treatment algorithm. The uncontrolled BP in the overall trial populations were probably not determined by RAS which might have been hemodynamically insignificant in these small population studies.
Even in the meta-analysis by Ives et al., [53] of all the relatively small randomized studies there was no clear benefit for angioplasty when the systolic and diastolic BP was compared for the two groups at 6 months [Figure 1] and [Figure 2]. There was, however, some suggestion of benefit for angioplasty when the mean change (between baseline and 6 months) in BP was compared between groups [Figure 3] and [Figure 4]. [53] The confidence intervals were wide and compatible either with no (or an unimportantly small) benefit, or with a moderate but clinically worthwhile benefit. Though the small numbers taken together may have compensated for small patient population, but the overall follow-up was also less (maximally 12 months), thereby preventing any inference regarding cardiovascular as well as overall morbidity and mortality. Another meta-analysis by Pierdomenico et al., [54] in a similar group of patients did not support the superiority of PTRA over medical therapy in cardiovascular risk reduction. | Table 2: Flaws in prospective randomized trials of percutaneous renal artery revascularization
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ASTRAL trial [50] is the latest in the randomized trials with a long mean follow-up for 33.6 months and a low crossover rate (6%). PTRA with stents was done in 95% patients in the procedure group. The investigators not only determined the change in renal function, but also the BP response, the time to the first renal event, the time to the first major cardiovascular event, and mortality. Total 806 asymptomatic patients with uncontrolled or refractory hypertension or unexplained renal dysfunction were enrolled. Though 59% of patients had stenosis of more than 70% by visual estimation and 60% had a serum creatinine level of 1.7 mg/dL or more or both, but large number of patients with hemodynamically insignificant RAS diluted the results [Table 2]. Obviously after 5 years there was no statistical difference in systolic, diastolic, and mean BP amongst the two groups. Similarly, the time to a first renal event did not differ significantly between the two groups (hazard ratio in the revascularization group, 0.97; 95% CI: 0.67-1.40; P=0.88) nor was there difference amongst the cardiovascular event rates (hazard ratio in the revascularization group, 0.94; 95% CI: 0.75-1.19; P=0.61). There was neither any significant difference in the overall survival (hazard ratio in the revascularization group, 0.90; 95% C: 0.69-1.18; P=0.46). Once again the trial did not put an end to controversy surrounding the renal angioplasty due to the design flaws [Table 2]. The symptoms which should have taken an upper hand in deciding the patient populations were totally neglected and asymptomatic patients included. | Figure 1: Mean systolic blood pressure at 6 months. Relative to the medical therapy group, the mean (95% CI) systolic BP was 2.9 mmHg (−9.1, 3.4) lower in the angioplasty group (P=0.4)
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 | Figure 2: Mean diastolic BP at 6 months. Relative to the medical therapy group, the mean (95% CI) diastolic BP was 0.35 mmHg (−3.6, 2.9) lower in the angioplasty group (P=0.8)
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 | Figure 3: Mean change in systolic BP. A difference of 6.3 mmHg (95% CI = −11.7, −0.8) in the mean change between the two groups (P=0.02) favoring the angioplasty group
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 | Figure 4: Mean change in diastolic BP. A difference of 3.3 mmHg (95% CI = −6.2, −0.4) in the mean change between the two groups (P=0.03) favoring the angioplasty group
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The confusion regarding need to revascularize persists and warrants more discussion and guidelines. It is clear that hemodynamically stable unilateral RAS related hypertension will neither worsen with medical therapy nor improve with renal artery revascularization. The hypertension might get controlled using less number of drugs, but shall not get cured. The risks associated with renal artery revascularization certainly overweigh the cardiovascular morbidity of "drug controlled" hypertension in the presence of RAS. Renal artery revascularization should be offered only after proper antihypertensive drug trial. Medical management of these patients particularly with renin angiotensin aldosterone system (RAAS) blockers is definitely warranted before labeling them as resistant hypertensives. Properly selected patients for revascularization may show significant fall in both systolic and diastolic BP over long time. [55] Nevertheless, hemodynamically significant unilateral RAS supplemented by positive lateralizing signs in the form of carefully performed renin estimation post captopril, or causing symptoms associated with accelerated hypertension like flash pulmonary edema/congestive heart failure (CHF) or worsening of CAD or ischemic nephropathy will benefit from the renal revascularization. [56] PTRA should always be supplemented with stenting which is associated with increased renal artery patency rates and better technical success. [44],[45],[50]
| :: Ischemic Nephropathy | | |
Treatment of RAS with restoration of renal perfusion may stabilize and improve the renal function only if it is bilateral and severe enough to decrease the GFR. The ultimate goal is to prevent or delay the need for renal replacement therapy. Gert Jenson et al., [39] used radiorenography with '311-hippuran to monitor recovery of renal function with 1 year follow-up. Seventy-four percent of the atherosclerotic vascular disease (AVD) patients had an increased or unchanged GFR, while 26% deteriorated. Significant increase in GFR of 11%, 1 year after angioplasty was observed and the increment in renal function was caused by recovery of the stenotic kidney as measured with renography. In patients with renal insufficiency, defined as GFR 30 mL/min/l. 73 m 2 body surface area (BSA), and with severe renal failure (GFR < 15 mL/min/l. 73 m 2 BSA) an increased or unchanged GFR was in fact recorded in 50 and 25%, respectively; thus, indicating that in patients with impaired renal function, PTRA has the most benefit when renal impairment is moderate, [57] but less evident in patients close to end-stage renal failure, where irreversible damage of the renal parenchyma is inevitable. Similarly in the meta-analysis by Middleton, [58] 25-53% of patients undergoing PTRA had some improvement of renal function. On the other hand, creatinine levels did not differ in either group after 24 months in The Scottish and Newcastle Renovascular Collaborative Group study [59] and after 27 months in a study by Blum et al., [44] irrespective of baseline serum creatinine levels. These findings are also clinically important, because untreated stenosis may have progressed in severity, resulting in renal artery occlusion, loss of renal mass, and a subsequent decrease in kidney function. [60],[61]
In the recent randomized trials, PTRA has failed to have a significant impact on renal function, similar to the BP response. In the Dutch RAS Intervention Cooperative study, [24] though creatinine and creatinine clearance were similar in both treatment groups, abnormal scintigrams were statistically less in the angioplasty group at 12 months. Total occlusion was also less in the angioplasty group compared to the medical management group (none vs 9%). Creatinine clearance remained same after 6 months in the study by Plouin et al., [49] and Webster et al., [51] did not find any significant differences or trends in serum creatinine observed during follow-up (range 3-54 months). Moreover, major outcome events (death, myocardial infarction, heart failure, stroke, and dialysis) were similar in the angioplasty and medical groups during follow-up. Ives et al., [53] in his meta-analysis also found that though there was some suggestion of benefit for angioplasty in terms of changes in serum creatinine, but it was not significant (P=0.06).
In the ASTRAL trial [50] during the 5-year study period, there was no difference in the mean serum creatinine levels amongst the two groups. This was true even for 163 patients with severe anatomical disease (103 patients with bilateral RAS of more than 70% and 60 patients with RAS of more than 70% in a single functioning kidney). Time to first renal event, acute kidney injury and development of ESRD was equal amongst the medical treatment group and in the revascularization group. Thus, asymptomatic patients with or without chronic kidney disease (CKD) should not be taken up for revascularization unless warranted by deteriorating renal function. An effective medical management is adequate enough to delay renal function deterioration.
STAR trial was primarily meant to determine 20% or greater decrease in creatinine clearance. The secondary end points included safety, cardiovascular morbidity, and mortality after 2 years of follow-up. [33] Eligibility criteria were impaired renal function (creatinine clearance less than 80 mL/min per 1.73 m 2 according to the Cockcroft and Gault formula), ostial ARAS detected by various imaging studies, and stable BP. Exclusion criteria included renal size less than 8 cm, renal artery diameter less than 4 mm and estimated creatinine clearance less than 15 mL/min per 1.73 m 2 [Table 2]. The groups did not significantly differ in achieving primary end point (22 and 16%, respectively with wide CI's around the estimate of effect), BP control, and cardiovascular morbidity and mortality or in the incidence of the composite outcome of worsening renal function and death. In fact there was more harm in the form of complications in the renal artery stenting group. Though few patients in the trial had insignificant RAS with only 3% dropout rate, but based on the natural history of ARAS mere revascularization may not be the answer to salvage the already deteriorating renal function in the presence of unilateral or bilateral RAS in stable patients. Never the less renal revascularization might have benefitted patients with deteriorating renal function precipitated by either poorly controlled BP or associated comorbidities like diabetes mellitus. Severe hypertension, complete repair of global RVD including renal artery occlusion, and rapid deterioration in preoperative renal function were associated with the best response after open repair of RVD [62] and there is no reason to believe, why this shall not apply to percutaneous repair. The reason why newer randomized trials did not show benefit with respect to renal function is poorly designed trials with exclusion of needy patients while performing revascularization in respectively normal asymptomatic population [Table 2].
Ischemic nephropathy is a complex disorder with an important intrarenal (parenchymal) component strongly affected by risk factors for atherosclerosis. Impaired renal function in these patients is assumed to be caused not only by reduced blood flow to the kidney, but also by loss of microvascular renal perfusion and renal fibrosis. [63] Numerous signaling pathways lead to up regulation of cytokines and inflammatory mediators, including transforming growth factor (TGF)-beta, within the poststenotic kidney. [64],[65] Over time, rarefaction of the distal arterioles develops, associated with fibrogenesis and loss of viable function. [66],[67],[68],[69] Improvement of GFR in the dilated kidney is biphasic; half of it occurs within 1 st week of the procedure, and the remaining during the following 6 months. This suggests that the preservation of the renal function depends not only on the restoration of renal blood flow, but also on the wearing off of other ischemia-induced mechanisms of renal damage that may require a long period of time to fully regress. [70],[71],[72] Meaningful recovery of kidney function after revascularization is limited once fibrosis is established. [73],[74] Renal perfusion as measured by quantitative PET did not change after revascularization in a group of ARVD patients probably because of microvascular disease. [41] BP cure and early incremental increase in excretory function has demonstrated significant and independent associations with survival free from dialysis dependence, but this is not true for patients with established disease and preoperative serum creatinine >1.8 mg/dL. [62],[75]
| :: Unresolved Issues and Ongoing Trials | | |
Studies have not addressed the effect of aggressive medical therapy on the intrarenal component of the disease. None of the randomized trials or meta-analysis so far has detected significant benefit of renal artery stenting over and above the medical management group. This could be because of decrease strength of benefit of the intervention tested or because of increase benefit demonstrated by the cardiovascular risk management. In recent years, newer antihypertensives and lipid-lowering drugs were used in both study groups. Statins have been shown to reduce proteinuria in patients with chronic kidney disease [76] and to reduce loss of kidney function in patients with cardiovascular disease. [77] They slow the progression of tissue injury in ARAS and are associated with substantially less interstitial fibrosis in kidneys removed for total arterial occlusion. [68],[69] Work needs to be done on infusion of autologous endothelial and undifferentiated progenitor cells which increases renal blood flow and GFR even without renal revascularization as seen in swine model [78] particularly by facilitating recovery of viable tissue. Two studies could not find significant importance of brain natriuretic peptide (BNP) levels in determining the need for renal artery angioplasty and moreover the BP response to such a procedure. [79] The HERCULES trial [80] did not find any correlation between BNP levels at baseline and systolic BP reduction or between BNP reduction and BP response; though the BNP levels significantly decreased 30 days post procedure. It was also showed that in appropriately selected patients with hemodynamically significant RAS and uncontrolled hypertension, there was impressive reduction in systolic (and to a lesser degree diastolic) BP.
The ongoing CORAL trial is under way and is expected to answer some difficult questions regarding overall beneficial effects of renal artery stenting. [81] It is a multicenter study which will have more than 900 patients with greater than 60% stenosis randomized either to optimal medical therapy alone or optimal medical therapy plus renal artery stenting. Inclusion criteria are a documented history of hypertension on two or more antihypertensive drugs or renal dysfunction, defined as stage 3 or greater CKD based on the National Kidney Foundation classification (estimated GFR <60 mL/min/1.73 m 2 calculated by the modified Modification of Diet in Renal Disease (MDRD) formula). The primary end point is survival free of cardiovascular and renal adverse events, defined as a composite of cardiovascular or renal death, stroke, myocardial infarction, hospitalization for CHF, progressive renal insufficiency, or need for permanent renal replacement therapy.
| :: Current Guidelines | | |
As per American College of Cardiology/American Heart Association (ACC/AHA) guidelines [34] for hypertension, PTRA is reasonable for patients with hemodynamically significant RAS with accelerated hypertension, resistant hypertension, and malignant hypertension (class IIa, level of evidence B). For preservation of renal function, PTRA is recommended for patients of RAS and progressive CKD with bilateral renal artery disease or a stenosis to a solitary functioning kidney (class IIa, level of evidence B). PTRA remains a class I indication for patients with hemodynamically significant RAS (on angiography or intravascular ultrasonography) and recurrent, unexplained CHF or sudden, unexplained pulmonary edema. Renal artery revascularization in an asymptomatic individual with hemodynamically significant RAS is a class IIb indication.
| :: Conclusion | | |
ARAS treatment plan should consist of medical management including ACEI's with or without renal artery angioplasty. Mere presence of anatomic RAS is not enough to warrant revascularization. The timing of catheter based intervention is mostly dependent upon clinical symptoms, signs, physiological significance, and rate of progression of stenosis. RVH declares underlying rapidly progressing ischemic nephropathy. Indications of renal artery angioplasty have been summarized in [Figure 5]. Moreover "time is kidney" and significant stenosis should be identified before the structural changes associated with secondary hypertension set in. | Figure 5: Indications for percutaneous transluminal renal angioplasty based upon various clinical presentations collectively labeled as "manifest RAS". *Revascularization is warranted only after adequate drug trial including renin angiotensin aldosterone system blockade
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Need for search of valid markers identifying favorable renal function and hypertension outcomes of PTRA should be stressed in the forthcoming randomized trials. There are no tests available except for chronological sequence of events and clinical acumen to identify manifest RAS. The overlap of primary hypertension and RVH should be identified and such patients should be treated on individualized basis. Medical treatment permits the same degree of BP control achievable with the dilation procedures and should be offered in asymptomatic long standing renovascular hypertensives unless warranted by bilateral nature and impending closure of a functioning kidney. Decision to undertake expanded diagnostic testing should be based upon the commitment to consider renal revascularization if studies are positive. The immediate risks and the potential long-term benefits of angioplasty should be weighed for each individual patient, possibly by including patient preference. Merely treating arterial patency makes the patient susceptible to the inherent side effects and complications of the revascularizing procedure. More randomized studies should focus on hard points like cardiovascular mortality, prevention or delay of end stage renal failure, and cure of hypertension and its related morbidities.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]
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