clinical queries: nephrology 1 (2012) 268e278 Available online at www.sciencedirect.com journal homepage: www.elsevier.com/locate/cqn Review article Ischemic nephropathy Anupama Kaul a, *, Harsh Vardhan b a Associate Professor, Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India b Senior Resident, Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India article info Article history: Received 15 October 2012 Accepted 15 October 2012 Available online 24 October 2012 Keywords: Ischemic nephropathy Chronic kidney disease Renal transplantation Azotemic renovascular disease abstract Term ischemic nephropathy (IN) means impairment of renal function beyond occlusive disease of the main renal arteries. Time to ESRD or death does not correlate with renovascular anatomy despite vessels showing varying presentation from non occlusion to stenosis of varying degree. The parenchymal injury is multifactorial in origin ranging from cholesterol emboli, long-standing hypertension to prolonged ischemic damage. Time to intervention in RAS is challenging as efforts must be made at a stage when these ischemic changes are reversible and much before parenchymal injury can happen. The predictors of renal improvement are also still elusive. Unexplained renal failure in the background of uncontrolled hypertension, CAD or PVD or renal function worsening following use of angiotensin-converting enzyme inhibitor (ACEI), flash pulmonary edema are clinical situations associated with IN. The main aim of treatment is to reduce cardiovascular mortality, to improve or stabilize renal function and blood pressure control. Treatment options include medication, surgical reconstruction and transluminal angioplasty with or without stenting. Revascularization should be considered in RAS with rapid worsening of renal function or resistant HTN (four or more antihypertensive agents especially in the setting of CHF or recurrent flash pulmonary edema). When the kidney size is <8.0 cm long or the RI is >0.80, there is little chance of BP improvement or recovery of GFR. Medication having proven role in preventing cardiovascular mortality including statins, renineangiotensin antagonists, and low dose aspirin are also effective secondary prevention of IN. Copyright ª 2012, Reed Elsevier India Pvt. Ltd. All rights reserved. 1. Introduction The term ischemic nephropathy (IN) means impairment of renal function beyond occlusive disease of the main renal arteries. 1 Azotemic renovascular disease is other term coined by some authors suggesting that loss of renal viability may not directly be associated with impairment in oxygenation of renal tissue as less than 10% of the blood is needed to fulfill the metabolic requirement. 2,3 There has been major refinements in the management of renal artery stenosis over the last two decades due to improvement in imaging modality and evidence-based interventions. But still it is not clear whether these interventions are likely to benefit or do more harm. The predictors of renal improvement are also still elusive. Unexplained renal failure in the background of uncontrolled hypertension, CAD or PVD or renal function worsening following use of angiotensin-converting enzyme inhibitor (ACEI), flash pulmonary edema are clinical situations associated with IN. * Corresponding author. E-mail address: anupa@sgpgi.ac.in (A. Kaul). 2211-9477/$ e see front matter Copyright ª 2012, Reed Elsevier India Pvt. Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cqn.2012.10.001
clinical queries: nephrology 1 (2012) 268e278 269 2. Epidemiology Various studies have reported different prevalence rates. The prevalence of ARAS ranged from 5% to 28% depending upon the percentage used as significant stenosis. In unselected patients a study of 5194 consecutive autopsies between 1980 and 1988, 225 (4.3%) demonstrated atherosclerotic renal artery stenosis (ARAS), and subsequent medical record review revealed a documented diagnosis of ARAS in only 7.3% of these 225 individuals. 4 The prevalence of ARAS as defined by a stenosis of >60% using renal duplex sonography in a single populationbased study group showed an incidence of 6.8% and only 53% of participants with radiographic ARAS had clinically evident hypertension. 5 Numerous other studies have tried using angiography among patients with CVD undergoing cardiac catheterization to look for prevalence of ARAS. 6e14 The prevalence of IN has been found to be increasing with age and was found to be responsible for 5%e22% cases of renal dysfunction in patients above 50 years. 15 However its progression to ESRD varies, evidenced by various series accounting for 12% progressing to ESRD with an average decline in GFR of 8 ml/min/ year 16 while others reported annual increase of ESRD due to IN at a rate of 12.4% much higher than that for diabetes mellituseesrd (8.4%) or all-cause ESRD (5.4%). 17 The Spanish Group of Ischemic Nephrology (GEDENI) study observed a mean age of patients with IN to be 68.7 years of which 97.4% were hypertensive, 69.8% smokers and 62.95% having hypercholesterolemia suggesting its closer association. There was evidences of atherosclerosis at other vascular beds in 82% of these patients, 65% showing peripheral aeteriopathy among 156 patients in 20 Spanish hospitals. Besides predominance of ischemic cardiomyopathy. 18 occurs with an occlusion >70% i.e., critical stenosis. The role of renineangiotensin system (RAS) in the pathogenesis has been known for many years and the famous Goldblatt experiment also proposed its role. But it s being the sole mechanism is debatable as fibromuscular disease rarely causes kidney damage despite hemodynamic effects severe enough to activate the systemic presser mechanisms. Hence mechanism causing renal damage seems to be more complex. Hypoperfusion is induced in distal arterial segment beyond stenotic segment, sometimes below the level of autoregulation. This activates presser mechanisms to restore renal perfusion, including activation of the renineangiotensin system, adrenergic stimuli, and other mechanisms. 19 Further occlusion again reduces perfusion and triggers a repeat cycle of elevation of systemic pressures. Malignant-phase of hypertension is produced if this process is not interrupted. 20 Tissue fibrogenic cytokines are stimulated in the kidney, reflected by increased transforming growth factor-b, NF kappab pathways, and others. 21 Recent evidence suggests microvascular changes distal to a stenosis in swine models, induced by cholesterol feeding (a surrogate for early atherosclerosis) and subsequent rarefaction of renal small vessels. 22,23 This rarefaction of the arterioles is associated with fibrogenesis and loss of viable function. 21,24e26 Thus mere reversal of blood flow does not lead to improvement in renal function as addressed in recent trial as tissue remodeling occurs. This has been proved with blood oxygen level-dependent magnetic resonance (BOLD-MR) which measures the concentration of tissue deoxy-hemoglobin and provides an assessment of overt tissue ischemia. 26 Some injurious pathways responsible for remodeling can be modified using intensive therapy with either antioxidants or statins. 27,28 3. Etiology By far the most common renovascular lesion is atherosclerotic renal artery stenosis (ARAS). It can be detected in 6.8% of community-based subjects above age 65.6. 5 The other important causes are elaborated in Table 1. 3.1. Pathophysiology The exact pathogenesis of ischemic nephropathy is still unclear. Hemodynamically significant occlusion usually Table 1 e Major causes of ischemic nephropathy. Atherosclerotic renal artery stenosis Fibromuscular dysplasia (FMD) Renal artery aneurysm Arterial embolus Arteriovenous fistula (congenital/traumatic) Segmental arterial occlusion Stenosis to a solitary functioning kidney Aortic coarctation Systemic vasculitis (Takayasu s, polyarteritis) Atheroembolic disease Vascular occlusion due to endovascular aortic stent graft 4. Natural progression Due to poor definition of endpoints for progression of disease, the natural history of RAS is difficult to understand. 29 Various studies have tried using surrogate endpoints to define progression but none of them are conclusive like decrease in renal artery diameter, fall in GFR and renal atrophy. Time to ESRD or death did not correlate with renovascular anatomy despite vessels showing varying presentation from nonocclusion to stenosis of varying degree. The probable reason may be that loss of GFR in RAS is not primarily due to proximal vessels lesion The most likely explanation is that GFR losses in RAS are not determined primarily by the proximal large vessel lesion but with parenchymal damage downstream of the lesion. The parenchymal injury in such situation is multifactorial in origin ranging from cholesterol emboli, long-standing hypertension to prolonged ischemic damage. This explanation is substantiated by observation suggesting that despite the repair of RAS there was no uniformity in stabilizing of GFR. Time to intervention in RAS is challenging as efforts must be made at a stage when these ischemic changes are reversible and much before parenchymal injury can happen. Anatomical progression of renovascular lesions has not been extensively studied in the modern era, but there is some evidence that it has decreased with current therapies. It is evident from literature that RAS is progressive an observation
270 clinical queries: nephrology 1 (2012) 268e278 in a subgroup of 1189 patients who underwent cardiac catheterization showing significant disease in 2.4% (>50% of renovascular disease) which progressed in 13.5% of population studied. Another study 29 observed progression of RAS among patients followed up with serial renal artery duplex scans suggesting baseline RAS severity being 18, 28, and 49% for renal arteries that initially were classified as normal, <60% stenosis, and >60% stenosis respectively. 26,29 Though fall in GFR may be a useful end put for progression of disease but this association is not tightly correlated. Leertouwer et al 30 compared the need for renal replacement therapy among untreated RAS with >50% stenosis and control age and gender matched subjects and observed that none of these patients required RRT on 10 years follow-up. Of 68 patients with incidental RAS (>70% stenosis) without revascularization only 12% had clinical progression requiring revascularization or progression of renal failure. 31 Site of stenosis i.e., proximal RAS and its severity are not clinically related to degree of renal failure 32 as renal dysfunction was evident with mild proximal disease as with severe narrowing or unilateral renal artery occlusion. Irrespective of nonocclusive artery to stenosis of varying significance time to ESRD or death did not correlate with renovascular anatomy. 33 main and branch renal artery stenoses. However, this method shows large interobserver variation for the location and grade of stenosis (k concordance coefficients 0.26e0.70). 35,36 A report compared resting and hyperemic (after intraarterial infusion of papaverine) systolic transstenotic pressure gradients, and findings of intravascular ultra sonography and quantitative angiography in 62 patients with RAS 37 showed that hyperemic systolic transstenotic pressure gradient of at least 21 mmhg was the most accurate and the only independent predictor of improvement in hypertension at 12 months, with a predictive accuracy of 84%. An important advantage of catheter angiography is that a hemodynamically significant stenosis can be immediately treated in the same session. Improvements in imaging techniques with greatly increased contrast resolution and optimized catheter shapes, have resulted in reduction iodinated contrast exposure. Use of carbon dioxide or gadolinium instead of iodinated contrast to reduce nephrotoxicity has been explored with equivocal results. This invasive intervention is associated with the risk of contrast induced renal dysfunction, atheroembolic episodes, bleeding, dissection and arterial injury and thus is not a suitable screening technique as RAS is responsible for only a small group of patients with uncontrolled hypertension and renal failure. 5.2. Ultrasound 5. Diagnostic approach When to suspect? Onset of hypertension at >55 years of age Accelerated, treatment resistant or malignant hypertension Unexplained difference in kidney size >1.5 cm Recurrent unexplained pulmonary edema Worsening renal function after ACE inhibitor treatment Unexplained renal dysfunction Evidence of peripheral artery disease or CAD Variety of imaging studies are available. The screening test should be readily available noninvasive, nonnephrotoxic provide an anatomic diagnosis indicate its functional significance identify patients likely to benefit from intervention [Zalunardo N, Tuttle KR. Atherosclerotic renal artery stenosis: Current status and future directions. Curr Opin Nephrol Hypertens. 2004;13:613e621]. 5.1. Catheter angiography Catheter angiography using X-radiation and iodinated contrast injected by catheters is the gold standard for the diagnosis of renal artery stenosis. 34 It offers the highest spatial and temporal resolution available for anatomically visualizing Ultrasounds seem to be an ideal screening modality for RAS as it is noninvasive with low cost and free from risks of radiation exposure and contrast related renal dysfunction. It is an excellent tool for transplant kidney as the organ is very close to skin surface and the higher resolution transducers can accurately pick up the site and degree of narrowing, though it is observer dependant its accuracy varies between 60 and 90% especially transplant kidney. 38,39 The major drawback of this modality is poor visualization of the entire renal artery missing the highest peak systolic velocity at a stenosis using spectral Doppler tracing. Besides this accessory renal arteries are generally not well visualized. Due to abdominal gas and fat limits the visualization of renal vasculature resulting in increased rate of technical failure in comparison to other modalities. RAS can be both proximal and distal based on certain criteria. 5.2.1. Doppler criteria for RAS 5.2.1.1. Proximal criteria. These are direct signs obtained at the site of the stenosis. - Four criteria are used to diagnose significant proximal stenosis or occlusion of the RA. - The first and most important sign is the increase in peak systolic velocity (PSV). Velocities >180 cm/s suggest stenosis of >60%, while an end-diastolic velocity >150 cm/s suggests a degree of stenosis >80%. - In a meta-analysis, PSV was the best predictor of RAS, with a sensitivity and specificity of 85% and 92%, respectively. 40 - The third criterion is the identification of RAS with no detectable Doppler signal, a finding that indicates occlusion. - The fourth criterion is the visualization of color artifacts such as aliasing at the site of the stenosis and the presence
clinical queries: nephrology 1 (2012) 268e278 271 of turbulence at Doppler evaluation indicating the presence of a significant stenosis upstream. - Usually, these two patterns are the first and immediate signs of a stenosis. 41 5.2.1.2. Distal criteria - The difficulties related to the direct evaluation of the stenosis (the mean examination time was 69 min for the complete examination and 14 min for the distal evaluation) have led several investigators to search for and to identify waveform alterations, other than increased velocity, distal to the stenosis in arterial segments more accessible with Doppler US (i.e., hilar or interlobar arteries). - The rationale is that the flow at the renal hilum downstream to a hemodynamically significant stenosis should become damped and show a slow rise to the peak systole. - This phenomenon has been called the tardus parvus effect. - Tardus means slow and late and parvus means small and little. - Tardus refers to the fact that systolic acceleration of the waveform is slow with consequent increase in time to reach the systolic peak. - Parvus refers to the fact that the systolic peak is of low height, indicating a slow velocity. - A retarded acceleration of less than 3.0 m/s 2, and increased acceleration time greater than 0.08e0.10 s. However, these findings may be less specific than peak systolic velocity in the main renal artery and ideally should be used to support the diagnosis based on peak systolic velocity. 5.2.1.3. Resistive index. RI measures the degree of intrarenal arterial impedance and is calculated using the following formula: ([PSV end-diastolic velocity] / PSV). RI values measured in healthy subjects show a significant dependence on age and the area sampled. The values in the main RA are higher in the hilar region (0.65, 0.17) than in the more distal small arteries, and they are lowest in the interlobar arteries (0.54, 0.20). Intrinsic renal diseases (i.e., nephroangiosclerosis, hypertension, tubularinterstitial disease, diabetes mellitus, and severe bradycardia) can cause an increase of RI, even in the presence of normal serum creatinine levels. RI >0.8 suggests reduced benefit from intervention. 42e53 5.3. Computed tomographic angiography Advances in CT technology can provide accurate anatomic images of even small renal arteries. A review of 8 studies reveals an average sensitivity of CTA for a diagnosis of significant stenosis (typically 50% by DSA) of 92% (range 64%e 100%), an average specificity of 90% (range 56%e99%), and an average positive predictive value of 88% (range 68%e 98%). 38,54e62 Compared to conventional angiography, CTA is less invasive with faster acquisition, offers better soft tissue visualization, and allows multiplanar imaging of the renal arteries in any obliquity. The accuracy is comparable to MRA; however, CTA has the risks of ionizing radiation and nephrotoxicity from iodinated contrast agents. Also, when there is severe calcification in the renal arteries, the luminal narrowing may be obscured. However, a major limitation of CTA is that it provides only an anatomic but not a physiologic assessment of the stenosis. So the widely accepted anatomic criterion of a 75% decrease in cross-sectional area for diagnosing severe and significant stenosis to predict the functional significance of the stenosis without considering the influence of renal blood flow may not be correct. A morphologically severe stenosis might not induce a pressure gradient if the artery has slow flow due to renal parenchymal impairment. There is no benefit from dilating a severe stenosis when the ischemic nephropathy is already end-stage. It is a class I, LOE B recommendation based on ACC/AHA guidelines to establish the diagnosis of RAS in patients with normal renal function. 61 5.4. Magnetic resonance angiography 3-dimensional (3D) gadolinium magnetic resonance angiography (MRA) is accurate for diagnosing renal artery stenosis, comparable to CTA and superior to ultrasound and captopril renography. 63e65 The median sensitivity and specificity, compared to conventional catheter angiography, respectively, are 92% and 93.5% without contrast and 96% and 93% with contrast. It not only provides high-quality noninvasive anatomic images but also has the distinct advantage of providing a functional assessment of blood flow and organ function. Some of the divergence in the MRA literature results from some investigators defining stenosis based solely on anatomic criteria. The variety of pulse sequences in MRI that assess organ function complement anatomic information. Combining luminal imaging with functional pulse sequences may offer more comprehensive evaluation of the kidneys without markedly increasing scanning time or cost. 5.5. Nephrogenic systemic fibrosis Nephrogenic systemic fibrosis (NSF) is a rare, but debilitating and largely untreatable disease, varies in severity and is hypothesized to be related to the deposition of gadolinium in the skin after dissociation from the chelated form of gadolinium used in MRI contrast agents. 66,67 Several factors have been reported to contribute to the development of NSF including the type of gadolinium chelate; the total dose administered and host factors including renal failure; an inflammatory state (lupus, recent major vascular surgery recent thrombosis); and comorbidities of renal failure including acidosis, elevated phosphate levels, and high-dose epoetin therapy. At centers where all the NSF risk factors combined together, the incidence of NSF ranges from 1% to 6% for dialysis patients and patients with GFR less than 30 ml/ min. 68,69 Recently FDA has issued an alert that gadolinium should be avoided with a GFR less than 30 ml/min. 5.6. Other screening tests Other noninvasive screening tests, such as an intravenous pyelogram, plasma renin activity, the captopril renogram, and renal vein renin measurements are no longer considered suitable for screening patients because of their poor sensitivity and specificity. Some of the important ones are going to be discussed below.
272 clinical queries: nephrology 1 (2012) 268e278 5.6.1. Plasma renin activity The baseline plasma renin activity (PRA) is elevated in only 50e80 percent of patients with renovascular hypertension. The utility of peripheral PRA is reportedly enhanced when measured in the morning with the patient in the seated position and when indexed against urinary sodium excretion; when measured under these exacting circumstances, a high peripheral PRA is found in 75%e80% of patients with proven renovascular hypertension. A very low PRA (e.g., less than 0.3 ng/ml/h) indexed against a normal urinary sodium excretion in the absence of drugs known to suppress renin argue against RAS. 70 The predictive value can be increased by measuring the rise in the plasma renin activity 1 h after the administration of 25e50 mg of captopril, a rapidly acting ACE inhibitor. The sensitivity and specificity of the captopril renin test have ranged in different studies from 75 to 100 percent and 60 to 95 percent, respectively. The general utility of this test is limited by the need to discontinue antihypertensive medications that can affect the plasma renin activity (such as ACE inhibitors, alpha-blockers and diuretics), the low sensitivity, and somewhat decreased predictive value when compared to the renogram after ACE inhibition. 71 5.6.2. Captopril renogram Oral captopril (25e50 mg) is given 1 h before the isotope is injected. The efficacy of this test is based upon the typical ACE inhibitor-induced decline in GFR in the stenotic kidney, often accompanied by an equivalent increase in GFR in the contralateral kidney due to removal of angiotensin II-mediated vasoconstriction. The net effect is that the difference between the two kidneys is enhanced. A marker of glomerular filtration, such as DTPA, or compounds that are secreted by the proximal tubule, such as hippurate and MAG3, have been used. The latter may be more reliable in patients with renal insufficiency. Three criteria were established for diagnosing renal artery stenosis: - A percent uptake of DTPA by the affected kidney of less than 40% of the combined bilateral uptake - A delayed time to peak uptake of DTPA, which was more than 5 min longer in the affected kidney than in the contralateral kidney - A delayed excretion of DTPA, with retention at 15 min, as a fraction of peak activity, more than 20% greater than in the contralateral kidney The sensitivity and specificity of the ACE inhibitor scan may, in high-risk populations, exceed 90 percent for highgrade stenotic lesions and for a successful antihypertensive response to correction of the stenosis. It has got a high negative predictive value (90%). 72,73 In 2005 ACC/AHA guidelines suggested that it should not be used as a screening test for the diagnosis of renal artery stenosis. 63 5.6.3. Renal vein renin levels These measurements are obtained by sampling renal vein and inferior vena cava blood individually. The level of the vena cava is taken as comparable with the arterial levels into each kidney and allows estimation of the contribution of each kidney to total circulating levels of plasma renin activity. Lateralization is usually defined as a ratio exceeding 1.5 between the renin activity of the stenotic kidney and that of the nonstenotic kidney. The greater the degree of lateralization, the more probable benefit will accrue from surgical or other revascularization. More recent series indicate that overall sensitivity was no better than 65% and that positive predictive value was 18.5%. For many reasons, renal vein assays are performed less commonly than before. 73 6. Treatment Treatment of RAS has undergone many phases of development. The earlier enthusiasm about intervention with PTRA or surgical correction has recently been challenged and put under intensive clinical trials. The main aim of treatment is to reduce cardiovascular mortality, to improve or stabilize renal function and blood pressure control. Treatment options include medication, surgical reconstruction and transluminal angioplasty with or without stenting. Medication having proven role in preventing cardiovascular mortality including statins, renineangiotensin antagonists, and low dose aspirin are also effective in secondary prevention of IN. 74 Renineangiotensin antagonists are more effective than other antihypertensive agents in reducing blood pressure and preventing death in animal models of RAS. 75 But no major randomized control trial has been carried out to compare standard treatment with renineangiotensin antagonists with the exception of one inconclusive trial that included only six patients 76 and another that was poorly designed. 77 Few other studies have also proved the protective role of RAS inhibition in IN. An increased survival was associated with the use of renineangiotensin antagonists in a single-center cohort study involving 195 patients with RAS, renal revascularization did not affect mortality. 78 In another population-based cohort that involved 3570 patients with RAS, patients who received renineangiotensin antagonists had a lower incidence of death and cardiovascular events, a higher incidence of AKI and a lower incidence of long-term dialysis than patients who did not receive such treatment. 79 The authors suggested that renineangiotensin inhibition could provoke AKI in a small subset of vulnerable patients with RAS, whereas it still provides long-term renoprotective benefits for most patients. Their finding highlights the importance of monitoring renal function in patients who are at risk of developing RAS and are treated with renineangiotensin antagonists. Patients who suffer AKI during renineangiotensin inhibition frequently have bilateral, severe RAS. There have been few concerns about RAS inhibition accelerating renal hypoperfusion by reducing poststenotic dilatation. 6.1. Surgical reconstruction 6.1.1. Percutaneous angioplasty with or without stent Endovascular treatment for ARAS includes balloon angioplasty and angioplasty with placement of a stent. Use of stents is the preferred method for endovascular treatment today because of documented improvements in technical success and lower rate of restenosis. A meta-analysis of 24
clinical queries: nephrology 1 (2012) 268e278 273 studies comparing angioplasty with and without stenting demonstrated an average technical success rate of 98% with stent use, and the average rate of restenosis was 17% at 6e29 months of follow-up. 80 These results compared favorably to balloon angioplasty alone, which showed an average technical success of 77% and a restenosis rate of 26%. 81 Formerly the only option for renal artery revascularization, surgical correction is now less frequent than endovascular intervention. Although long-term patency appears to be superior with surgical compared to endovascular revascularization (82%e 94% at 5 years), the complication rate is significantly higher. 82e84 A recent review of 42 published prospective or retrospective cohort studies of either endovascular or surgical treatment of ARAS documented 30-day mortality rates that were 3.1% higher (1.8%e4.4%) among surgically treated patients, despite the fact that these patients who underwent surgical repair were younger (62 versus 68 years), less likely to have ischemic heart disease (53% versus 60%), and less likely to have diabetes (14% versus 26%). 84 In various series, operative mortality has been reported to be 2%e6%, and serious complications such as MI and stroke have been reported with frequencies as high as 9%. Surgical revascularization for ARAS has been compared with other therapies in 2 trials. Uzzo et al 85 randomized 52 patients with 75% stenosis in one or more renal arteries, CKD (creatinine levels 1.5e4.0 mg/dl), and controlled hypertension to surgical repair or optimal medical therapy. After >6 years median follow-up, there was no difference in the primary endpoint (composite of poorly controlled BP, decline in renal function, CV endpoint such as MI or stroke, or death). Data pertaining to surgical morbidity or mortality were not provided. In a study by Balzer et al 86 ARAS patients underwent either surgery or angioplasty, as decided by surgeons and radiologists. Surgery was associated with a nonsignificantly (NS) higher mortality (25% versus 18%) during 4 years of follow-up. The substantial differences in the 2 groups at baseline e those undergoing angioplasty were older and more likely to have diabetes and CVD e may have biased the surgical group to a lower mortality rate than would have been observed had the study been truly randomized. Because surgical revascularization carries a higher overall risk of morbidity and mortality, and without any proven superiority in clinical endpoints, the remainder of this review will focus upon the decision between optimal medical versus endovascular therapy. The Dutch Renal Artery Stenosis Intervention Cooperative (DRASTIC) study group trial 87 randomized 106 patients with either unilateral or bilateral ARAS (50% stenosis), treatment-resistant hypertension, a serum creatinine 2.3 mg/dl, and kidney size (on the affected side) 8 cmto angioplasty without stent or medical therapy. The target diastolic BP was 95 mmhg. The primary endpoints were BPs at 3 and 12 months. Mean BP was not significantly different between the angioplasty and medical therapy groups at either 3 months (P ¼ 0.25) or 12 months (P ¼ 0.51). The average number of antihypertensive drugs taken by the angioplasty group (1.9) was significantly lower than the number taken by the medical therapy group (2.4) at 12 months (P ¼ 0.002). Renal function was better in the angioplasty group at 3 months, but was similar between the groups at 12 months. Thus some argued that DRASTIC failed to find a significant benefit to angioplasty because 22 of the 50 medical therapy patients crossed over to angioplasty after 3 months. The Essai Multicentrique Medicaments versus Angioplastie (EMMA) trial 88 enrolled 49 patients with hypertension and a creatinine clearance 50 ml/min plus angiographic evidence of unilateral ARAS (stenosis 75% or else 60% in the setting of a confirmatory functional test). Patients were randomized to either medical therapy or to angioplasty. The primary endpoint was ambulatory BP at 6 months of follow-up; secondary endpoints included the number of antihypertensive medications taken and the rate of complications. The reduction in BP in the angioplasty group relative to the medical therapy group was 4/ 5 mmhg (P ¼ 0.46 and 0.12, respectively), reflecting higher BP in the angioplasty group at baseline. Patients in the angioplasty group were on significantly fewer medications at 6 months (P ¼ 0.001). The EMMA trial excluded individuals whom many would consider high risk and potentially in greatest need for revascularization. Furthermore, few patients received a stent, which is associated with better technical success and patency. In the Newcastle Renal Artery Stenosis Collaborative (NRASC) trial 89 patients with unilateral or bilateral ARAS (50% stenosis by DSA) and treatment-resistant hypertension were randomized to medical therapy or angioplasty (without stent). The primary endpoints of the study were the changes in mean BP and serum creatinine from baseline to 6 months. In patients with bilateral stenosis, the difference in the change in BP at 6 months with angioplasty versus medical therapy was 17/ 2 mmhg (P ¼ NS), and was 26/ 10 mmhg (P ¼ 0.02) at the final follow-up. There were no significant differences in changes in BP between the 2 treatment groups with unilateral disease at either 6 months or final follow-up. There were no significant differences in renal function or in major events (heart failure, MI, stroke, dialysis, death) between the treatment groups. Angioplasty resulted in significant complications. 90 The presence of patients without hemodynamically significant stenosis could have reduced the statistical power to detect a benefit from angioplasty. In this study use of angiotensin-converting enzyme (ACE) inhibitors was disallowed, which arguably could have impaired the effectiveness of medical therapy. Furthermore, a goal BP was not stated by the study, and the mean number of antihypertensive drugs used in the medical therapy group was <3, suggesting the BP was not aggressively controlled in the medical therapy group. The Stent Placement Atherosclerosis Renal Artery (STAR) trial 91 compared optimal medical therapy to endovascular intervention plus optimal medical therapy over 2 years in 140 patients. Patients had an estimated creatinine clearance of <80 ml/min (mean 46 ml/min), a stable BP treatment regimen, and 50% stenosis in one or both main renal arteries. Patients allocated to medical therapy could undergo angioplasty if they developed malignant hypertension, pulmonary edema, or had a mean BP >160/ 95 mmhg despite maximum doses of all 6 prespecified classes of antihypertensive medications. The primary endpoint was a 20% reduction in creatinine clearance on 2
274 clinical queries: nephrology 1 (2012) 268e278 consecutive measurements, as compared to baseline. In the intention-to-treat analysis, angioplasty and stent plus optimal medical therapy was no better than optimal medical therapy alone in preventing the primary endpoint (relative risk [RR] ¼ 0.73; 95% confidence interval [CI], 0.33e1.61). The STAR trial has been criticized for enrolling a population with mild disease given the large percentage with mild or moderate stenosis. Furthermore, some argue that patients with CKD but unilateral (as opposed to bilateral) stenosis would not be expected to benefit from revascularization. On the other hand, analyzing the study as they were treated, rather than intention-to-treat, failed to detect a benefit, and the presence of bilateral disease did not predict a benefit from revascularization. The Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trial 92 is, to date, the largest randomized controlled trial comparing therapies for ARAS. The trial had many strengths, including a large sample size (806 patients), a 5-year follow-up, a near uniform (95%) employment of stents, and collection of information on numerous endpoints including change in renal function, BP, and CV events. Patients were eligible for inclusion if they had either uncontrolled or refractory hypertension or else unexplained renal impairment, in combination with significant (not defined by the study authors) ARAS. Critics of ASTRAL have pointed to the exclusion of patients who would definitely have a worthwhile clinical benefit from revascularization as a reason to disregard the results of the study. This raises the important issue of whether clinical benefit from revascularization can, in fact, be accurately predicted. Results from randomized, controlled trials, particularly from STAR and ASTRAL, favor a conservative approach (that is, medication only) for most patients with atherosclerotic raps. NRASC study suggested that patients with bilateral ARAS may constitute a population likely to derive benefit from revascularization. Revascularization however leads to serious complications without significant improvement in long-term cardiovascular mortality. 93 But revascularization has been found to be of some value in patients with critical atherosclerotic RAS and AKI or flash pulmonary edema; to patients with malignant, accelerated or treatment-resistant hypertension; in patients with RAS and acute deterioration of renal function on renineangiotensin inhibitors; or to patients with unexplained renal dysfunction, including patients who start renal replacement therapy. Patients with atherosclerotic RAS and a stable condition should be treated first with medication. The immediate risks and the potential long-term benefits of revascularization should be weighed up for each patient and the patient s preference should also be considered. 93 To address many such issues the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial is underway and is expected to release its findings soon. In this trial, 1080 patients with atherosclerotic RAS will be randomized to receive optimal medication plus stenting or optimal medication alone. 94 Selection criteria are more stringent in terms of definition of atherosclerotic RAS (>60% at catheter angiography or >80% on CT angiography or magnetic resonance angiography approved by a core laboratory) and either drug resistant hypertension (defined as a systolic blood pressure >155 mmhg in patients who are treated with two or more antihypertensive drugs) or a glomerular filtration rate <60 ml/min. A statin and an angiotensin receptor antagonist are the optimum medication in both groups. The primary endpoint is survival free from composite cardiovascular and renal events. Patients will be monitored for 3e5 years. 6.2. FMD The management of hypertension related to fibromuscular dysplasia involves revascularization and/or medication. Current recommendations are based on the available evidence on atherosclerotic renovascular hypertension. 81 However, angioplasty has a better blood pressure outcome and is thus more strongly indicated in fibromuscular dysplasia than in atherosclerotic RAS. 95 The standard procedure for revascularization involves balloon angioplasty, and, if necessary, stent placement. For patients with a macroaneurysm (an aneurysm larger than 2 cm in diameter) or with complex lesions that affect segmental arteries, surgical reconstruction is indicated. 3 Antihypertensive medication is indicated for patients with long-standing hypertension or persistent hypertension after revascularization. 7. Approach 7.1. Who are likely to benefit? The big question even after analysis of so many studies is that who are the lucky ones. Radermacher et al 96 suggested that the success of these procedures is dependent on the extent of downstream renal parenchymal injury rather than vascular stenosis. When the RI was >0.80 (an excellent indicator of nephrosclerosis or glomerulosclerosis), little benefit was seen with interventional radiology or surgery. In this study, 35 patients with an RI of at least 0.80 and 96 patients with an RI of <0.80 underwent revascularization. In the patients with an RI >0.80, the mean arterial pressure did not decrease by 10 mmhg or more (97% patients) and renal function declined (decrease in CrCl of at least 10%) in 28 patients (80%). Among patients with an RI <0.80, the mean arterial pressure decreased (>10%) in 90 patients and renal function worsened in only three patients. In addition to the predictive effect of RI, data indicate that patients with recent loss of GFR are more apt to benefit from revascularization as well. Muray et al 97 found that renal function improved in 58% of patients who underwent PTA. He concluded that the slope of the reciprocal serum creatinine plot before PTA was significantly associated with favorable changes in progression rate after PTA. Revascularization should be considered in RAS with rapid worsening of renal function or resistant HTN (four or more antihypertensive agents especially in the setting of CHF or recurrent flash pulmonary edema). When the kidney size is <8.0 cm long or the RI is >0.80, there is little chance of BP improvement or recovery of GFR.
clinical queries: nephrology 1 (2012) 268e278 275 8. Summary CLINICAL SUSPICION OF RAS gfr<50 gfr >50 imaging(mra or arteriogram) scan or doppler usgace positive b/l high grade ras not responding to drugs recurrent flash pulmonary edema htn not responding to drugs rapidly worsening renal failure solitary functioning kidney YES NO RENAL INTERVENTION PTRA OR SURGERY CONTINUE MEDICAL THERAPY CONSIDER INTERVENTION IF REASSES EVERY 3-6 MONTHS Consider surgery (ACC/AHA guidelines 2005) - FMD, especially when it extends into segmental arteries (class I, LOE B) - For ARAS when it involves multiple small renal arteries or - Early branching primary renal artery (class I, LOE B); and - For patients with RAS undergoing pararenal aortic reconstruction for aortic aneurysms or - Aortoiliac occlusive disease (class I, LOE C) Predictors of renal salvagibility - Kidney size >9 cm - Resistive index <0.80 - Recent rise in Sr. Creatinine - Decrease in GFR with ACE inhibitor or ARB therapy - Absence of glomerular or interstitial fibrosis on kidney biopsy Conflicts of interest All authors have none to declare. references 1. Textor SC. Ischemic nephropathy: where are we now? JAm Soc Nephrol. 2004;15:1974e1982. 2. Textor SC, Wilcox CS. Renal artery stenosis: a common, treatable cause of renal failure? Annu Rev Med. 2001;52:421e442. 3. Epstein FH. : Oxygen and renal metabolism. Kidney Int. 1997;51:381e385. 4. Sawicki PT, Kaiser S, Heinemann L, Frenzel H, Berger M. Prevalence of renal artery stenosis in diabetes mellitus e an autopsy study. J Intern Med. 1991;229:489e492. 5. Hansen KJ, Edwards MS, Craven TE, et al. Prevalence of renovascular disease in the elderly: a population-based study. J Vasc Surg. 2002;36:443e451. 6. Kalra PA, Guo H, Kausz AT, et al. Atherosclerotic renovascular disease in United States patients aged 67 years or older: risk factors, revascularization, and prognosis. Kidney Int. 2005;68:293e301.
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