Natural History

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Natural History

  1. 1. Renovascular Disease Michael Shomaker, MD Resident Grand Rounds January 7, 2003 Overview Renal artery stenosis is becoming increasingly common because of atherosclerosis in an aging population. Our understanding of the clinical presentation, epidemiological characteristics, and natural history of atherosclerotic renovascular disease has recently increased, thus focusing renewed interest on this condition. The goals of this presentation are fourfold: • Review the pathophysiology, natural history, and clinical features of the disease and how this effects therapeutic decisions. • Provide a brief overview of the different diagnostic tests and their performance profiles • Critically review the literature as it pertains to the different treatment options • Provide house-staff with an evidence-based, practical algorithm for the evaluation and treatment of ARAS at Wake Forest. Epidemiology Atherosclerotic renovascular disease affects older patients (>55 y/o) with risk factors for generalized atherosclerosis. The prevalence increases with age, particularly in patients with diabetes, aortoiliac occlusive disease, coronary artery disease, or long standing hypertension. Hansen et al recently (Sept.2002) published the first large, population-based study estimating the prevalence of ARAS. A large cohort of patients >65 years old with cardiovascular risk factors underwent renal artery duplex ultrasound serially and found the point prevalence of ARAS to be 6.8%. Age, hypertension, and low HDL were independently associated with the presence of ARAS. Pathophysiology Atherosclerosis accounts for 90% of cases of renal artery stenosis and usually involves the ostium and proximal third of the main renal artery and the peri-renal aorta. The relations among ARAS, renovascular hypertension (RVH), and ischemic renal disease (IRD) are complex. ARAS may occur alone (isolated anatomical renal artery stenosis) or in association with renovascular hypertension, ischemic nephropathy, or both. Most of what is known about the mechanism of hypertension in ARAS is based on animal models. Intraglomerular pressure remains constant during wide swings in systemic blood pressure secondary to renal autoregulation. Renal autoregulation fails to maintain GFR when renal perfusion pressure dips below 70-85mmHg, generally correlating with a greater than 70% narrowing of the renal artery lumen. It has been hypothesized that this critical reduction in perfusion pressure is required in order to set off the cascade of events that lead to RVH and/or IRD. A decrease in the renal perfusion pressure activates the rennin-angiotensin system, which leads to the release of renin and the production of angiotensin II; this has direct effects on sodium excretion, sympathetic nerve activity, intra-renal prostaglandin concentrations, and nitric oxide production and causes renovascular hypertension. When hypertension is sustained, plasma renin activity decreases, likely mediated by sodium retention via aldosterone. This partially explains the limitations of renin measurements for identifying patients with RVH (more on this in the diagnosis section). The pathophysiology of IRD is complex. There are several adaptive changes and irreversible parenchymal sequela associated with chronic ischemia. When critical ARAS compromises function unilaterally, there is a compensatory increase in function and sometimes size of the contra-lateral, normally functioning kidney. Though the overall renal function may be normal in this setting, the unilateral vascular compromise can ultimately result in hyperfiltration and glomerulosclerosis in the normally functioning kidney. Atrophy, decrease in GFR, and collateral flow are adaptive changes the affected kidney enlists as protective mechanisms. Renal atrophy may be restored by reperfusion; however, more commonly, renal atrophy is associated with irreversible patchy areas of cortical scarring, sclerotic glomeruli and interstitial fibrosis. In addition to these changes, a number of external factors, such as age, hyperlipidemia, diabetes,
  2. 2. hypertension, microatheroembolic disease, and so on, modify the degree of recovery from transient ischemic insults and ultimate potential for renal salvage by reperfusion. Natural History It is clear, ARAS is a progressive disorder. However, predicting the rate of progression for any individual patient is challenging. Crowley et al. in 1997 followed >1,100 patients who underwent abdominal aortography for other reasons. He found a point prevalence of 6.3%. Over a 6 year follow up period, 28% of those enrolled in the cohort had disease progression, defined as at least 50% decrease in renal artery diameter. In addition, disease progression was associated with a decline in renal function. Patients in whom stenosis progressed from normal to >75% showed a significant rise in serum creatinine compared with those with less significant progression. The variable most predictive of anatomic disease progression is the degree of initial stenosis: • Patients with bilateral ARAS with an occluded renal artery are 3 times as likely to progress to ESRD within 2 years than those with bilateral disease without occlusion. • The rate of loss of functional renal tissue (implied by ultrasound evidence of renal atrophy) is 3 times higher in patients with bilateral disease than for those with unilateral disease (43% vs. 13%). Also, the incidence of ESRD secondary to IRD is increasing. The elderly are the fastest growing group starting dialysis and Mailoux et al projects IRD as the cause of ESRD in 10-18% in this population. Patients with IRD who do reach dialysis do extremely poorly. They have the highest mortality rate among all etiologies of ESRD: • Median survival is 25 months • 2, 5 and 10 year survival rates are 56%, 18% and 5% respectively Clinical Features ARAS is a commonly overlooked cause of renal insufficiency. These patients often have a paucity of specific clinical findings, and it is therefore particularly important to identify high-risk groups in which suspicion of this condition should be heightened. The following clinical features should raise the suspicion of renovascular disease: • Young hypertensive patients with no family history (FMD) or new onset HTN in patients > 50y/o
  3. 3. • Abrupt onset of HTN • Severe or resistant HTN • Deteriorating BP control in long-standing, compliant hypertensive patients • Deterioration in renal function with ACEI • Evidence of secondary hyperaldosteronism (low plasma potassium, high rennin) • Recurrent “flash” pulmonary edema and hypertensive urgency (more common with bilateral RAS) • Elderly patients with PVD • Abdominal bruit (OR = 11.5) • Unexplained renal azotemia • >1.5 cm difference in kidney size on US If the diagnosis of critical ARAS is made, it is important to search for evidence of underlying irreversible parenchymal renal disease, as this subgroup will not likely benefit from therapy: • Moderate to severe protenuria – patients with irreversible, chronic ischemic changes consistent with advanced IRD tend to develop significant protenuria likely related to the increased degree of glomerulosclerosis. • Severe renal atrophy distal to the obstruction – although atrophy has been shown to also be an adaptive response, severe renal atrophy (<8 cm) is almost always irreversible. • Unilateral RAS with renal insufficiency – true IRD is only seen in patients with bilateral RAS or effective bilateral RAS. Thus, these patients likely have significant irreversible, hypertensive renal disease in the contralateral kidney or another underlying primary renal disease. Diagnosis There are two groups of diagnostic studies used to evaluate RAS, anatomic studies and functional studies. Methods of measuring the response of the rennin-angiotensin system include renal vein renin assays, renin-sodium profiling, and captopril renography to assess differential renal perfusion. These tests are not recommended in most elderly patients with ARAS and hypertension, since hypertension in these patients is not always renin-dependent and the results do not reliably predict the course of RVH after revascularization. Because of the limited usefulness of physiological studies in elderly patients with ARAS, imaging techniques are preferable as a means to identify stenosis in such patients. However, the one case in which ACEI renography is useful is screening for renovascular hypertension in patients with normal renal function. Renal angiography remains the gold standard for the identification of ARAS. However, given its invasive nature and propensity to cause contrast nephropathy in patients with moderate to severe renal insufficiency, non-invasive tests such as CT angiography and MRA are becoming the diagnostic tests of choice at most facilities. Functional Studies Diagnostic Study Pros Cons Renal Vein Renin Measurements • Useful in confirming the functional significance of a lesion demonstrated by anatomical studies – particularly if bilateral disease is present • Poor sensitivity • Nonlateralization not predictive of the failure of HTN to improve with therapy (likely related to the fact that renin activity decreases with sustained HTN) Nuclear Imaging with Tc99-MAG or Tc99-DTPA to estimate fractional flow to each kidney • Allows calculation of single kidney GFR and/or RBF • Difficult to differentiate reversible from intrinsic disease Conventional Renography • Useful as both a screening test and • Lower sens/spec compared to ACEI renography
  4. 4. functional study ACEI Renography • Test of choice for the diagnosis of RVH in many centers • Reduced sens/spec in patients with renal insufficiency (Pcr>2.0) • Operator dependent Anatomic Studies Diagnostic Study Pros Cons Renal Arteriography • Gold standard • Can visualize accessory vessels and intrarenal branches well • Direct contrast load to kidneys • Sometimes difficult to distinguish between critical and non-critical lesions Doppler ultrasonography • Noninvasive • Inexpensive; widely available • Extremely operator dependent • Does not evaluate accessory vessels well • Bowel gas patterns/Obesity interfere CT angiography • Excellent visualization of the vessel in 3D • High-contrast requirement • Less reliable for visualizing distal segments and small accessory arteries MRA • Noninvasive • Provides excellent images • Non-nephrotoxic, thus useful in patients with renal insufficiency • Expensive • Prior stents produce artifacts • Blood flow turbulence can exaggerate measured stenosis The diagnostic work up of RVH or IHD should proceed as follows: Evaluation of RVH: • If the patient has normal renal function, the first test should be ACEI renography or Doppler US, based on the local experience and equipment. • If this test is positive, an anatomic study should be performed to confirm the diagnosis. Evaluation of IRD: • Doppler US is the test of choice if local expertise adequate followed by a more definitive study to delineate the anatomy. • If not: – CT angiogram or conventional angiography should be performed if renal failure is mild – MRA if renal failure is moderate/severe or due to diabetic nephropathy Therapy Multiple non-experimental reports have described improvements and, in some cases, cures of renovascular hypertension as well as improvements in renal excretory function following surgical or endovascular interventions aimed at restoring normal renal perfusion. These reports, coupled with the growing application and acceptance of endovascular interventions, have resulted in an increased interest in this disorder. To date, there have been no large randomized, controlled clinical trials comparing medical therapy to surgery or newer stenting procedures. As a result, no improvements in survival, freedom from dialysis, or protection from adverse cardiovascular disease events have been demonstrated relative to an equivalent non-interventional comparison group.
  5. 5. The effect of balloon angioplasty on hypertension in atherosclerotic renal artery stenosis. van Jaarsveld, et al. NEJM, Apr. 2000. Objective – The long-term effects of renal artery angioplasty on RVH are not well understood. This study was conducted to define the efficacy of angioplasty on RVH Methods – 106 pts. with ARAS were randomly assigned to undergo PTRA or receive antihypertensive therapy. All patients were followed monthly for a total of 1 year. Target DBP was <95mmHg. The patients in the drug therapy group underwent “rescue” angioplasty after three months, if their DBP was greater than target despite 3 or more meds or if their creatinine had risen by greater than 0.2mg/dl. Primary outcome measure was BP at 3 and 12 months. Secondary outcomes were number and defined daily doses of anti-HTN meds, serum creatinine, creatinine clearance and results of ACEI renography. Intention to treat analysis was performed. Results – There was no difference in mean blood pressure at 3 and 12 months; however, 22 of the 50 patients assigned to the control group crossed over at 3 months. The dose of anti-HTN drugs used by patients was significantly lower than those used in the control group at 3 months, but this difference was no longer significant at 12 months. HTN was “cured” (goal BP on no anti-HTN meds) in only 7% of the angioplasty group. Median serum creatinine levels and creatinine clearance did not significantly change in either group. In the treatment group, the presence of an abnormal ACEI renogram did not predict BP control after angioplasty. Conclusions – This study provides little insight given the large amount of cross over; however, it appears PTRA is likely not the initial treatment of choice for RVH secondary to ARAS. Stent placement for renal artery stenosis: where do we stand? A meta-analysis. Leertouwer et al. Radiology; Jan 2000. Objective – To present a meta-analysis of all of the major PTRA/PRTAS non-experimental reports. Methods – All studies dealing with PTRA (10 articles; 644 patients) and PTRAS (14 articles; 678 patients) between 1991-1998 were selected. The patient populations in the majority of studies were similar (mild- moderate renal insufficiency, age 60-75 y/o, renal insufficiency as indication for therapy). Criteria for RAS did vary amongst studies (>40% to >70%). Most criteria for renal improvement was Pcr decrease by 20%. Primary outcome measures were similar (change in renal function, change in HTN control, and angiographic patency). Results – # Patients Age Procedure success Restenosis Rate Complications HTN cured HTN improved RF improved RF Stabilized PTRA 644 64 77% 26% 13% 10% 53% 38% 41% PTRAS 678 66 98% 17% 11% 20% 50% 30% 38% • The criteria used in most studies to describe BP improvement was poor. Most studies considered a 10mmHg reduction in SBP or DBP as significant and many patients who were “cured” were still on BP meds. Also, BP meds were not actively followed. • Harm: 7% in the stent group had severe complications (5% of which was ARF). Overall mortality rate was 1%. Conclusions – PTRAS appears to be a better technical therapy than PTRA given the higher initial success rate and lower re-stenosis rate. BP control cannot be ascertained by these studies given the weak criteria for improvement and poor follow up. However, these studies suggest that 65-70% of patients do have stable or improved renal function after PTRA/S. Surgical management of atherosclerotic renovascular disease. Cherr et al. J Vasc Surg. Feb 2002.
  6. 6. Objective – This review describes the clinical outcome of surgical intervention for atherosclerotic renovascular disease. It is the largest review to date of the surgical management of ARAS. Methods – From 1987 to 1999, 626 patients underwent operative renal artery repair at Wake Forest. The patient population had a high burden of vascular disease: 63% of patients had bilateral ARAS; renal artery obstruction was present in 155 patients, and 41% underwent aortic or mesenteric reconstruction in addition to RA revascularization. The vast majority of patients had treatment-resistant hypertension. Preoperative mean Pcr was 2.3 with a mean estimated GFR of 40.5 +/-23.2. Results – RVH was considered cured in 12% and improved in 73%. 43% had an improvement in estimated GFR (defined as >20% increase) and 47% had unchanged renal function. 28 patients were removed from dialysis dependence following surgery. However, on follow up, patients with renal function unchanged by surgery continued to have a progressive decline of renal function unchanged from before the operation. Conclusions – This non-experimental report shows that surgical revascularization seems to slow the progression of IRD in a subgroup of patients. However, the operative risk for the subgroup that does not respond is unacceptable. It appears that both surgery and PTRA/S slow the progression of IRD in a subgroup of patients; however, the morbidity and mortality of these procedures are too high to recommend therapy to all patients. Are there reliable clinical predictors of who will respond to therapy? The following studies attempt to answer this question. Rapid decline in renal function reflects reversibility and predicts the outcome after angioplasty in renal artery stenosis. Muray et al. AJKD, Jan 2002. Objective – To identify factors influencing clinical success after PTRA. Methods – 73 patients with IRD (Crcl <50 ml/min) underwent PTRA for critical ARAS defined as >60%. The rate of renal failure was assessed by the slope of the regression line of serum creatinine versus time. Response was assessed by comparison of the slope before and after PTRA. Mean follow up was 627+/-284 days. Results – 58% of patients had improvement in renal function, including 3 out of 6 who became dialysis independent. Only the slope of 1/Cr was significantly associated with a favorable decline in renal failure progression (p=0.004). Conclusion – Subacute or rapidly progressive renal failure is associated with a favorable response after PTRA, as they are likely to have less parenchymal disease. Use of doppler ultrasonography to predict the outcome of therapy for renal artery stenosis. Radermacher et al. NEJM, Feb 2001. Objective – to evaluate whether a high level of resistance to flow in segmental renal arteries can be used prospectively to select appropriate patients for treatment. Methods – 138 patients who had either bilateral (47 patients) or unilateral (91 patients) ARAS underwent PTRA/S or surgery. Crcl and BP were measured before the intervention and 3, 6 and 12 months and then yearly after the intervention. Patients were grouped by a segmental artery RI of >80 (35 patients) or <80 (96 patients). Mean follow up was 32+/-21 months. Results – For patients with RI <80 and a Crcl < 40ml/min, RI has a 95% sensitivity and 85% specificity for predicting an improvement in renal function. RI >80, Crcl <40 ml/min, and male sex are independently associated with a higher risk of a decline in renal function after revascularization. The mean rate of ESRD at 2 years: 50% of RI>80 and 5% for a RI <80. Conclusions – A renal resistive-index value of at least 80 reliably identifies patients with renal artery stenosis in whom angioplasty or surgery will not improve renal function, blood pressure or kidney survival. Conclusions Atherosclerotic renal artery stenosis is a common manifestation of generalized atherosclerosis and is frequently associated with hypertension and renal failure. However, the association of renal-artery
  7. 7. stenosis with hypertension or renal insufficiency does not establish causation, and although the methods for the diagnosis and treatment of renal-artery stenosis have improved, the use of invasive diagnostic techniques and treatment early in the course of the disease still have no proven benefit. Moreover, there seems to be a shift away from identifying patients with renovascular hypertension, because of the known benefits of medical therapy and the lack of sustained cure after percutaneous or surgical revascularization, and a shift toward identifying patients with renal-artery stenosis who are at risk for ischemic renal disease. Once identified using non-invasive screening measures, an initial conservative approach with medical therapy with yearly screening for disease progression is appropriate. Progressive renal insufficiency and uncontrolled hypertension are the main indications to consider invasive therapy, as long as there is no evidence of irreversible parenchymal renal disease. As for the optimal therapy (surgery vs. PTRAS), this decision should be based on individual operative risk factors, vascular anatomy, local surgical/radiological expertise and patient preference. Because most patients with IRD are high-risk surgical candidates on the basis of age, degree of renal insufficiency, and diffuse vascular disease, most patients will likely be treated percutaneously. The ASTRAL (angioplasty and stent for renal artery lesions) is a British randomized controlled trial that will compare surgery, PTRA, and PTRAS against drug treatment in 1000 patients with ARAS. Our future approach to the management of ARAS will depend the result of these and other relevant controlled trials. Practical Algorithm for the Management of ARAS
  8. 8. Clinical findings of ARAS Diagnostic Evaluation Unilateral ARAS Bilateral ARAS Medical Management Medical Management Evidence of Irreversible disease? Invasive Treatment PTRAS Medical Management Surgery Evidence of Irreversible Disease RI >80 Slow prog. RI Proteinuria Severe atrophy Progression of RF or uncontrolled HTN YesNo Uncontrolled HTN Low preoperative Risk High vasc. disease burden Poor surgical candidate Predictors of operative mortality Age >70 Unstable CHF Advanced RI Diabetes Bibliography 1. Cherr GS; Hansen KJ. Surgical management of atherosclerotic renovascular disease. J Vasc Surg. 2002; 35; 236-245. 2. Conlon PJ, O’Riordan E. New insights into the epidemiologic and clinical manifestations of atherosclerotic renovascular disease. AJKD. 2000; 35(4): 573-587. 3. Crowley JJ. Progression of renal artery stenosis in patients undergoing cardiac catheterization. Amer Heart J 1998; 136: 913-918). 4. Greco B; Breyer J. Atherosclerotic Ischemic Renal Disease. AJKD. 1997; 29(2): 167-187. 5. Greco B; Lewis J. “Atheromatous Renovascular Disease”. Comprehensive Clinical Nephrology. Section 13. pp65.1-14. 6. Kaplan NM. “Renovascular Hypertension”. Clinical Hypertension. Chapter. 10. pp381-403.
  9. 9. 7. Leertouwer TC, Gussenhoven, EJ. Stent placement for renal arterial stenosis: where do we stand? A meta-analysis. Radiology 2000; 216: 78-85. 8. Mailloux LU. Renal vascular disease causing end stage renal disease. Incidence, clinical correlates and outcomes: a twenty-year clinical experience. AJKD. 1994; 24(4): 622-629. 9. McLaughlin K. Renal Artery Stenosis. BMJ. 2000; 320: 1124-1127. 10. Muray S. Rapid decline in renal function reflects reversibility and predicts the outcome after angioplasty in renal artery stenosis. AJKD. 2002; 39(1): 60-66. 11. Pedersen EB. New tools in diagnosing renal artery stenosis. Kid Int 2000; 57: 2657-2677. 12. Radermacher J. Use of doppler ultrasonography to predict the outcome of therapy for renal-artery stenosis. N Engl J Med. 2001; 344: 410-417. 13. Safian RD, Textor SC. Renal Artery Stenosis. N Engl J Med. 2001; 344(6): 431-442. 14. Textor SC. Pathophysiology of renal failure in renovascular disease. AJKD. 1994; 24(4): 642-651. 15. Tu, O. “Effect of PTRAS on renal function in patients with ARAS.” Powerpoint presentation. 16. van Jaarsveld BC. The effect of balloon angioplasty on hypertension in atherosclerotic renal-artery stenosis. N Engl J Med. 2000; 342(14): 1007-1014. 17. Vasbinder GBC. Diagnostic tests for renal artery stenosis in patients suspected of having renovascular hypertension. Ann Intern Med 2001; 135: 401-411.
  10. 10. 7. Leertouwer TC, Gussenhoven, EJ. Stent placement for renal arterial stenosis: where do we stand? A meta-analysis. Radiology 2000; 216: 78-85. 8. Mailloux LU. Renal vascular disease causing end stage renal disease. Incidence, clinical correlates and outcomes: a twenty-year clinical experience. AJKD. 1994; 24(4): 622-629. 9. McLaughlin K. Renal Artery Stenosis. BMJ. 2000; 320: 1124-1127. 10. Muray S. Rapid decline in renal function reflects reversibility and predicts the outcome after angioplasty in renal artery stenosis. AJKD. 2002; 39(1): 60-66. 11. Pedersen EB. New tools in diagnosing renal artery stenosis. Kid Int 2000; 57: 2657-2677. 12. Radermacher J. Use of doppler ultrasonography to predict the outcome of therapy for renal-artery stenosis. N Engl J Med. 2001; 344: 410-417. 13. Safian RD, Textor SC. Renal Artery Stenosis. N Engl J Med. 2001; 344(6): 431-442. 14. Textor SC. Pathophysiology of renal failure in renovascular disease. AJKD. 1994; 24(4): 642-651. 15. Tu, O. “Effect of PTRAS on renal function in patients with ARAS.” Powerpoint presentation. 16. van Jaarsveld BC. The effect of balloon angioplasty on hypertension in atherosclerotic renal-artery stenosis. N Engl J Med. 2000; 342(14): 1007-1014. 17. Vasbinder GBC. Diagnostic tests for renal artery stenosis in patients suspected of having renovascular hypertension. Ann Intern Med 2001; 135: 401-411.

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