Ischemic nephropathy: where are we now?

Identification and reversing the loss of kidney function beyond occlusive disease of the renal arteries poses a major clinical challenge. Recent studies indicate that atherosclerotic renal artery stenosis develops as a function of age and is commonly associated with other microvascular disease, including nephrosclerosis and diabetic nephropathy. The risks of renal artery stenosis are related both to declining kidney function and to accelerated cardiovascular disease, with increased morbidity and mortality. Newer drugs, including agents that block the renin-angiotensin system, have improved the level of BP control for renovascular hypertension. Progressive renovascular disease during medical therapy can produce refractory hypertension, congestive heart failure, and renal failure with tubulointerstitial fibrosis. Recent studies indicate a complex interplay of oxidative stress, endothelial dysfunction, and activation of fibrogenic cytokines as a result of experimental atherosclerosis and renal hypoperfusion. Advances in imaging and interventional devices offer major new opportunities to prevent progressive loss of kidney function. Recent series indicate that although 25 to 30% of patients with impaired renal function can recover glomerular filtration after revascularization, many have no apparent change in kidney function and 19 to 25% experience a significant loss of kidney function, in some cases as a result of atheroemboli. To select patients who are most likely to benefit from vascular intervention, clinicians should understand the pathophysiology of developing ischemic nephropathy and the potential hazards of revascularization in the setting of diffuse atherosclerotic disease. Further research should be directed toward identification of critical disease, regulation of fibrogenesis, and the interaction with other atherosclerotic processes.     

Evidence-based medicine in renal artery stenting

Atherosclerotic renovascular disease is an increasingly recognized cause of severe hypertension and declining kidney function. Patients with atherosclerotic renovascular disease have been demonstrated to have an increased risk of adverse cardiovascular events. Over the course of the last two decades renal artery revascularization for treatment of atherosclerotic renal artery stenosis (RAS) has gained great increase via percutaneous techniques. However the efficacy of contemporary revascularization therapies in the treatment of renal artery stenosis is unproven and controversial. The indication for renal artery stenting is widely questioned due to a not yet proven benefit of renal revascularization compared to best medical therapy. Many authors question the efficacy of percutaneous renal revascularization on clinical outcome parameters, such as preservation of renal function and blood pressure control. None of the so far published randomized controlled trials could prove a beneficial outcome of RAS revascularization compared with medical management. Currently accepted indications for revascularization are significant RAS with progressive or acute deterioration of renal function and/or severe uncontrollable hypertension, renal function decline with the use of agents blocking the renin-angiotensin system and recurrent flash pulmonary edema. The key point for success is the correct selection of the patient. This article summarizes the background and the limitations of the so far published and still ongoing controlled trials.     

Atherosclerotic renovascular disease in United States patients aged 67 years or older: risk factors, revascularization, and prognosis

BACKGROUND: Although atherosclerotic renovascular disease is increasingly recognized in chronic kidney disease, few national level studies have examined its clinical epidemiology. METHODS: Claims data from a 5% random sample of the United States Medicare population were used to select patients without atherosclerotic renovascular disease in the 2 years preceding December 31, 1999 (N= 1,085,250), followed until December 31, 2001. RESULTS: The incidence of atherosclerotic renovascular disease was 3.7 per 1000 patient-years. Major antecedent associations [P < 0.05, with adjusted hazards ratios (HR) > 1.5] included chronic kidney disease (adjusted HR 2.54), hypertension (2.42), peripheral vascular disease (2.00), and atherosclerotic heart disease (1.70). Adverse event rates after incident atherosclerotic renovascular disease greatly exceeded those in the general population (P < 0.0001): atherosclerotic heart disease, 303.9 per 1000 patient-years (vs. 73.5 in the general population); peripheral vascular disease, 258.6 (vs. 52.2); congestive heart failure, 194.5 (vs. 56.3); cerebrovascular accident or transient ischemic attack, 175.5 (vs. 52.9); death, 166.3 (vs. 63.3); and renal replacement therapy, 28.8 (vs. 1.3). Among atherosclerotic renovascular disease patients, 16.2% underwent a renal revascularization procedure, percutaneously in 96%. Revascularization was not associated with renal replacement therapy, congestive heart failure, or death but was associated with atherosclerotic heart disease (adjusted HR 1.42) (P= 0.004) and peripheral vascular disease (adjusted HR 1.38) (P= 0.002). CONCLUSION: Atherosclerotic renovascular disease is strongly associated with cardiovascular disease, both past and future. Absolute cardiovascular risk exceeds that of renal replacement therapy. Renal revascularization is used selectively and shows inconsistent associations with cardiovascular outcomes, renal replacement therapy, and death.     

Pathogenesis and management of renovascular hypertension and ischemic nephropathy

Renovascular disease is an important cause of secondary hypertension and renal impairment. Atherosclerotic renal artery stenosis (ARAS) is the most important cause of renal artery stenosis (RAS), and has been linked to increased cardiovascular risk. The pathogenesis of renovascular hypertension is complex, but is mainly due to the over-activation of Renin-Angiotensin-Aldosterone system. A major consequence of untreated RAS is ischemic nephropathy, which is due to the sustained reduction in renal perfusion leading to derangement of microvascular function, and eventual development of interstitial fibrosis. Diagnosis of these conditions can be complex, sometimes needing invasive testing. Aggressive medical management is key to preventing progression of disease, as the role of revascularization in the management of ARAS is still not well defined.     

Angioplasty of the renal artery: antihypertensive and renal effects

Percutaneous transluminal angioplasty of the renal artery (PTRA) has been increasingly used over the past 20 years for treating renovascular hypertension (RVH). From the experience gathered so far it is justified to state that this technique is the first choice for patients with fibromuscular renal artery stenosis (RAS) because their cure rate is 50% and 42% improve. In contrast in patients with atherosclerotic RAS the cure rate after PTRA is 8-10% although 40-50% still improve. Since PTRA is associated with a 23% rate of major/minor complications and 30% restenosis (23% requiring stent implantation), it is obvious that in patients with atherosclerotic RAS the decision to attempt this procedure must be taken after careful selection of those who may actually benefit from the dilation. PTRA can be used more extensively for salvaging the function of the ischemic kidney than for treating hypertension because of the progressive nature of the atherosclerotic RAS and the lack of effective agents against such progression. After PTRA 35% of patients have some improvement in renal function and another 35% are stabilized. Yet most studies addressing the renal effects of PTRA suffer the limitation of having used serum creatinine levels as an indicator of glomerular filtration rate (GFR). More recent studies which used radioisotopic techniques to evaluate the changes of GFR induced by PTRA in the stenotic kidney indicate that after a successful procedure the increase is, on average, 8-10 ml/min. Interestingly it appears that this improvement is slower in kidneys of patients with atherosclerotic RAS than in those with fibromuscular RAS.     

The management of atherosclerotic renovascular disease

Atherosclerotic renovascular disease (ARVD) seems to be a common clinical condition. ARVD is clinically presented as: 'silent' renal artery stenosis, renovascular hypertension, ischemic nephropathy leading to deterioration of renal function and recurrent 'flash' pulmonary edema. Management of ARVD involves both revascularization and medical treatment. However, the impact of revascularization on kidney function and blood pressure control is a matter of great controversy in view of the results of recent randomized clinical trials. At present, concerted medical management (includes lifestyle modifications, such as smoking cessation) remains the main treatment option for patients with ARVD. However, there is a need to accurately identify individuals who may benefit from renal revascularization.     

Atherosclerotic renovascular disease: diagnosis and treatment

The technical expertise and tools required to treat renovascular obstruction have become commonplace, and many series of patients revascularized with surgery, balloon angioplasty or endovascular stenting have been reported. Nevertheless, although hypertension and renal failure are easy to diagnose, their cause often remains elusive. Evidence is developing that patients with hypertension and atherosclerotic renal artery stenosis may often have hypertension and renovascular disease but not hypertension because of renovascular disease. As a result, diagnosis and therapy are increasingly directed towards the preservation of renal function, and the future of renal revascularization will depend on how well potential therapies address this goal.     

Epidemiology and clinical presentation

Renovascular disease appears to be increasing in prevalence, particularly in older subjects with atherosclerotic disease elsewhere. Its clinical manifestations and presentation are changing because of rapid advances in medical therapy and other comorbid events. Although fibromuscular dysplasia and other diseases affecting the renal artery can produce the syndrome of renovascular hypertension, atherosclerotic renal artery stenosis is the most common clinical entity. It can produce a spectrum of manifestations, ranging from asymptomatic ("incidental"), identified during angiographic evaluation of other conditions, to progressive hypertension to accelerated cardiovascular disease with pulmonary edema and advanced renal failure. With the widespread application of drugs which block the renin-angiotensin system, including angiotensin-converting enzyme inhibitors and angiotensin antagonists, many cases of renovascular hypertension remain unsuspected and never produce adverse effects. Clinicians need to be alert to the potential for disease progression, with the potential for total renal artery occlusion and/or loss of viable renal tissue. Selection of patients for renal revascularization depends on individual balance of risks and benefits regarding the likely outcomes regarding both improvements in blood pressure control and preservation of renal function.     

Is duplex scanning the best screening test for renal artery stenosis?

Screening for renal artery stenosis is indicated in patients with suspected renovascular hypertension or ischemic nephropathy to identify those who could benefit from renal artery interventions. The critical requirements for a clinically useful screening test include safety, low cost, and a high sensitivity or low false-negative rate. Arteriography remains the "gold standard" for the anatomic diagnosis of renal artery disease, but it is unsuitable for screening because of its high cost and invasive nature. Although renal duplex scanning technically is difficult, experienced laboratories have been able to achieve sensitivities and specificities in the range of 93% to 98% for identification of stenoses in the main renal arteries. Renal duplex scanning also provides a method for assessing the renal parenchyma and predicting the clinical outcome of renal revascularization. The principal limitation of renal duplex scanning is failure to identify accessory renal arteries. The finding of one or more widely patent main renal arteries makes ischemic nephropathy unlikely, because this condition results from "total" renal ischemia. However, renovascular hypertension can be present with normal main renal arteries when there are isolated stenoses involving accessory renal arteries, so further testing may be indicated in selected hypertensive patients with normal main renal arteries by duplex scanning. Currently, duplex scanning in a qualified vascular laboratory arguably is the best screening test for renal artery stenosis. Other methods for assessing the renal arteries, particularly spiral computed tomography and magnetic resonance angiography, are evolving rapidly and also may play a role in screening of selected patients.     

Renovascular hypertension

Renovascular hypertension is the most common cause of secondary hypertension. Interest in identifying patients with renal artery stenosis has been stimulated recently by advances in three areas. First, is the realization that not only can renal artery stenosis cause renovascular hypertension, but it can also lead to progressive renal failure (ischemic nephropathy) caused by progression of disease, usually atherosclerotic in nature. Second, advances in percutaneous transluminal renal angioplasty and, especially, the recent use of renal stents has led to a less invasive management of these patients as compared with traditional renal revascularization. Finally, the development of newer less invasive diagnostic techniques, both for the identification of patients with renal artery stenosis and to follow patients with known renal artery stenosis, has simplified the diagnostic aspect of the disease.     

Surgery of the renal arteries

Hypertension is a pervasive disease affecting between 10% and 15% of the population. Hypertension is manifested silently by an accelerated rate of atherosclerosis leading to increased incidence of cardiovascular, cerebrovascular, and peripheral vascular morbidities and deaths. Through activation of the renin-angiotensin axis, renovascular disease (RVD) accounts for approximately 5% of this hypertensive population. Recently, the relationship between renovascular occlusive disease and progressive renal insufficiency has been delineated and termed ischemic nephropathy. Patients with ischemic nephropathy present with hypertension in conjunction with elevated serum creatinine. It has been estimated that 15% of patients initiating dialysis each year have renovascular disease as the origin of their renal dysfunction. Renal dysfunction is due to a global reduction in renal perfusion, most often as a result of bilateral renal artery occlusive disease, although a mild form of renal insufficiency can be brought on by unilateral occlusive disease due to the effects of the renin-angiotensin system on the contralateral kidney. Historically, treatment of RVD has been centered on interrupting the renin-angiotensin axis and curing the resultant hypertension and its associated morbid disease. Currently, repair efficacy has been realized with concurrent retrieval of excretory renal function and cure of renovascular hypertension.      

Vascular reconstruction in urology

Vascular reconstructive surgery in urology includes techniques of revascularization of the renal artery for renovascular hypertension or ischemic nephropathy in situ or extracorporeal renal artery reconstruction. The indications for aortorenal bypass, extra-anatomic bypass, or simultaneous aortic substitution and renal revascularization are based on the cause, location, and extent of the vascular lesion. Techniques of bench surgery mainly depend on location of the renal artery disease and availability of autologous graft material.     

Atherosclerotic process, renovascular disease and outcomes from bench to bedside

PURPOSE OF REVIEW: Atherosclerotic renal artery stenosis has become an important cause of secondary hypertension and renal dysfunction in the aging population. Its presence increases cardiovascular morbidity and mortality independent of other atherosclerotic risk factors. Therefore, novel renoprotective strategies are needed to decrease the impact of this disease. RECENT FINDINGS: Although medical therapy can be effective in patients with atherosclerotic renal artery stenosis and mild renal dysfunction, revascularization is desirable for patients with target-organ injury. Technical developments (such as drug-eluting or low-profile stents and distal protection devices) have increased the safety and effectiveness of renal revascularization, but in a significant proportion of patients renal function is not fully restored. Recent experimental evidence suggests that atherosclerotic renal artery stenosis is associated with the activation of intrarenal fibrogenic and inflammatory pathways, oxidative stress, and microvascular remodeling, and blocking these mechanisms can improve renal hemodynamics and function. SUMMARY: Despite significant advances in revascularization techniques, it remains unclear why the kidney affected by atherosclerotic renal artery stenosis often does not improve or even progressively deteriorates. In addition to the restoration of blood flow, targeted interventions to attenuate injurious intrarenal mechanisms should probably become part of a comprehensive management plan to preserve the ischemic kidney.     

Ischemic nephropathy: diagnosis and treatment

Recent epidemiologic studies have shown that ischemic nephropathy secondary to stenosis or obstruction of the main renal arteries in the cause of renal insufficiency in a growing number of subjects. The clinicians dealing with renovascular disease need non-invasive diagnostic tools and effective therapeutic measures to successfully face the problem. Duplex ultrasound scanning is a non-invasive, non expensive diagnostic tool and when an experienced, dedicated technologist is available, it should be suggested as the first-step test. Magnetic resonance angiography and spiral CT angiography play an ancillary role in detecting patients with renovascular disease. Captopril-enhanced (CE) scintigraphy when positive indicates the activation of intrarenal renin-angiotensin system and may be useful in detecting patients with renal artery stenosis. Moreover, CE scintigraphy can play an important role in the choice between the revascularization and a wait-and-see approach. As a matter of fact, the presence of an activated intrarenal renin-angiotensin system furnishes theoretical as well practical reasons in favour of the revascularization. In the recent years percutaneous transluminal renal angioplasty has become the cornerstone of therapeutic strategy. The introduction of the metallic stent has dramatically improved its efficacy in ostial stenoses and has reduced the indication for surgical revascularization.     

Familial clustering of chronic kidney disease

The incidence and prevalence rates of most forms of chronic kidney disease (CKD) had steadily been increasing for the past 30 years, although these rates now appear to have reached a plateau. It is clear that an individual's likelihood of developing progressive CKD results from complex interactions between multiple genetic and environmental factors. Familial clustering of CKD and end-stage renal disease (ESRD) is observed among all the common etiologies of nephropathy. This article reviews the epidemiology of the familial clustering of kidney disease, as well as potential environmental and genetic contributors. The related impact of familial clustering of cardiovascular disease (CVD) and the impact of CVD on the current epidemic of ESRD is also discussed. It is imperative that nephrologists and primary care physicians recognize that individuals who have relatives with advanced nephropathy are themselves at high risk for subsequent kidney disease, proteinuria, and atherosclerotic cardiovascular complications. Until kidney failure genes are identified, it is reasonable to use "family history" (FH) as a surrogate marker for risk of future nephropathy. The detection of kidney disease genes holds great promise for detecting novel pathways that initiate renal fibrosis and lead to progressive loss of renal function. These pathways are likely to offer new therapies that may slow or halt development of chronic kidney failure.     

Ischemic nephropathy

Ischemic nephropathy is an independent pathway towards end-stage renal disease. Its prevalence is estimated to be significant and increasing among populations with vascular disease, hypertension, and chronic renal failure. Angiography remains the gold standard for evaluation of ischemic nephropathy; however, selection by clinical criteria and noninvasive screening with ultrasound are recommended for most patients. Surgical revascularization of ischemic kidneys can halt or reverse deterioration of renal function and is preferable to medical treatment. Direct comparison of angioplasty and stent placement with surgery is needed.     

Medical management of renovascular hypertension

Summary The preferred treatment for renovascular hypertension is revascularization of the ischemic kidney, which helps to preserve renal function as well as lower blood pressure. Medical management plays an important role, however, both as initial therapy for patients who are undergoing revascularization and as maintenance therapy when this cannot be undertaken or has been unsuccessful. The relative merits of the different types of treatment depend on a variety of factors such as the age of the patient, the etiology of the renal artery stenosis, and the presence or absence of concomitant disease.     

Evaluating patients with renal failure for renal artery stenosis with gadolinium-enhanced magnetic resonance angiography

The incidence and prevalence of end-stage renal disease (ESRD) continues to increase, especially in the elderly population. The role of renovascular disease in contributing to ESRD is still not well defined. The objective of this study was to determine the utility of gadolinium (Gd)-enhanced magnetic resonance angiography (MRA) in evaluating elderly patients with renal insufficiency for renal artery stenosis (RAS). A 7-month prospective study conducted in a tertiary referral center evaluated 40 consecutive patients with progressive renal insufficiency (18 men and 22 women; mean age, 70 +/- 5.6 [standard deviation] years) and high clinical suspicion for renovascular disease with Gd-enhanced MRA. Digital subtraction angiography (DSA) was obtained in only those patients with significant RAS detected by MRA. Twelve patients had significant RAS. Six of these patients had percutaneous transluminal renal angioplasty (PTRA), five patients had renal artery bypass surgery, and one patient had a stent placed after PTRA. Seventy-eight renal arteries were satisfactorily evaluated by MRA. Twenty-two renal arteries were evaluated by both MRA and DSA. Of the 12 significant stenoses detected by the MRA, 11 were confirmed by DSA and 1 was confirmed at the time of surgical revascularization. It is concluded that Gd-enhanced MRA is a useful test for the evaluation of RAS in patients with compromised renal function.     

Long-term outcome after surgical kidney revascularization for fibromuscular dysplasia and atherosclerotic renal artery stenosis

PURPOSE: At a time of minimally invasive surgery in urology, the role of surgical kidney revascularization in the management of renal artery disease has changed during the last decade. Our experience with surgical kidney revascularization, and the long-term clinical outcomes of fibromuscular dysplasia (FMD) and atherosclerotic renal artery stenosis are reviewed. MATERIALS AND METHODS: The study group comprised 140 patients with renovascular hypertension, 72 with FMD and 68 with atherosclerotic renal artery disease, who underwent surgical revascularization between 1982 and 1999. The indications for surgical revascularization were the treatment of hypertension and the preservation of renal function in 17 patients with renal artery occlusion, 55 with ostial stenosis, 52 with branch stenosis, 6 with bilateral artery stenosis, 7 with solitary kidney renal artery stenosis and 3 with solitary kidney renal artery occlusion. RESULTS: Postoperative blood pressure and renal function were monitored for 1 to 17 years (mean 11.3). Long-term blood pressure control was observed in 93% of patients with FMD and in 71% of those with atherosclerosis. Improvement or stabilization of renal function was observed in 92% of patients with FMD and in 68% of those with atherosclerosis. The preoperative estimated glomerular filtration rate compared to postoperative was significantly increased in both groups. CONCLUSIONS: Surgical kidney revascularization is effective in secondary hypertension with a high long-term efficacy in the normalization of blood pressure and in the preservation of renal function, especially in patients with a solitary or 1 functional kidney.     

Atherosclerotic renal artery stenosis: epidemiology,cardiovascular outcomes,and clinical prediction rules

Atherosclerotic renal artery stenosis is the most common primary disease of the renal arteries, and it is associated with two major clinical syndromes, ischemic renal disease and hypertension. The prevalence of this disease in the population is undefined because there is no simple and reliable test that can be applied on a large scale. Renal artery involvement in patients with coronary heart disease and/or heart failure is frequent, and it may influence cardiovascular outcomes and survival in these patients. Suspecting renal arterial stenosis in patients with recurrent episodes of pulmonary edema is justified by observations showing that about one third of elderly patients with heart failure display atherosclerotic renal disease. Whether interventions aimed at restoring arterial patency may reduce the high mortality in patients with heart failure is still unclear because, to date, no prospective study has been carried out in these patients. Increased awareness of the need for cost containment has renewed the interest in clinical cues for suspecting renovascular hypertension. In this regard, the DRASTIC study constitutes an important attempt at validating clinical prediction rules. In this study, a clinical rule was derived that predicted renal artery stenosis as efficiently as renal scintigraphy (sensitivity: clinical rule, 65% versus scintigraphy, 72%; specificity: 87% versus 92%). When tested in a systematic and quantitative manner, clinical findings can perform as accurately as more complex tests in the detection of renal artery stenosis.