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.     

The natural history of atherosclerotic and fibrous renal artery disease

Summary Individuals with atherosclerotic or fibrous renal artery disease may develop renovascular hypertension and/or renal dysfunction. Traditionally, the motivation for identifying patients with renal artery stenosis was the treatment of renovascular hypertension. However, recent interest has centered on the investigation of patients suspected of having renal artery stenosis that might account for progressive azotemia. While specific forms of fibrous and/or atherosclerotic renal artery disease can lead to a compromise in renal function, differences may exist in the age of presentation, predominat sex, angiographic appearance and overal natural history. Recognition of these differences is helpful in deciding on the most likely lesion type, appropriate workup and treatment. Since renal artery stenosis can lead to radiologic and functional alterations, clinical markers of progression, such as renal size and serum creatinine measurements, are helpful in identifying patients with advancing disease. The regulators of fibrous disease progression are less clear than those responsible for atherosclerotic progression in the renal artery. Uncontrolled systemic hypertension, intrarenal hypertension, hyperlipidemia, cigarette smoking, and obesity all may potentially contribute to progressive atherosclerosis. Individuals identified with progressive azotemia due to renal artery stenosis may benefit from improved perfusion flow by renal revascularization or balloon angioplasty provided no significant parenchymal disease is present.     

Atherosclerotic renal artery disease diagnosis update

Atherosclerotic renal artery disease represents a cause of which little is known but not a cause to be neglected for hypertension and renal insufficiency. Even though its occurrence remains badly defined, atherosclerotic renal artery disease is constantly on the rise due to the aging population, the never prevailing hypertension and diabetes mellitus. This review aims to give a clinical profile of patients presenting with atherosclerotic renal artery disease and to discuss, in the light of study results, which diagnostic evaluation should be used considering the sequence and the benefit and risk of each in order to initiate a personalized treatment. Patients affected by atherosclerotic renal artery disease are likely to have more complications and more extensive target-organ damage than patients without renal artery stenosis. The evolution of the atherosclerotic renal artery disease is in general slow and progressive. Nevertheless, certain clinical cases manifest themselves with the onset of acute renal failure bought upon by the administration of blockers of the rennin-angiotensin-aldosterone system, or by some other causes responsible for a sudden drop in renal plasma flow (e.g., thrombosis of the renal artery). The relationship between atherosclerotic renal artery disease and atherosclerosis is complex, and mediators implicated in the pathophysiology of renovascular disease may also contribute to the progression of cardiovascular damage. An early assumption of the atherosclerotic renal artery stenosis is warranted to determine the adapted treatment (i.e., medical treatment, revascularisation...) just as the assumption and the correction of the more general cardiovascular risk factors.     

Renovascular hypertension: current concepts

Hypertension produced by renal artery occlusive disease is an important secondary form of hypertension. Clinicians commonly encounter forms of renal arterial disease of varying severity, many of which are of little hemodynamic significance when first detected. Experimental studies emphasize that transient activation of the renin-angiotensin-aldosterone system is necessary for initiation of renovascular hypertension. At some point, angiotensin II activates additional mechanisms responsible for sustained increased blood pressure including sodium retention, endothelial dysfunction, and vasoconstriction related to production of reactive oxygen species. Widespread application of agents that block the renin-angiotensin system, including angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, render many patients with unilateral renal arterial disease manageable primarily by medical means for many years. In the setting of high a priori likelihood of renovascular disease, recognizing the potential for disease progression during medical therapy and individually evaluating the risks and benefits of renal revascularization are important tasks. Recent prospective studies show limited, but real, benefit regarding blood pressure control for patients with atherosclerotic disease. Whether earlier renal revascularization offers benefits regarding improved morbidity and mortality from cardiovascular end point reduction is an important question to be addressed in multicenter, prospective, randomized trials. Our paradigm stresses the fact that patients with renovascular hypertension require intensive blood pressure control and cardiovascular risk factor intervention, both before and after revascularization. Hence, management of such patients requires close attention and periodic review regarding restenosis and progression of vascular disease.     

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.     

Paradigm Shifts in Atherosclerotic Renovascular Disease: Where Are We Now?

Results of recent clinical trials and experimental studies indicate that whereas atherosclerotic renovascular disease can accelerate both systemic hypertension and tissue injury in the poststenotic kidney, restoring vessel patency alone is insufficient to recover kidney function for most subjects. Kidney injury in atherosclerotic renovascular disease reflects complex interactions among vascular rarefication, oxidative stress injury, and recruitment of inflammatory cellular elements that ultimately produce fibrosis. Classic paradigms for simply restoring blood flow are shifting to implementation of therapy targeting mitochondria and cell-based functions to allow regeneration of vascular, glomerular, and tubular structures sufficient to recover, or at least stabilize, renal function. These developments offer exciting possibilities of repair and regeneration of kidney tissue that may limit progressive CKD in atherosclerotic renovascular disease and may apply to other conditions in which inflammatory injury is a major common pathway.     

Fibromuscular dysplasia of the renal artery: Management and outcome

SUMMARY: Renovascular hypertension may be caused by atherosclerotic disease or less commonly by fibromuscular dysplasia (FMD) of the renal arteries. Fibromuscular dysplasia is the commonest cause of renal artery stenosis in the younger age group and affects women predominantly. A review of our clinical database identified all patients with renovascular hypertension. All relevant clinical, biochemical and radiological findings on those with FMD were noted. the outcome of percutaneous transluminal renal angioplasty (PTRA) or reconstructive surgery was evaluated. Eight out of 62 (13%) patients with hypertension secondary to renovascular disease had FMD (all female; bilateral in four; mean age at diagnosis 37.6 years; age range 12–70 years). the mean duration of hypertension before the diagnosis of FMD was 3.3 years (range 3 months-10 years). A renal artery bruit was detected in five, hypertensive retinopathy in three and one had mild renal insufficiency. Twelve PTRAs were attempted on 10 stenotic lesions in six women. This cured the hypertension in three, while the other three have required less antihypertensive therapy. Percutaneous transluminal renal angioplasty was complicated by a trivial renal artery dissection in one, and a small upper pole infarction in another. One patient required a repeat PTRA. the other two women presented before the availability of PTRA and had successful reconstructive surgery. Fibromuscular dysplasia was the cause of hypertension in eight out of 62 (13%) patients with renovascular hypertension. Percutaneous transluminal renal angioplasty has shown encouraging results with a low complication rate. If technically feasible, PTRA should be attempted on all patients with FMD of the renal artery.     

Fibromuscular dysplasia of the renal artery: Management and outcome

Renovascular hypertension may be caused by atherosclerotic disease or less commonly by fibromuscular dysplasia (FMD) of the renal arteries. Fibromuscular dysplasia is the commonest cause of renal artery stenosis in the younger age group and affects women predominantly. A review of our clinical database identified all patients with renovascular hypertension. All relevant clinical, biochemical and radiological findings on those with FMD were noted. The outcome of percutaneous transluminal renal angioplasty (PTRA) or reconstructive surgery was evaluated. Eight out of 62 (13%) patients with hypertension secondary to renovascular disease had FMD (all female; bilateral in four; mean age at diagnosis 37.6 years; age range 12–70 years). The mean duration of hypertension before the diagnosis of FMD was 3.3 years (range 3 months–10 years). A renal artery bruit was detected in five, hypertensive retinopathy in three and one had mild renal insufficiency. Twelve PTRAs were attempted on 10 stenotic lesions in six women. This cured the hypertension in three, while the other three have required less antihypertensive therapy. Percutaneous transluminal renal angioplasty was complicated by a trivial renal artery dissection in one, and a small upper pole infarction in another. One patient required a repeat PTRA. The other two women presented before the availability of PTRA and had successful reconstructive surgery. Fibromuscular dysplasia was the cause of hypertension in eight out of 62 (13%) patients with renovascular hypertension. Percutaneous transluminal renal angioplasty has shown encouraging results with a low complication rate. If technically feasible, PTRA should be attempted on all patients with FMD of the renal artery.     

Renal artery stenosis and chronic ischemic nephropathy: epidemiology and diagnosis

Atherosclerotic renal artery stenosis (RAS) is the most common primary disease of the renal arteries and results in renovascular hypertension and ischemic nephropathy. Ischemic nephropathy from atherosclerotic RAS is increasingly recognized as a cause of chronic kidney disease (CKD) and in severe cases can lead to end-stage renal disease. The exact prevalence of atherosclerotic RAS is unknown because the disease is often asymptomatic and few are screened unless they have significant traditional cardiac risk factors or symptoms. A high prevalence of atherosclerotic RAS is seen in patients with advanced age, congestive heart failure, and extrarenal atherosclerosis. The primary reason for diagnosing ischemic nephropathy from renovascular disease is that the loss of kidney function is potentially reversible through treatment of the occlusion with surgical revascularization or percutaneous transluminal renal angioplasty. However, the benefits of revascularization have to be considered in the context of other comorbid disease and remain controversial. There are several tests available for the screening and diagnosis of atherosclerotic RAS; however, the diagnostic test of choice should be based on patient factors and institutional expertise because the best test is the one performed most often at the individual medical facility.     

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.     

Advances in the medical management of renovascular hypertension

Although clinical reports have suggested that antihypertensive therapy can control blood pressure in patients with renovascular hypertension, adequate randomized studies comparing medical versus surgical management are lacking. It is well recognized that progressive deterioration in renal function can occur despite good blood pressure control. Recent experience suggests that higher-risk patients with atherosclerotic renovascular hypertension can benefit from an aggressive surgical approach, whereas newer medical therapies capable of specific inhibition of the renin-angiotensin system suggest greater potential benefits to other patients. Properly performed randomized trials comparing medical versus surgical therapy of renovascular hypertension are needed.     

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.     

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.     

Atherosclerotic renovascular disease causing renal impairment--a case for treatment

Renovascular disease is a potentially curable cause of renal failure. In a prospective survey over an eighteen month period atherosclerotic renal artery disease was the cause of renal failure in 14% of patients over the age of fifty years accepted for renal replacement therapy at this hospital. Ten patients were found to be suffering from atherosclerotic renovascular disease causing renal failure but in only one was treatment able to reverse renal failure. The major problem with this group of patients is the widespread nature of their disease affecting many other organs. Significant morbidity is associated with their investigation. Although potentially curable, atherosclerotic renovascular disease is a frequent cause of renal failure in patients over the age of fifty years but is also difficult to treat.     

The natural history of atherosclerotic and fibrous renal artery disease

From 1969 to 1979, 169 patients with two or more renal angiograms for renovascular disease (85 atherosclerotic, 75 fibrous, 9 atherosclerotic and fibrous) were reviewed in an attempt to characterize progression of disease and to determine clinical markers of progression. Progression of renal artery atherosclerosis was observed in 37 patients (44 per cent); progression to complete occlusion was observed in 14 patients (16 per cent). In the 66 patients with medial fibroplasia, progression was observed in 22 patients (33 per cent). Serial serum creatinine measurements in conjunction with measurements of kidney size may be used as markers of progressive atherosclerotic renovascular disease. These clinical markers did not represent progressive disease for individuals with medial fibroplasia.     

Natural history of atherosclerotic and fibrous renal artery disease: clinical implications

Atherosclerotic renal artery disease and the fibrous renal artery diseases are described with respect to their radiographic and clinical characteristics. In a retrospective review, serial renal arteriograms of 85 patients with atherosclerotic renal artery disease and 66 patients with the medial fibroplasia type of fibrous renal artery disease were analyzed to characterize their natural history. Atherosclerotic renovascular disease progressed in 37 patients (44%) with total arterial occlusion occurring in 14 patients (16%). Medial fibroplasia of the renal artery progressed in 22 patients (33%) with no patient progressing to complete occlusion. Reduction in kidney size and increase in serum creatinine were good clinical markers for progressive atherosclerotic renal artery disease, but failed to discriminate between progressive and nonprogressive medial fibroplasia. The adequacy of BP control did not correlate with progressive occlusive disease in patients with either renal artery atherosclerosis or medial fibroplasia. The clinical implications of these observations are discussed with a view toward renal revascularization or transluminal angioplasty for preservation of renal function.     

Hyponatremic Hypertensive Syndrome Presenting as Malignant Hypertension in a Four-Year-Old Girl

The prevalence of renal and renovascular hypertension in the general population is not known precisely; in children it probably accounts for the majority of cases of secondary hypertension. The symptoms of renovascular hypertension vary, and sometimes it can be asymptomatic. In rare cases, clinical manifestations can include electrolyte disorders including hyponatremia. An uncommon etiology of true hyponatremia of renal origin is the hyponatremic hypertensive syndrome. It has been reported in adults with malignant hypertension, but was considered as an unusual form of presentation of renovascular disease in children. In this report, a four-year-old girl presented with hypertensive encephalopathy related to the hyponatremic hypertensive syndrome caused by right renal artery stenosis. Treatment with percutaneous angioplasty was successful, with total resolution of symptoms. This case emphasizes the importance of routine blood pressure evaluation as a major contribution to the prevention of morbidity and mortality associated with severe forms of hypertension in children.     

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 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.     

Use of the hepatic arterial circulation for renal revascularisation.

Renal artery stenosis is increasingly being diagnosed as a cause of hypertension and renal impairment. Surgical intervention can restore function and improve hypertension in selected cases. Over a 42 month period, 12 patients with atherosclerotic renovascular disease underwent surgical revascularisation using the hepatic arterial circulation. All had disease of both renal arteries and 11 had some degree of renal impairment, with five requiring dialysis before operation. There were two deaths within 30 days of operation, eight patients had improved renal function after operation and three of the patients previously on dialysis became dialysis free. The hepatorenal method of renal revascularisation is described and its advantages discussed.