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Invited Commentary |
1 Department of Radiology, Long Island Jewish Medical Center, New Hyde Park, New York
RVH comprises a small but curable subset of hypertension. Although there is general agreement on the benefits of a cure, the most cost-effective means of diagnosing RVH continues to be the subject of much debate. This controversy may be due to a number of factors, including uncertainty in relating anatomic stenosis of the renal artery to its hemodynamic effects and rapid change in the diagnostic imaging technologies. Herein we offer our thoughts on this controversial topic.
Pathophysiology of RVH
RVH is caused by a hemodynamically significant stenosis of one or both renal arteries related to atherosclerotic disease or fibromuscular dysplasia. The renal secretion of renin and subsequent formation of angiotensin II are responsible for the development of RVH (1–4). Renin is secreted in response to stimuli from baroreceptors in the afferent glomerular arteriole and chemoreceptors of the macula densa located in the first part of the distal tubule. Decreased stretching of the afferent arteriolar wall resulting from decreased blood flow is sensed by the baroreceptors, which signal the juxtaglomerular cells to secrete renin. Significant stenosis also decreases GFR and consequently tubular flow, so that larger amounts of sodium and chloride are reabsorbed. In response to a reduction of these solutes in the distal tubule, the macula densa stimulates the release of renin.
The released renin converts circulating angiotensinogen, an 
2-globulin, to angiotensin I. The latter is converted to angiotensin II by ACE, which is present in the vascular endothelium. Angiotensin II is formed both systemically and within the kidneys and helps counter the GFR-lowering effect of RAS. Angiotensin II does so primarily by preferential constriction of the efferent glomerular arteriole, which increases glomerular capillary hydrostatic pressure and GFR. The systemic effects of angiotensin II, including increased vascular tone and stimulation of aldosterone secretion, lead to RVH.
Clinical Considerations and Diagnostic Evaluation
The potential benefits of identification and treatment of RVH are twofold. First, the untoward effects of systemic hypertension, including those on the contralateral normal kidney, are minimized. Second, progressive renal arterial occlusion and renal dysfunction, particularly in severe stenosis, are avoided. An important first step in diagnosis is clinical assessment of the risk of RVH, since imaging is cost-effective only for patients with moderate to high clinical suspicion of RVH. Typically, such patients have moderate or severe hypertension associated with progressive renal insufficiency, occlusive atherosclerotic vascular disease elsewhere, advanced hypertensive retinopathy, or onset of renal failure following initiation of ACE inhibitor therapy, which is a characteristic of bilateral stenosis or stenosis involving a solitary kidney (4).
A variety of tests have been used to screen for RVH. The simplest of these is the plasma renin assay, which is often combined with measurement of the renin response to captopril administration. This test has been highly variable in accuracy, presumably related to its lack of specificity and susceptibility to a number of factors including salt intake, antihypertension medications, and renal function (5,6). Measurement of renal vein renin levels with or without the renal vein renin response to captopril, although somewhat more specific, has had only limited success (5,7). This test is also invasive and unsuitable as a screening study.
Optimally, a screening test for RVH should not only demonstrate significant RAS but also allow identification of the stenotic side so that corrective measures are facilitated. Imaging tests, including Doppler US, MR angiography, and ACE inhibitor scintigraphy, have the potential to do both. However, review of the literature suggests a lack of consensus regarding the most cost-effective imaging algorithm for RVH. This lack is understandable because the imaging technologies are relatively new and their success or failure may not be evident until several years after their introduction. Furthermore, rapid change in the technology itself can render an algorithm obsolete in a short period. In addition, algorithms are affected by varying pretest probabilities, which affect test accuracy.
Doppler US
Doppler US has been investigated for the evaluation of RVH over the last decade or so, with mixed results (8–13). As pointed out by Soulez and co-workers in the preceding article
, two types of Doppler examinations have been evaluated: direct assessment of flow velocity in the main renal artery and evaluation of Doppler waveform morphology of the intrarenal arteries (distal to the stenosis). The first approach requires insonation of all segments of the renal artery, a requirement not consistently met because of such factors as bowel gas and obesity, making up to about 40% of examinations technically inadequate. Furthermore, accuracy has been reasonable in only a handful of studies and poor in many others. The second method involves assessment of waveform changes in early systole in the intrarenal arteries. Unfortunately, initial enthusiasm with the tardus-parvus waveform changes, which are believed to result from decreased pressure distal to the stenosis, has been tempered by later reports questioning the specificity of this finding for RVH, presumably because a number of factors can influence the pressure flow dynamics in the intrarenal vessels. These factors may include such characteristics of the intrarenal vessels as their diameter, tortuosity, compliance, and proximity to the main renal artery, as well as the patient's cardiovascular status. Analysis of captopril-induced changes in the intrarenal vessels, as proposed by Soulez and colleagues, is an interesting concept and certainly merits additional study.
In summary, although Doppler US has been successful in select hands, little consensus exists regarding the optimal methods and interpretation, and the technique has failed to gain wide acceptance for diagnosis of RVH.
MR Angiography
MR angiography with gadolinium enhancement, a newer tool for evaluation of RVH, has several advantages over US (14–19). First, the test is less operator dependent, with far more consistent results, although the processing time is longer. Second, the reported sensitivity and specificity for angiographically demonstrated stenosis are higher, although some difficulties remain in evaluating the distal renal artery and accessory vessels, which are often involved in fibromuscular dysplasia. Third, rapid technologic advances are likely to further enhance the accuracy of MR angiography. In addition, MR angiography demonstrates the lesions in an "angiographic" format, which is easier for referring physicians to understand, a factor that may affect referrals for revascularization procedures.
However, MR angiography is primarily an anatomic tool, and although severe anatomic stenosis of the renal artery generally is associated with RVH, the hemodynamic significance of a less severe lesion is not always predictable. A large postmortem study found significant (at least 50%) RAS in 17% of normotensive individuals (20). Also, stenoses have been incidentally noted in patients undergoing abdominal aortography (21). These reports indicate that the degree of stenosis does not correlate well with the hemodynamic effects and that diagnosis of RVH with MR angiography alone may needlessly subject some patients to the cost and morbidity of interventional treatment. Indirect proof that a given stenosis is the cause of hypertension may be obtained by demonstrating a clinical response (eg, amelioration of hypertension or decreased need for medications after technically successful revascularization). Although such studies of clinical outcome are difficult because of changing antihypertension regimens and effects of nephrosclerosis of the normal kidney from long-standing RVH, they are clearly needed to validate the accuracy of MR angiography.
ACE Inhibitor Scintigraphy
ACE inhibitor scintigraphy is a functional tool for portraying the hemodynamic consequences of RAS (3,22,23). In RAS, a fall in GFR is limited by preferential constriction of the efferent glomerular arteriole by angiotensin II, which increases hydrostatic pressure in the glomerular capillaries. Consequently, baseline scintigraphy usually demonstrates normal or only mildly decreased renal function. Administration of an ACE inhibitor decreases angiotensin II formation, relaxes efferent arteriolar tone, and decreases glomerular capillary hydrostatic pressure. The resulting fall in GFR characteristically decreases the uptake of Tc-99m DTPA, which is excreted by means of glomerular filtration. In addition, the decrease in GFR also decreases tubular flow of urine, so that cortical retention of Tc-99m DTPA and of tubular radiopharmaceuticals, including Tc-99m MAG3 and I-131 OIH, is prolonged. Instead of the traditional 2-day protocol (baseline study on day 1, ACE inhibitor study on day 2), the ACE inhibitor study may be performed first. If the kidneys are normal, RVH is highly unlikely and a baseline examination need not be performed. Scintigraphic changes can be demonstrated in both unilateral and bilateral disease. Renal insufficiency, unless severe, does not affect the outcome (24). Scintigraphy has also been effective in kidneys with multiple renal arteries (25).
Earlier results with ACE inhibitor scintigraphy were mixed, largely due to nonuniformity of technique. With a clearer understanding of physiologic and pharmacologic factors that influence scintigraphic findings (eg, false-positives), standardization of methods and interpretation, and use of Tc-99m MAG3 instead of I-131 OIH (26), results are generally better. In patients judged clinically to be at risk of RVH, ACE inhibitor scintigraphy has been found to be accurate when compared with the clinical outcome after revascularization, with an average sensitivity of about 90% when Tc-99m DTPA or Tc-99m MAG3 is used (6,24,27–31). Although this result is encouraging, additional prospective studies, particularly performed in conjunction with MR angiography, are needed. These studies would go a long way toward clarifying and simplifying the diagnostic work-up of RVH.
Performing scintigraphy prior to a revascularization procedure serves another purpose. Preservation of renal function is one of the most important goals in management of RVH, and scintigraphy provides a baseline for future comparison and helps determine whether a kidney is worth salvaging with angioplasty or other interventional techniques.
Summary and Algorithms
Of the three noninvasive imaging tests, ACE inhibitor scintigraphy appears to have had the most extensive validation in RVH. In addition, it is a functional tool that evaluates a clearly defined physiologic parameter (ie, hemodynamic consequences of RAS). Therefore, as suggested by Soulez and colleagues, ACE inhibitor scintigraphy is an appropriate initial imaging procedure for suspected RVH. In patients with positive results and patients with equivocal or nondiagnostic results and a high clinical suspicion of RVH, scintigraphy is followed by conventional angiography or revascularization.
For an alternative screening test, MR angiography, which is widely available in the United States, is probably more suitable than Doppler US, since the latter is limited by inherent technical difficulties, operator dependence, lack of reproducibility, and limited acceptance by radiologists. However, pending sufficient validation in RVH, only patients with severe stenosis at MR angiography may proceed to conventional angiography or revascularization, preferably after a baseline scintigraphic examination without ACE inhibition for functional assessment. For other patients with positive results at MR angiography, ACE inhibitor scintigraphy is desirable prior to interventional procedures to confirm the hemodynamic significance of the stenosis.
References
Department of Radiology, Notre-Dame Hospital, Montreal, Quebec, Canada
We appreciate the editorial commentary of Drs Sarkar and Siegel regarding our article. Despite the several advantages of MR angiography, we agree with them that this investigation essentially represents noninvasive diagnostic angiography and therefore has the limitations of digital subtraction angiography in predicting potential cure of RVH. However, we must emphasize the potential of MR imaging for performing functional imaging. For example, with perfusion imaging, it is now possible to obtain time-intensity curves with sufficient spatial resolution to selectively measure cortical and medullary perfusion (1). Blood pool agents will improve functional imaging of the renal vasculature without interference from parenchymal disease (1). Measurement of renal blood flow volume is also possible with cine phase-contrast imaging (2). Thus, the value of MR imaging in evaluation of RVH is likely to increase in the near future by combination of functional and anatomic information.
As for Doppler US, it is true that the technique has failed to gain wide acceptance for diagnosis of RVH due to mixed results. However, by combining the direct and indirect (extrarenal and intrarenal) approaches, recent studies have shown improved results, with sensitivities of 85%–89% for detection of RAS (3–5). In addition, it has been shown that measurement of intrarenal resistive indexes with Doppler US provides important prognostic information for patients undergoing revascularization (6). Owing to the expected technologic progression in color and power Doppler imaging, the improvement of spatial resolution, and the use of US contrast agents, we diverge from the opinion of Drs Sarkar and Siegel and predict an increasing role for Doppler US in detection of RAS.
We are in accordance with Drs Sarkar and Siegel when they state that ACE inhibitor scintigraphy has had the most extensive validation in RVH. However, results in terms of sensitivity are still extremely controversial, and many authors have discouraged use of this technique in screening for RVH (7,8). We acknowledge that scintigraphy is a functional test and that it can be valuable in prediction of successful renal artery revascularization (9). Yet, one-third of cases of proved RVH are missed with ACE inhibitor scintigraphy (10). Consequently, the recommendation to choose ACE inhibitor scintigraphy over Doppler US as the initial imaging procedure for suspected RVH should be questioned. When the appropriate medical expertise is available, we believe that Doppler US is superior to scintigraphy in terms of accuracy and cost-effectiveness. The combination of MR angiography with a functional test such as Doppler US or scintigraphy is worthwhile for confirming the presence of RAS as well as documenting its severity.
With the technical evolution and the refinement of new contrast agents, we are convinced that both Doppler US and MR imaging will play an increasingly important role in management of RVH in the near future.
References
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