ASTRAL and Beyond: Who is Appropriate to Consider for Renal Artery Revascularization?

Abstract

ASTRAL and the four randomized, controlled trials preceding have shown that unselected revascularization in atherosclerotic renovascular disease (ARVD) is not an appropriate intervention. Despite this, there are clinical situations where renal artery revascularization is of great benefit to the patient. In this review we discuss the different presentations of ARVD and the effects of revascularization for each.

VASCULAR DISEASE MANAGEMENT 2011;8(2):E12–E20

Key words: atherosclerotic renovascular disease (ARVD); renal artery stenosis; renal revascularization; vascular intervention

Introduction

Atherosclerotic renovascular disease (ARVD) is an endemic condition that presents the clinician with challenging treatment decisions. The ASTRAL trial (Angioplasty and Stenting for Renal Artery Lesions)¹ was a landmark prospective trial comparing standard medical therapy to standard medical therapy with renal revascularization in 806 patients with ARVD. Its main findings were that there was no difference between the two arms in terms of renal function, blood pressure, cardiovascular events or mortality outcomes. Given that over 6% of patients suffered a significant complication during revascularization, the trial results have been important in minimizing patient exposure to potentially harmful procedures. However, there is increased uncertainty among clinicians as to when revascularization is appropriate. In this article we set out to highlight the different ways in which ARVD can present and discuss the arguments for revascularization in each clinical situation.

Clinical Presentations and Arguments to Revascularize

The often silent nature of ARVD makes exact determination on its incidence hard to estimate. A large study of Medicare patients aged > 65 years found an incidence of 0.5% or 3.7 per 1,000 patient years;² this is likely to be an underestimate because disease screening would only have been undertaken in symptomatic or other selected patients, and community Doppler ultrasound screening has shown a 7% prevalence in the elderly U.S. population,³ whereas the United Kingdom Registry data defines ARVD as the primary disease in over 10% of incident dialysis patients.⁴ Given the heterogeneous renal artery anatomy, renal parenchymal damage and extrarenal vascular associations of ARVD, a variety of clinical syndromes are observed, each of which carries its own arguments for and against revascularization. These are: • Hypertension; * Refractory hypertension; * Facilitation of renin-angiotensin-aldosterone system (RAAS) blockade; • Chronic kidney disease; * Rapidly declining renal function; • Acute kidney injury (AKI); * Dialysis-dependent ARVD; • Flash pulmonary edema; • Congestive heart failure; • Severe anatomical ARVD; • Incidental ARVD.

Hypertension. Over 95% of patients with ARVD will have hypertension, and up to 2% of all hypertensives will have renal artery stenosis (RAS), but a causal association is unlikely in the majority of these patients.⁵ Indeed, the role of revascularization for hypertension is a contentious area. RAS reduces perfusion to the kidney, triggering activation of the RAAS and resulting in marked vasoconstriction with salt and water retention and other detrimental effects. In addition to increasing blood pressure, this contributes to ongoing renal function deterioration and other target-organ damage.

Prior to commencement of ASTRAL, there had been three small randomized, controlled trials (RCTs) that compared revascularization to medical therapy and assessed blood pressure outcomes in ARVD.^6–8 The DRASTIC study (Dutch Renal Artery Stenosis Intervention Cooperative) demonstrated a reduction in systolic blood pressure at 12 months in the angioplasty group, though this was only seen when blood pressure was checked with an automated machine, and not replicated when a sphygmomanometer was used.⁷ DRASTIC also reported improved blood pressures in the patient population that crossed over from the medical arm to revascularization because of refractory hypertension at 3 months. These benefits were not seen in the other RCTs, though EMMA⁶ (Essai Multicentrique Medicaments vs. Angioplastie) and DRASTIC both suggested a minor reduction in the need for oral antihypertensive medications following revascularization. Meta-analysis of these trials was limited due to their heterogeneity and did not support renal revascularization to treat hypertension.⁹ The Dutch-led START study (Stent Placement in Patients with Atherosclerotic Renal Artery Stenosis and Impaired Renal Function) recruited 140 patients and was published just prior to ASTRAL. Patients were randomized between percutaneous revascularization and medical therapy, and no differences were observed in terms of blood pressure control.¹⁰ Over a median follow-up period of 34 months in ASTRAL, the homogeneity of blood pressure in each arm was confirmed, with no difference in the systolic or diastolic blood pressures in either limb of the trial (Figure 1). Patients enrolled in ASTRAL did have lower baseline blood pressures (around 150/76 mmHg) than those in the other trials, but were on comparable numbers of antihypertensive agents.

In light of the available data, it would seem that the idea of undertaking renal revascularization for most cases of hypertension has been rebuffed. However, two areas remain open for discussion: refractory hypertension and revascularization to facilitate renin-angiotensin blockade.

Refractory hypertension. Refractory hypertension is defined as uncontrolled blood pressure (> 160/90 mmHg) despite the use of three or more different antihypertensive medications. Treatment can present serious challenges to the clinician, with past decisions escalating as far as nephrectomy to control blood pressure. Thankfully, this approach is now rarely considered, but the use of renal revascularization for resistant hypertension is a poorly understood area with no specific trial data. When the patient groups in STAR¹⁰ and ASTRAL are taken as a whole, neither fits the above definition, making it difficult to draw conclusions. However, some patients did fit the criteria, and post-hoc analysis of these trials in collaboration with results from CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) may further enlighten us in the future. Until then, the best information can be drawn from the DRASTIC⁷ data in which the baseline demographics meet the definition for resistant hypertension. As mentioned above, revascularization did not improve blood pressure control, but did reduce the number of antihypertensive medications required in this study. Until more data are available, many clinicians will feel obliged to attempt revascularization when RAS exists in association with multidrug-resistant hypertension, or when drug-related renal dysfunction limits therapeutic options as discussed below.

One final point of interest on this topic is the potential role of biomarkers. Brain natriuretic peptide (BNP) is one biomarker with promising data. A small single-center, prospective study in patients with ARVD and resistant hypertension found that patients with serum BNP levels of > 80 pg/ml prior to intervention were much more likely to benefit from revascularization.¹¹ In animal models, BNP synthesis and release are stimulated by the release of angiotensin II.¹² BNP antagonizes the RAAS and promotes natriuresis. Therefore, it may be that the elevated BNP levels are a marker of an overactive RAAS, a marker of cardiac strain secondary to chronic atrial overstretch, or a combination of these and other factors. These pilot data are interesting, but more investigations are needed to validate their significance.

RAAS blockade. Effective blockade of the RAAS is one of the most significant advances in recent years, with effective blood pressure control, antiproteinuric effects and benefits to cardiac function all possible results of treatment. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor-blockers (ARBs) are excellent treatments for renovascular-driven hypertension, but there are widely held reservations about their use in the setting of ARVD, especially in patients with significant bilateral disease. It cannot be disputed that ACEi or ARB use can precipitate a fall in glomerular filtration rate (GFR); however, in the setting of unilateral RAS with a normally functioning contralateral kidney, most patients avoid this fate. Furthermore, experience with the use of RAAS blockade in the setting of significant bilateral ARVD, without detriment to renal function, is now growing.¹³

Despite this general tolerance to therapy, there are some patients who cannot tolerate RAAS blockade without a significant reduction in renal function. In view of the high prevalence of CKD and proteinuria in ARVD, these patients will be missing out on the specific renoprotective effects of these medications, as well as the potential benefits of reduced cardiovascular events and mortality and reduced chronic dialysis initiation.¹⁴ Hence, the indication of renal revascularization to permit ACEi or ARB use is an attractive one. The RAVE study (Renal Atherosclerotic Revascularization Evaluation)¹⁵ is a single-center, randomized, prospective pilot study comparing revascularization over standard medical therapy. One of three specified secondary objectives is a comparison of blood pressures and type of antihypertensive agents used in each arm of the trial. Though only a pilot study with a target of 20 patients enrolled, this may provide prospective data regarding antihypertensive tolerance after revascularization. Until the results are available, we are reliant on retrospective data, which show that revascularization can safely permit RAAS blockade in significant bilateral ARVD in those patients who were intolerant prior to the procedure.^13,16

We would therefore advocate consideration of revascularization when patients with RAS have a strong clinical need for, and yet biochemical proof of intolerance to, RAAS blockade. Chronic kidney disease (CKD). Before ASTRAL was published, over 15% of patients with a new diagnosis of ARVD in the U.S. were undergoing revascularization procedures.² Prior to ASTRAL, the previous RCTS had significant shortcomings that limited the quality of evidence provided: small patient groups, short follow-up periods and high cross-over rates from the conservative therapy arm. In the STAR study, only 60% of patients in the interventional arm truly underwent revascularization.¹⁰ ASTRAL enrolled 806 patients with an average age of 70 years and an estimated GFR (eGFR) of 40 ml/min at baseline. The primary endpoint of progressive loss of renal function was common in all of these studies. Neither ASTRAL nor any of the other RCTs has demonstrated a significant difference in renal function between arms of optimal medical therapy (OMT) or OMT and revascularization. The CORAL trial¹⁷ is ongoing, but it will be some time before results are available, thus current advice is built upon the available information. Hence, there is no evidence that renal revascularization is indicated in ARVD with otherwise asymptomatic stable CKD.

Again, however, there are subtleties that merit discussion. For example, increased levels of proteinuria are predictive of poor outcomes in ARVD-related CKD,¹⁸ and this is likely to be a major marker of parenchymal injury. A one-size-fits-all approach to intervention is rarely, if ever, appropriate, and patient selection must be considered. If intervening in stable CKD is not beneficial overall, then the question of intervening in the subgroup of patients with more rapid loss of function must be considered as a separate issue.

Rapidly declining function. ASTRAL prespecified a secondary analysis of a subgroup of patients with rapidly declining renal function (defined as a 20% or 100 umol/l increase in creatinine within the previous year), and there were 96 patients who eventually fulfilled these criteria. At 1 year, patients in the revascularization arm had a reduction in their serum creatinine, but confidence intervals were wide and the result not statistically significant (Figure 2). There will be CORAL patients who fit this clinical category, but it may take a meta-analysis drawn from CORAL, ASTRAL and STAR to provide a reliable answer regarding the benefit of revascularization in this clinical setting. Until then, the decision will remain discretionary, but given the prognostic, financial and emotional costs of dialysis, revascularization may be appropriate for this patient group.

Acute kidney injury (AKI). Despite a lack of firm evidence and the impossibility of undertaking a meaningful trial, there is a consensus that the occurrence of oligo-anuric AKI in patients with significant ARVD is a strong indication for renal revascularization, and this is supported by case reports of patient rescue from dialysis.¹⁹ Most case reports and series describe patients with bilateral ARVD or with a chronic unilateral occlusion and a high-grade contralateral lesion.²⁰ In a chronic setting, as renal blood flow drops below that of the kidney’s ability to regulate glomerular flow, function is reduced, but viability of renal parenchyma is preserved by development of collateral circulation (e.g., from the lumbar and capsular vessels). Should another insult subsequently compromise perfusion further, the system decompensates and AKI follows. This is a different physiological process to acute renal artery occlusion, where acute renal parenchymal ischemia is the predominant process.

The key questions in the setting of AKI are patient selection and investigation. The rate of decline in kidney function has been shown to be a predictor of success following revascularization, while there are conflicting data over the usefulness of renal size and baseline creatinine.²¹ This may be a reflection of the different pathophysiological processes involved (i.e., severity of ischemia vs. chronic parenchymal damage) and its applicability to clinical practice is uncertain.

Options for investigation for underlying severe RAS in the patient with AKI appear very limited as magnetic resonance angiography (MRA) is not a safe tool because of risk of nephrogenic systemic fibrosis, and there are justifiable concerns regarding the repeated use of iodinated contrast in acute renal impairment. In skilled hands, Doppler ultrasound is the best option, providing reliable information about both kidney size and blood flow noninvasively. MAG3 nuclear scans have also been used to detect potentially viable tissue.

Timing of revascularization is the final issue, and naturally the earliest possible intervention seems most logical. The differentiation between acute vascular occlusion (which would require immediate intervention) and an acute insult developing on the background of chronic ischemia and a collateral supply (there are reports of recovery from dialysis up to 42 days after loss of renal perfusion),²² can sometimes be made in light of clinical history (e.g., acute loin pain, prior angiography) but this will not always be the case.

Consensus advocates consideration of renal artery revascularization in the setting of AKI in the presence of known or new bilateral ARVD.

Revascularization to escape dialysis. There are also reports in the literature of chronic hemodialysis patients becoming independent of dialysis following renal revascularization. Although anecdotal, these cases have occurred when intervention was undertaken primarily to try to assist with uncontrolled hypertension, or when preserved renal volume (see later) was an important factor in predicting dialysis discontinuation.²³ These reports are interesting but they almost certainly describe a minority of patients who commence chronic dialysis without prior investigation for RAS.

Flash pulmonary edema (FPE). The complex interplay between the heart and the kidneys is well recognized. ARVD provides a clear clinical environment for this interconnection to occur, as it is commonly associated with increased ventricular stiffness and left ventricular hypertrophy, with 95% of patients with ARVD having abnormalities of cardiac structure or function²⁴ and little physiological reserve to adjust to changes in the circulating volume.

AVRD drives hypertension primarily through RAAS activation. In addition to perturbations in salt and water homeostasis, with reduced natruresis, excess RAAS stimulation increases pulmonary capillary permeability and mediates endothelial dysfunction, with potential consequences of salt and water retention and cardiac dysfunction. In some cases of unilateral RAS, a normally functioning contralateral kidney can suppress its own renin secretion, thus acting as a homeostatic safety valve. When disease is bilateral, or if there is only a single functioning kidney, this escape route is lost and acute pulmonary edema can occur. Almost 95% of patients with ARVD who present with FPE have bilateral disease.²⁵

There are no prospective randomized data to inform our treatment of FPE in the setting of ARVD. Several case reports or series describing successful treatment have been published5 and are summarized in Table 1. In one retrospective series of 207 patients who underwent renal revascularization, 39 patients with recurrent episodes of heart failure requiring hospital admission were identified. All of these latter patients had bilateral disease and, if both kidneys were considered viable, underwent bilateral revascularization. Admissions to the hospital for symptomatic pulmonary edema reduced from 2.4 to 0.3 admissions per year over a 21-month average follow-up period.²⁶

There is clear current consensus to advocate renal revascularization for recurrent pulmonary edema in the setting of significant bilateral ARVD, as the procedure can be life-saving for some.²⁷

Congestive cardiac failure (CCF). Chronic RAS activation and the neurohormonal repercussions have been shown to contribute to left ventricular remodeling and dilatation leading to symptoms of CCF. As up to 30% of patients with CCF have been shown to have some degree of ARVD,²⁸ a mechanistically attractive proposition is to reduce RAAS stimulation and activity by revascularizing this patient population.

Published trials do not provide any evidence to support renal revascularization in patients with more chronic heart failure, although case reports and retrospective series (Table 1) again highlight the potential benefit, but these risk positive reporting bias. Two substudies of ASTRAL using cardiac MRI and echocardiography (due to a report in 2011) have been designed to assess the impact of revascularization on cardiac structure and function, as has an Italian echocardiographic study, RASCAD (Stenting of Renal Artery Stenosis in Coronary Artery Disease).²⁹ These will provide the first firm data, and may be supplemented by CORAL, which has specified hospitalization for CCF as a primary endpoint.

Until then, the most robust RCT data are available from ASTRAL’s secondary endpoint of major cardiac events. One of these was hospitalization for fluid overload and/or heart failure, and this occurred in 12% of the revascularized patients and 15% of those medically treated (p = 0.22).¹

We feel that the issue of renal artery revascularization for patients with chronic heart failure is worthy of RCT investigation in the future, but at present there is little evidence to support intervention except in potentially life-threatening situations (e.g., acute decompensation).

Severe anatomical ARVD. Severe stenosis is a difficult term to define, as outside of animal models the relationship between the degree of RAS and alteration of flow or perfusion to the kidney has been poorly characterized. Lesions that could be considered mild or moderate at 30 giving them clinical significance. However, in patients with coexistent coronary artery disease (CAD), mortality does relate to the grade of RAS, where patients with RAS lesion stenosis > 75% have a significantly higher mortality rate than those with lesion stenosis

So is renal revascularization indicated simply because a patient has a high degree of RAS, irrespective of clinical presentation? The DRASTIC study did not find a difference in the blood pressure outcomes for the revascularization arm when stenosis of > 70% was compared to that of 50–70%.⁷ This finding was further studied in a post-hoc analysis of ASTRAL. Here, cases of bilateral stenosis > 70% or stenosis > 70% in a single functioning kidney were assessed, and no difference in renal function or mortality was seen between the two randomized arms in a total of 163 patients with this anatomy (Figure 3).

Accepting the limitations highlighted in critiques of these studies, which correctly suggest that there may have been an overestimation of RAS severity in some cases, it is still difficult to recommend revascularization based on an angiographic finding alone. The increased mortality with increasing grade of stenosis is interesting but does not prove a causal relationship, as, for example, more severe RAS is known to occur in patients with greater CAD burden.³¹ Hence, ARVD forms part of a systemic process, and this diffuse disease process is more likely to be the cause of increased mortality than the grade of stenosis alone.

In the absence of specific clinical complications, we do not recommend revascularization based on the grade of stenosis alone. The possible caveat to this is preservation of functional renal mass in patients who can be shown to have a “functionally significant” RAS, as discussed below.

Preservation of renal mass in patients with “functionally significant stenosis.” Historically, many renal revascularization procedures were undertaken with the aim of preserving functioning renal mass. The term “hibernating parenchyma” has been applied to describe kidneys that show functional improvement after revascularization, supposedly indicative of renal tissue that has not yet undergone permanent damage.³² In these situations the hypothesis is that the hemodynamic consequence of a given RAS is the cause of renal dysfunction and that irreversible parenchymal injury has yet to occur. As such, the term “functionally significant stenosis” may be a suitable alternative term.

Renal bipolar length, though a widely used measurement, has been shown to be poor at predicting remaining parenchymal volume (PV), but magnetic resonance imaging (MRI) studies have shown that the latter is the best predictor of single kidney glomerular filtration rate (SK-GFR).³³ Recently, the assessment of the ratio of kidney volume to function (PV:SK-GFR) by MRI scanning has demonstrated that patients with a high ratio and significant ARVD are much more likely to have renal functional benefit from revascularization compared to those with low PV:SK-GFR.³⁴

We hypothesize that the above findings are explained by a disproportionately low GFR for a given PV, reflective of a reduced plasma flow caused by a functionally significant stenosis. Further insights are gleaned from the finding that chronically ischemic kidneys have higher renal vein oxygen saturations when compared to non-stenosed contralateral kidneys. This could suggest that oxygen uptake is more reduced than renal blood flow in these situations, but whether this is a cause or effect of renal injury is unknown.³⁵ Blood oxygen level-dependent MRI (BOLD) provides measurements that correlate with tissue deoxyhemoglobin levels. Although this is not a specific marker for renal ischemia in AVRD, it provides reproducible data in both native kidneys and allografts and provides both structural and functional information. Studies have demonstrated that BOLD imaging can distinguish between potentially viable kidneys with ARVD (> 70% stenosis) and non-viable kidneys,³⁶ and there is hope that BOLD imaging may help in selecting patients most likely to benefit from revascularization. Until then, assessments of parenchymal or cortical volume in relation to individual kidney function in kidneys with RAS may help clinicians in the decision-making process, especially when the clinical presentation is not compellingly in favor of intervention.

Incidentally discovered RAS. Vascular disease is a systemic process, and significant ARVD is highly prevalent in those patients undergoing investigations for disparate disease (e.g., for CAD and peripheral vascular disease [PVD]). Between 15% and 29% of patients being investigated by coronary angiography have ARVD discovered, with 5% of the total number having bilateral disease.³⁷ The incidence is even higher in patients being investigated for lower-limb arterial disease or aortic disease, with around 40% of patients being found to have significant ARVD.³⁸ Retrospective data have shown incidental ARVD in the setting of PVD to be a significant independent predictor for mortality, though this does not inform us as to whether it is a cause or marker of poor outcomes.³⁹

The justification for further assessment and treatment of incidentally discovered RAS has little evidence-based support. In one retrospective case review in which 124 patients noted to have ARVD during an alternative angiographic procedure underwent formal imaging of the renal vessels demonstrated a > 70% stenosis in 78 patients. Of these, 58 underwent percutaneous revascularization (38 were followed for 12 months). Renal function did not significantly alter between the groups, and the suggestion that revascularization may have improved blood pressures was only noted in the group that underwent increases in pharmacotherapy.⁴⁰

The strongest evidence again derives from ASTRAL. Many of the 806 patients within the study were asymptomatic, and it is likely that a high proportion of cases were incidentally diagnosed. The results clearly showed that unselected revascularization for patients with RAS in whom there were no compelling clinical reasons for intervention provided no overall health benefit. Therefore, in the absence of other indications, we would view incidental ARVD as an indication for standard medical therapy, not revascularization.

Complications of Renal Revascularization

When recommending any interventional procedure, one must balance the risks and benefits for the individual patient. The technical success of renal revascularization by percutaneous angioplasty and stenting is high, with an initial angiographic success rate of 94–100%.⁴¹ This applies irrespective of whether the definition for success is a post-revascularization residual stenosis of 41 In ASTRAL there was a 6.8% risk of serious adverse events in patients receiving intervention.¹ Lesser complications such as groin hematoma, puncture-site trauma or minor renal dysfunction associated with contrast agents are much more common at up to 10%^.41

An additional issue that must be considered is long-term procedural success. In one study with duplex ultrasound follow-up after renal intervention, restenosis-free survival was 50% at 12 months and 40% at 18 months.⁴² Further, use of drug-eluting stents may improve long-term patency, but they have not been validated to the extent that has occurred with their use in the treatment of CAD.⁴³ Another measure that must be considered is how best to utilize antiplatelet agents. Aspirin has a historical perspective in treatment of ARVD, and most RCTs allow antiplatelet use in line with local policy. This lack of standardization may confound some of the published data and warrants further consideration when future trials are designed.

There is also developing interest in the use of embolic protection devices (EPDs) to accompany stenting, aiming to capture the atheromatous fragments which may be dislodged during the procedure and cause subsequent downstream occlusions and parenchymal damage. Complete EPDs capture more of this debris, but have not demonstrated superior results to partial devices.⁴⁴ Some prospective trials have suggested that EPD use is more likely to lead to improved renal function post procedure,⁴⁵ however, this is not a consistent finding and some results suggest EPD in conjunction with glycoprotein IIb/IIIa inhibition may be a superior approach.⁴⁶ Theoretically here, the EPD collects large particles, while the glycoprotein inhibitor attenuates the effects of the particles too fine to be trapped (Figure 4). A proportion of patients in CORAL have used EPDs, and this may add further information.

Conclusion

In conclusion, despite a landmark RCT, decisions to undertake revascularization in certain clinical presentations of ARVD remain contentious. Definitive advice to revascularize patients is still largely based upon consensus opinion. ASTRAL has helped steer clinicians away from undertaking “carte blanche” intervention in those patients with RAS and stable CKD, moderate hypertension, and especially in largely asymptomatic patients or those with incidentally discovered disease. This is highly important given the significant risks that can accompany revascularization. However, some patients undoubtedly benefit from revascularization, and further investigation is merited to help identify the patient subsets who will potentially benefit. Currently, compelling support for renal revascularization exists for:

• Severe or dialysis-dependent AKI;

• Acute pulmonary edema;

• Patients with very resistant hypertension;

• Facilitation of RAAS blockade in patients who need therapy but in whom renal functional intolerance is present.

Other potential areas merit further study. Most clinicians would feel uncomfortable not intervening in a patient with RAS and rapidly declining renal function, and until a possible meta-analysis of STAR, ASTRAL and CORAL is available, this remains a reasonable rationale for revascularization. Further information from ASTRAL and RASCAD on the effects of revascularization on cardiac structure and function will be available in the near future, but until then — and better still — until a randomized trial on the effects of intervention on RAS in CCF is undertaken, revascularization for chronic heart failure has a limited evidence base.

Most new data over the next few years will likely address the role of biomarkers in patient selection, or the issue of determining which kidneys have hibernating parenchyma associated with functionally significant stenoses. Available evidence does not support revascularization based on stenosis severity, but in the future we will learn more about the importance of renal volumes and how to select patients who have not yet developed downstream irreversible renal parenchymal damage.

The final message is that screening for ARVD in asymptomatic CKD patients or in those with treatable hypertension will add little to their care and only increase therapeutic uncertainty.

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From The University of Manchester, Manchester Academic Health Science Centre, Salford Royal Hospital, Salford, United Kingdom. The authors report no financial relationships or conflicts of interest regarding the content herein. Address for correspondence: Professor Philip A. Kalra, Department of Renal Medicine, Salford Royal Hospital, Stott Lane, Salford M6 8HD, United Kingdom. E-mail: philip.kalra@srft.nhs.uk