Version May 2024
INTRODUCTION — Fibromuscular dysplasia (FMD) is a noninflammatory, nonatherosclerotic disorder that leads to arterial stenosis, aneurysm, dissection, and arterial tortuosity [1]. It has been observed in nearly every arterial bed. The most often involved arteries are the renal and internal carotid arteries, followed by the vertebral, iliac, and visceral arteries. When FMD occurs in the coronary arteries, the patient usually presents with an acute coronary syndrome resulting from a spontaneous coronary artery dissection (SCAD) [2-7].
Disease presentation may vary widely, depending upon the arterial segment involved and the severity of disease. The most common presenting manifestations are hypertension, headaches, pulsatile tinnitus, and dizziness. Less common are transient ischemic attack, stroke, and myocardial infarction [8].
Treatment options for patients with renal artery FMD include medical therapy alone, or revascularization by either percutaneous transluminal angioplasty (PTA) or surgery [9]. However, independent of angioplasty, hypertension should be treated.
The treatment of renal artery FMD will be reviewed here. The clinical manifestations and diagnosis of this disorder and the management of atherosclerotic renovascular disease and chronic kidney disease due to renal ischemia are discussed separately:
●(See "Clinical manifestations and diagnosis of fibromuscular dysplasia".)
●(See "Treatment of unilateral atherosclerotic renal artery stenosis".)
●(See "Chronic kidney disease resulting from atherosclerotic renal artery stenosis".)
TREATMENT OF RENAL ARTERY FIBROMUSCULAR DYSPLASIA — The most common manifestation of renal artery FMD is hypertension that is due to renal artery stenosis (see "Clinical manifestations and diagnosis of fibromuscular dysplasia", section on 'Clinical manifestations'). Options for management of hypertension in patients with FMD include antihypertensive drug therapy and revascularization.
Antihypertensive therapy — Most patients with multifocal FMD of the renal arteries and hypertension will require antihypertensive therapy, even if they undergo revascularization. However, the majority of patients with focal FMD have their blood pressure cured (normal blood pressure, no antihypertensive medications) after angioplasty [10].
The reasons why angioplasty frequently cures hypertension in focal FMD, but not in multifocal FMD, are related to the age of the patient and the duration of hypertension. In one study, for example, patients with focal as compared with multifocal FMD had an earlier mean age of hypertension onset (26 versus 40 years), and an earlier mean age of FMD diagnosis (30 versus 49 years) [10]. In a similar study of 105 patients with focal FMD, onset of hypertension occurred an average of just 3.3 years before FMD was diagnosed [11]. The younger the patient and shorter the duration of hypertension, the more likely angioplasty will result in a cure of the hypertension.
Choice of drug — The underlying pathogenesis of the hypertension includes activation of the renin-angiotensin-aldosterone system and, in patients with bilateral disease or disease to a single functioning kidney, retention of sodium and water. Thus, the initial drug class of choice in FMD is an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) [1,12,13]. If goal blood pressure is not reached with angiotensin inhibition alone, a thiazide diuretic or a long-acting dihydropyridine calcium channel blocker would be the next class of drug recommended [12]. (See "Choice of drug therapy in primary (essential) hypertension".)
The major potential complication of ACE inhibitors and ARBs is a hemodynamically mediated decline in glomerular filtration rate (GFR), especially if the stenotic lesions are severe and bilateral or occurring in a solitary kidney. The normal autoregulatory response to maintain GFR in the setting of reduced renal perfusion involves an angiotensin II-mediated preferential increase in resistance at the efferent (postglomerular) arteriole. This is blunted by blocking angiotensin II formation with an ACE inhibitor or an ARB, and the effect is more pronounced with volume depletion [14,15]. When it occurs, the rise in the plasma creatinine concentration is usually mild (10 to 30 percent increase) and acceptable. However, reversible acute kidney injury can occasionally occur. For reasons that are not completely understood, this occurs less frequently in patients with multifocal FMD as compared with individuals with atherosclerotic renal artery stenosis [12]. (See "Renal effects of ACE inhibitors in hypertension".)
ACE inhibitors and ARBs can also increase the plasma potassium concentration, particularly in patients with decreased GFR, an effect that may be countered by the concomitant use of a diuretic. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers".)
Thus, patients with FMD should have follow-up laboratory testing approximately one to two weeks after initiating an ACE inhibitor or ARB to assess for these potential adverse events. The drug should be discontinued if acute kidney injury occurs or if hyperkalemia develops that is severe and cannot be managed with other means, such as dietary potassium restriction or diuretic therapy. (See "Treatment and prevention of hyperkalemia in adults".)
Blood pressure goal — Goal blood pressure in patients with FMD is the same as in similarly aged hypertensive patients who have an etiology other than FMD. Goal blood pressure is discussed elsewhere. (See "Goal blood pressure in adults with hypertension".)
Indications for revascularization — There are no randomized trials comparing revascularization with medical therapy alone in patients with FMD of the renal arteries, and revascularization trials in patients with atherosclerotic renal artery stenosis are not applicable to the FMD population because the two disorders have differing pathophysiology and natural history. Our suggestions pertaining to revascularization are therefore guided by lower-quality data [1,12].
We suggest that the following patients with FMD of the renal arteries and hypertension undergo renal artery revascularization:
●Those with recent-onset hypertension, particularly younger patients with focal FMD who are less likely to have underlying atherosclerotic disease, in whom the goal is to cure hypertension.
●Those with resistant hypertension despite compliance with an appropriate three-drug regimen. (See "Definition, risk factors, and evaluation of resistant hypertension" and "Treatment of resistant hypertension".)
●Those who are unable to tolerate antihypertensive medications or who are noncompliant with their medication regimen.
●Adults with bilateral FMD, or unilateral renal artery FMD to a single functioning kidney, who have otherwise unexplained progressive renal insufficiency that is thought to result from renal artery stenosis (ie, "ischemic nephropathy"). The clinical manifestations of ischemic nephropathy are presented elsewhere. (See "Chronic kidney disease resulting from atherosclerotic renal artery stenosis".)
●Hypertensive children with renal artery FMD.
Rationale — Most patients with multifocal FMD can be well controlled on an average of two antihypertensive agents [10]. By contrast, patients with focal FMD often have difficult-to-control blood pressure, and this type of FMD can lead to an atrophic kidney and chronic kidney disease if not treated with revascularization [10,12].
Thus, in adult patients with well-controlled hypertension, the risks of revascularization may outweigh the benefits. However, children with FMD (most often of the focal type) may be at higher risk than adults for progressive renal parenchymal loss, and therefore may benefit from revascularization, even if their hypertension can be well-controlled with one or two antihypertensive medications [16].
In contrast to patients with atherosclerotic renal artery stenosis, hypertension is cured or improved (better blood pressure control on fewer antihypertensive agents) following revascularization in a large proportion of patients with FMD. The reported hypertension cure rate varies considerably from study to study, although hypertension control improves in most patients [9,17,18]. Variability in cure rates depends in large part upon the definition of cure. As an example, a systematic review of 47 angioplasty studies reported a mean cure rate of 46 percent [19]. However, only 58 of 190 patients (31 percent) were cured when cure was defined as achievement of a blood pressure less than 140/90 mmHg without requiring antihypertensive medications [19,20]. In a subsequent large series of 1191 patients from 36 studies, angioplasty was associated with improved hypertension control in 37 percent and cure in 18 percent; approximately 5 percent of patients had a significant procedural complication [21]. It is important to recognize that the studies included in these meta-analyses were heterogenous, and success rates with angioplasty may be higher (and complication rates lower) in centers that have extensive experience treating FMD.
The rate of cure of hypertension may also be lower if FMD affects multiple vascular beds, or if the intrarenal vessels are involved. In one report, hypertension was cured following angioplasty in 62 versus 28 percent of patients with unilateral, isolated renal artery FMD versus systemic FMD, respectively [17]. In addition, older patients, those with longer durations of hypertension, and those with multifocal FMD have lower likelihoods of cure after revascularization [5,10,12,19,22].
There is also the possibility of delaying or preventing loss of renal mass and therefore chronic kidney disease by revascularizing patients with focal FMD of the renal arteries. Progressive renal loss is uncommon in adult patients [8], except in adults with focal (rather than multifocal) FMD due to intimal fibroplasia or, more commonly, in those with renal artery dissection. However, renal parenchymal loss is more common in children with FMD of the renal arteries because such patients typically have intimal fibroplasia or perimedial fibroplasia, which are associated with a higher risk of progressive renal disease [16].
Angioplasty versus surgery — The two options for revascularization include percutaneous transluminal angioplasty (PTA, typically without placing a stent) or surgery. There are no comparative trials, but PTA achieves similar technical success and is associated with a lower risk of adverse events in observational studies. Thus, we suggest that most adult patients with FMD who are selected for renal revascularization have PTA rather than surgery. If PTA is not technically successful, or if a dissection occurs, stent implantation should be considered [1,12]. With improvements in technique and equipment, even branch renal artery disease can be treated with percutaneous therapy. The need for surgical revascularization is almost never required for failed PTA. The two main indications for surgery include revascularization in children with focal FMD (usually intimal fibroplasia) and if FMD is associated with renal artery aneurysm(s) [1,23].
Most patients have improvement of hypertension with PTA (better blood pressure control on fewer antihypertensive agents), although in only approximately one-third is blood pressure reduced to <140/90 mmHg without requiring antihypertensive medications [10,18-20,24-29]. Cure rates tend to be higher in series of surgical revascularization, in large part because of younger patient populations in such studies [19,30-33]. There are no contemporary studies assessing blood pressure response to surgery because virtually all patients (without an aneurysm) are treated with angioplasty.
The best data come from a meta-analysis of observational studies that included 47 PTA series (1616 patients) and 23 surgery series (1014 patients) [19]. There was substantial heterogeneity among studies. Major findings from this analysis are as follows:
●Improvement in blood pressure (including those with and without cure) was similar with PTA as compared with surgery (86 versus 88 percent).
●Cure rates were higher with surgery (54 versus 36 percent).
●Major adverse events were more frequent with surgery (15 versus 6 percent).
●Older age and longer duration of hypertension prior to revascularization were significantly associated with a lower cure rate.
Percutaneous transluminal angioplasty — Percutaneous transluminal angioplasty (PTA) is typically performed without placement of stent (unlike PTA for atherosclerotic renal artery stenosis). In general, stents are only placed when a dissection results from the performance of PTA or in the rare instance in which a perforation of the renal artery occurs during angioplasty. There are several reasons why a stent should not be used as first-line endovascular therapy in patients with FMD:
●Patients do very well with angioplasty alone, so there is no reason to place a stent. If the lesion is so fibrotic that the pressure gradient cannot be obliterated with an angioplasty, a stent will not correct this problem (and stent deformation will likely occur). Such patients should be referred for surgery.
●Patients with FMD of the renal arteries usually have stenoses in the mid and distal portions of the artery and its branches rather than at the ostium or proximal portion (as occurs with atherosclerosis). Should surgical revascularization become necessary, for example, because of in-stent restenosis, patients may require more complex branch repair to bypass the occluded stent since the stent often covers the renal artery up to the point of the first intrarenal branch.
The reported technical (angiographic) success rates for PTA range from 83 to nearly 100 percent [24,25]. Procedural success rates are lower for angioplasty alone in non-medial FMD (ie, intimal or perimedial FMD) [34-36].
For patients who undergo PTA, the rate of restenosis ranges from 12 to 34 percent over follow-up intervals of six months to two years [37,38]. However, as noted below, it is difficult to determine if patients with FMD develop restenosis, or if the lesion was not completely treated correctly the first time [1,39,40].
In addition, restenosis is not necessarily associated with recurrent hypertension. Over long-term follow-up (mean 7.0±4.7 years), FMD patients who underwent successful PTA showed significant and sustained reductions in systolic blood pressure, diastolic blood pressure, serum creatinine, and number of antihypertensive agents. Systolic blood pressure response was better in patients with FMD affecting the main renal artery than in patients with branch vessel involvement [37].
Advances in guidewires, catheters, and balloons, as well as improvement in operator skill, have made it possible to perform PTA for even the most complex renal artery lesions. Cutting balloon angioplasty should be avoided if possible for lesions that do not respond to balloon angioplasty because the chance of rupture of the renal artery is much higher with a cutting balloon [12].
While many clinicians use visual inspection to determine if the angioplasty was adequate, it is becoming apparent visual inspection alone is not accurate. Thus, other methods are important to assure that the stenosis has been adequately treated [1,12,35,36,40,41]:
●Physiologic assessment should be performed using a pressure wire to determine the hemodynamic significance of the lesions [1,35,36]. A pressure gradient threshold of 10 percent of the mean (aortic) pressure can be used to decide whether to perform angioplasty (ie, Pd/Pa <0.90) [1,42]. The balloon diameter size should be increased by 0.5 mm until the translesional gradient is resolved or until there is a mean translesional gradient of less than 10 percent. If the patient experiences pain during balloon inflation, the procedure should be immediately terminated to prevent renal artery dissection or rupture [1].
It is important to measure pressure gradients both before and after angioplasty to be certain that all of the intraluminal fibrous webs have been adequately disrupted.
●Postprocedure renal artery duplex ultrasound scanning should also be used to assess the adequacy of intervention. In successfully treated patients, the degree of turbulence is less prominent, and velocity elevation in the mid-distal renal artery substantially improves [40].
●Intravascular ultrasound or optical coherence tomography (OCT) is occasionally used to evaluate the elimination or reduction of various endoluminal defects [43].
In patients with atherosclerotic renal artery stenosis, stenting in the renal artery is associated with a restenosis rate of up to 10 to 20 percent [44], although lower rates may be seen if a drug-eluting stent is used. If the patient either has no improvement in blood pressure or an initial improvement followed by recurrence of hypertension a few weeks after PTA, we recommend a repeat angiogram, with measurement of pressure gradients, and PTA if there is still a hemodynamically significant lesion. In this case, "restenosis" may actually represent inadequate angioplasty during the first procedure [12,37,41]. There are also reports of late recurrence after a technically and clinically successful prior angioplasty [35,36].
Hypertension that persists despite technically successful PTA, particularly if confirmed using intravascular ultrasound or a pressure wire, suggests that the cause of hypertension is unrelated to fibromuscular disease or is related to small vessel disease within the kidney (nephrosclerosis) due to longstanding hypertension.
Complications of PTA are mostly related to vascular access. In rare cases, renal artery perforation, dissection, or segmental renal infarction may occur [18]. The rate of complications has decreased, a trend attributed in part to use of more flexible guiding catheters, improved balloon technology, improved operator technique, and lower heparin doses. As an example, in a series of 268 patients who underwent 320 procedures, the complication rate decreased from 16 percent in 1998 to 3 percent in 2001 [45].
Surgery — Aortorenal bypass with a saphenous vein graft is the most commonly performed surgical revascularization procedure in patients with FMD of the renal arteries, although artificial graft material is occasionally used [12]. In pediatric patients, hypogastric artery grafts are used or else aortic reimplantation of the renal artery is performed because vein grafts may become aneurysmal.
Renal artery aneurysms may be identified in patients with FMD. The aneurysms may rupture or lead to infarction from embolization of thrombus within the aneurysm. Renal artery aneurysms may be treated percutaneously using a covered stent graft or coils or may be repaired surgically with minimal morbidity or mortality [46-48].
Although both surgery and PTA lead to similar technical success rates, surgery is associated with markedly higher morbidity [19,49]. Perioperative mortality appears to be very low (eg, 1.2 percent in a meta-analysis of 17 surgical studies) [19,50]. Given that surgical revascularization is usually limited to complex cases, reported success and complication rates are probably higher than if simpler cases were included. In one series of 26 patients, 6 of whom had failed PTA and 20 who were unsuitable for PTA, there were two bypass occlusions resulting in renal loss, and five significant nonrenal complications during a median follow-up of 2.4 years [38]. Cumulative patency at one and three years was 89 and 82 percent, respectively.
Monitoring and follow-up — All patients with FMD of the renal arteries should undergo one-time cross-sectional imaging with either computed tomographic angiography (CTA; our preference because of better resolution) or magnetic resonance angiography (MRA) from the head to the pelvis in order to identify FMD in other vascular beds and, more importantly, to identify aneurysms and/or dissections [23,51,52]. (See "Clinical manifestations and diagnosis of fibromuscular dysplasia", section on 'Diagnosis of fibromuscular dysplasia'.)
Patients with FMD in one vascular bed frequently have FMD, including tortuosity, aneurysms, and dissections, in other vascular beds:
●Among 921 patients from the United States Registry for Fibromuscular Dysplasia, 200 patients (22 percent) had one or more aneurysms and 237 (26 percent) had one or more dissections [23]. These newly identified lesions may require repair or frequent surveillance imaging.
●In the ARCADIA-POL Registry, 232 consecutive patients with FMD underwent whole-body imaging [52]. New FMD lesions were found in 34 percent, aneurysm in 31 percent, and dissection in 12 percent of patients. Twenty-five percent of all patients qualified for interventional treatment due to newly diagnosed FMD lesions or other vascular abnormalities [52].
●Among 1022 patients in the European/International FMD Registry, 488 (49 percent) underwent complete head-to-pelvis imaging. Among that subset, 57 percent had multivessel involvement, 22 percent had one or more aneurysms, and 6 percent of patients had one or more dissections [53].
In addition, all patients diagnosed with FMD of the renal arteries should be prescribed antiplatelet therapy (ie, aspirin) unless contraindicated [1,12].
Monitoring of patients with FMD of the renal arteries varies somewhat depending upon whether or not the patient has undergone revascularization:
●Patients treated with medical therapy alone – An important limitation of pursuing medical therapy alone is that renal artery stenosis and kidney dysfunction may progress despite good blood pressure control. This most often occurs in patients with focal FMD and intimal fibroplasia, although it can occur in patients with rarer forms of FMD such as perimedial fibroplasia [10,22]. As a result, every patient with FMD should have measurement of serum creatinine and renal artery duplex ultrasound every 12 months.
●Patients treated with revascularization – Patients who undergo percutaneous revascularization should have duplex ultrasonography and serum creatinine measurements performed on the first office visit post procedure, then every six months for two years, and then yearly, if stable [1,41]. If the patient develops worsening or new onset hypertension, or unexplained increase in the serum creatinine, they should be imaged at that time with duplex ultrasound (or CTA if the ultrasound is equivocal or poor quality).
TREATMENT OF NONRENAL LESIONS — FMD of the internal carotid and vertebral arteries occurs with a similar frequency as renal artery FMD [1,8,12,40]. FMD in the extracranial cerebrovasculature may be associated with dissection, stenosis, pulsatile tinnitus, intracranial aneurysm, transient ischemic attack (TIA) and stroke, or may be entirely asymptomatic. FMD may also affect other arterial beds such as mesenteric, iliac, and coronary arteries. Spontaneous coronary artery dissection (SCAD) may be a manifestation of FMD [2]. Depending upon the series, FMD may be present in 32 to 75 percent of patients with SCAD [5,54].
In general, our approach to management of FMD of nonrenal arteries is as follows:
●Antiplatelet therapy with aspirin is reasonable in all patients unless contraindicated [1]. However, we do not prescribe statins unless the patient has another indication.
●In patients with TIA, stroke, claudication, or intestinal ischemic, FMD is typically treated with revascularization (usually percutaneous transluminal angioplasty [PTA]). Stenting is reserved for patients with suboptimal angioplasty results or for patients with a dissection who fail anticoagulation therapy. Patients with carotid or vertebral artery dissection are often treated medically if neurologically stable (aspirin alone, aspirin and clopidogrel, or anticoagulation) or with stenting if they have progressive neurologic symptoms [55]. Patients with SCAD are generally treated medically (aspirin and clopidogrel) unless they are clinically unstable (ie, shock, persistent chest pain) and/or have TIMI 0 to 1 flow. Complications are higher when angioplasty or stenting is performed in patients with SCAD than in patients with atherosclerosis [2,4,6,56].
The management of aneurysms and arterial dissections associated with FMD is similar to the treatment in patients without FMD:
•Extracranial carotid aneurysms (see "Extracranial carotid artery aneurysm" and "Unruptured intracranial aneurysms" and "Treatment of cerebral aneurysms")
•Dissection of extracranial carotid vertebral arteries (see "Cerebral and cervical artery dissection: Treatment and prognosis")
•Coronary artery dissection (see "Spontaneous coronary artery dissection")
•Mesenteric ischemic (see "Nonocclusive mesenteric ischemia")
●The management of migraine, other headache types, and pulsatile tinnitus, which are common in patients with FMD, is similar to the treatment in patients without FMD [1]. (See "Acute treatment of migraine in adults" and "Preventive treatment of episodic migraine in adults" and "Chronic daily headache: Associated syndromes, evaluation, and management" and "Treatment of tinnitus".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fibromuscular dysplasia" and "Society guideline links: Hypertension in adults".)
SUMMARY AND RECOMMENDATIONS
●Fibromuscular dysplasia (FMD) is a noninflammatory, nonatherosclerotic disorder that leads to arterial stenosis, aneurysm, dissection, and arterial tortuosity. It has been observed in nearly every arterial bed. The most often involved arteries are the renal and internal carotid arteries, and less often the vertebral, iliac, visceral, and coronary arteries. (See 'Introduction' above.)
●The most common manifestation of renal artery FMD is hypertension that is due to renal artery stenosis. Options for management of hypertension in patients with FMD include antihypertensive drug therapy and revascularization. Most patients with FMD of the renal arteries and hypertension will require antihypertensive therapy, even if they undergo revascularization. (See 'Treatment of renal artery fibromuscular dysplasia' above.)
●The initial antihypertensive drug class of choice in FMD is an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). If goal blood pressure is not reached with angiotensin inhibition alone, other antihypertensive drugs (such as a thiazide diuretic or a long-acting calcium channel blocker) should be added as necessary. Goal blood pressure in patients with FMD is the same as in similarly aged hypertensive patients who have an etiology other than FMD. (See 'Antihypertensive therapy' above.)
●We suggest that the following patients with FMD of the renal arteries and hypertension undergo renal artery revascularization rather than antihypertensive therapy alone (see 'Indications for revascularization' above) (Grade 2C):
•Those with recent-onset hypertension, particularly younger patients who are less likely to have underlying atherosclerotic disease, in whom the goal is to cure hypertension or significantly reduce the number of antihypertensive medications.
•Those with resistant hypertension despite compliance with an appropriate three-drug regimen.
•Those who are unable to tolerate antihypertensive medications or who are noncompliant with their medication regimen.
•Adults with bilateral FMD of the renal arteries, or unilateral FMD of the renal arteries to a single functioning kidney, who have otherwise unexplained progressive renal insufficiency that is thought to result from renal artery stenosis (ie, "ischemic nephropathy"). The clinical manifestations of ischemic nephropathy are presented elsewhere.
•Hypertensive children with FMD of the renal arteries.
●In most patients with FMD who are selected for renal revascularization, we suggest percutaneous transluminal angioplasty (PTA) rather than surgery (Grade 2C). However, surgery is preferred if angioplasty is not possible or if there is also a renal artery aneurysm present. (See 'Angioplasty versus surgery' above.)
●PTA is typically performed without placement of stent (unlike PTA for atherosclerotic renal artery stenosis). In general, stents are only placed when a dissection results from the performance of PTA or in the rare instance in which a perforation of the renal artery occurs during angioplasty. When PTA is performed, physiologic assessment should be made using a pressure wire; resolution of the gradient is the desired result. It is important to measure pressure gradients both before and after angioplasty to be certain that all of the intraluminal fibrous webs have been adequately disrupted. Postprocedure renal duplex ultrasound scanning should also be used to assess the adequacy of intervention. In successfully treated patients, the degree of turbulence is less prominent, and velocity elevation in the mid-distal renal artery improves. (See 'Percutaneous transluminal angioplasty' above.)
●If surgery is performed, aortorenal bypass with a saphenous vein graft is the most commonly performed revascularization procedure in patients with FMD of the renal arteries. (See 'Surgery' above.)
●An important limitation of pursuing medical therapy alone is that renal artery stenosis and kidney dysfunction may progress despite good blood pressure control. This is common in focal FMD but rarely occurs in multifocal FMD. As a result, every patient with FMD should have periodic measurement of serum creatinine every 6 months and duplex ultrasound every 12 months. Patients who undergo percutaneous revascularization should have duplex ultrasonography and serum creatinine measurements performed on the first office visit post procedure, then every six months for two years, and then yearly if stable. (See 'Monitoring and follow-up' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David P Slovut, MD, PhD, who contributed to earlier versions of this topic review.
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