The authors report two cases of early transplant renal vein thrombosis after kidney transplantation. In the two cases, the graft had to be removed. Many difficulties prevented the diagnosis of this fortunately unusual (0.8% of all transplantations performed) vascular injury.
There are many causes of left main coronary artery disease, the first of which is atherosclerosis. Other rarer causes may be observed, such as acute and chronic occlusions, spasm and primary and secondary dissection. The prevalence of stenosis of the left main coronary artery at coronary angiography is about 5%. The risk factors are the same as for coronary artery disease. The symptoms are angina, especially unstable angina. The diagnosis is suspected on the finding of an extremely positive exercise stress test, confirmed by coronary angiography. The results of the prospective large scale Veterans Administration trial showed surgery to be the treatment of choice with a 30 months survival of 80% in the surgical group compared with 64% in the medical group. The operative morbidity and mortality is less than 10% at present. Recent studies have reported a medium-term mortality of 4.3 to 10.25% with follow-up periods of 24 and 43 months respectively. The long-term survival and functional improvement are excellent, with values of nearly 80%. Chronic occlusion of the left main stem is rare, 0.01 to 0.7% in coronary angiographic studies. There is no difference in presentation, electrocardiographic or stress test features compared with other severe coronary artery disease. The diagnosis is angiographic and the treatment surgical because of the mediocre natural history with risks of sudden death and severe infarction. Acute occlusion of the left main coronary is rare for generally fatal. The mechanism is acute thrombosis and the clinical presentation is that of extensive infarction usually with cardiogenic shock.(ABSTRACT TRUNCATED AT 250 WORDS)
The prevalence of symptomatic renal fibromuscular dysplasia (FMD) in the general population is estimated to about 4/1000 and cervico-cephalic FMD is probably half as common as renal FMD. Renal FMD can lead to hypertension (HTN) and progressive renal atrophy [1]. Cervico-cephalic FMD can result in ischaemic or haemorrhagic stroke, cervical artery dissection and may be associated with intracerebral aneurysms, with risk of subarachnoid haemorrhage [2]. In some patients, the diagnosis of FMD can lead to invasive procedures such as percutaneous angioplasty, reconstructive surgery or intracranial aneurysm clipping. Thus, both the disease and its treatment can lead to significant morbidity [1]. Unfortunately, there are no specific guidelines for the diagnosis and treatment of FMD, which is at least partly explained by the absence of randomised clinical trials and, until recently [3], of systematic reviews or meta-analyses dealing with this condition, most of the evidence being derived from small and old cohorts and expert opinions. This article is a summary of a recent 'formalised expert consensus' (extended version: see Data S1), developed by French and Belgian experts upon request of the French 'Haute Autorité de la Santé' (http://www.has-sante.fr). It includes recommendations for the definition, classification, diagnosis and management of FMD in adult patients (≥ 18 years) with symptomatic FMD of the renal arteries, supra-aortic trunks and digestive and peripheral arteries. The rationale underlying each recommendation is discussed, and the, usually low, grade of evidence [4] is indicated in square brackets. The medical subject headings (MeSH) definition of FMD is 'an idiopathic, segmental, nonatheromatous disease of the musculature of arterial walls, leading to stenosis of small and medium-sized arteries. There is true proliferation of smooth muscle cells and fibrous tissue'. Three main types of renal FMD have been identified according to the arterial wall layer that is mostly affected [5, 6]: Intimal FMD (about 10% of renal artery FMD cases) is characterised by irregularly distributed mesenchymal cells within a loose matrix of subendothelial connective tissue and a fragmented internal elastic lamina. Medial FMD (80–90% of renal artery FMD) consists of homogeneous deposits of elastic tissue leading to multiple stenoses interspersed with aneurysmal segments, with a preserved, sometimes fragmented, internal elastic lamina. Adventitial FMD (< 5% of adult renal artery FMD cases) involves hypertrophy of the connective tissue at the junction of the media and adventitia. However, these categories are not mutually exclusive, as involvement of more than one layer in the same diseased artery is not uncommon [7]. Although these different subtypes were initially described in patients with renal FMD, similar lesions have been observed in patients with cervical or intracranial FMD [2]. Later on, Kincaid et al. [5] proposed an angiographic classification, based on the pathological–angiographic correlations found in 60 patients who underwent angiography and from whom pathological renal artery FMD specimens were obtained. Three angiographic types of renal artery FMD have been described: multifocal ('string-of-beads' appearance), unifocal (solitary stenosis < 1 cm in length) and tubular (stenosis at least 1 cm in length) (Fig. 1). As the two last categories only differ by the length of the diseased segment, it was proposed to group them under the generic term unifocal [1]. Angiographic classification of renal artery fibromuscular dysplasia (FMD). From left to right, 'string-of-beads' appearance of multifocal FMD, unifocal FMD and tubular FMD (adapted from Plouin et al. [1]). The 'string-of-beads' aspect accounts for over 80% of cases, and its histological substrate is medial FMD [5]. It affects mainly women between 30 and 50 years old [1, 8]. The lesions commonly involve the medium or distal thirds of the main renal artery, and there is often extension into the proximal portion of the first-level branches. Lesions are bilateral in 60% of cases [1]. Although the 'string-of-beads' appearance is almost pathognomonic of multifocal (medial) FMD, aspects of multifocal stenosis have been described following intoxication by sympathomimetic agents and ergotamine derivatives. Congenital aortic hypoplasia may also be associated with RAS, especially in children [9] and histological lesions similar to those of medial FMD may be observed on examination of renal arteries or even the aorta [10]. Unifocal FMD can be found at the ostium, the trunk or the bifurcation of the renal arteries. As this feature lacks specificity, the diagnosis can be established in young (usually < 40 year old) patients with no atherosclerosis or other less frequent diseases. The differential diagnosis of unifocal FMD includes compression of the proximal renal artery by the median arcuate ligament, Takayasu arteritis and other rare diseases (type 1 neurofibromatosis, vascular Ehlers–Danlos syndrome, Alagille syndrome, Williams syndrome, etc) [1]. As FMD-related RAS is now usually treated by percutaneous transluminal angioplasty (PTA) rather than surgery, histological verification is seldom available, and the angiographic classification has progressively replaced the histological classification. The angiographic features of carotid and vertebral artery FMD are very similar to those described in renal FMD. However, atypical forms of FMD exist, with diaphragmatic stenoses because of intimal dysplasia at the origin of the internal carotid artery [2] (Fig. 2). Classification of fibromuscular dysplasia (FMD) of the cervico-cephalic arteries. From left to right, 'string-of-beads' appearance of multifocal FMD (MRI angiography), unifocal FMD (conventional angiography), tubular FMD (CT angiography) and atypical form of FMD with a diaphragmatic stenosis at the internal carotid artery origin (large arrow; associated typical 'string-of-beads' lesions are indicated by thin arrows) (adapted from Touzéet al. [2]). Renal artery FMD. The most common presentation of renal artery FMD is renovascular HTN. In the general population, the prevalence of this presentation is estimated to roughly 4/1000 [1]. The majority of patients are women between 15 and 50 years of age [8]. The AHA/ACC has proposed the following indications of RAS screening [4]: However, these practice guidelines are only derived from an expert consensus and are not specific to FMD. In subjects aged < 50 years, screening for FMD may also be considered in milder HTN cases. FMD of the cervico-cephalic arteries. The frequency of symptomatic FMD of cervico-cephalic arteries is lower than that of renal FMD. The mean age at diagnosis in most series of patients with cervical FMD was over 50 years [2]. However, it should be kept in mind that none of these symptoms is specific of FMD. In particular, the existence of intracranial aneurysms is not sufficient to establish the diagnosis of FMD. FMD of other vascular territories. Finally, FMD stenotic lesions of the mesenteric territory may cause nausea, digestive pain and weight loss. Several clinical cases describing severe forms have been reported [10, 11]. Some cases of claudication of the upper or lower limbs have been associated with FMD in the subclavian or iliac arteries. Renal artery FMD. Echo-Doppler: Echo-Doppler is inferior to MRI- and CT angiography for atherosclerotic [4, 8] and FMD-related [8] lesions. Nevertheless, it allows detecting stenoses and measuring kidney height, is less expensive than CT-, MRI-or conventional angiography and is therefore a reasonable first-line screening technique. CT- and MRI angiography: CT- and MRI angiography display a good specificity in detecting renal artery FMD [12, 13], especially of the multifocal subtype [14], and are thus the recommended imaging techniques to confirm the diagnosis. They can also be considered as the first screening test when the results of echo-Doppler are expected to be suboptimal (obese patients, apnoea difficult or impossible), especially when the clinical suspicion is high (Fig. 3). However, they do not allow accurate quantification of the degree of stenosis. As a result of its higher spatial resolution, CT angiography is probably superior to MRI angiography, especially for the detection of FMD lesions limited to distal renal branches and/or segmental renal arteries and may thus be preferred. Nevertheless, systematic studies assessing the diagnostic performance of CT- or MRI angiography in multifocal FMD have yet to be conducted. Proposed algorithm for establishing the diagnosis of renal artery fibromuscular dysplasia (FMD). PTA, percutaneous transluminal angioplasty. Conventional angiography: As FMD is associated with spontaneous dissections [2], the per-procedure risk of dissection might be increased. However, as FMD lesions are usually distal, they are probably unaffected by diagnostic arteriography. Thus, in patients with FMD, the risk of the procedure is probably very low, at least in the absence of associated atherosclerotic lesions. Nevertheless, it is recommended to reserve arteriography for patients in whom performing a simultaneous revascularisation procedure is medically justified. Arteriography is also advised in the case of a high clinical suspicion of FMD-related stenosis, when the diagnosis remains uncertain after performing the noninvasive tests [4] (Fig. 3). FMD of the cervico-cephalic arteries. To the best of our knowledge, no study compared the performance of noninvasive tests with conventional angiography for the diagnosis of cervico-cephalic FMD. Echo-Doppler may reveal an irregular stenosis compatible with the diagnosis. However, CT- and MRI angiography are likely to perform better, especially because FMD usually affects the middle and distal portions of the carotid and vertebral arteries, which are less accessible to Echo-Doppler [8]. Moreover, CT and MRI have the advantage to allow the detection of associated intracranial aneurysms. FMD of other vascular territories. In patients with mesenteric or limb ischaemia symptoms, involvement of mesenteric or limb arteries must be screened for using CT angiography or ultrasound [15]. Although this strategy was recommended for detecting atherosclerotic stenoses, it can logically be applied to the rarer cases in which dysplasia-induced stenosis is detected. In rare cases of FMD with limb ischaemia where the affected artery is superficial, echo-Doppler is the first-line imaging technique. Renal artery FMD. Usually, revascularisation of FMD lesions is only considered if there are arguments in favour of a significant stenosis, i.e. a stenosis responsible for downstream ischaemia, stimulation of the renin angiotensin system and renovascular HTN. Although of the utmost practical importance, the diagnosis of significant renal artery stenosis in humans remains elusive. The threshold proposed by the AHA to confirm the existence of a RAS is 60% [16] of diameter reduction, which corresponds to an 80% reduction in the luminal surface area. This applies to both atherosclerotic RAS and unifocal FMD-induced RAS, which are generally unifocal. By contrast, in multifocal FMD, assessment of luminal diameter reduction is imprecise because of the frequent absence of a healthy reference segment and the difficulty in visualising precisely and quantifying diaphragmatic stenoses. Furthermore, given a similar reduction in the luminal diameter, the haemodynamic obstacle may be aggravated by the length of the lesions and the presence of multiple diaphragms. The quantification of multifocal RAS is therefore notoriously difficult [5, 8]. Several studies suggest that echo-Doppler velocimetric indexes, particularly acceleration time, may reliably predict the existence of a significant stenosis [17, 18]. However, these studies included only few patients with FMD. Renal scintigraphy and/or assessment of renin activity in renal veins before and after captopril are no more recommended in the assessment of RAS, in view of their poor performance in bilateral RAS [4], which is often the case for FMD [1]. Trans-stenotic gradient measurements may help to localise the haemodynamic obstacle. However, the significance of such measures is unclear owing to intrarenal resistances [19], which also depend on the duration of HTN and renal function. Indirect signs such as total lesion length, number of diaphragms or pseudo-aneurysms, the presence of collateral circulation or jet image, or small downstream kidney, may all be taken into account. However, these criteria are poorly defined and not based on consensus. FMD of the cervico-cephalic arteries. A cervico-cephalic stenosis can be considered haemodynamically significant if it leads to downstream consequences. For atherosclerosis, a threshold of 70% is generally accepted [20]. As in atherosclerosis, techniques assessing cerebral perfusion, such as transcranial Doppler, MRI angiography or cerebral scintigraphy can be used. However, the prognostic value of potential abnormalities in the context of FMD has not been established. Fibromuscular dysplasia lesions most commonly involve the renal arteries and the extracranial portion of the cervico-cephalic arteries. Involvement of the mesenteric, axillary, iliac, hepatic, intracranial and, in a few cases, coronary arteries has also been reported. The frequency of lesions of different vascular beds in an old series from Zürich [21] and more recent series from Paris (P.-F. Plouin, personal communication) and Brussels [22] is indicated in Fig. 4. In these series, the prevalence of FMD lesions affecting two or more vascular beds was in the range of 16–28%. However, these figures are likely underestimated as exploration was not systematic in all vascular beds. As expected, the most frequent association was that of renal and cervico-cephalic FMD [21, 22]. Frequency (%) of involvement of different vascular beds and of multiple-site involvement in series of patients with fibromuscular dysplasia from Paris (Hôpital Européen Georges Pompidou, P.-F. Plouin, personal communication), Zürich [17] and Brussels [18]. In addition to the usual angiographic features of supra-aortic FMD, patients with renal artery FMD often show abnormal echographic patterns at the common carotid artery, a site that is usually not affected by macroscopic FMD lesions [1, 23]. This observation, made using high-resolution echotracking, suggests that arterial abnormalities without concomitant clinical or angiographic manifestations are common during the course of FMD. In view of these elements, it appears appropriate to screen for cervico-cephalic FMD in patients with renal FMD and vice-versa, provided there are arguments that identification of lesions in the second vascular bed could modify management. In particular, in patients with renal artery FMD, screening for asymptomatic cervico-cephalic lesions may help to establish the diagnosis of FMD and may have practical implications in cases of intracranial aneurysm (see infra) or for the management of blood pressure in cases of severe stenotic cervico-cephalic lesions. Conversely, screening for renal FMD in hypertensive patients with cervico-cephalic FMD may lead to revascularisation of a significant FMD-related RAS. Renal artery aneurysms were identified in four of 716 (0·6%) potential kidney donors, all four presenting with lesions suggestive of FMD; furthermore, 12 of 125 (9·6%) patients with symptomatic renal artery FMD also had renal artery aneurysms [1]. Similarly, the prevalence of intracranial aneurysms in patients with cervico-cephalic FMD was estimated to 5·1–9·5% [24], i.e. higher than in the general population. An association between renal artery FMD and cerebral aneurysm was also documented [25]. However, there are no data on the prevalence of this association. Algorithms for the treatment of unruptured intracranial aneurysms have been proposed, taking into account factors such as the size of the aneurysm and its location, as well as the patient's preferences [26]. However, no study has been specifically devoted to the management of FMD-related aneurysms. The AHA guidelines nevertheless recommend that patients with cervico-cephalic FMD should be screened for intracranial aneurysms [4]. A retrospective analysis of 104 patients with renal artery FMD revealed that 11% had familial FMD, as documented by the detection of renal artery FMD lesions by arteriography in at least one other first-degree family member [27]. In cases of hereditary FMD, renal artery lesions were usually multifocal and more often bilateral compared with sporadic FMD cases. Conducting FMD screening among asymptomatic parents of a patient with established FMD remains a research topic. However, if the parent is symptomatic, i.e. if he/she presents precocious HTN or unexplained neurological symptoms, the notion of FMD within the family may provide an aetiological clue. To our knowledge, there are no published controlled studies comparing revascularisation to medical treatment only or revascularisation by PTA to surgical revascularisation in patients with FMD. Usually, revascularisation is only considered in cases of symptomatic FMD (renovascular HTN or documented renal atrophy for renal FMD, ischaemic symptoms for FMD of other vascular beds). In the absence of evidence-based recommendations, the best therapeutic option should be discussed within a multidisciplinary team including clinicians, interventional radiologists or cardiologists and vascular surgeons with considerable experience of FMD. By contrast with atherosclerotic RAS, recovery of HTN is fairly common following revascularisation of FMD-induced RAS (30–50% according to the definition of HTN) [3]. In addition, patients with FMD-induced RAS do not require any cardiovascular or renal prevention once the HTN has been cured. As shown by a recent meta-analysis [3], recovery rates are higher in younger subjects (Fig. 5), those with more recent onset of HTN and in unifocal FMD compared with multifocal FMD. Thus, in hypertensive patients with FMD-related RAS, revascularisation is usually proposed, especially if HTN is recent and in case of treatment failure. By contrast, in FMD without HTN and with normal renal function, the value of revascularisation has not been established [1, 28]. However, if there is a downstream reduction in renal size exceeding 1 cm during two successive examinations (excluding a congenital asymmetry in kidney size), revascularisation may be justified [28]. Meta-regression analysis assessing the relationship between the hypertension cure rate following percutaneous angioplasty and mean age (adapted from Trinquart et al. [3]). It is impossible to reliably compare the results of PTA and surgery because they are not performed in patients with similar characteristics. Furthermore, surgical revascularisation has been performed for a longer time than PTA revascularisation, and the assessment methods therefore also differ in series using PTA or surgery. PTA is proposed as a first-line therapy for patients with uni- or multifocal truncal FMD lesions, whereas surgery is proposed as the primary approach for patients with complex lesions of arterial bifurcation or branches, stenoses associated with aneurysms, or following PTA failure [4, 8, 29]. A second PTA may be attempted following PTA failure, but a third PTA is not recommended so as to prevent arterial trauma that could jeopardise surgical results [30]. Fibromuscular dysplasia of the cervico-cephalic arteries has a good long-term prognosis and should thus not be considered as an indication of prophylactic surgery. The situation is more complex for symptomatic lesions. The risk of recurrence with medical treatment alone is probably low. Furthermore, the causal role of carotid FMD in the development of symptoms is difficult to establish in patients with emboligenic cardiopathy or concomitant atherosclerosis. However, certain symptoms, which are not threatening but debilitating, such as pulsatile tinnitus, may be considered as an indication of revascularisation. In conclusion, surgical indications are mainly based on individual decisions [2]. Fibromuscular dysplasia lesions of other sites are rarely symptomatic. For symptomatic stenoses of digestive or limb arteries, the first-line treatment is usually PTA. Renal artery FMD. If revascularisation is not considered, because the stenosis is not deemed significant, the patient declines intervention or for other reasons, the duration of clinical (monthly BP measurements until target BP values are reached, then every 3 months) and biological (annual monitoring of creatinaemia) follow-up is indefinite, as for any HTN with renal involvement [31]. Slovut and Olin [8] also recommend annual ultrasound monitoring of kidney height. This may be especially useful in cases of bilateral or nonmedial FMD, which are more likely to progress [32, 33]. In the latter, indefinite ultrasound monitoring is probably useful. Failing that, an annual surveillance over 2 years, reconducted in cases of BP or creatinine elevation, is acceptable. FMD of the cervico-cephalic arteries. In asymptomatic cervical and intracranial forms, an annual check of cervical and intracranial vessels (MRI angiography and echo-Doppler, followed by CT angiography if necessary) is recommended. In the absence of lesion progression, monitoring visits may be less frequent. In the forms diagnosed after an ischaemic accident: a new arterial check is usually necessary approximately 3 months after diagnosis in cases of acute dissection; a new arterial check is indicated after 6 months, in the absence of acute dissection, and then annually; in the absence of lesion progression, monitoring visits may occur less frequently. In symptomatic forms revealed by meningeal haemorrhage, no specific recommendations exist. Aneurysm follow-up options depend on the specific primary treatment implemented. Other FMD lesions are checked on an annual basis. In the absence of progression, monitoring visits may occur less frequently. Renal artery FMD. An early assessment at 1 month allows antihypertensive treatment to be adjusted, often by reducing doses or discontinuing treatment. As restenoses mostly occur within the first 6 months [34], an imaging assessment is performed within this time period, consisting of echo-Doppler in cases of trunk lesions and CT- or MRI angiography in cases of distal lesions. This check is performed before 6 months in cases of BP or plasma creatinine elevation. If the 6-month follow-up is satisfactory, subsequent monitoring is similar to that of FMD without significant stenosis. FMD of the cervico-cephalic arteries. Arterial imaging is usually performed in the days following the intervention, then again at 3–6 months. The arterial imaging technique used depends upon the surgical approach. The frequency of follow-up visits depends on postoperative evolution and the indications already discussed for nonrevascularised FMD. The major aims of current research are to unravel the pathophysiological mechanisms of FMD. This includes seeking genes that predispose to this condition, more accurate assessments of the risk of disease progression in focal or multifocal FMD and in FMD affecting renal or extrarenal arteries, and improvements in the detection and quantification of renal artery stenosis [1]. Several projects exploring these topics are currently under way. Accordingly, an update of this consensus will be considered within 3–5 years. Leaflets for patients derived from these recommendations are also under preparation. The authors wish to acknowledge the valuable contribution of Mrs Karine Petitprez (Haute Autorité de la Santé) and of all members of the scoring group (see below) and reading group (see Data S1) to improve the quality and applicability of the present guidelines. The authors are also grateful to Mrs Sophie Guiquerro (Hôpital Européen Georges Pompidou, Paris) for performing the primary literature search. Members of the scoring group: S. Alamowitch (neurologist, Paris), J.-P. Beregi (radiologist, Lille), L. Boyer (radiologist, Clermont-Ferrand), A. Branchereau (surgeon, Marseille), P. Bruneval (pathologist, Paris), P. Garnier (neurologist, Saint-Etienne), J.-M. Krzesinski (nephrologist, Liège), X. Jeunemaitre (geneticist, Paris), C. Laurian (surgeon, Paris), C. Mounier-Vehier (vascular medicine, Lille), F. Silhol (internist, Marseille). All authors provided a detailed conflict of interest statement to the French 'Haute Autorité de la Santé'. However, none of them was related to the current topic. Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 10 Avenue Hippocrate, 1200 Brussels, Belgium (A. Persu); Department of Neurology, Université Paris Descartes, INSERM UMR S894, Pôle neuroscience, Hôpital Sainte-Anne, Paris, France (E. Touzé); Department of Radiology, Université Paris Descartes, Hôpital Européen Georges Pompidou, Paris, France (E. Mousseaux); Department of Vascular Surgery, CHU Hôpital Nord, Saint-Etienne, France (X. Barral); Department of Radiology, Rangueil University Hospital, Toulouse, France (F. Joffre); Université Paris-Descartes; Assistance Publique-Hôpitaux de Paris; Hôpital Européen Georges Pompidou, Hypertension unit, Paris, France (P.-F. Plouin). Data S1. Extended version of the expert consensus. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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