Hipertension Renovascular - 5th

SECTION VII Renovascular Disease
41
Renovascular Hypertension and
Ischemic Nephropathy
Barbara A. Greco, Kausik Umanath
NORMAL RENOVASCULAR ANATOMY prevents development of hypertension.4 Studies in transgenic mice

without receptors for angiotensin confirm that development of RVH
The clinical presentations of renovascular disease are influenced by the requires an intact RAAS.5 In the absence of RAAS blockade, systemic
acuity, nature, and site of renal vascular compromise. In most individu- arterial pressures increase until renal perfusion is restored. Studies in
als, the kidney has a single renal artery (RA) with a lumen diameter of experimental models and humans indicate that additional mechanisms
3 to 7 mm. The main RA branches in a double or triple fork pattern contribute to long-term BP elevation in the presence of RA stenosis,
or, less commonly, a ladder pattern.1 The incidence of multiple RAs is including activation of the sympathetic nervous system, impairment
about 31%, with bilateral supernumerary arteries in 11%.2 The right of NO generation, release of endothelin, and hypertensive microvascular
RA usually passes posterior to the inferior vena cava (IVC), but rarely injury to the kidney.6
can be precaval. The collaterals to the kidney, depicted in Fig. 41.1, can Mechanisms responsible for sustained RVH differ depending on
maintain renal parenchymal viability in the face of main RA occlusion. whether one or both kidneys are affected and have been studied in
The factors determining the development and caliber of these vessels animal models in which RA perfusion is reduced by clipping the vessel
are poorly understood but include individual anatomy, status of the proximally. The nomenclature distinguishes between a situation in which
aorta, rate of progression of main RA narrowing, and condition of the one clip is present with a normal contralateral unclipped kidney
intrarenal perforating arteries. (“1-clip–2-kidney hypertension”) and a situation in which the entire
renal mass is affected (“1-clip–1-kidney hypertension”). Both these
CLINICAL SYNDROMES ASSOCIATED WITH situations begin with impaired renal perfusion and initial activation of
RAAS with sodium retention. However, in the 1-clip–2-kidney hyper-
RENAL VASCULAR DISEASE tension model, the elevated pressure generated by RAAS activation
Reduction or loss of renal arterial or venous blood flow is associated mediates a pressure natriuresis in the nonstenotic kidney. This restores
with one or more distinct clinical syndromes. These are summarized plasma volume and results in sustained hypoperfusion of the postste-
in Box 41.1. Discussion of these syndromes as distinct entities is meant notic kidney and RAAS activation. This sequence of events produces
to help with recognition and understanding. However, more often in angiotensin II (Ang II)-dependent hypertension (Fig. 41.2A).
clinical practice there is significant overlap. The first section will focus By contrast, 1-clip–1-kidney hypertension represents a model in
on the three most common clinical presentations of RA stenosis: reno- which the entire renal mass is exposed to reduced perfusion pres-
vascular hypertension (RVH), ischemic renal disease (IRD), and unstable sure. As a result, sodium retention leads to expanded blood volume
cardiac syndromes. The second section will address the distinct clinical and sustained elevation in pressure, which then restores renal perfu-
presentations of renal infarction, atheroembolic disease, and renal vein sion pressure beyond the stenosis and inhibits RAAS activation (see
thrombosis. Fig. 41.2B).
Box 41.2 lists causes of RVH based on these mechanisms. Some
screening tests for RVH rely on comparison of the different physiologic
RENOVASCULAR HYPERTENSION responses of the two kidneys to maneuvers and are less sensitive in the
A seminal observation in blood pressure (BP) regulation is the observa- setting of bilateral renovascular disease. Also, 1-clip–1-kidney hyperten-
tion that a reduction in renal perfusion pressure activates a series of sion is typically more volume than Ang II dependent. It may be less
hormonal and neuronal responses that raise systemic arterial pressure responsive to RAAS blockade than 1-clip–2-kidney hypertension.
to restore RA perfusion pressures.3 RVH is defined as a syndrome of A fall in renal perfusion pressure sufficient to activate the RAAS
elevated BP (systolic and/or diastolic) produced by any condition that occurs when luminal stenosis is relatively severe, usually in the range
leads to reduced perfusion of the kidneys. of at least 60% to 80% cross-sectional diameter reduction (Fig. 41.3).
Central to the pathogenesis of RVH is activation of the renin- In experimental models, the relative importance of pressor mechanisms,
angiotensin-aldosterone system (RAAS) with release of renin from the including measurable activation of the RAAS, changes with time.
juxtaglomerular apparatus. This is mediated in part by stimulation of Levels of circulating plasma renin activity tend to decrease. Several
neuronal nitric oxide (NO) synthase and cyclooxygenase-2 in the macula mechanisms have been proposed to explain such changes, including a
densa. Blockade of RAAS during creation of an experimental RA stenosis slowly developing pressor action of Ang II, transition to alternative
482
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CHAPTER 41 Renovascular Hypertension and Ischemic Nephropathy 483
pressor mechanisms, and hypertensive injury to the nonstenotic kidney.

Renal Collateral Blood Supply In experimental models, this translates into a time limit for reversibility
of RVH by removal of the clip. Clinically, this makes it difficult to
determine when patients are most likely to benefit from endovascular
or surgical RA revascularization.
Recent guidelines emphasize the need for effective population-wide
Intercostal BP control while limiting the cost of evaluation and management. As
artery a result, most patients with hypertension simply are treated and sub-
Adrenal jected to few laboratory investigations. For those who reach target BP,
artery no further studies are performed. Widespread application of RAAS
blockers in the management of hypertension, congestive heart failure
(CHF), and diabetic and other proteinuric nephropathies has increased
the exposure of individuals with undetected RVH to these agents. There-
Gonadal
fore many cases of RVH go undiagnosed unless hypertension becomes
artery more difficult to control or kidney dysfunction develops. Patients who
typically undergo diagnostic evaluation for RA stenosis are a subset of
patients with more severe or resistant hypertension or those presenting
Lumbar with unstable renal or cardiac syndromes.
artery
BOX 41.1 Clinical Syndromes Associated

Ureteral
artery With Renovascular Disorders
• Renovascular hypertension • Renal infarction
• Ischemic renal disease • Atheroembolic renal disease
Fig. 41.1 Renal collateral circulation. Diagrammatic representation • Unstable cardiac syndromes • Renal vein thrombosis
of the potential collateral arterial vessels to the kidney.
Unilateral Renal Artery Stenosis Bilateral Renal Artery Stenosis
Stenosis of
Bilateral solitary kidney
Reduced renal perfusion Increased renal perfusion
Reduced renal perfusion

↑ Renin-angiotensin system (RAS) Suppressed Increased
↑ Renin RAS Na+ excretion
↑ Angiotensin II (pressure natriuresis)
↑ Aldosterone ↑ Renin-angiotensin system (RAS) Impaired Na+ and
↑ Renin water excretion
↑ Angiotensin II
↑ Aldosterone Inhibit RAS
Angiotensin II dependent
hypertension Volume expansion
Normal or low angiotensin II
Increased arterial
pressure
Effect of blockade of RAS Effect of blockade of RAS
Reduced arterial pressure Reduced arterial pressure only after volume depletion
Enhanced lateralization of diagnostic tests May lower GFR
Glomerular filtration rate (GFR) in stenotic kidney may fall
Diagnostic tests Diagnostic tests
Plasma renin activity elevated Plasma renin activity normal or low
Lateralized features, e.g., renin levels in renal veins, Lateralized features: none
captopril-enhanced renography
A B
Fig. 41.2 Pathogenesis of renovascular hypertension in one-kidney versus two-kidney model.
(A) In unilateral stenosis with two kidneys, opposing forces between the stenotic kidney, which has reduced
perfusion pressures, and the nonstenotic contralateral kidney, which has increased perfusion pressures,
result in laboratory and clinical features of angiotensin-dependent hypertension. (B) In unilateral stenosis with
a solitary functioning kidney or in a patient with bilateral critical renal artery stenosis, reduced perfusion
pressure to the stenotic kidney in the absence of a normal kidney excreting sodium leads to sodium and
volume retention, ultimately associated with hypertension without persistent activation of the RAS.
484 SECTION VII Renovascular Disease
Hemodynamic Effects of Stenotic Lesions
Blood flow and Perfusion pressure

renal stenosis and stenosis
100 100
Blood flow (% of normal)
Perfusion pressure (%)

80 80
60 60
40 40
82% 80%
20 20
0 0
0 20 40 60 80 100 0 20 40 60 80 100
Stenosis (%) Stenosis (%)
Fig. 41.3 Hemodynamic effects of stenotic lesions. Changes in blood flow and arterial pressure across
a carefully quantitated arterial lesion are barely detectable until cross-sectional area diminishes by 75%
to 80%.
BOX 41.2 Classification of BOX 41.3 Clinical Features of

Renovascular Hypertension Renovascular Hypertension
Two-Kidney Hypertension* • Activation of renin angiotensin system (early)
• Unilateral fibromuscular dysplasia • Early-onset (<30 years) or late-onset (>60 years) hypertension
• Unilateral atherosclerotic renovascular disease • Activation of sympathetic nervous system
• Renal artery aneurysm • Abnormal circadian rhythm: Loss of nocturnal fall
• Renal artery embolism and infarction • Secondary aldosteronism: Hypokalemia
• Traumatic arterial occlusion • Accelerated target organ damage
• Arteriovenous fistula • Microvascular disease
• Renal artery dissection or thrombosis • Left ventricular hypertrophy
• Aortic dissections with compromise to renal ostium • Renal injury
• Page kidney • Hyponatremic hypertensive syndrome
• Takayasu arteritis • Unstable cardiac syndromes
• Metastatic tumor compressing renal parenchyma • Rarely, nephrotic range proteinuria
• Pheochromocytoma compressing renal artery
• Phakomatosis pigmentovascularis type IIb
• Neurofibromatosis
• Behçet disease Clinical differentiation of RVH and primary hypertension is dif-
• Covering of origin of renal artery by aortic stent graft ficult, and they may be superimposed. RVH secondary to unilateral
• Renal artery spasm RA stenosis, for example, often can be easily controlled with the use
of RAAS blockers. Certainly, some cases of RVH present with acceler-
One-Kidney Hypertension† ated, resistant, or hypertension urgency or emergency. Clinical studies
• Stenosis to solitary kidney suggest that for any level of BP, patients with RVH have higher nocturnal
• Bilateral arterial stenosis or dissection pressures (“nondippers”) and have more severe target organ manifes-
• Coarctation of the aorta tations such as left ventricular hypertrophy (LVH) and albuminuria,
• Vasculitis involving renal arteries than patients with essential hypertension.7 Patients with RVH may
• Congenital vascular anomalies present with hypokalemia and metabolic alkalosis, clues to secondary
• Atheroembolic renal disease aldosteronism. Clinical suspicion for RVH arises when hypertension
develops either very early (<30 years) or later in life (>70) or when BP
*Two-kidney hypertension implies that a contralateral, nonaffected that was previously easily or well controlled becomes more resistant.
kidney is present.
† Some cases of RVH may rarely be associated with renin-mediated and
One-kidney hypertension implies that the entire renal mass is
beyond the vascular lesion, either bilateral disease or a solitary
hemodynamically induced nephrotic range proteinuria that regresses
functioning kidney. with treatment. A syndrome of polydipsia associated with hyponatremia
attributed to the dipsogenic action of Ang II also has been observed
in patients with RVH. Clinical features of RVH are summarized
in Box 41.3.
tissue deposits result in discrete stenoses alternating with aneurysmal

Renal Artery Stenosis sections characterized by fragmented internal elastic lamina. This pro-
The most common cause of RVH is RA stenosis. RA fibromuscular duces the recognizable “string of beads” appearance on angiography as
dysplasia (FMD) and atherosclerotic disease are the two most common shown in Fig. 41.4. The loss of elastic structural integrity leads to bal-
causes of RVH. The unique clinical presentations of inflammatory looning or beading of the vessels such that the diameter of the beaded
arteritides as exemplified by Takayasu arteritis (TA) and aortic coarcta- segment is larger than the diameter of the artery lumen. RA aneurysms
tion also will be discussed. may develop in patients with FMD, and 17% of patients with an aneu-
rysm at any vascular site have more than one vascular site involved,
Fibromuscular Dysplasia with some having up to four. FMD generally involves the segment of
FMD is a noninflammatory, nonatherosclerotic arteriopathy character- RA beyond the first 2 cm from the ostium. FMD and atherosclerotic
ized by arterial medial smooth muscle cell proliferation and fibrosis. It renovascular disease may coexist.15
is the most common cause of RVH in children and young adults. FMD The most common adult clinical presentation is early-onset hyper-
is defined by pathognomonic arteriographic aberrancies involving the tension in young to middle-aged women. Cerebrovascular lesions may
middle to distal RA or branches. The vascular distribution of FMD manifest with headaches, pulsatile tinnitus, and bruits over the carotid
involves primarily the renal and cerebral arteries. RAs are involved with arteries, epigastrium, or femoral regions. FMD should be considered
FMD in 65% to 80% of cases. Bilateral RA involvement is seen in 25% in younger patients presenting with hypertension and stroke, transient
to 35% of adult cases, in up to 78% of syndromic childhood FMD, and ischemic attacks, subarachnoid hemorrhage, or amaurosis fugax. Clinical
in most familial cases.8 Cerebrovascular involvement is present in up presentations of FMD and associated disorders are shown in Box 41.4.
to 65% of adult cases with renovascular FMD.9 Less common extrarenal The natural history of FMD has not been adequately studied. Pro-
sites of involvement with FMD include coronary, mesenteric, celiac, gression of disease may manifest with new focal lesions within the same
splenic, aortic, and peripheral vasculature. arterial bed, worsening arterial luminal narrowing within a specific
The prevalence of clinically apparent renovascular FMD is estimated lesion, involvement of a new vascular territory, or development or
at 4 in 1000.10 Data from screening angiography in potential kidney enlargement of arteriovenous fistulas or aneurysms. Up to 37% of
donors suggest that the prevalence may be higher, with FMD observed patients may demonstrate angiographic progression of FMD.16 This
in 3.8% to 6.6% of individuals.11 About 90% of FMD cases occur in appears to be limited to younger patients, with few patients developing
women. Of those enrolled in the U.S. registry of patients with FMD, new or progressive lesions after the age of 40 years. Progression may
95% are White, and the mean age of onset of hypertension is 43 years.12 be associated with kidney cortical thinning, but rarely causes advanced
This racial predilection could represent recruitment or geographical kidney failure.
bias. Familial FMD occurs in approximately 10% of patients and has
been associated with subclinical evidence of carotid flow abnormali- Atherosclerotic Renal Artery Stenosis
ties in first-degree relatives, consistent with an autosomal dominant Atherosclerotic RA stenosis is the most common cause of RVH in patients
inheritance pattern.13 FMD also may complicate hereditary and collagen over the age of 50. Estimates of the prevalence of atherosclerotic RA
vascular syndromes. stenosis depend on the population screened. One population-based
The pathophysiology of FMD is unknown. It is likely that numerous study of 870 patients older than 65 screened with RA duplex ultrasound
disturbances in vascular collagen and structural processes can result in found a 6.8% prevalence of atherosclerotic RA stenosis defined as greater
the FMD angiographic phenotypes. No unifying genetic mutation has than 60% stenosis.17 Autopsy series report an overall prevalence of 4%
been identified. Other factors implicated in the etiology of FMD include to 20%, with progressively higher rates for those older than 60 years
cigarette smoking, hormonal influences (based on the female predilec- (25% to 30%) and 75 years (40% to 60%). It has been estimated that
tion), and vascular trauma or stretching of the RA during development.14 atherosclerotic RA stenosis is a contributor to the development of end-
Histologically, abnormal vascular wall structure is associated with stage renal disease (ESRD) in up to 22% of incident ESRD. Among
irregular bands of collagen deposits and in some cases disruption of patients with chronic CHF, RA stenosis has been reported in up to
the elastic membrane. In up to two thirds of cases more than one arte- 50%.18
rial wall layer is involved. The histologic features coincide with the Atherosclerotic RA stenosis generally occurs in patients with more
arteriographic phenotypes outlined in Table 41.1. The most common generalized atherosclerosis involving the aorta, peripheral vasculature,
variant of FMD is medial fibroplasia, accounting for 85% to 100% of and coronary arteries.19 In patients undergoing coronary angiography,
cases. Here, alternating thin and thick ridges of collagen and elastic coexistent RA stenosis is found in 11% to 16% and in up to 42% of
TABLE 41.1 Histologic Classification of Fibromuscular Dysplasia and Angiographic Phenotypes

Type Frequency (%) Histology Angiographic Appearance
Medial “String of beads”
Medial fibroplasia 85-100, most common Alternating ridges of collagen/loss of elastic Medial: Bead diameter is larger than lumen diameter
membrane
Perimedial fibroplasia Rarer (10-15) Perimedial: Bead diameter is smaller than lumen diameter
Medial hyperplasia Rarest True smooth muscle hyperplasia: No fibrosis Medial hyperplasia: Smooth stenosis without beads
Intimal <10 Circumferential deposition of collagen in intima: Concentric smooth stenosis: Long smooth narrowing
Fragmented or duplicated internal elastic lamina
Adventitial <1 Dense collagen replaces fibrous tissue in Smooth stenosis or diffuse attenuation of vessel lumen
adventitia and surrounding tissue
A B
Fig. 41.4 Fibromuscular dysplasia. (A) Selective renal arteriogram illustrating the beaded appearance of
fibromuscular dysplasia with multiple webs characteristic of medial fibroplasia in a 39-year-old woman. (B)
Selective injection of the same renal artery after technically successful percutaneous transluminal renal
angioplasty. (Courtesy Michael McKusick, MD, Mayo Clinic, Rochester, Minn.)
patients undergoing peripheral angiograms.20 Predictors of RA stenosis

BOX 41.4 Clinical Manifestations include a history of hypertension, presence of CKD, coexisting peripheral
and Disorders Associated With vascular or coronary artery disease, the presence of abdominal bruits,
Fibromuscular Dysplasia and a history of smoking. Atherosclerotic RA stenosis is bilateral in
Clinical Manifestations 20% to 40% of patients. In many of these cases, the degree of stenosis
• Incidental finding (e.g., living • Neck pain is below the threshold to cause activation of RAAS or have other clinical
kidney donors) • Dizziness implications. Given its association with older age and more diffuse
• Renovascular hypertension • Imaging finding of aneurysm atherosclerosis, atherosclerotic RA stenosis is associated with increased
• Renal infarction dissection cardiovascular and mortality risk.21 Accordingly, the identification of
• Loin or flank pain • Amaurosis fugax atherosclerotic disease should prompt clinical attention to cardiovascular
• Hematuria • Myocardial infarction risk factors, including the use of high-dose statin therapy, efforts to
• Retroperitoneal hemorrhage • Ischemic chest pain/dyspnea promote smoking cessation, and optimal control of BP and metabolic
• Cerebrovascular accident (stroke) • Postprandial abdominal pain syndrome.
• Transient ischemic attack • Weight loss Some patients with atherosclerotic RA stenosis will experience pro-
• Headaches • Hemobilia gressive RA luminal narrowing and develop RVH or other clinical
• Pulsatile tinnitus • Claudication syndromes described later. Progression is usually defined as a greater
• Horner syndrome than 25% further luminal diameter narrowing or progression to vascular
occlusion. Prospective studies between 1990 and 1997 using Doppler
Associated Disorders
ultrasound in patients with atherosclerotic RA stenosis indicated pro-
• Tuberous sclerosis • Cigarette smoking
gression in 30% over 3 years, varying by degree of initial stenosis, with
• Marfan syndrome • Collagen III glomerulopathy
progression more common in those with more than 60% stenosis. Total
• Ehlers-Danlos syndrome • Atherosclerotic renovascular
occlusion is rare, reported in only 3%.22 Statins appear to reduce the
• Cystic medial necrosis disease
risk for progression and occasionally induce regression of stenosis.23
• Coarctation of the aorta • Alagille syndrome
There are few prospective data assessing progression in patients treated
• Alport syndrome • Ask-Upmark kidney
with optimal medical therapy targeting atherosclerotic risk factors
• Renal agenesis or dysgenesis • Celiac disease
in the modern era. Atherosclerotic RA stenosis often presents as
• α1-Antitrypsin deficiency • Cocaine exposure—intrauterine
RVH but also is associated with other clinical syndromes that will be
• Medullary sponge kidney • Crohn disease
described later.
• Pheochromocytoma • Homocystinuria
• Infantile myofibromatosis • Macrophagic myofasciitis
Takayasu Arteritis
• Ergotamine preparation, • Neurofibromatosis
Initially described in 1761, TA, often termed pulseless disease, is one of
methysergide • Williams syndrome
several inflammatory disorders involving the renal vasculature causing
RVH. Though rare in the United States, its prevalence varies geographi-
cally, with reports as high as 1 in 3000 in Japan.24 TA usually presents
between the ages of 25 and 41 years but, like FMD, can present in
childhood. It most often presents as RVH and should be considered in
any child or young adult with hypertension and/or asymmetric periph-
eral pulses or bruits. Concomitant inflammatory aortic coarctation may
be present. In half of cases, identification of arterial stenosis is preceded
by a prodromal illness characterized by fever, night sweats, malaise,
and weight loss. Inflammatory markers are often elevated during
this phase. After this active inflammatory phase, vascular stenoses can
lead to sequelae including RVH, kidney dysfunction, stroke, cerebral
hemorrhage, myocardial infarction, or CHF, depending on sites of
involvement.
Diagnostic criteria are still somewhat controversial. The diagnosis
requires arteriographic narrowing or occlusion of a vascular territory
of the aorta, its branches, or large arteries not attributable to athero-
sclerosis, middle aortic syndrome, or FMD. One distinguishing angio-
graphic feature of TA is the presence of inflammatory thickening or
edema of the vascular wall seen on magnetic resonance angiography
(MRA), computed tomographic angiography (CTA), or duplex or posi-
tron emission tomography.25
The pathophysiology of TA is unclear. Theories include autoim- Fig. 41.5 Middle aortic syndrome. Angiogram showing typical smooth
munity and hypersensitivity response to a variety of proposed antigens, narrowing of the aorta. Bilateral stenosis of paired renal arteries is present.
including heat shock protein and Mycobacterium tuberculosis. Histologi- (From Panayiotopoulos YP, Tyrrell MB, Koffman G, et al. Mid-aortic syn-
cally, granulomatous inflammation involves all layers of the vessel wall drome presenting in childhood. Br J Surg. 1996;83:235-240.)
during the active phase of disease, followed by fibrotic stenosis.
Treatment is controversial but generally starts with corticosteroids
or other immunomodulatory therapy during the inflammatory phase
of disease followed by medical or interventional treatment to reduce A rare entity, middle aortic syndrome is a segmental or diffuse nar-
organ ischemic injury.24,26 rowing of the abdominal or distal descending aorta, causing RVH usually
noted in infancy (Fig. 41.5). Concomitant proximal RA stenosis occurs
Coarctation and Middle Aortic Syndrome in up to 80% of cases, with variants including RA atresia, hypoplasia,
Coarctation occurs in about 1 in 1550 births and accounts for about or dysplasia.28 The cause is congenital in many cases, but associations
one third of all causes of RVH in infants. Yet, only 35% of isolated with FMD, congenital anomalies, neurofibromatosis, Williams syndrome,
coarctation cases present during the first year of life, and milder forms and TA have been reported and these cases can present later in life.
may be missed in childhood. Furthermore, cases treated in childhood Middle aortic syndrome can cause claudication of the lower extremities
can develop restenosis of the coarct segment later in life. It is estimated as well as mesenteric ischemia. Angioplasty and stenting of stenotic
that 1 in 150 adults have congenital heart disease, with aortic coarcta- segments, surgical bypass grafting, and autotransplantation of ischemic
tion comprising 5% to 10%. organs are among the approaches to treatment of this disorder.
Adult presentations of RVH associated with coarctation include
signs and symptoms of collateral development. Bruits may be heard Renal Artery Aneurysms
over the carotids, and intercostal pulses may be palpable. A radial- RA aneurysms are a rare cause of RVH that is present in up to 75% of
femoral pulse delay is a sensitive physical examination finding. Present cases. Aneurysms are associated with atheromatous, fibromuscular, and
in only about 50% of cases, a harsh systolic blowing murmur is heard vasculitic RA disease. Thrombosis within an aneurysm can lead to distal
best over the posterior thorax. Although echocardiography with Doppler emboli and renal infarcts. Aneurysms with diameters of more than
flow analysis with special attention to the aortic arch provides excellent 1.5 cm have a higher risk for rupture. Elective repair of large renal
diagnostic accuracy in infants, MRA or CTA is necessary to confirm aneurysms should be considered in women of childbearing age because
coarctation in adults. Indications for the treatment of coarctation in of the risk for rupture during the third trimester of pregnancy. Other
adults include upper limb hypertension and a greater than 20 mm Hg complications of RA aneurysms include vessel dissection and arterio-
systolic BP gradient across the stenosis with evidence of significant venous fistula formation.
collateral flow. These patients have a fivefold risk for cerebral aneurysms,
and screening cerebrovascular CTA or MRA is recommended. Current
guidelines recommend multispecialty consultation among cardiologists,
ISCHEMIC RENAL DISEASE
interventionalists, and surgeons to determine the optimal approach Activation of the RAAS can occur without loss of kidney function.
(endovascular vs. surgical) to repair. Success rates in terms of cure of However, a common clinical scenario in patients with atherosclerotic
hypertension range from 69% to 80%, with highest chance for cure RA stenosis is the presence of both hypertension and kidney dysfunc-
and best survival data when treated in childhood under the age of 10. tion. In recent randomized controlled trials evaluating treatment options
In adults with prior coarctation, the risk for late-onset hypertension for atherosclerotic RA stenosis, 40% to 50% of the enrolled patients
exceeds that in the general population. Causes of this late hypertension had concomitant CKD. In clinical practice, it remains difficult to dis-
include vascular noncompliance, reduced aortic arch baroreceptor sen- tinguish CKD secondary to hypertensive nephrosclerosis from reduced
sitivity, early kidney injury with sustained RAAS activation, and, in kidney function resulting from atherosclerotic RA stenosis, sometimes
some cases, development of restenosis of the repaired coarct segment.27 called IRD.
The term IRD has been used to describe both the hemodynamic pressure and Ang II. In some cases, the kidney with the patent RA has
and structural consequences of reduced RA perfusion on the kidney. worse function than the poststenotic kidney.35
Critical RA stenosis or occlusion can lead to reduced glomerular filtra- The diagnosis of IRD always should be considered in patients with
tion rate (GFR) by reducing renal blood flow and hence glomerular known RA stenosis who present with rapidly declining renal function
capillary pressure below the level of renal autoregulatory compensation. or episodes of AKI. In patients with high-grade RA stenosis, AKI can
GFR improves once perfusion pressure is restored. The term ischemic follow normalization of systemic BP with any agent. The sudden reduc-
is a misnomer in this context. Indeed, basal kidney energy requirements tion in systemic BP can reduce RA pressure below levels needed to
are met with less than 10% of renal blood flow. When there is reduced sustain GFR. With the use of RAAS inhibitors, these alterations in glo-
perfusion to a kidney, energy delivery tends to match filtration and merular hemodynamics may be more common or pronounced.36 Nor-
transport functions. Reductions in GFR and associated energy-dependent mally, activation of Ang II causes efferent arteriolar vasoconstriction,
solute transport allow adaptation to reduced blood flow without devel- which preserves transcapillary filtration pressures at the glomerulus
opment of tissue hypoxia. Studies using blood oxygen level–dependent when preglomerular pressures are reduced, thereby maintaining GFR.
magnetic resonance imaging (MRI) indicate that, despite reductions The loss of this compensatory mechanism induced by agents that inhibit
in blood flow and GFR, many patients with RA stenosis maintain normal or block the RAAS can result in functional AKI. This typically occurs
renal cortical and medullary tissue oxygenation.29 Thus many postste- within a few days from the start of therapy and is usually, but not
notic kidneys have no more ischemia than normal kidneys. These always, reversible. This change in GFR after initiation of RAAS inhibi-
observations explain the relative stability and infrequent progression tors is not specific for the presence of RA stenosis and is seen frequently
of kidney injury in prospective trials of medically treated patients with in patients with cardiac or hepatic dysfunction or patients with intra-
atherosclerotic RA stenosis. vascular volume depletion because, in these settings, maintenance of
However, under more chronic conditions of reduced blood flow GFR is also Ang II dependent.37
with persistent filtration and tubular function, levels of deoxygenated
hemoglobin may increase in the renal medulla, representing true med- HEART FAILURE AND UNSTABLE
ullary hypoxia beyond that which is physiologic.30,31 When more severe
vascular occlusion develops beyond the limits of functional adaptation,
CARDIAC CONDITIONS
ischemia develops. Some patients with RA stenosis present with recurrent episodes of
Reduced renal perfusion and ischemia ultimately activate numerous relatively sudden onset “flash” pulmonary edema.38 This has been attrib-
mechanisms of tissue injury. 32 This results in macrophage accumulation uted in part to rapid loss of contractile strength of the left ventricle
with progressive tubular cell loss and fibrosis.33 Glomeruli are usually caused by sudden increases in afterload. Many of these patients have
preserved but often appear collapsed. The ischemic kidney develops hypertensive urgency or emergency, hypervolemia resulting from aldos-
microvascular rarefaction contributing to ongoing irreversible structural terone excess and effects of Ang II on sodium reabsorption, and echo-
and functional changes.34 Often, the kidney atrophies with time. The cardiographic evidence of diastolic dysfunction.39 Such patients have
term IRD comprises both the potentially reversible hemodynamic com- increased mortality and hospitalization rates compared with those who
ponent and these adaptive and structural changes, some of which will have CHF without renovascular disease.40 Case series and retrospective
not be reversible by merely revascularizing the kidney. reviews suggest that renal revascularization can facilitate fluid volume
Clinical presentations that should prompt consideration of the pres- management, reduce hospitalizations, and improve GFR and cardiac
ence of IRD are outlined in Box 41.5. IRD can present as CKD or acute function in this high-risk subgroup of patients with atherosclerotic RA
kidney injury (AKI). IRD should be considered in the setting of unex- stenosis.41,42 However, in two large prospective trials comparing medical
plained CKD in patients with generalized atherosclerosis, resistant or therapy to RA stenting in atherosclerotic RA stenosis, endovascular
accelerated hypertension, or small or asymmetric kidneys. Unilateral treatment did not confer a protective effect on cardiovascular end-
atherosclerotic RA stenosis may lead to atrophy of the poststenotic points, including hospitalizations for CHF.43,44 However, this cohort of
kidney. The contralateral kidney with a patent RA often hypertrophies patients was underrepresented in randomized controlled trials. Some
and compensates with hyperfiltration. However, over time, this kidney believe that chronic stimulation of the RAAS secondary to RA stenosis
develops parenchymal injury mediated by the combined effects of high contributes to the abnormal left ventricular remodeling in patients with
chronic systolic heart failure as well as the frequency of episodes of
decompensation.45
Finally, some patients with RA stenosis and LVH can present with
BOX 41.5 Clinical Presentations of chest pain syndromes with no significant lesions in the coronary arteries
Ischemic Renal Disease Associated With (although microvascular disease may be present).
Atherosclerotic Renal Artery Stenosis
• Acute kidney injury with control of blood pressure: angiotensin-converting IMAGING RENOVASCULAR HYPERTENSION
enzyme inhibitors or angiotensin receptor blockers AND RENAL ARTERY STENOSIS
• Acute kidney injury with aggressive diuresis in patients with congestive
heart failure Conventional direct angiography remains the reference standard to
• Chronic kidney disease otherwise unexplained in atherosclerotic age range define the RA anatomy against which other screening modalities are
• Chronic kidney disease with asymmetric renal size compared. Noninvasive screening options include RA duplex (or Doppler)
• Acute or chronic kidney disease and renovascular hypertension ultrasound, CTA, and MRA, each with their limitations and strengths.
• Acute on chronic kidney injury with episodes of “flash” pulmonary edema RA duplex scanning is often used to identify and follow hemody-
• Unexplained rapid decline in glomerular filtration rate in chronic kidney namic effects of RA stenoses. It is relatively inexpensive and carries no
disease risk. It is most effective in detecting lesions of the main RA near the
• Oligo-anuric kidney failure not otherwise explained in a patient with ath- ostium and thus is better for identifying atherosclerotic RA stenosis
erosclerosis and hypertension than FMD. The reliability of duplex ultrasound depends on the skill
and experience of the operator and the body habitus of the patient.
Duplex ultrasound provides little functional information regarding the

kidney beyond the vascular lesion, although structural features such as
kidney size and echogenicity can be determined. The duplex diagnostic
criteria for hemodynamically significant RA stenosis consider the com-
parative rates of blood flow in the stenotic area to that in the remaining
segments of the RA and the aorta. Parameters measured include peak
systolic velocity (PSV) at various sites along the RA and in the suprarenal
aorta; the renal aortic ratio (RAR), which compares the PSVs at these
segments; acceleration time and index, which help evaluate the RA
wave form; and the intrarenal resistive index (see Chapter 5). The resis-
tive index has been associated with intrinsic small vessel renal disease,
and a value greater than 80 has a strong negative predictive value on
likelihood of BP response to intervention.46 Normal PSV in the RA will
depend on the lumen diameter of the vessel and ranges from about
120 to 160 cm/sec. PSV readings greater than 200 to 220 cm/sec and a
RAR greater than 3.5 usually indicate RA stenosis of greater than 60%
narrowing.47,48 Clinicians should be aware of the significant heterogene-
ity among vascular laboratories in terms of how the data are reported.
Most laboratories provide assessment of whether parameters support
at least 60% luminal diameter narrowing. More precise assessments are
not usually provided. Generally, the higher the PSV, the more severe is
the stenosis. Clinicians should be familiar with aortic and RA velocities
and waveforms to evaluate the validity of these interpretations. For A
example, a very blunted RA waveform can represent critical RA stenosis
in the absence of an elevated PSV. RA duplex allows for serial testing,
hence monitoring for progression and changes in kidney size. It is the
preferred test for evaluating for restenosis of a stented RA segment.
Three-dimensional MRA with gadolinium enhancement provides
excellent visualization of the arteries and functional information about
the kidneys (Fig. 41.6). Limitations include interobserver variability, a
tendency to overestimate luminal narrowing, interference by motion
and breathing artifact, and limited sensitivity for middle and distal
vascular lesions and small accessory vessels. MRA is less sensitive than B
CTA for the diagnosis of FMD.49 It has the advantage of avoiding radia-
tion exposure. Caution is advised in the use of gadolinium agents in Fig. 41.6 Magnetic resonance angiogram with and without gado-
patients with reduced GFR, based on reports of nephrogenic systemic linium contrast enhancement. (A) High-grade stenosis affecting the
fibrosis in patients with advanced CKD exposed to these agents. Some left inferior renal artery is evident, with functioning kidney tissue as
reflected by gadolinium nephrogram (arrow). Concerns about the role
centers have reported success in the use of modified steady-state free
of gadolinium in the development of nephrogenic systemic fibrosis have
precession MRA pulse sequences without contrast for visualization of
greatly reduced the use of this contrast agent. (B) As a result, methods
RA stenoses. to image the vasculature without contrast material are being developed
CTA with vascular reconstruction provides imaging definition nearly that produce excellent reconstructed images (arrow).
equal to that of conventional angiography but requires significantly
more contrast, usually 100 to 125 ml. Focal vascular calcification often
obscures accurate assessment of stenoses. CTA is highly sensitive for
identifying lesions in the mid and branch vessels often associated with
FMD and is a good screening test for these patients who generally have kidney and demonstrates the rate of isotope appearance as an index of
good kidney function. renal blood flow and filtration. It detects the presence of a differential
Angiography remains the gold standard for defining the degree role of Ang II on GFR between the kidneys. This test has a high negative
of stenosis associated with atherosclerotic RA stenosis and for confir- predictive value for the presence of RVH when completely normal.50
mation of FMD or other arteritides. It is the most reliable modality Fig. 41.7 illustrates a captopril-enhanced renogram in a patient with
for identifying distal and branch or small vessel disease, which may RA stenosis. This examination provides no direct image of the renal
be missed by other screening modalities. Aortography provides the vessel. Many intrinsic renal abnormalities unrelated to the main RA
opportunity to measure pressure gradients across a stenosis, an aide in may change these curves, which limits its value in the presence of reduced
determining the hemodynamic significance of a lesion. When there is kidney function.
complete proximal arterial occlusion, direct aortography can identify Renal vein renin measurements may help predict the BP response
distal reconstitution by collateral and a renal “blush” confirming paren- to renal revascularization. Previous studies indicated that lateralization
chymal viability. Limited selective renal angiography can be performed of renal vein levels (>1.5 : 1 stenotic-to-nonstenotic kidney ratio) predicts
with as little as 20 ml of contrast. In cases at highest risk for contrast- a favorable BP response for more than 90% of patients. Because failure
induced AKI, carbon dioxide can be used instead of nonionic iodinated to lateralize also carried a favorable response in almost half of patients,
contrast. the negative predictive value is limited. Some clinicians use these mea-
In cases of unilateral RA disease, captopril renography provides surements to verify the role of a pressor kidney before undertaking
functional information regarding the size and excretory capacity of the nephrectomy.
revascularization may be required. Endovascular management can

Captopril-Enhanced Renography sometimes be achieved by use of covered stents. Women of childbearing
age with RA aneurysms should be treated before pursuing pregnancy
because of the risk for rupture during pregnancy or delivery.
The optimal treatment of atherosclerotic RA stenosis presenting
with RVH or other clinical syndromes has been the subject of much
controversy. In the early 1990s, before the widespread use of RAAS
blockade in the treatment of RVH, endovascular approaches to treating
atherosclerotic RA stenosis emerged as an option for managing RA
stenosis. Initially application of PTRA was associated with unacceptable
rates of early restenosis. Subsequently, primary percutaneous renal artery
stenting (PTRS) became standard treatment in many centers. Target
vessel patency rates using PTRS regularly exceeds 95%. Between
A 1996 and 2005, enthusiastic application of PTRS in the treatment of
atherosclerotic RA stenosis led to a marked rise in stent placement in
Appearance Peak
right left right left
these patients. Most case series and observational studies reported sta-
60,000 bilization of BP and renal function in half of patients undergoing PTRS,
54,000 Delayed isotope improvement in up to 25%, and a decline in kidney function after
48,000 excretion of left kidney PTRS in 25%.
42,000 The relative effectiveness of endovascular treatment of RA stenosis
Activity (counts)
36,000 compared with medical therapy has now been studied in several ran-
30,000 domized controlled trials. These are summarized in Table 41.2. The
24,000 two largest trials, the Angioplasty and Stent for Renal Artery Lesions
18,000 (ASTRAL) and Cardiovascular Outcomes in Renal Atherosclerotic Lesions
12,000 (CORAL), comparing medical therapy and stenting to medical therapy
Left kidney alone demonstrated no differences in the primary end-points between
6000 Right kidney
0 groups.43,44,53 The end-points were different for the two studies. In
0 3 6 9 12 15 18 21 24 27 30 ASTRAL, 806 subjects with hypertension, many with CKD, were ran-
Time (min) domized to PTRS versus medical therapy and followed for a mean of
B 33.6 months. Of the enrolled patients, 53% had bilateral RA stenosis;
Fig. 41.7 Captopril-enhanced renography. (A) Scan in a patient the mean degree of luminal narrowing was 75.5%. ASTRAL reported
with newly developing hypertension. (B) Renogram demonstrates delayed no difference in the primary end-point of change in kidney function
arrival and excretion of isotope (MAG3) in the affected left kidney.
as measured by reciprocal creatinine. CORAL investigators enrolled
947 patients, all treated with well-defined medical therapy addressing
all cardiovascular risk factors, used RAAS blockade as the cornerstone
TREATMENT OF ATHEROSCLEROTIC of antihypertensive therapy, and randomized half the group to medical
RENAL ARTERY STENOSIS AND therapy plus stent. CORAL had an imaging oversight laboratory and
allowed enrollment based on angiographic as well as CTA, MRA, and
FIBROMUSCULAR DYSPLASIA
duplex ultrasound definition of RA stenosis greater than 60%. At a
Because RA FMD usually presents early in life and endovascular therapy median of 43 months of follow-up, there were no differences in the
has a high rate of cure of hypertension, FMD of hemodynamic signifi- composite end-point of mortality, cardiovascular and renal events, or
cance should be treated with revascularization. The treatment of choice any of the individual components between the treatment groups.
for FMD is percutaneous renal artery angioplasty (PTRA) usually without Based on these data, the current consensus opinion is that the initial
stenting. Successful PTRA results in disruption of the abnormal collagen treatment of patients with RVH and CKD associated with atherosclerotic
bands in the lumen of the artery and the vascular wall leading to larger RA stenosis should be a focused medical management approach to
lumen diameter and less turbulent RA blood flow. Complete cure, defined addressing all cardiovascular and renal risk factors, including hyperten-
as normalization of BP without the need for medications, occurs in sion. Most patients with RVH secondary to RA stenosis can achieve BP
35% to 45% of cases. In over 85% of cases of FMD treated with PTRA, control by applying antihypertensive algorithms that include the use
BP is improved with reduction in the number of antihypertensive medi- of RAAS blockade. In CORAL, there was no difference in number of
cations.51 Predictors of response to intervention include lower prein- medications required to control BP between groups. For those patients
tervention systolic BP, younger age at treatment, shorter duration of with diabetes and CKD, attention to achieving hemoglobin A1c as well
hypertension, and a positive pretreatment captopril renogram.52 Primary as CKD mineral bone disease and anemia targets are important thera-
technical success rates are high (>90%). Inadequate initial treatment peutic goals associated with their general care. Statins are usually rec-
or restenosis has been reported in up to 34% of treated cases. This is ommended in these patients both for cardiovascular risk reduction and
most common with the string of beads angiographic variant, which is with the goal of slowing progression of the RA lesion; there are also
multifocal and can require more than one procedure to adequately experimental data suggesting that statins attenuate renal parenchymal
address all areas of stenosis. Some interventionalists recommend the injury associated with atherosclerotic renovascular disease.23,54
use of intravascular ultrasound to guide adequate endovascular treat- Whether all patients with RA stenosis should be treated with RAAS
ment of these lesions. The intimal and adventitial variants of FMD are blockade remains controversial.55 RAAS blockers pose the risk for induc-
associated with higher rates of PTRA failure and may require surgical ing AKI, and this risk is higher in patients with bilateral RA stenosis
revascularization for optimal management. When FMD is associated or stenosis to a single functioning kidney.56 Although the unique prop-
with aneurysmal dilatations exceeding 1.5 cm in diameter, surgical erties of RAAS blockers allow more effective BP control in patients
TABLE 41.2 Randomized Controlled Trials Comparing Medical Therapy to Medical Therapy
With Renal Artery Stenting for Renal Artery Stenosis
Year 2009 2009 2014
Study ASTRAL43 STAR44 CORAL53
Cohort Hypertension Hypertension and CKD Hypertension and/or CKD
Entry BP No BP threshold required BP <140/90 mm Hg and stable for 1 SBP >155 mm Hg on two or more
month and eGFR <80 mL/min medications or eGFR <60 mL/min
Stenosis >50% by MRA, CTA, angiography >50% by MRA, CTA, or angiography >60% by MRA, CTA, angiography, DUS
Excluded Clinician certain patient would benefit Malignant hypertension Entry creatinine >4 mg/dl
from stent or require stent within 6 Pulmonary edema with bilateral RAS Kidney Length <7 cm
months Intolerance to ACEI/ARBs as evidenced
by >20% drop in CrCl
% Stenosis 75.5 mean % NA 67.3%/66.2%
CKD Mean creatinine 2.0 mg/dl Mean creatinine 1.7 mg/dl Mean eGFR 58 mL/min
% Bilateral 53.5% 47.9% 22%
Subjects per arm (N/N) 403/403 76/64 459/472
F/u 33.6 months 24 months 43 months
Treatment Stent Stent Stent
Medical treatment At discretion of sites BP control with BP target <140/90 mm Hg BP target <140/90 mm Hg
or without ACEI or ARB ACEI/ARB last resort 130/80 mm Hg for DM and CKD
No specified target BP ASA ACE/ARB first-line
Statin ASA
Smoking cessation counseling Statin goal LDL <70 mg/dl,
HbA1c <7.0% for DM
Smoking cessation counseling
End-point Rate of progression of CKD based on ≥20% decrease in CrCl Composite cardiovascular and renal events
reciprocal creatinine over time
Outcome No significant difference No significant difference No significant difference
From references 43, 44, 53.

ACEI, Angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ASA, aspirin; ASTRAL, Angioplasty and Stenting for Renal
Artery Lesions; BP, blood pressure; CKD, chronic kidney disease; CORAL, Cardiovascular Outcomes in Renal Atherosclerotic Lesions; CrCl,
creatinine clearance; CTA, computed tomography angiography; DM, diabetes mellitus; DUS, Doppler ultrasound; eGFR, estimated glomerular
filtration rate; F/u, follow-up; GFR, glomerular filtration rate; HbA1c, hemoglobin A1c; LDL, low-density lipoprotein; MRA, magnetic resonance
angiography; N/N, number of subjects in each arm; RAS, renal artery stenosis; SBP, systolic blood pressure; STAR, Stent Placement in Patients
with Atherosclerotic Renal Artery Stenosis and Impaired Renal Function.
with RVH, there is the potential for early loss of filtration pressure in
BOX 41.6 Clinical Indications to Consider
patients with critical RA stenosis.
Clinical experience with RAAS blockers in the treatment of RVH is Renal Artery Revascularization
reassuring, however. Registry data and prospective follow-up studies • Worsening kidney function due to ischemic renal disease
in patients with atherosclerotic RA stenosis indicate that blockade of • Uncontrolled hypertension failing medical therapy
the RAAS is usually well-tolerated.57,58 In the CORAL Trial, most patients • Intolerance to medical therapy
received an ARB or ACE inhibitor. The lack of differences in renal • Recurrent hospitalizations for pulmonary edema without other obvious cause
end-points suggests that this was generally well tolerated. However, it • while on optimal medical therapy
is strongly advised that patients with atherosclerotic RA stenosis who • Other unstable cardiac or renal trajectories
are prescribed these agents have electrolytes and creatinine measured • Progressive renal atrophy (controversial)
within 2 to 4 weeks after starting these agents and frequently (at least • Potentially reversible dialysis dependence due to ischemic renal disease
quarterly) over the course of follow-up.
Indications to Consider Renal Revascularization in should prompt evaluation for all potential causes of resistance. Some
Atherosclerotic Renal Artery Stenosis patients will be intolerant of the very medications they need to control
Despite the lack of randomized controlled data and the risks, some BP. Others may present with hypertensive urgency or emergency despite
patients may benefit from RA revascularization when medical therapy therapy. Some of these patients may respond to PTRS. Second, when
falls short. Indications to consider renal revascularization are listed in RA stenosis critically reduces glomerular capillary pressure such that
Box 41.6. First, uncontrolled hypertension despite all efforts to optimize there is a rapid decline in GFR, renal revascularization may improve
pharmacologic and dietary interventions and to enhance adherence or retrieve renal function and avoid the need for dialysis. In these cases,
Evaluation and Management

of Renovascular Disease
Clinical syndrome
suggestive of renovascular disease
• Hypertension (see text)
• Ischemic renal disease
Stable kidney function No ?Progressive disease

BP control ?Total renal mass
Comorbid risk: life expectancy
Noninvasive imaging
Captopril renography
Duplex ultrasound
CTA/?MRA
Yes
No ?Bilateral disease
?High-grade stenosis
?Progressive
Yes
Optimize medical therapy Surgery:
RAAS blockade OR Complex disease
Endovascular: PTRA
with ACEI/ARB, Failed stent
Stent (atherosclerosis)
statin therapy, Aortic disease
smoking cessation, aspirin
BP/Creatinine rise?
Re-image: ?Restenosis
Follow-up imaging
(such as Doppler) to
look for progression
Goal: Stable kidney function,

excellent BP control
Fig. 41.8 Evaluation and management of renovascular disease. The intensity of imaging and revas-
cularization depends on both the level of kidney function and the blood pressure (BP), in addition to the
comorbid disease risks for the individual patient. The overall goal should focus on stable kidney function and
BP levels. As with any other vascular disease, monitoring for disease progression and recurrence is an
important element of long-term management. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin
receptor blocker; CTA, computed tomographic angiography; F/U, follow-up; MRA, magnetic resonance angi-
ography; PTRA, percutaneous transluminal renal angioplasty; RAAS, renin-angiotensin-aldosterone system.
there are often multiple other potential contributors to declining GFR Fig. 41.8 outlines a proposed clinical algorithm for managing patients
that need to be considered. Given the risks for interventions in these with atherosclerotic RA stenosis.
patients, it is advised that a multidisciplinary group of clinicians
with expertise in this area provide recommendations when interven- Surgical Renal Revascularization
tions are considered. Finally, some patients with recurrent hospitaliza- Before the introduction of PTRA and PTRS, surgical revascularization
tions for flash pulmonary edema not resulting from other causes was the standard treatment for patients with IRD and RVH. Such pro-
and attributed to medically resistant RA stenosis may benefit from RA cedures carry considerable risk, cost, and morbidity. As a result, surgical
revascularization.59 intervention for renovascular disease is generally reserved for patients
failing best medical therapy and in whom endovascular therapy is not hyperlipidemia, smoking, and elevated serum creatinine at discharge
feasible or who have associated aortic disease that is not amenable to from transplantation.
endovascular therapy. Despite these caveats, successful surgical revas- Renal duplex ultrasound is the screening test of choice for transplant
cularization in well-selected cases provides durable restoration of kidney RA stenosis because the vessel is superficial and easy to interrogate; the
blood supply with good long-term patient survival.60 Overall, the effects sensitivity and specificity range from 90% to 100% and 87% to 100%,
of surgical revascularization on BP and renal function response in respectively.67 MRA provides excellent anatomic definition but is associ-
patients with atherosclerotic RA stenosis mirror those for PTRS. Surgical ated with clip artifact at the anastomosis and high false-positive rates.
revascularization in the modern era may provide more durable patency CTA is comparable to renal arteriography but requires a large amount
than PTRS with lower complication rates and risk for restenosis.61 of contrast material.
Surgical revascularization should be considered in patients with PTRA with or without stenting is the preferred initial approach to
total occlusion of the RA and abrupt loss of GFR for retrieval of kidney transplant RA stenosis.68 Surgical renal revascularization of allografts is
function. Some dialysis-dependent patients and some with advanced difficult and associated with high complication rates. Extensive fibrosis
CKD with IRD experience recovery of kidney function after revascu- develops around the allograft and often involves the renal vessels, making
larization.62 Treatment involves assessment of the risks versus potential surgical access to the renal vessels risky. Complications include graft
benefits of heroic revascularization procedures. The status of the contra- loss (in 15% to 30% of cases), ureteral injury (14%), and death (5%).
lateral kidney and overall residual kidney function should be weighed
against the potential retrievable function from the underperfused kidney,
as well as the perioperative risk associated with surgical thrombectomy
RENAL INFARCTION
or bypass. Predictors of GFR recovery with revascularization in the Abrupt interruption of blood flow to the kidney without adequate
setting of critical RA occlusion include preserved kidney size, evidence collateral blood supply can result in renal infarction. Small areas of the
of a renal blush or nephrogram by imaging, recent decline in GFR, and cortex or medulla or the entire kidney may be involved. Autopsy series
recent baseline creatinine concentration below 3 mg/dl.63 suggest the incidence is between 0.5% and 1.5%. The most common
When considerable renal atrophy with poor function and RVH presenting symptoms include loin, flank, or abdominal pain with nausea
refractory to optimal medical therapy are present, nephrectomy of and/or vomiting. Urinalysis often demonstrates microhematuria and
the ischemic kidney may improve BP control with minimal impact on proteinuria. Transient or accelerated hypertension (i.e., RVH) may occur
total GFR. as a result of release of renin from the infarcted portion of the kidney.
Transient elevations of the serum creatinine are not uncommon. Sys-
temic signs of renal infarction may be present and include leukocytosis
TRANSPLANT RENAL ARTERY STENOSIS and fever. Up to one quarter of cases are asymptomatic, identified only
Transplant RA stenosis is a common post-transplantation complication by enhancement or functional defects on renal imaging. When bilateral
occurring most often in the period between 3 months and 2 years after occlusion of the renal arteries or infarction of a single functioning
transplantation. The incidence ranges from 1.3% to 23% depending kidney occurs, the patient will present with oliguric or anuric AKI.
on the screening tests used.64 In many cases, anastomotic stenoses are Tissue injury results in elevations of serum enzymes, most commonly
not hemodynamically significant. Renovascular complications, including lactate dehydrogenase, however transaminases, creatine kinase, and
RA stenosis, are more common in deceased donor than in living donor alkaline phosphatase may also be elevated.69-71
transplants and in allografts with multiple renal vessels.65 The use of A high clinical suspicion is required for the diagnosis of renal infarc-
pediatric kidneys in adult recipients is associated with a higher rate of tion because the presenting symptoms are common to those of a number
stenosis because of smaller donor vessel size, leading to greater turbu- of other disorders. CT with intravenous contrast administration is the
lences and mismatch between donor and recipient vessels. As the trans- imaging modality of choice for demonstrating areas of renal cortex
plant population ages, there has been increasing recognition of another that are not perfused. CT findings can include focal wedge-shaped areas
subset of patients with pseudo–transplant RA stenosis, in which vascular of decreased attenuation or global infarction with or without a rim
disease proximal to the allograft artery, particularly involving the iliac sign indicating intact collateral circulation to the renal cortex as dem-
vessel, results in reduced kidney perfusion. onstrated in Fig. 41.9. Perinephric stranding also may be seen. Simul-
The pathophysiologic basis for transplant RA stenosis may include taneous infarcts in the liver and spleen are not uncommon. Other
atheromatous disease in the donor artery, intimal scarring, and hyper- potential imaging techniques include MRA with gadolinium or nuclear
plasia in response to trauma to the vessel during harvesting, and anas- scintigraphy with dimercaptosuccinic acid (DMSA). When the entire
tomotic stenosis, which is most commonly associated with end-to-end kidney is not perfused well, it is often difficult to determine if there
anastomoses and may be related to suture technique. In end-to-side is any salvageable renal parenchyma. Studies in experimental animals
anastomoses, stenosis is typically postanastomotic, suggesting that tur- with acute RA occlusion have shown that the collateral circulation can
bulence or other hemodynamic factors play a role. Immunologic causes maintain renal viability for up to 3 hours after occlusion.72 Patients
of transplant RA stenosis also have been proposed on the basis of his- with atherosclerotic RA disease may have developed collateral vessels,
tologic similarities with chronic vascular rejection and association with resulting in the maintenance of renal viability for days to weeks. In
prior acute rejection. Other proposed pathogenic mechanisms include these patients, urgent arteriography to identify the location of the arte-
calcineurin inhibitor toxicity and cytomegalovirus infection. RA stenosis rial thrombosis or embolus may allow renal salvage via percutaneous
occurring many years after transplantation most often represents ath- or surgical revascularization.
erosclerotic disease. Causes of renal infarction are listed in Box 41.7. The most common
Patients typically present with new-onset or worsening hyper- are trauma, RA embolism from cardiac thrombus, dissection, and iat-
tension with or without decline in allograft function. Patients may rogenic complications of endovascular procedures. Spontaneous RA
present with IRD with rapid decline in GFR or episodes of AKI. When thrombosis or dissection is most often associated with atherosclerotic
pseudo–transplant RA stenosis occurs, the patient often presents with disease of the aorta or RAs, but other inflammatory vascular disorders
ipsilateral lower extremity claudication associated with hypertension can lead to infarction.
and worsening function in the allograft.66 Risk factors for the develop- Renal infarction secondary to traumatic RA injury occurs in 1% to
ment of transplant RA stenosis include male gender, diabetes mellitus, 4% of all nonpenetrating abdominal trauma. Types of injuries
A B
Fig. 41.9 Computed tomography angiogram of renal artery aneurysm with area of renal infarc-
tion in right kidney. (A) Coronal image demonstrates area of intact tissue with no blood perfusion within
the kidney parenchyma (white arrow). (B) Reconstructed view with vascular aneurysm (arrow) and minimal
flow in the distribution beyond this segment, consistent with near-total occlusion. This patient presented
with accelerated renovascular hypertension treated primarily with renin-angiotensin system (RAS) blockade.
myocardial infarction, atrial myxoma or other cardiac tumors, endo-

BOX 41.7 Causes of Renal Infarction
carditis, paradoxical emboli, and aortic thrombus represent most of
Renal Artery Thrombosis • Thrombotic microangiopathies the conditions associated with renal embolism. Atrial fibrillation is the
Spontaneous • Genetic most common cause, with a rate of embolism four times higher than
• Renal artery atherosclerosis or • Ehlers-Danlos vascular variant that of the general population; the highest risk is during the first year
fibromuscular dysplasia after the diagnosis of atrial fibrillation and when anticoagulation is
• Renal artery or aortic dissection Renal Embolism subtherapeutic.75 When echocardiography is performed, cardiac thrombus
• Renal or aortic aneurysms • Atrial fibrillation is only rarely detected. Other causes of renal emboli include fiber or
• Cardiac mural thrombi foam related to cardiac bypass procedures, calcium from valve annuli,
Traumatic • Valvular heart disease and even “bullet emboli” in the setting of trauma. Aortic endovascular
• Postprocedure • Paradoxical embolism stenting has been associated with a 10% incidence of new renal infarcts,
• Endovascular stents • Tumor or fat embolism presumably of embolic origin.76 There is a 30-day mortality rate of 10%
• Renal transplantation • Atheroemboli to 13% among patients experiencing renal embolism in the setting of
• Hypercoagulable disorders atrial fibrillation. Up to 40% of cases of renal embolic events have at
• Malignancy Renal Vein Thrombosis least transient reduction in kidney function.
• Antiphospholipid syndrome • Nephrotic syndrome Paradoxical RA embolism may occur in patients with right-to-left
• Renal artery vasculitis • Post–renal transplantation cardiac shunts most commonly due to atrial septal defects present in
• Vascular rejection • Traumatic up to 9% to 35% of the general population. The diagnosis of paradoxi-
cal embolism requires clinical, angiographic, or pathologic evidence of
systemic embolism, as well as the presence of a venous thrombus along
associated with RA or kidney injury include deceleration injury and with an abnormal communication between the right and left circula-
direct blunt trauma to the loin or flank regions. Evidence of lumbar tions with a favorable pressure gradient (typically diagnosed by “bubble”
vertebral injury should raise suspicion in the emergency department echocardiography) for the passage of clot from the right to the left side
for renovascular trauma. Traumatic renal vascular occlusion often leads of the heart.
to renal infarction within 3 to 6 hours. The success rate for revascular- Less common causes of infarction include hypercoagulable states,
ization of RA thrombosis after trauma remains low, even when diagnosed inflammatory diseases of the retroperitoneum, and thrombotic micro-
early.73 angiopathies. Antiphospholipid antibody syndrome is associated with
A common cause of renal infarction is RA embolism. The kidneys both arterial and venous thrombotic events and is the most common
are frequently the target for emboli from thrombi originating in the cause of spontaneous arterial thrombosis.77 Rare causes of renal infarc-
heart. In one series, 1.4% of the general population had RA embolism tion include autoimmune diseases and drug abuse, such as intravenous
at autopsy, of which only 2 of 205 cases (1%) were diagnosed clinically.74 injection or nasal insufflation of cocaine or even marijuana smoking.
Emboli to the right and left RA occur with equal frequency, with The exact mechanism involved in the pathogenesis of renal infarction
12% of cases being bilateral. Atrial fibrillation, cardiac thrombus after in some of these conditions is unclear.
echocardiogram is usually indicated to evaluate for intracardiac or aortic

arch thrombi and valvular abnormalities. Systemic anticoagulation is
indicated to prevent recurrent embolic events, except when the source
is septic emboli.
Thrombosis of atherosclerotic RAs (because of prior collateral
development in most cases) often results in marked ischemia but
not overt infarction of the kidney; in this setting surgical and, some-
times, percutaneous endovascular revascularization can restore kidney
function.81,82
ATHEROEMBOLIC RENAL DISEASE

Atheroembolic renal disease is common and is estimated to account
for up to 10% of unexplained renal failure in the elderly. It is typically
associated with arterial manipulation that occurs during arteriogra-
phy, vascular surgery, angioplasty, and stent placement. Spontaneous
atheroemboli may occur in patients with extensive atherosclerosis and
unstable plaques, especially after administration of oral or intravenous
Fig. 41.10 Thrombosis of renal artery complicating renal artery anticoagulants or thrombolytic agents. Atheroembolism may be expected
stenting. Right and left renal artery stents. The left renal stent (arrow)
to occur in up to 30% of patients with extensive aortic atherosclerosis
is triangular, indicating crimping of the proximal portion, which in this
patient was associated with thrombosis of the renal artery, seen here
after endovascular intervention. Careful studies using filters to capture
as no contrast entering the vessel. The right renal stent is patent. embolic material confirm that PTRA and PTRS release thousands of
atheromatous particles of various sizes in 70% to 100% of cases.83
Preprocedure treatment with antiplatelet agents and intraprocedural
Aortic dissection can lead to RA occlusion, reduced renal blood use of embolic protection devices during PTRS is under investigation,
flow, or infarction. In this setting the predictors of renal salvage are the with some positive results as means of reducing the frequency of this
same as those for occlusion caused by atherosclerotic RA stenosis and underdiagnosed cause of renal infarction and CKD.84,85
include preserved renal size, collateral circulation permitting renal Ipsilateral RA stenosis may be present in up to 80% of patients with
viability, and blush on imaging studies. Aortic dissection occurs renal cholesterol embolization. Cholesterol embolization may contribute
most commonly in association with atheromatous aneurysmal vascular to the loss of renal function in patients with atherosclerotic IRD; cho-
disease of the thoracic aorta, but it can occur in collagen disorders, lesterol emboli were found in the kidneys of 36% of patients undergoing
such as Ehlers-Danlos type IV or Marfan syndrome, and with arteritis, surgical revascularization.86
such as TA. Most patients are older than 50 years with generalized atherosclerosis
RA thrombosis, dissection, laceration, or embolism can occur sec- and have a history of recent endovascular procedures or signs and
ondary to vascular interventions, especially those involving placement symptoms of atherosclerotic vascular disease. These signs and symptoms
of endovascular stents. Endovascular aortic stents commonly used to can include claudication or ischemic ulcers, abdominal pain, angina,
treat infrarenal abdominal aortic aneurysms can cross the RA orifice, myocardial infarction, transient ischemic attacks, amaurosis fugax, stroke,
impair renal perfusion or cause RA thrombosis.78,79 RA stent placement abdominal aortic aneurysm, RVH, or IRD. Most patients have athero-
similarly may cause intimal dissection, atheroembolism, and thrombosis sclerotic risk factors, including hypertension, hypercholesterolemia,
of the RA. Stent fracture also can be associated with thrombosis, as diabetes, and smoking.
demonstrated in Fig. 41.10.
In-stent stenosis remains a significant complication occurring in up Clinical Presentation
to 33% of post-PTRS cases and can occur at any time after stent place- Acute or subacute renal impairment caused by renal microinfarctions
ment, with the highest risk within the first year after PTRS. Whether developing as long as 6 months after the atheroembolic insult is the
duplex surveillance should be performed at various intervals after PTRS most common presentation leading to the diagnosis of cholesterol
is unclear, but clinicians should be aware that RA stenosis and occlusion embolization. The clinical picture is multisystemic and involves the
can occur within stents, sometimes without clinical clues. Clinicians kidneys in about 75% of patients.
need to inform patients with atherosclerotic RA stenosis regarding the If a large atheroembolic shower induces significant renal tubular
risk and uncertain benefits of PTRS.80 damage, the resulting AKI may manifest with an oliguric phase char-
acterized by a high fractional excretion of sodium. More often, the renal
Treatment of Acute Renal Infarction failure is nonoliguric. A slowly progressive, often stair-stepping subacute
Investigations should be done to determine whether the infarction is renal impairment is common. Some patients will have only moderate
embolic or thrombotic. Treatment of the infarction itself is usually impairment in renal function, whereas others progress to ESRD. Uri-
conservative and includes pain control and treatment of associated nalysis findings are nonspecific but may include mild proteinuria,
RVH, which can be labile. If RA occlusion is caused by thrombosis microhematuria, pyuria, and eosinophiluria. Renin release by ischemic
associated with a hypercoagulable state or an embolism from a central zones in areas of embolization can lead to labile hypertension early in
source, systemic anticoagulation is indicated. Salvage of the kidney by the course, sometimes associated with transient marked proteinuria.
acute thrombolytic therapy also has been attempted, with limited success. Fever, often low grade, is characteristic.
There is no evidence that thrombolytic therapy can limit infarct size if Although the kidneys are the organs most commonly involved,
it is administered in the acute setting. extrarenal cholesterol embolization will provide clues to aid in the
When an embolism from a central source results in renal infarction diagnosis. Cutaneous findings are seen in up to 60% of patients during
or RA occlusion, a search for the source should be undertaken. An initial presentation. These findings include blue or purple toes, mottled
Fig. 41.13 Cholesterol emboli in kidney biopsy specimen. Biconvex

cholesterol clefts with giant cell reaction and recanalization of the lumen
of a medium-sized renal vessel. (Periodic acid–Schiff stain.) (Courtesy
Dr. R. Horn, Vanderbilt University, Nashville, Tenn.)
Many laboratory abnormalities indicative of tissue injury are associated

with cholesterol embolization, including elevated erythrocyte sedimen-
tation rate (in 97% of cases), elevated serum amylase (60%), leukocytosis
(57%), anemia (46%), hypocomplementemia (especially low C3) (25%
to 70%), and elevated lactate dehydrogenase and creatine kinase (38%
to 60%). Peripheral eosinophilia, which may be transient, is seen in up
Fig. 41.11 Livedo reticularis. The mottled skin changes associated to 57% of patients. The presence of eosinophilia should raise suspicion
with peripheral cholesterol embolization may be seen over the legs, for atheroembolic renal disease in the appropriate clinical setting. Serum
buttocks, back, or flank and may be transient. lactate elevation is usually seen only if concomitant ischemic bowel is
present. In most circumstances, the diagnosis is made clinically. However,
a definitive diagnosis can be made by biopsy of an involved organ or
tissue. A skin or muscle biopsy in an involved area may preclude the
need for kidney biopsy.
Differential Diagnosis
In this setting, often after vascular interventions, other considerations
include contrast nephropathy, acute tubular necrosis, renal infarction,
or vascular occlusion. Peripheral eosinophilia and eosinophiluria, rash,
fever, and renal dysfunction may also be misdiagnosed as acute inter-
stitial nephritis. Acute cholesterol embolization syndrome may mimic
vasculitis, occult infection, neoplasm, or thrombotic microangiopathy.
Chronic cholesterol embolization syndrome may appear similar to
hypertensive nephrosclerosis or IRD. In the kidney transplant recipient,
renal atheroembolism may mimic acute rejection or chronic allograft
Fig. 41.12 Hollenhorst bodies. Cholesterol embolus of a retinal arte- nephropathy.
riole (arrow). (Courtesy Richard Mills, University of Washington, Seattle,
Wash.) Pathology and Pathophysiology
If clinical or other pathologic evidence has not secured the diagnosis,
kidney biopsy may be helpful. Diagnosis is based on the presence of
serpiginous rash (livedo reticularis; Fig. 41.11), petechiae, and purpura birefringent, biconvex, elongated cholesterol crystals or biconcave clefts
or necrotic ulceration in areas of skin embolization, such as the lower within the lumina of small vessels left behind in formalin-fixed tissue
back, buttocks, lower abdomen, legs, feet, or digits. Fig. 41.13. Due to the patchy nature of this disorder, open wedge kidney
Other organs often involved include the spleen (in 55% of cases), biopsy has a higher likelihood of successful diagnosis relative to a per-
pancreas (52%), gastrointestinal tract (31%), liver (17%), and brain cutaneous approach because it allows visualization and direct sampling
(14%). This involvement can result in a number of associated clinical of areas of ischemic infarction of the cortex. The pathologist should
symptoms, including abdominal or muscle pain, nausea, vomiting, ileus, be alerted by the clinician that cholesterol embolization is in the dif-
gastrointestinal bleeding, ischemic bowel, hepatitis, angina, Hollenhorst ferential diagnosis before the biopsy specimen is processed. In frozen
plaques (Fig. 41.12), and visual and neurologic deficits. sections of tissue, the cholesterol material can be identified with polar-
ized light microscopy. The pathologic findings also may include intimal
Diagnosis thickening and concentric fibrosis of vessels, giant cell reaction to the
Atheroembolic renal disease should be suspected when renal failure cholesterol particles, vascular recanalization, endothelial proliferation,
develops after a vascular intervention in the presence of livedo reticularis. tubulointerstitial fibrosis with both eosinophil and mononuclear cell
infiltrates, glomerular ischemia, and even focal segmental glomerulo- renal veins empty into the IVC. The left renal vein is three times longer
sclerosis. In the kidney, the most commonly affected vessels are the than the right (7.5 vs. 2.5 cm) and traverses behind the splenic vein
arcuate and interlobular arterioles, leading to patchy ischemic changes and body of the pancreas before it crosses in front of the aorta near its
distal to these vessels. termination at the IVC. About 25% of people have retro-aortic or cir-
cumaortic renal veins.
Natural History Renal vein thrombosis is rare and primarily observed in children
The natural history is determined by the extent of organ involvement with severe dehydration (with an incidence in neonates of 0.26% to
and the degree of the embolization. In one series of cases, renal func- 0.7%) or in adults with nephrotic syndrome, renal tumors, or hyper-
tion declined rapidly in 29%, with a more slowly progressive course coagulable states and after surgery or trauma to the renal vessels.90
seen in 61%.87 Among the latter group, the decline in renal function When it occurs in adults, the diagnosis is often never considered.
was thought to result from a combination of cholesterol embolization Thrombosis of the longer left renal vein also may involve the ureteral,
and IRD. Patients also may manifest acute or subacute renal impairment gonadal, adrenal, and phrenic branches that drain into the left vein,
followed by partial recovery of renal function. Conversely, the outcome whereas on the right side, the adrenal and gonadal veins drain directly
can be dismal, particularly when cerebral embolization occurs or when into the IVC. The renal veins also communicate with perirenal veins
there is a large unstable atheromatous burden. Some patients with cho- outside of the Gerota fascia as part of the retroperitoneal collateral
lesterol embolization may develop ESRD. venous network: tributaries of the portal system, lumbar, azygos, and
hemiazygos. Because of this network of venous complexes, occlusion
Treatment of the left renal vein results in enlargement of the systemic collateral
There is no specific therapy for the cholesterol embolization syndrome. vessels and provides some protection against infarction (Fig. 41.14).
Therefore its risk should be considered before angiographic and vascular
surgical procedures are undertaken in patients with diffuse, extensive Acute Versus Chronic Renal Vein Thrombosis
atherosclerotic disease. Prevention is the most effective management Experimentally, acute RVT is associated with immediate enlargement
strategy, so patients with extensive aortic atherosclerosis should be of the kidney, with a marked increase in renal vein pressure, leading to
considered for alternative approaches to cardiac catheterization, such a significant decrease in renal arterial flow. Complications include hem-
as through the brachial artery. When it is feasible, distal embolic protec- orrhagic infarction, kidney rupture, and retroperitoneal hemorrhage.
tion devices should be used to trap embolic material for removal from In the dog, the kidney enlarges over the course of a week, then proceeds
the circulation to avoid end-organ damage by embolic debris. to atrophy as a result of progressive fibrosis. In contrast, slow, progres-
Once the diagnosis of cholesterol embolization has been established, sive (chronic) thrombosis may allow collateral formation, resulting in
further endovascular interventions should be avoided. Poor outcomes minimal symptoms.
have been reported in patients with cholesterol emboli who subsequently
undergo coronary artery bypass surgery. When clinical factors dictate Clinical Presentation
the need for aortic, renal, or peripheral arterial surgery, optimal timing Acute RVT is usually symptomatic and associated with loin, testicular,
and surgical approach are critical. Conversely, there is a growing surgical or flank pain and even the development of scrotal swelling or hydrocele.
experience with segmental aortic replacement to remove the source of The patient may present with fever, leukocytosis, and, in the setting of
emboli, particularly when atheroembolic disease occurs spontaneously. a single kidney or renal transplant, oliguric AKI. Acute RVT is associ-
Transesophageal echocardiography is often used to identify mobile ated with renal edema and swelling. Nausea and vomiting often accom-
ulcerative plaque in the aorta to guide intervention. pany acute RVT, and symptoms might be confused with those of acute
ACE inhibitors are effective in managing the labile hypertension pyelonephritis. Hematuria is nearly universal and most often is micro-
seen early in the course of cholesterol embolization. Corticosteroids scopic. The high venous pressures result in a marked increase in pro-
have been used with some success in patients with systemic cholesterol teinuria. Urinalysis sometimes reveals evidence of proximal tubule
embolization and associated inflammatory symptoms.88 There also have dysfunction, such as glycosuria. In some patients, RVT is diagnosed
been several reports documenting improvement or stabilization of skin only after the patient has developed an acute pulmonary embolus and
signs of cholesterol embolization after administration of statins,89 which the source of the embolus is investigated or with worsening of renal
should be part of the treatment of the generalized atherosclerosis in function in the setting of proteinuric CKD.
these patients. Cholesterol embolization also has occurred after treat- Chronic RVT may be asymptomatic. Extensive venous collaterals
ment with anticoagulants. Although direct causality between antico- may allow for minimal impairment of kidney function and structure.
agulants and cholesterol embolization has not been established, the Often, however, microhematuria, proteinuria, and evidence of reduced
proposed mechanism is that anticoagulants prevent thrombus organiza- GFR or tubular dysfunction are present, particularly when indices of
tion over the ulcerative plaques. Therefore anticoagulation should be differential renal function are sought, such as with nuclear studies.
avoided in the acute setting of cholesterol embolization unless a critical When RVT causes renal infarction, the distribution of the hypoper-
life-threatening indication for anticoagulation is present. This has impli- fused region tends to be medullary or subcortical. The renal impairment
cations for the delivery of renal replacement therapy, if indicated. tends to be patchy and subtotal. These patients can develop severe
hypertension acutely. The swollen kidney can rupture the capsule and
result in massive retroperitoneal hemorrhage.
RENAL VEIN THROMBOSIS
Renal veins begin in the subcapsular region of the kidney. These stellate Etiology
veins communicate with perirenal and cortical venous channels and The causes of RVT are listed in Box 41.8. Renal vein thrombosis occurs
empty into interlobular and then arcuate veins. The venae rectae drain in neonates in situations of dehydration and thrombophilia. The classic
the pyramids and join the arcuate veins, which leave the renal paren- presentation triad includes a palpable abdominal mass, hematuria, and
chyma through interlobar vessels, converging into four to six trunks thrombocytopenia. Proteinuria, tubular dysfunction, reduced GFR, and
near the hilum of the kidney. Two or more renal veins have been described hypertension may be associated. There is a greater predilection for
in up to 20% of people; this is more common on the right. The main development of RVT in male infants, with 67% of the reported cases
BOX 41.8 Causes of Renal

Renal Vein Anatomy
Vein Thrombosis
Malignant neoplasia
Direct invasion of tumor into the renal vein
Retroperitoneal adenopathy, fibrosis, or tumor compressing the renal vein
Extension of inferior vena cava (IVC) obstruction by tumor invasion
Hypercoagulable state associated with malignant disease
Complication of IVC filters
Complication of PICC lines
Nephrotic Syndrome
Membranous nephropathy
Adrenal vein
Lupus Nephritis
Acute pyelonephritis
Complicating inflammatory bowel disease
Acute Pancreatitis
Lumbar vein Inflammatory aortic aneurysm
Neonatal
Congenital
Gonadal vein Dehydration
Thrombophilia
Complication of umbilical vein catheterization
A
Transmission of maternal procoagulant factors
Hypercoagulable states
Antiphospholipid antibody syndrome
Factor V Leiden mutation
Antithrombin III deficiency
Protein S and C abnormalities
Hyperhomocysteinemia
Elevated levels of clotting factors VIII, IX, and XI
Heparin-induced thrombocytopenia
Birth control pill
Renal artery
and vein Thrombophilia
Chuvash polycythemia
Post Renal Transplantation
Acute rejection, OKT3
Renal pelvis Vascular rejection
Compression or kinking of renal vein
Hypercoagulable disorders
Sticky platelet syndrome
Calcineurin inhibitors
B Viral infection of the allograft
Fig. 41.14 Renal vein anatomy. (A) There is extensive communica- Complication of surgical compression
tion between the renal venous plexus and lumbar, gonadal, and adrenal After aortic aneurysm surgery
veins, which provide alternative outflow in the setting of renal vein
After pyeloplasty
thrombosis, particularly on the left. (B) Transverse section of the kidney
After partial nephrectomy
showing relative position of vascular structures in the renal pelvis.
(Redrawn from Graham SD, Keane TE, Glenn JF, eds. Glenn’s Urologic Traumatic renal vein thrombosis
Surgery. 7th ed. Philadelphia: Wolters Kluwer/Lippincott Williams & Pregnancy
Wilkins Health; 2010.) Compression
Preeclampsia, eclampsia
Complication of embolization of gastric varices
occurring in boys.91 Most cases are unilateral, with the left renal vein Budd-Chiari syndrome
more commonly affected. In neonates, the diagnosis is made by renal Behcet’s disease
ultrasound and Doppler study of the renal veins. The strongest predic-
PICC, peripherally inserted central catheter
tor of poor renal outcome is marked decrease in perfusion detected on
initial Doppler ultrasound.92 The optimal treatment approach to neonatal
RVT is controversial. Fibrinolytic therapy may be associated with bleed-
ing complications, including adrenal hemorrhage, and is usually not unclear because it is largely undiagnosed; studies report frequencies
successful in restoring renal function unless it is undertaken within 24 from 5% to 62%.94 Numerous abnormalities promoting a prothrombotic
hours of the thrombotic event.93 state occur secondary to heavy proteinuria. It is interesting to note that
Patients with nephrotic syndrome have increased risk for venous RVT appears to be more common in membranous nephropathy and
thromboembolism. The prevalence of RVT in nephrotic syndrome is lupus nephritis, but RVT can complicate any cause of proteinuric renal
Treatment
Treatment is controversial and depends on the setting, acuteness, and
renal consequences. If there is no contraindication, most patients are
treated acutely with systemic anticoagulation. In adults with acute RVT
that is compromising renal function, catheter-directed thrombolytic
therapy with urokinase or tissue plasminogen activator with or without
percutaneous mechanical thrombectomy can restore vessel patency.97
The long-term benefit of this approach is unclear, and it is less success-
ful when the thrombotic process begins in the small intrarenal venules
rather than in the major veins, as is often the case when primary renal
disease or a hypercoagulable state initiates the process. In neonatal RVT,
which often results in renal nonfunction, thrombolytic therapy and
anticoagulation have been used with variable results.
Surgical interventions include nephrectomy, thrombectomy, and
retroperitoneal surgery for non–renal-associated abnormalities, such
Fig. 41.15 Computed tomography venogram demonstrating left
as tumor, retroperitoneal fibrosis, aortic aneurysm, and acute pancre-
renal vein thrombosis (arrow). (Courtesy Dr. S. Rankin, Guy’s Hospital,
London.)
atitis. Surgery tends to be reserved for situations in which the RVT
results in hemorrhage from renal capsular rupture or for long-term
consequences of RVT, such as hypertension or infection of a nonfunc-
disease. In this setting, RVT can lead to an increase in baseline protein- tioning kidney.
uria and present with AKI superimposed on CKD. A conservative approach may be favored when left RVT occurs
RVT after transplantation is rare and occurs in less than 0.5% to because of the extensive collateral venous supply on that side, ultimately
4% of transplants, usually within the first week after transplantation.95 allowing venous drainage and delayed improvement in renal function.
It usually leads to graft infarction, but rupture of the allograft also can Systemic anticoagulation is indicated acutely to prevent extension of
occur. Causes include technical issues related to the anastomosis, com- thrombus into the IVC and prevent pulmonary emboli. Anticoagulation
pression of the renal vein by fluid collections, volume depletion, acute should be continued indefinitely in patients with a persistent hyperco-
rejection, and hemostatic and hypercoagulable states. Factor V Leiden agulable state after RVT.
mutation, which occurs in 2% to 5% of the population, is a risk factor
for transplant RVT and should be sought when it occurs. Another
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CHAPTER 41 Renovascular Hypertension and Ischemic Nephropathy 501.e1
4. An 83-year-old woman presents with congestive heart failure and

SELF-ASSESSMENT hypertension. She has a history of peripheral vascular disease and
QUESTIONS chronic kidney disease with a baseline creatinine of 1.5 mg/dl
1. A 24-year-old woman presents with hypertension and bruits over and a single kidney because she donated one to her son with diabetic
her carotid arteries. She does not know the onset of her hyperten- nephropathy 30 years earlier. She is admitted and treated with diuret-
sion, which was discovered during a regular gynecologic check-up. ics and achieves a net negative fluid balance of 6 liters over 3 days.
In evaluating her, you discover the presence of a heart murmur Her BP, which was 180/90 on admission, is now 120/80. An echo
heard loudest over the posterior thorax. She has no abdominal bruits. shows left ventricular hypertrophy with diastolic dysfunction, pre-
There is no difference between blood pressure (BP) measurements served ejection faction, and no valvular abnormalities. Over the past
taken in each arm. She has a radial-femoral delay, and otherwise 24 hours her creatinine has risen to 3.8 and she has produced almost
her pulses are equal and present. Which of the following is the most no urine. She has no flank pain. Despite stopping her diuretics, her
likely cause of her hypertension? creatinine does not improve over the next 72 hours and she is oli-
A. Takayasu arteritis guric. She appears euvolemic and does not respond to empiric
B. Fibromuscular dysplasia of the renal artery intravenous fluids for 24 hours. Her medications are reviewed, and
C. Coarctation of the aorta she is receiving no nephrotoxic agents and all diuretics and antihy-
D. Vasculitis pertensives are on hold. An ultrasound and Doppler examination
E. Atherosclerotic renal artery (RA) stenosis show a blunted waveform concerning for possible critical renal artery
2. A 76-year-old woman comes to see you because her primary care stenosis. What test would be best to rule out critical RA stenosis?
doctor has had difficulty getting her BP controlled. She tells you A. MRA of renal arteries
she never had hypertension until about 4 or 5 years ago. She has a B. CTA of RAs
history of smoking one pack per day of cigarettes for 40 years. She C. Captopril renography
had coronary artery bypass grafting 8 years ago and has been well D. Direct renal angiography with carbon dioxide
without chest pain or dyspnea since then. Examination is notable E. Peripheral renin level
for systolic BP of 180. She has a left carotid bruit audible and dimin- 5. A 62-year-old man with a history of hypertension presents with
ished dorsalis pedis pulses. Her creatinine is 1.3 mg/dl and potassium acute left flank pain with no dysuria. Urinalysis shows hematuria
is 3.4 mg/dl. A renal duplex shows normal velocities in the left RA without pyuria. He has a temperature of 99.8° F and a white blood
but a peak systolic volume of 350 cm/sec in the proximal portion cell count of 12,000. He is in new-onset atrial fibrillation. His cre-
of the right RA. She is on the following antihypertensive medica- atinine is noted to be 1.3, above his recent normal level of 0.9 mg/
tions: metoprolol 50 mg twice daily, amlodipine 5 mg/day, hydro- dl 1 month previously. An abdominal ultrasound is done, and the
chlorothiazide 25 mg/day, and atorvastatin 80 mg/day and is taking kidneys appear normal. Which of the following tests would help
aspirin. What is the most appropriate next action? sort out the cause of his flank pain?
A. Refer right for RA stent A. Echocardiogram
B. Start angiotensin-converting enzyme (ACE) inhibitor and follow B. CT without contrast
BP response and potassium and creatinine closely C. CT with and without contrast and serum lactate dehydrogenase
C. Refer to vascular surgery for RA bypass (LDH)
D. Stop aspirin and atorvastatin D. Urine culture
E. Add doxazocin E. Brain natriuretic peptide
3. A 32-year-old woman with lupus nephritis class V is currently being 6. A 60-year-old White man with a history of hypertension and diabetes
treated with induction therapy with mycophenolate mofetil 1500 mg undergoes cardiac angiography with stent placement after presenting
twice daily and oral steroids. She continues to have proteinuria, and to the emergency department with symptoms consistent with unstable
her last 24-hour quantitative protein concentration was 6 g. Fortu- angina. Three days later he is noted to have a rise in serum creatinine
nately, her creatinine has remained normal at 0.8 mg/dl. She presents from a baseline of 0.8 to 1.9. Along with this rise he is noted to have
to the emergency department with pleuritic chest pain. A ventilation/ a slight increase in eosinophils on his complete blood count. On
perfusion (V̇ /Q̇ ) scan shows high probability for pulmonary embo- examination the patient is noted to have a serpiginous rash on the
lism. When you see her, you note that her creatinine is 1.8 and urine bilateral lower extremities to the level of the ankles. Which of the
protein/creatinine is 30 g/g. She is started on anticoagulation therapy following is the likely cause for the AKI?
and admitted. As the renal consult, which of the following tests A. Cardiorenal syndrome
would you recommend the team order? B. Cholesterol emboli
A. Antiphospholipid antibody C. Contrast-induced nephropathy
B. Renal vein Doppler study and renal ultrasound D. Acute interstitial nephritis
C. Computed tomographic angiography (CTA) of pulmonary E. Renal infarction
arteries
D. Both a and b
E. None of the above

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SECTION VII Renovascular Disease

NORMAL RENOVASCULAR ANATOMY prevents development of hypertension.4 Studies in transgenic mice

pressor mechanisms, and hypertensive injury to the nonstenotic kidney.

BOX 41.1 Clinical Syndromes Associated

Unilateral Renal Artery Stenosis Bilateral Renal Artery Stenosis

Reduced renal perfusion

Hemodynamic Effects of Stenotic Lesions

Blood flow and Perfusion pressure

Perfusion pressure (%)

BOX 41.2 Classification of BOX 41.3 Clinical Features of

tissue deposits result in discrete stenoses alternating with aneurysmal

TABLE 41.1 Histologic Classification of Fibromuscular Dysplasia and Angiographic Phenotypes

patients undergoing peripheral angiograms.20 Predictors of RA stenosis

Duplex ultrasound provides little functional information regarding the

revascularization may be required. Endovascular management can

From references 43, 44, 53.

Evaluation and Management

Stable kidney function No ?Progressive disease

Goal: Stable kidney function,

myocardial infarction, atrial myxoma or other cardiac tumors, endo-

echocardiogram is usually indicated to evaluate for intracardiac or aortic

ATHEROEMBOLIC RENAL DISEASE

Fig. 41.13 Cholesterol emboli in kidney biopsy specimen. Biconvex

Many laboratory abnormalities indicative of tissue injury are associated

BOX 41.8 Causes of Renal

4. An 83-year-old woman presents with congestive heart failure and

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