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Vascular Disorders of the Kidney

Abdallah Geara, Jeffrey S. Berns

INTRODUCTION

The spectrum of vascular disorders of the kidneys is broad as a result of high renal blood ﬂow and the intimate relationship between blood supply and fundamental glomerular and tubular functions. In this chapter, emphasis is placed on the clinical manifestations of hypertension, chronic kidney disease (CKD), end-stage kidney failure, and the many other causes of acute kidney injury (AKI).

RENAL VASCULAR ANATOMY

With a volume of around 150 mL each, the kidneys compromise less than 1% of the body mass and yet receive 20% to 25% of the cardiac output. The renal arteries arise directly from the aorta and enter the renal hilum. The right renal artery passes anterior to the inferior vena cava (IVC) and is longer than the left renal artery. In up to 30% of the population, accessory renal arteries arise from the aorta to provide blood to portions of one or both kidneys, which may become important when evaluating patients for renovascular hypertension.

The renal arteries give rise to segmental, interlobar, and arcuate arteries (Fig. 28.1). Arcuate arteries course along the corticomedullary junction and give rise to interlobular arterioles, which extend outward into the cortex before branching into afferent arterioles, from which the glomerular capillary tufts arise. The postglomerular efferent arterioles from more superﬁcial glomeruli form a capillary network in the renal cortex, and those extending from glomeruli nearer the cortical-medullary junction (i.e., juxtamedullary glomeruli) form capillaries that extend deeper into the medulla in association with thin, descending and ascending loops of Henle as the vasa recta. The vasa recta provide the sole blood supply for the renal medulla, making this portion of the kidney particularly susceptible to ischemic injury. Venules from the ascending vasa recta and the cortical capillary network empty into the renal veins.

The left renal vein returns to the IVC anterior to the aorta and inferior to the inferior mesenteric artery, which may rarely cause compression of this vein, causing what is known as the “nutcracker syndrome,” typically presenting with hematuria with or without left ﬂank pain. The left gonadal vein also empties into the left renal vein, and a left varicocele may be evident if the renal vein is occluded by thrombosis or tumor involvement. The right renal vein is much shorter and empties directly into the IVC. The right gonadal vein empties directly into the IVC rather than into the right renal vein.

We categorize vascular diseases of the kidney based on the blood vessels typically involved (glomerulonephritis is addressed in Chapter 26):

 • Mainrenal artery and segmental branches: Renovascular dis-

ease,bromusculardysplasia(FMD),aorticdissection,throm-

boembolic diseases and large and medium vessels vasculitis.

 • Interlobulararteriolesandglomerular arterioles: Hypertensive

nephrosclerosis, atheroembolic disease, preeclampsia, sclero-

derma renal crisis, thrombotic microangiopathy (TMA) and

antiphospholipid antibody syndrome (APS).

 • Renalveins:Renalveinthrombosis(RVT).

RENOVASCULAR DISEASE

Any process that narrows the lumen of the main or branch renal arteries sufﬁciently can elicit a humoral response mediated by increased renin release from the ipsilateral kidney, which leads to increases in circulating angiotensin II and aldosterone levels. Activation of the renin-angiotensin-aldosterone system increases systemic blood pressure and renal arterial perfusion pressure and single nephron glomeru-

larltrationrate(GFR)beyondthestenosis.Thisismediatedthrough

angiotensin II-mediated preferential efferent arteriolar vasoconstriction that counterbalances the increase in resistance imposed by narrowing of the main or branch arteries.

Hemodynamicallysignicantrenalartery stenosis (RAS) requires

a reduction in lumen diameter of at least 50% to 60%. In the stenotic kidney, a decrease in the glomerular capillary pressure results in activation of the renin-angiotensin-aldosterone system, systemic vasoconstriction mediated by angiotensin II, and increased renal sodium and ﬂuid reabsorption, resulting in elevation of systemic blood pressure. If the contralateral kidney has no stenosis, the increased systemic blood pressure increases sodium excretion by that kidney (i.e., pressure natriuresis). Thus, clinically, a patient with unilateral renal artery stenosis and two functioning kidneys has hypertension secondary to angiotensin II-mediated systemic vasoconstriction without signiﬁcant hypervolemia. Because hypertension in this setting is maintained by increased vasoconstriction due to angiotensin II, treatment is aimed at blocking the synthesis or effect of the elevated angiotensin II levels with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-re-

ceptorblocker(ARB).

If the arteries to both kidneys are narrowed, pressure natriuresis does not occur, and hypertension is maintained chronically by the resulting intravascular volume expansion rather than by increased total peripheral resistance. Treatment with diuretics becomes more important in this circumstance. The latter situation also occurs when there is only a single functioning kidney that has stenosis or when an initially normal contralateral kidney suffers microvascular damage from long-standing hypertension (Fig. 28.2).

The pathophysiology of hypertension with RAS is such that its treatmentmayalsocompromisekidneyfunctionandreducetheGFR.

If the kidney contralateral to the one with hemodynamically signiﬁcant RAShasnormalfunction,loweringthesystemicbloodpressuremaintains the kidney with the stenosis in a hemodynamically compromised

312

Renal ar

Interlobar

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arteries

CHAPTER 28 Vascular Disorders of the Kidney

313

tery

Segmental

arteries

Efferent arteriole

Glomerulus

Arcuate

arteriole

Arcuate artery

Arcuate vein

Peritubular

capillaries

Fig. 28.1 Top: Cross-section of the human kidney showing renal arter-

ies and veins. Bottom: Schematic of the microcirculation of each nephron. (From Guyton AC, Hall JE: Textbook of medical physiology, ed 11, 2016, Saunders, Chapter 26, 323-333.)

Bowman’s capsule

Arcuate arteries

Interlobula arterioles

Proximal tubule

Cortical collecting tubule

Distal tubule

Loop of Henle

Collecting duct

state. However, this may not be detectable by measurement of the serum creatinine concentration because of the normally functioning

contralateralkidney.AdeclineintheGFRmay,however,beevidentif

there is underlying dysfunction of the contralateral kidney, as is often the case in long-standing hypertension, diabetes, or vascular disease. When a solitary functioning kidney or both kidneys are affected (i.e.,

bilateralRAS),AKImayresultwhenACEinhibitororARBtreatment

is initiated.

Atherosclerotic Renovascular Disease

Clinical Presentation

AtherosclerosisistheprimarycauseofRASinadults,althoughanyprocess that narrows one or both renal arteries may cause renal ischemia; others are discussed later in this chapter. Atherosclerotic renovascular disease is a common form of secondary hypertension, affecting up to

5%ofpatientswithhypertension.AtheroscleroticRASrarelyoccursin

patients younger than 40 years, and it is more common in men, white individuals, smokers, diabetics, and patients with atherosclerotic disease

inother arterialsystems. The prevalence of RAS increases to between

10% to 45% in patients with other atherosclerotic risk factors such as coronary artery disease, peripheral vascular disease, and aortic disease.

RASshould be suspected in patients with refractory hypertension

or new-onset hypertension in patients older than 50 years, particularly if they have overt risk factors for atherosclerotic RAS (Table 28.1). Evaluation should always begin with a thorough history and physical examination, including attention to blood pressure and pulse amplitude in each extremity. A signiﬁcant discrepancy between extremities may indicate peripheral vascular disease and increase the likelihood

ofRAS.Anabdominalbruitisdetectedinabout 50%ofsubjectsbut

laretaliBlaretalinU

Equivalent to

bilateral disease

Fig. 28.2 Anatomy of renal artery stenosis. Renal artery stenosis may

be unilateral (A), bilateral (B), or unilateral with a solitary kidney (C). Aortic disease may serve functionally as bilateral renal artery stenosis (D).

TABLE 28.1 Clinical Findings of

Atherosclerotic Renovascular Disease

Onset of new, severe hypertension or sudden worsening of chronic

hypertension at >55 years of age Accelerated, resistant, or malignant hypertension Unexplained atrophic kidney or size discrepancy >1.5 cm between kidneys Sudden, unexplained (“ﬂash”) pulmonary edema Unexplained chronic kidney disease in an individual with atherosclerotic

vascular disease elsewhere Development of acute kidney injury or worsening of chronic kidney disease

after starting an ACE inhibitor or ARB

ACE, Angiotensin-converting enzyme; ARB, angiotensin II–receptor blocker.

isnotspecicforRAS.Edemaisnottypicallyfoundunlesssignicant

CKD or another edematous condition also exists.

Laboratory evaluation may reveal hypokalemia (K+<3.5mEq/L)or

metabolic alkalosis (HCO

steronism,although neither may be present. A reducedGFR withan

elevated serum creatinine concentration may be found, but a normal serum creatinine concentration does not rule out hemodynamically sig-

nicantRAS.Plasmareninactivityandaldosteroneconcentrationsmay

be elevated, but their measurement is of limited clinical utility in assess-

inghypertensivepatientsforRASorinmakingtherapeuticdecisions.

Urinalysis results are usually normal, although low-grade proteinuria

(usually<1g/day)fromlong-standinghypertensionmaybeseen.

Diagnosis

Standard renal ultrasound imaging may suggest the presence of under-

lyingRASifitrevealsasignicantdiscrepancyinkidneysizeorifboth

−

>28 mEq/L)duetosecondary hyperaldo-

314 SECTION V Renal Disease

are smaller than normal, because kidney size diminishes over time after prolonged ischemia. Renal ultrasound with Doppler analysis provides information about ﬂow velocity in the renal arteries that may be

helpfulindetectinghemodynamicallysignicantRAS.However,renal duplex ultrasonography is technically demanding, particularly in obese

patients. Since at any given center, the sensitivity, speciﬁcity, and positive and negative predictive values of renal duplex ultrasonography are likely to be unknown, its clinical utility is mainly when positive for RAS;anegativetestisnotinformativeinpatientswithhighclinicalsuspicion. Serial measurement of the kidney size and measurement of the renal resistive index ([peak systolic velocity − end-diastolic velocity] divided by peak systolic velocity) are helpful in assessing the potential beneﬁt of revascularization. A high resistive index reﬂects an advanced degree of likely irreversible intrinsic kidney damage.

Computed tomography (CT) with intravenous iodinated contrast (i.e., CT angiography [CTA]) permits high-resolution evaluation of the arterial vasculature and can be a very useful diagnostic imaging study, particularly in patients with normal or near-normal kidney function. Its use is limited in patients with more signiﬁcantly impaired kidney function due to the risk of contrast-induced AKI. Some newer CT imaging machines have a higher resolution and better tissue reconstructionallowingthevisualizationofRASwithloweramountsofcontrast exposure.

Magnetic resonance angiography (MRA) with intravenous contrast

isalsousefulfordetectingRAS.Gadoliniumadministrationtopatients withadvancedkidneydisease(GFR<15to30mL/min)maybecontra-

indicated because of the risk of nephrogenic systemic ﬁbrosis, although this appears to be much less of a concern with newer nonionic linear

andmacrocyclicgadoliniumcontrastagents.Overall,CTAandMRA

appear to have similarly high sensitivity and speciﬁcity in the assess-

mentofpatientswithatheroscleroticRAS.InRASsecondarytoFMD, CTAandMRAarelesssensitivebecausethediseaseinvolvesthemore

distal part of the renal artery.

A functional renal nuclear medicine test might seem pathophysiolog-

icallyidealtodetectRAS thatisimpactingkidneyperfusion.Nuclear

imaging has been used with various isotopes to assess isotopic uptake and excretion by each kidney before and after the administration of a short-acting ACE inhibitor (e.g., captopril). However, due to the high prevalence of baseline asymmetry of blood ﬂow in patients with CKD andinabilitytoaccuratelydiagnoseRASwhenitisbilateral,radionuclear tests have fallen out of favor due to limited speciﬁcity and sensi-

tivityforthediagnosisofRASandarenotcommonlyusedanylonger toassessforthepresenceofRASortodeterminewhetherRASmight

be amenable to revascularization.

The most sensitive and speciﬁc test—but also the most invasive—is renal arteriography, which remains the gold standard for the detection

ofRAS.Anadvantageofarteriographyisthatangioplastyandstenting

can be performed during the procedure (discussed later) if indicated. Becauseofthefrequentoccurrenceofaccessoryrenalarteries,anaortogram must be performed rather than selective renal angiography to ensure that all vessels are visualized. This also allows for detection of aortic atherosclerotic disease.

Treatment

PatientswithatheroscleroticRAStypicallyhavecoexistentcerebrovascular, coronary, and peripheral vascular disease as the result of a long history of multiple risk factors such as cigarette smoking and hyperlipidemia. Clinicians should recognize this high cardiovascular risk and understand that long-term outcomes for patients with atherosclerotic

RASareoftendeterminedby coexistingatheroscleroticdiseaseof the

cerebral, cardiac, or peripheral vascular circulations. The absolute risk

ofdevelopingend-stagerenaldisease(ESRD) is increased for patients

withatheroscleroticRAScomparedwiththosewithoutRAS,especially inpatientswithbilateralRASorRASofasolitarykidney.

As with atherosclerotic disease in other arterial circulations, athero-

scleroticRASshouldprompteffortsforintensivelipidlowering,useof

aspirin, smoking cessation, and control of hypertension and diabetes mellitus.

InterventionforatheroscleroticRASremainscontroversialdespite

several randomized clinical trials designed to investigate the beneﬁts and risks of medical management compared with angioplasty and renal artery stenting. Small clinical studies have suggested that renal artery angioplasty and stenting may improve blood pressure con-

trol in selected cases of atherosclerotic RAS, but identifying which

patients may beneﬁt has been problematic, and many have little or no improvement in blood pressure or are not able to signiﬁcantly reduce

the number of required antihypertensive medications. Two major randomized,controlledclinicaltrialsoftreatmentofRASwithangio-

plasty did not demonstrate signiﬁcant clinical beneﬁt in terms of blood pressure control, kidney function, or mortality for most patients with

atheroscleroticRAS,althoughboth have been criticizedforselection

bias (excluding some high-risk patients with recurrent ﬂash pulmonary edema and patients whose doctors felt they were likely to beneﬁt from revascularization) and recruiting signiﬁcant numbers of low-risk patients who were not on optimal medical therapy.

Renalarteryangioplastyandstentingcarryariskofacuteworsening

of kidney function due to atheroembolic disease, contrast nephropathy, or in-stent thrombosis, among other technical complications, and the procedures may lead to irreversible, progressive kidney dysfunctionand ESRD. Decisions tocorrectatheroscleroticRASwithangioplasty and stenting or surgery must be made on a case-by-case basis, considering:

 • Underlyingkidneyfunctionandpaceofkidneyfunctionloss,if

any.

 • Severityand duration of hypertension: persistence of uncon-

trolledHTNafteroptimalmedicaltherapy,intolerancetoopti-

mal medical therapy, and the short duration of blood pressure

elevationpriortothediagnosisofRAS.

 • Atheroscleroticdisease in other vascular beds and life expec-

tancy based on age and other comorbid conditions.

 • Flashpulmonaryedema.

There is no role for angioplasty alone without stenting in most

patientswith atherosclerotic RASdueto the highrisk of recurrent

stenosis.

Medicalmanagementofhypertensioninpatientswithatheroscle-

rotic RAS must take into consideration other comorbid conditions. Useof an ACE inhibitororARBanddiureticsisoftenveryeffective,

but patients treated with these agents must be monitored closely for further compromise of their kidney function.

Fibromuscular Dysplasia

FMD is a nonatherosclerotic, noninammatory disease that causes RAS.FMDtypicallyaffectsyoungwomenmorethanothergroupsbut

men and older age groups can be affected. The cause is not established,

butitisthoughttobeadevelopmentaldefect.FMDisresponsiblefor

35% to 50% of renovascular hypertension in children and 5% to 10% of renovascular hypertension in adults.

FMDmostcommonlyaffectstherenalarteries(bilaterallyinabout

35% of affected patients), but carotid and vertebral arteries can also be affected.

ClassicationofFMDisbasedonthehistologiclayeroftheartery

involved (i.e., intima, media, or adventitia) (Table 28.2).Medialbroplasia with a mural aneurysm is the most common cause of FMD

in adults (70% of cases). It consists of alternating ﬁbromuscular

CHAPTER 28 Vascular Disorders of the Kidney

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315

ridges and aneurysmal segments in the distal two thirds of the renal artery and has a classic string-of-beads appearance on angiography (Fig. 28.3). Perimedial ﬁbroplasia of the outer one half of the media

producesseveremultifocalstenosisandcausesabout15%ofFMDin adults.Becausehistologicspecimensarerarelyobtained,FMDisclas-

siﬁed by the angiographic appearance with multifocal disease identi-

edas FMDinvolvingthemediaand unifocaldiseaseasFMDof the intimaand/oradventitia.

Medial subtypes of FMD usually have a benign course and are

responsive to angioplasty. The intimal subtype may have a higher likelihood of ischemic events and multiorgan system involvement.

Symptomsare usually precipitated by stenosis, but FMD mayrarely cause dissection or macroaneurysms that require intervention. AlthoughCTAorMRAmaybeusefulinthedetectionofFMDinthe

main renal arteries and main branch arteries, arteriography is necessary for detection of stenosis in smaller arteries.

Treatment for FMD depends on the severity of complications.

Pharmacologictreatmentalonemaybeadequatetocontrolhypertensioninmanypatients,withanACEinhibitororARBtheantihyperten-

sives of choice. Intervention with angioplasty (with or without stenting) or surgery should be considered for patients with severe or difﬁcult to control hypertension or declining kidney function. Angioplasty without stenting is successful in many patients, but recurrent stenosis is

not uncommon, and new stenosis from FMD may develop at other

sites. For this reason, regular monitoring of blood pressure and serum

creatininelevelsisessential,andmanypatientsrequireimagingstudies

to detect new or recurrent lesions.

TABLE 28.2 Histologic Classiﬁcation of

Fibromuscular Dysplasia

Percentage of

Subtype

Medial ﬁbroplasia 60-70 String of beads with aneurysms

Perimedial ﬁbroplasia 15 String of beads without large

Medial hyperplasia 5-15 Smooth tubular stenosis

Intimal ﬁbroplasia 1-2 Focal or smooth stenosis

Adventitial ﬁbroplasia <1 Focal or smooth tubular stenosis

All Cases (%) Radiologic Appearance

aneurysms

Aortic Dissection

Aortic dissection occurs after disruption of the intimal layer of the aorta and propagation of blood ﬂow that dissects along the wall of the aorta, producing a false lumen and compression of the true aortic lumen. Aortic dissection is classiﬁed by the site of origin (i.e., DeBakey classiﬁcation) or the segment of the aorta involved (i.e., Stanford classiﬁcation). DeBakey type I and II dissections originate in the ascending aorta, and type III dissections originate in the descending aorta. Stanford type A refers to dissections involving the ascending aorta, and type B refers to all others not involving the ascending aorta.

Majorbranchvesselsoftheaorta,includingtherenalarteries,may

become obstructed or occluded as a result of extension of the dissec-

tion.Aorticdissectionfrequentlycompromisestherenalarteries(the

left more commonly than the right) when it extends into the abdominal aorta and causes renal failure in approximately 20% of patients with type B dissections. When disease is extensive enough to cause AKI, vascular compromise to the intestinal and cerebral vasculature and severe aortic regurgitation often contribute to the high mortality rate.

Aortic dissection most frequently affects older patients (>50

years of age) with coexistent vascular risk factors such as hyperten-

sion,smoking,andatherosclerosis.Menareaffectedmorecommonly

than women. Occasionally, a genetic connective tissue defect such as

Marfansyndromeor Ehlers-Danlos syndrome typeIV(about 5% of

cases) causes aortic dissection, and these conditions should be considered in younger patients (<40 years of age).

AKI occurs in about 20% of patients diagnosed with acute type B aortic dissection and is an independent predictor of in-hospital mortality. Trauma or procedures (e.g., aortic catheterization) can also cause dissection of the aorta or renal artery. Isolated, spontaneous renal artery dissection may rarely occur, most commonly in the setting

ofpolyarteritisnodosa(PAN)orFMD.Segmentalarterialmediolysisis

another uncommon condition of unknown origin that is characterized by vacuolar degeneration of smooth muscle cells in the arterial media, which leads to disruption of the arterial medial layer, vessel dissection, hemorrhage, and ischemia. Segmental arterial mediolysis can affect abdominal visceral arteries and virtually any other arterial system.

Themostfrequentsymptomduringaorticdissectionischestpain,

which may be described as a ripping sensation. Isolated loss of pulse in one or more extremities may provide a clinical clue, and the number of

A B

Fig. 28.3 (A) Typical medial ﬁbroplasia (i.e., string-of-beads appearance) on an angiogram of a right renal

artery. (B) Gadolinium-enhanced magnetic resonance angiography in the same patient, revealing bilateral medial ﬁbroplasia of the renal arteries and a large marginal artery of Drummond (arrow), indicates that there is disease of the superior mesenteric artery. (From Slovut DP, Olin JW: Fibromuscular dysplasia, N Engl J Med 350:1862-1871, 2004.)

316 SECTION V Renal Disease

arteries involved correlates with the severity of dissection. A common clue to the diagnosis on a routine chest radiograph is a widened mediastinum, with or without a pleural effusion (most often on the left).

After the diagnosis of aortic dissection is established, evaluation of renal artery involvement is best undertaken noninvasively to minimize further vascular injury. Contrast-enhanced CT, magnetic resonance

imaging, or MRA usually provide images capable of conrming or

excluding renal involvement, although each modality carries the same

limitations as outlined for the evaluation of RAS. Transesophageal

echocardiography is useful for establishing the diagnosis of aortic dissection, but it does not provide information about the aorta below the diaphragm.Renal duplexultrasonographymaybe usefulforevaluating renal perfusion in the setting of aortic dissection, but it is not recommended for the initial investigation of aortic dissection.

Aorticdissectionisahypertensiveemergencythatrequiresaggressive reduction of blood pressure; systolic blood pressure should be maintained between 100 and 120 mm Hg. Antihypertensive medications that reduce the rate of increase in blood pressure during the cardiac cycle, such as β-adrenergic receptor blockers, have a theoretical beneﬁt in managing aortic dissection by reducing the rate of progression.

Surgical treatment options for renal involvement due to aortic dissection depend on individual circumstances, and careful evaluation by an experienced vascular surgeon is recommended. Thoracic aor-

ticdissectionrequiressurgicalrepairduetothehighmortalityrate if

left untreated, but isolated abdominal aortic disease may be medically managed.

Thromboembolic Disease

Systemic arterial emboli, typically originating from the left atrium or left ventricle in patients with atrial ﬁbrillation, infectious endocarditis, cardiac valvular disease, or atrial myxoma, may cause acute obstruc-

tion of the renal arteries. Rarely, a paradoxical embolus may occur

from the venous system through an atrial septal defect.

Symptoms of acute renal ischemia and infarction include ﬂank pain, gross hematuria, and fever. Laboratory ﬁndings are nonspeciﬁc but include an elevated level of lactate dehydrogenase (LDH), hematuria, and leukocytosis. A deﬁnitive diagnosis can be based on the ﬁnding of a focal nonenhancing region on contrast-enhanced CT. Imaging studies are necessary to differentiate renal artery embolic disease from renal artery dissection.

The renal mass affected by a renal artery embolus is usually not large enough to reduce kidney function so that dialysis is necessary, although some worsening of kidney function may be observed. The diagnosis of renal infarction is rarely made early enough to initiate treatment with

intra-arterial thrombolysis or thrombectomy, and it is questionable

whether the risks and marginal beneﬁt of these procedures warrant aggressive treatment except in patients where the occlusion is affecting the main renal artery and is addressed soon after occurrence. Therapy should instead address the underlying source of renal emboli with symptomatic treatment of pain as necessary. Systemic anticoagulation may be indicated to reduce the risk of further thromboembolic events.

Large and Medium-Sized Vessel Vasculitis

Systemic vasculitides such as temporal (giant cell) arteritis and Takayasu’s arteritis affect primarily large and medium-sized arteries.

PANandKawasakidiseaseaffectprimarilymedium-sizedandsmaller

arteries. These vasculitides are not associated with antineutrophil

cytoplasmicantibodies (ANCAs) and donot typically cause glomerulonephritis. They are distinguished from ANCA-associated vascu-

litides that involve smaller blood vessels and more commonly cause glomerulonephritis.

Takayasu’s arteritis and giant cell arteritis are typically associated with a granulomatous vasculitis of the aorta and its branches. Giant cell arteritis typically involves the carotid, vertebral, and temporal arteries, and renal involvement is rare. Both occur much more commonly in women than men. Takayasu’s arteritis is usually diagnosed in patients younger than 50 years of age, whereas giant cell arteritis is diagnosed in those 50 years of age or older.

Involvement of the main renal arteries occurs in about 40% of patients with Takayasu’s arteritis, producing areas of stenosis with renal ischemia or renal infarction. Common clinical features are constitutional symptoms, claudication, bruits, and hypertension. Pulses are often diminished or absent in one or more extremities, and a blood pressure discrepancy more than 10 mm Hg in the limbs is common. The diagnosis of Takayasu’s arteritis is most often made on clinical grounds along with typical angiographic or other imaging ﬁndings. Corticosteroids are the primary treatment modality. The stenotic lesions are usually reversible when corticosteroid therapy is given during the early phase of the disease before the lesions becomes ﬁbrotic and irreversible. About half of patients have chronic, persistent or cor-

ticosteroid-dependentdiseaseand require therapy with additional or

alternative immunosuppressants such as azathioprine, mycopheno-

late,methotrexate,leunomideorcyclophosphamide.More recently

targeted immunosuppression with antagonists of interleukin-6 (such as tocilizumab) and blockers of the tumor necrosis factor alpha (TNFα) pathway (such as inﬂiximab or etanercept) may be effective in helping maintain remission.

PANisamedium-sized orsmallvesselvasculitiswithnogender

predilection that predominantly occurs in adults between 40 and 60 years of age. It is an idiopathic systemic necrotizing vasculitis. Some cases may be secondary to hepatitis B virus infection, hepatitis C virus infection, or hairy cell leukemia. Peripheral neuropathy in the

formofmononeuritismultiplexisoneofthemostfrequentndings withPAN.

PAN affects the main renal arteries and renal interlobar arteries

(less commonly, the arcuate and interlobular arteries) with a necrotizing vasculitis that typically produces microaneurysms of the intrarenal arteries. They can be seen on arteriograms in 40% to 90% of patients withrenalinvolvement.Renalischemia leads to loss ofkidneyfunction and renin-mediated hypertension. Low-grade proteinuria and hematuria may be seen, but the ﬁnding of acute glomerulonephritis

indicatessomeotherdisorder.Renalinfarctionmayoccur,andrarely,

a renal artery aneurysm may cause renal artery dissection or rupture.

The diagnosis is made on clinical grounds and by arteriography.

There are no conrmatory serologic tests; PAN is not an ANCA-

associated vasculitis. Arteriography appears to be superior for diag-

nosiscompared with CTAandMRA.Progressiverenaldiseaseis not

typical but may occur. Treatment with corticosteroids and immunosuppressive drugs is effective in reducing disease severity and mortality.

Kawasaki disease is an arteritis associated with the mucocutaneous lymph node syndrome that affects mostly medium-sized and small arteries, although the aorta may also be involved. It is primarily a

self-limiteddiseaseofinfantsandyoungchildren.Renalinvolvement

is extremely rare.

Hypertensive Nephrosclerosis

Chronic hypertension in susceptible individuals may lead to develop-

mentof proteinuria, CKD,and ESRD. Hypertensivenephrosclerosis iscitedasacauseofCKDandESRDinAfricanAmericansatamuch

higher rate than white individuals, even with similar levels of blood pressure control and despite good control.

The renal manifestations of chronic hypertension include renal arterial and arteriolar intimal thickening and luminal narrowing with medial

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hypertrophy and ﬁbroblastic intimal thickening of arteries and deposition of hyaline-like material (plasma proteins) in the walls of arterioles. Glomeruli show global and focal glomerulosclerosis; the former likely results from glomerular ischemia and the latter from increased intracapillary pressure and compensatory hypertrophy and injury in response to nephron loss. Wrinkled glomerular basement membranes due to glomerular ischemia are seen on electron microscopy. Chronic interstitial nephritis with tubular atrophy and interstitial ﬁbrosis is another manifestation of chronic ischemic tubular injury seen with hypertensive nephrosclerosis, particularly in patients with other disorders such as dia-

betesmellitus,atheroembolicdisease,andatheroscleroticRAS.

The overall risk of hypertensive nephrosclerosis with progressive CKD is low in the general hypertensive population, and most patients with hypertensive nephrosclerosis have mild hypertension. The risk is greater for those who have had poorly controlled hypertension and for those of African descent, who are at particularly high risk for hypertensive nephrosclerosis. Polymorphisms in the gene that encodes for apolipoprotein L1 (APOL1) is found more commonly in African Americans compared with European Americans and strongly associated with the risk of hypertensive nephrosclerosis. A diagnosis of hypertensive nephrosclerosis as the cause of otherwise unexplained CKD is much less likely to be made in white patients compared with black patients, particularly in the absence of long-standing, severe hypertension or a history of malignant hypertension.

The diagnosis of hypertensive nephrosclerosis is typically made clinically based on a history of long-standing hypertension that precedes development of proteinuria and CKD in the absence of other causes. Kidney biopsy is rarely performed except when other disorders are suggested clinically or by laboratory evaluation. The urinary sedi-

mentis typically bland,with only low-gradeproteinuria (<1 g/day).

Symmetrical loss of renal cortical thickness is commonly found on renal ultrasound.

Pharmacologic treatment of severe hypertension reduces the risk forprogressionofCKDtoESRDinmanypatientpopulations,providing further evidence for the causative role of hypertension. The optimal blood pressure for patients with hypertensive nephrosclerosis has not been determined. For black patients, this was best addressed by the African American Study of Kidney Disease (AASK) trial, which examined more than 1000 African Americans with long-standing hypertension, slowly progressive CKD, and low-grade proteinuria. Subjects were allocated to treatment with ramipril, metoprolol, or amlodipine

to a blood pressure goal of 125/75 mm Hg or 140/90 mm Hg. The meanrateofchangeinGFRandtherateofothersecondaryoutcomes

were similar in the two groups, suggesting that lowering blood pressure

tolessthan140/90mmHgdoesnotprovidefurtherbenetinslowing

CKD progression in black patients with hypertensive nephrosclerosis. However, there was a trend favoring the lower blood pressure goal for patients with higher baseline proteinuria.

Lower blood pressure goals may also be appropriate for patients with other comorbid conditions such as diabetes mellitus. Besides affecting CKD progression, blood pressure control reduces the risk of

heartfailureandstroke.MostpatientswithhypertensivenephrosclerosisandCKDrequiremultipleantihypertensivemedicationstocontrol

blood pressure, typically including a thiazide or thiazide-like diuretic

(whenGFRiswellpreserved)andaloopdiuretic(astheGFRdeclines toless than 25 to30mL/min),alongwithanACEinhibitor or ARB,

calcium-channel blocker, and β-blocker.

Atheroembolic Disease

Atheroembolic disease is the result of cholesterol embolization from atherosclerotic plaques, most commonly from the aorta and typically dislodged during an invasive arterial procedure such as cardiac

catheterization, aortic angiography, cardiac surgery, or surgery on the aorta. Cholesterol emboli may occur spontaneously or may be precipitated by systemic anticoagulation, such as with heparin, or during systemic administration of thrombolytic agents. Because patients must have underlying atherosclerosis, the incidence increases with age, and atheroembolic disease rarely occurs before 40 years of age.

Astheresultofsystemicembolizationfromatheromatousplaques,

cholesterol crystals lodge in small arterial vessels, including the arcuate

orinterlobulararteriesofthekidneys.Cholesterol emboli frequently

involve other organs, and the pattern of organ involvement depends

inpartonwhetherdisruptedplaqueisintheascendingordescending

aorta. The extremities are commonly affected with digital ischemia and gangrene, the skin with livedo reticularis, and the gastrointestinal tract with intestinal ischemia, but any organ can be affected. Embolization from the ascending aorta can cause cardiac ischemia, and emboli arising from the ascending aorta or carotid arteries (e.g., after carotid endarterectomy) can cause stroke.

Cholesterol embolization to the eye may be recognized by ﬁnding

Hollenhorstplaquesonfunduscopic examination, which arewhitish

yellow ﬂecks at retinal arteriole bifurcations. They are often asymptomatic but may cause retinal ischemia with usually transient visual ﬁeld defects.

Patients with atheroembolic disease may have fever, eosinophilia, eosinophiluria, and hypocomplementemia, particularly acutely. Laboratory ﬁndings include an elevated erythrocyte sedimentation rate and elevated levels of amylase or liver enzymes. The widespread systemic clinical and laboratory manifestations of atheroemboli can lead to a clinical picture suggesting systemic vasculitis.

The typical pattern of renal atheroembolic disease is a decline in kidney function that ﬁrst becomes apparent 3 or more days after an inciting procedure or other event. The degree of acute and chronic kidney injury that follows is determined by the magnitude of the embolic burden, whether atheroembolism is a one-time or ongoing process,

andthedegreeofinammationinducedbytheplaquematerial.Many

patients have stabilization of the process after the initial insult, whereas others progress with various patterns and tempos to advanced CKD andESRD.Cholesterolembolizationalsomaycauseseverehypertension due to acute renal ischemia leading to renin release.

Diagnosis of renal atheroembolic disease is usually made clinically in the appropriate setting, but for some patients, a kidney biopsy is needed to conﬁrm the diagnosis and exclude others. Because the ﬁxation process washes out the cholesterol crystals from the renal biopsy sample, the pathologic examination reveals a typical needle-shaped disruption in the arterial lumen surrounded by reactive inﬂammatory and ﬁbrous intimal proliferation leading to a luminal occlusion and distal ischemic injury.

There is no speciﬁc treatment for cholesterol emboli. Because an inﬂammatory reaction typically results from the emboli, some physicians advocate corticosteroids, but their use is unproved for preventing further atheroembolism or progression of kidney failure. Avoidance of anticoagulation has been recommended to prevent dissolution and

embolizationofthrombusthatmayoverlieanatheromatousplaque.

Statin therapy is recommended for most patients for treatment of their underlying atherosclerotic disease, but it has not been shown to inﬂuence the renal manifestation of atheroemboli. Treatment with

ACEinhibitors or ARBs maybeeffectiveforhypertensioncontrolin

the acute setting, but worsening kidney function may limit their use.

DialysismaybenecessaryifAKIandESRDdevelop.

Preeclampsia

Preeclampsia is characterized by the new onset of sustained hypertension (blood pressure ≥140/90mmHg)andproteinuria(>300mg/day)

318 SECTION V Renal Disease

that develops after 20 weeks’ gestation in a previously normotensive woman. Although hypertension and proteinuria are the principal features of preeclampsia, it is a systemic vascular disease that may also cause central nervous system symptoms (e.g., visual disturbances, headache, altered mental status), abdominal pain, nausea and vomiting, liver dysfunction, thrombocytopenia, pulmonary dysfunction, impaired fetal growth, nephrotic-range proteinuria, and AKI. If grand mal seizures develop without other explanation, a diagnosis of eclampsia is made. The HELLP syndrome, characterized by hemolysis, ele- vated liver enzymes, and a low platelet count, may be a manifestation of severe preeclampsia, although some consider it to be a separate disorder. It is also associated with increased maternal and fetal mortality. History of hypertension and CKD are risk factors for preeclampsia. Other major risk factors are nulliparity, preeclampsia in previous pregnancy, multifetal gestation, autoimmune disease, and family history of preeclampsia.

Preeclampsia should be distinguished from other hypertensive conditions that can occur during pregnancy, including preexisting hypertension that occurs before 20 weeks’ gestation and persists after delivery, preeclampsia superimposed on preexisting chronic hypertension, and gestational hypertension (i.e., new-onset hypertension after 20 weeks’ gestation without proteinuria or other related manifestations).

Progress has been made in understanding the pathogenesis of preeclampsia, and maternal and placental or fetal factors have been implicated. Abnormal development of placental vasculature in early pregnancy is thought to lead to some degree of placental hypoperfusion that releases antiangiogenic factors into the maternal circulation, disturbing the delicate balance of angiogenic and antiangiogenic factors. This causes systemic endothelial dysfunction in the mother that leads to hypertension, proteinuria, and other manifestations of the disease.

SolubleFMS-relatedtyrosinekinase1(sFLT1)isaplacenta-derived

circulating antiangiogenic factor that appears to play a central role in the pathogenesis of preeclampsia. It antagonizes the proangiogenic effects of vascular endothelial growth factor (VEGF) and placental growth factor (PGF) by binding to them and preventing interaction

withtheirreceptors.Solubleendoglin(sENG),anotherantiangiogenic

factor that is widely expressed on vascular endothelium, is thought to be an important mediator of preeclampsia. Endothelial dysfunction in preeclampsia is associated with increased sensitivity to vasopressor agents, including angiotensin II, systemic vasoconstriction, and reduced ﬁbrinolytic function.

Kidney biopsy ﬁndings include glomerular endothelial cell swelling (i.e., endotheliosis) and occlusion of the capillary lumen with ischemia. These ﬁndings are also seen with other microangiopathic disorders, although ﬁbrin thrombi in glomerular capillaries are less commonly seen than with other causes. Foot process effacement is not usually seen.

The only effective treatment for preeclampsia is delivery of the fetus and placenta. The timing of delivery must take into account gestational age, severity of preeclampsia, presence or absence of systemic features, and status of the fetus and mother. Proper obstetric care is essential to balance the risk to the mother against the risk for prematurity of the fetus. In high-risk pregnancies, low-dose aspirin is started in the second and third trimester to reduce the risk of developing preeclampsia.

Treatment of mild hypertension in women with preeclampsia should be avoided because it does not treat the underlying disease

process,alterthecourseofdisease,orreduce clinicalsequelae.Inthe

absence of clinical manifestations other than proteinuria, it is usually unnecessary to start antihypertensive medications unless the systolic blood pressure is greater than 150 mm Hg or the diastolic blood pressure is higher than 100 mm Hg. Labetalol and hydralazine, both of

which can be given intravenously or orally, are often recommended as ﬁrst-line therapy for acute management. For chronic treatment, methyldopa or labetalol are often recommended initially, with extended-release nifedipine added if necessary. Diuretics and dietary sodium restriction usually are avoided unless the patient has pulmonary edema.

The risk proﬁle of these medications is poorly deﬁned in pregnancy.ACEinhibitors,ARBs,anddirectrenininhibitorsarecontraindicated during pregnancy because of the risk of fetal abnormalities.

Magnesiumsulfateisusedinseverecasesofpreeclampsiatoreducethe

risk of seizures, but it does not treat other manifestations of the disease or reduce maternal or fetal mortality rates.

Mostmanifestationsofpreeclampsiabegintoimproveshortlyafter

delivery, but in some women, hypertension, proteinuria, and other manifestations may persist for several weeks or months before resolving completely. Because preeclampsia is a risk factor for future hypertension, kidney disease, and cardiovascular events, continued medical follow-up is essential.

Scleroderma Renal Crisis

Systemic sclerosis (i.e., scleroderma) is an idiopathic connective tissue disorder associated with deposition of collagen and other extracellular matrix proteins that produces inﬂammation and ﬁbrosis of the skin and internal organs. Proliferative endovascular lesions may lead to obliteration of the vascular internal lumina and renal ischemia, with hypertension, increased renin activity, and elevated levels of angiotensin II and aldosterone.

AKI and rapidly worsening hypertension in patients with scleroderma is called scleroderma renal crisis. It occurs in approximately 5% to 10% of patients with scleroderma, typically within the ﬁrst few years after onset and primarily in those with systemic rather than localized cutaneous scleroderma who also have progressive skin and cardiac involvement. Subclinical renal involvement with mild proteinuria, hypertension, and elevated serum creatinine concentration occurs

muchmorefrequently.Sclerodermarenalcrisisoccasionallydevelops

before the clinical diagnosis of scleroderma has been made.

Scleroderma renal crisis is often associated with rapid and severe loss of kidney function, oliguria, hypertensive encephalopathy, and

heartfailure. Microangiopathic hemolyticanemia(MAHA)mayalso

occur. Low-grade proteinuria is often present but the urinalysis is not usually otherwise “active” (red blood cells, casts, etc.). About 10% of patients with scleroderma renal crisis do not have hypertension. This occurs more commonly among patients being treated with ACE inhibitors or high-dose corticosteroids.

Anti–RNApolymerase III antibodiesare strongly associatedwith

the risk of scleroderma renal crisis and have been suggested as markers for scleroderma renal crisis. Other risk factors include diffuse and rapidly progressive skin involvement and high-dose glucocorticoid use.

Renalbiopsymayrevealinterlobulararteryinvolvementwithintimal thickening, endothelial cell proliferation, and edema with obliteration of the vessel lumen with concentric onion-skinning of the wall of arterioles. Fibrinoid necrosis occurs in afferent arterioles with intravascular ﬁbrin accumulation extending into the glomeruli, often with ischemic collapse, but without features of glomerulonephritis.

Activation of the renin-angiotensin-aldosterone system appears to play an important role in the progression of the disease. Before the advent of ACE inhibitors and hemodialysis, scleroderma renal crisis was fatal in about 75% of patients at 1 year. ACE inhibitor therapy has reduced this 1-year mortality rate to less than 15%. Captopril is often recommended as the ACE inhibitor of choice due to its short half-life and ease of dose titration. If the diagnosis of scleroderma renal crisis is made before advanced renal failure is established, ACE inhibition may halt or reverse the decline in renal function. Some experts recommend

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continuing ACE inhibitors even if kidney function declines and temporary dialysis is necessary, citing an increased chance of renal recovery, which has been described in scleroderma renal crisis patients even after 18 to 24 months of dialysis dependence. ACE inhibitors are not useful for prevention of scleroderma renal crisis, and their use in this setting has been associated with a poorer outcome, including greater

riskofrequiringpermanentdialysisifrenalcrisisoccurs.UseofACE inhibitorsratherthanARBsisrecommendedbecauseofthelongtrack

record of success with ACE inhibitors in this disease. Patients with

ESRDsecondary tosclerodermarenalcrisishavea highmortalityon

dialysis, poor dialysis access maturation, and reduced allograft survival following renal transplantation.

THROMBOTIC MICROANGIOPATHY OF THE KIDNEY

TMAis a pathologic lesionsecondary to variousdistinct pathogenic

mechanisms leading to endothelial injury, microvascular thrombo-

sis,andMAHA.Thesesyndromeseachleadtoorgandysfunctiondue

to microvascular thrombosis, but each syndrome has distinct clinical, pathophysiologic, and epidemiologic features. AKI is commonly

seeninTMAduetothepropensityoftheglomerularendotheliumto

damage.

ThetraditionalclassicationofTMAintothromboticthrombocy-

topenic purpura (TTP) and hemolytic uremic syndrome (HUS) has

undergoneevolutionand currently TMAsare subclassied based on

the underlying pathogenic process (Fig. 28.4 and Table 28.3). Although many processes cause microvascular endothelial injury, renal involvement from these disorders affects the vasculature at different levels.

RenalinvolvementbyHUSandTTPprimarilyaffectsthe glomeruli,

whereas scleroderma often extends to the interlobular arteries, and malignant hypertension more often affects the afferent arterioles. However, there is signiﬁcant overlap and similar histologic features among these diseases, making careful clinical evaluation essential for accurate determination of the cause.

Thrombotic Thrombocytopenic Purpura

TTPischaracterizedbyMAHAandthrombocytopenia.Patients mayalso

have fever, AKI, and neurologic impairment. Purpura is only rarely observed, and it is not necessary to make the diagnosis. TTP occurs with a female-tomale ratio of 4:3 and a peak incidence in the third and fourth decades of

life.MAHAandthrombocytopeniamanifestingsimilartoTTPmayoccur

in response to some drugs (e.g., ticlopidine, cyclosporine, tacrolimus), after stem cell transplantation, in association with human immunodeﬁciency virus (HIV) infection, and in patients with malignant hypertension, sepsis, disseminated intravascular coagulation, or advanced cancers.

TTPis caused by a deciency or reduced activityof ADAMTS13

(a disintegrin-like and metalloproteinase with thrombospondin-1–like

domains).ADAMTS13isaplasmaproteasethatnormallycleavesvon

Willebrand factor (VWF) and limits the extent of intravascular thrombosis (Fig. 28.5).Microthrombicomposed primarily of plateletsand VWF accumulate in the vascular bed of multiple organs, leading to a

MAHA.DeciencyinADAMTS13 may be acquired,causedbyantiADAMTS13 autoantibodies (mostly immunoglobulin G [IgG]), or,

much less commonly, genetic.

Other laboratory abnormalities are manifestations of the MAHA

and include thrombocytopenia; an elevated LDH concentration, indirect bilirubin concentration, and reticulocyte count; and a low haptoglobin concentration. Coagulation laboratory test results (e.g., prothrombin time, activated partial thromboplastin time, ﬁbrinogen level) are typically normal, although levels of ﬁbrin split products may be elevated. AKI, microscopic hematuria, and low-grade proteinuria

arefrequentlydetected.

Without treatment, TTP has a mortality rate of about 90%, with

most deaths occurring within 3 months of the onset of symptoms.

Treatment with plasma infusion can normalize ADAMTS13 levels,

reducing intravascular hemolysis and mortality rates. Plasmapheresis and replacement with fresh-frozen plasma has the advantage of remov-

inginhibitoryautoantibodiesinadditiontonormalizingADAMTS13

levels because of the large volume of plasma that can be infused.

ADAMTS13activitymustbeassayedbeforetherapyisinitiatedto

obtain accurate results, but treatment should not be delayed for the resultsto return. Theseverity of ADAMTS13 deciency (<5%)predicts future relapse, although those with severe deﬁciency are just as likely to respond initially to plasmapheresis as those with a mild deﬁ-

ciency.PatientswithMAHAduetoothercausesnot associated with ADAMTS13 deciency usually have a minimal response to plasma-

pheresis or plasma infusion. Patients with HUS do not have abnormal-

itiesinADAMTS13levelsorfunction.

Hemolytic-Uremic Syndrome

Shiga Toxin-Producing Escherichia coli

Gastrointestinal tract infection with the Shiga-toxigenic Escherichia coli (STEC) strain O157:H7 produces a diarrheal illness that is complicated

inabout15%ofcasesbyaMAHAwithintraglomerularthrombosisand

AKI. STEC-HUS most commonly affects infants and children, although adults may also be affected. Cases are often clustered because of outbreaks of E. coli O157:H7, with peaks occurring in summer and autumn. E. coli is endemic in the gastrointestinal tract of cattle, and cases are often tracked to undercooked meat, exposure to bovine fecal matter, animal exposure,

orothercontaminatedfoodproducts.InMay2011,anoutbreakofSTEC-

HUS in Germany was tracked back to fenugreek sprouts grown from contaminated seeds. The pathogenic agent, E. coli O104:H4, was particularly virulent with 30% of infected patients, mostly adults, developing HUS.

Shiga-toxigenic bacterial strains commonly produce a prodrome of painful, bloody diarrhea, which precedes the development of HUS by 2 to 12 days (median, 3 days). Shiga toxin is directly thrombogenic in the renal vasculature. Although intravascular coagulation in STEC-HUS is usually limited to the kidney, the heart, gastrointestinal tract, and central nervous system may also be affected.

Laboratory abnormalities in HUS include elevated creatinine levels, anemia, schistocytes on the peripheral smear, elevated reticulocyte count, and thrombocytopenia. In contrast to disseminated intravascular coagulation, ﬁbrinogen levels are normal or high, and the prothrombin time is normal or only slightly prolonged. Fresh stool should be sent for culture of E. coli O157:H7, which can aid in tracing the source of an outbreak. Stool studies should also be performed for patients without diarrhea because E. coli O157:H7 may rarely cause HUS in the absence of intestinal symptoms. If E. coli O157:H7 is not detected, culture for other Shiga-toxigenic organisms should be pursued.

The pathologic renal lesions of HUS include vessel wall thickening with endothelial cell swelling and intraglomerular thrombosis with platelet- and ﬁbrin-rich thrombi. Fragmentation of red blood cells may be seen in the renal vasculature and within the vessel wall.

Treatment of STEC-HUS is supportive, including adequate volume repletion with isotonic intravenous ﬂuids, transfusion for severe anemia, and avoidance of other nephrotoxic agents (e.g., nonsteroidal anti-inﬂammatory drugs, aminoglycoside antibiotics, iodinated contrast). Platelet transfusion is not recommended because it may worsen the ongoing microvascular thrombosis. Antibiotic treatment of patients with bloody diarrhea is controversial. Corticosteroids, anticoagulation (e.g., aspirin, heparin), thrombolytic agents, and plasma administration have proved ineffective for the treatment of STEC-HUS. In very severe cases, especially with central nervous system involvement, eculizumab (a complement pathway inhibitor) can be used.

320 SECTION V Renal Disease

Thrombotic microangiopathy

Infection-related HUS

TTP (ADAMTS13 deficiency)

Complement-atypical HUS

Pregnancy-associated TMA

Drug-associated TMA

Shiga toxin-producing

(STEC-HUS)

coli

Pneumococcal HUS

Hereditary deficiency

Acquired antibody:

• Spontaneous

• Ticlopidine-mediated

Hereditary (mutation of the alternative complement pathway)

Acquired (autoantibody altering the alternative complement pathway)

Complement-mediated atypical HUS

TTP (ADAMTS13 deficiency)

Preeclampsia, (sFLT-1 mediated endothelial injury) HELLP syndrome

Acquired antibody (e.g. quinine)

VEGF inhibition (e.g. bevacizumab, tyrosine kinase inhibitors)

Escherichia

Associated with autoimmune disease

Associated with kidney disease (primary glomerular diseases, malignant hypertension)

Post-solid organ and bone marrow transplant

Fig. 28.4 Thrombotic microangiopathy (TMA). CNI, Calcineurin inhibitor; HELLP, hemolysis, elevated liver

enzymes, and a low platelet count; HUS, hemolytic uremic syndrome; IFN, interferon; sFLT-1, soluble fmslike tyrosine kinase-1; TTP, thrombotic thrombocytopenic purpura; VEGF, vascular endothelial growth factor.

With supportive care alone, most patients with STEC-HUS recover

with normalization of renal function or only mild residual CKD,

althoughabout 25% maydevelop advanced CKDor ESRD overthe next 1 to 2 decades of life. Risk for CKD is increased with cortical

necrosis and involvement of more than 50% of glomeruli identiﬁed on renal biopsy. The risk for complications and death increases with age, with the mortality rate increasing from about 5% to 10% for children to about 30% for adults.

Complement-Mediated Atypical HUS

The alternative complement pathway is the ampliﬁcation loop of the complement system. Dysregulation of this pathway due to either

hereditary or acquired causes may lead to complement-mediated endothelial damage and atypical HUS (aHUS).Mutationsofgenesfor

Direct endothelial toxicity (e.g. IFN, CNI, gemcitabine)

Systemic lupus erythematosus (SLE)

Catastrophic antiphospholipid syndrome

Scleroderma renal crisis

components of the alternative complement pathway, including C3, fac-

torB,regulatorsoffactorH(CFH/CFHRfusions),factorI,andCD46,

have been implicated. These mutations have an incomplete penetrance andfrequentlyatriggeringfactorsuchasinfectionorpregnancyprecedes the onset of clinical manifestations. In some childhood forms of complement-mediatedaHUS, an acquired autoantibody againstfactor H can be detected and gastrointestinal prodrome is often reported. Failure to detect a genetic maturation or autoantibody does not rule out this disease because it is likely that not all responsible causes have been identiﬁed.

Complement-mediated aHUS historically has had a very poor

prognosis with high likelihood of ESRD and death. The disease frequently recurs in a renal allograft with the recurrence rate depend-

ing on the underlying mutation, with the highest risk for CFH, CFB,

CHAPTER 28 Vascular Disorders of the Kidney

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321

TABLE 28.3 Pathogenesis, Clinical/Diagnostic Characteristics, and Management of Main

Thrombotic Microangiopathic Syndromes

Pathogenesis Clinical Characteristics Diagnostic Characteristics Management

Shiga toxin–producing

Escherichia coli (STEC-HUS)

TTP

Complement-mediated

aHUS

Pneumococcal HUS

Quinine-induced TMA

ADAMTS3, A disintegrin and metalloproteinase with thrombospondin-1–like domains; anti-FH Ab, anti-factor H antibody; CNS, central nervous system; GP, glycoprotein platelets; HUS, hemolytic uremic syndrome; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura; VWF, von Willebrand factor.

Enteric infection with Shiga

toxin–producing pathogen (E. coli O157; E. coli O104)

ADAMTS 13 deﬁciency (heredi-

tary or acquired autoantibody)

Ticlopidine-induced autoantibody

Dysregulation of the alternative

complement pathway:

Hereditary or acquired (anti-FH

Ab)

Neuraminidase-mediated

exposure of the endothelium antigens leading to endothelial injury

Autoantibodies against GP Ib/IX

or IIb/IIIa

All age groups with peak inci-

dence in children for the E. coli O157 pathogen

Enteric prodrome is common

(5% do not have diarrhea)

Other affected family members if

hereditary

In women with predisposition

presents clinically in the 2nd and

3rd trimester of pregnancy No diarrheal prodrome Neurologic symptoms predom-

inate Diarrhea can be present (30% at

presentation) Hereditary disease has incomplete

penetrance Trigger (e.g., infection, pregnancy)

often identiﬁed High recurrence in kidney allograft Mainly children <2 years Frequently associated with pneu-

monia and empyema

Not dose related Can occur early (after single

exposure) or late (up to 10 years

after exposure)

Fibrin predominates intravascular

thrombi Swollen endothelial cells STEC isolated in the stool

Low ADAMTS 13 activity (<10%)

VWF predominates Intravascular

thrombi Absence of swollen endothelial

cells

C3 can be low (normal levels do

not exclude the disease) ADAMTS13 activity >10% Negative genetic and autoanti-

body testing does not exclude

the diagnosis

Positive Coombs test Supportive care

ADAMTS13 activity ≥10% Supportive

Supportive No role for plasma exchange Possible role for eculizumab

in severe CNS involvement Antibiotics (controversial) Plasma exchange Immunosuppression (e.g.

rituximab for acquired

autoantibody) Stop ticlopidine

Eculizumab Partial response to plasma

exchange Liver transplant may be

considered

Treatment of the infection

Plasma exchange not

effective

and C3 mutations and the lowest with CD46 mutations. Eculizumab is a humanized monoclonal antibody that binds with high afﬁnity to complement protein C5 and prevents the generation of C5a, C5b, and the terminal complement complex C5b-9. In patients with complement-mediated HUS, eculizumab inhibits complement-mediated

TMA. It is used both to treat the disease andto prevent recurrence

after kidney transplantation. Because complement components are mainly produced by the liver, a combined liver kidney transplant can be curative.

systemicTMA candevelop,oftenassociated withuseofhigherdoses ofthecancertherapeuticagents.Mostofthesedisordersarereversible

after stopping the medication.

OtherchemotherapeuticagentsassociatedwithTMAincludegem-

citabine, mitomycin C, vincristine, and proteasome inhibitors (e.g.,

bortezomib, carlzomib, and ixazomib). Gemcitabine-related TMA

is directly related to the cumulative dose. Usually treated conserva-

tively, in severe cases with persistent TMA eculizumabtherapy may

be considered.

In patients receivingan allogenicbone marrowtransplant, TMA

Malignancy-Associated TMA

Inpatientswithacancerdiagnosis,TMAcanbeduetothecanceror

its therapy. Disseminated malignancy can produce embolic tumor cells leading to endothelial damage and erythrocytes shearing. It has a very

occurs in 10% to 40% of patients and is considered a manifestation of graft versus host disease (GVHD) or radiation therapy. Therapy for

thisformofTMAiscontroversialandmainlydirectedtowardtreating

GVHD, although eculizumab may be tried. poorprognosis.TMAhas also been described withcancertherapeutic agents that interfere with the VEGF pathway such as bevacizumab and tyrosine-kinase inhibitors (e.g., sunitinib). The VEGF pathway is upregulated in the majority of human tumors and it is thought to be important for expanding neovascularization of the tumor. In the kidney glomeruli, VEGF is produced locally by podocytes and endothelial cells express tyrosine kinase VEGF receptors. A disruption of this bal-

ancewillleadtoendothelialinjuryandTMA.Clinically,mostpatients

present with hypertension and proteinuria. In rare cases, a severe

Pregnancy-Related TMA

Pregnancy acts as a trigger for both TTP and complement-mediated

aHUS. TTP occurs mainly during the second and third trimester of

pregnancy.Normalpregnancyis associated with an augmentation of

VWF antigen release leading to TTP in patients who are already predis-

posedbyacongenitaloracquiredADAMTS13deciency.

Pregnancy-related aHUS occurs in the postpartum period. Delivery

acts as a triggering factor for aHUS in patients with certain genetic

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