2297Acute Kidney Injury CHAPTER 310

and coronary vessels. Mediators of this response include angiotensin II,

norepinephrine, and vasopressin (also termed antidiuretic hormone).

Glomerular filtration can be maintained despite reduced renal blood

flow by angiotensin II–mediated renal efferent vasoconstriction, which

maintains glomerular capillary hydrostatic pressure closer to normal

and thereby prevents marked reductions in GFR if renal blood flow

reduction is not excessive.

In addition, a myogenic reflex within the afferent arteriole leads

to dilation in the setting of low perfusion pressure, thereby maintaining glomerular perfusion. Intrarenal biosynthesis of vasodilator

prostaglandins (prostacyclin, prostaglandin E2

), kallikrein and kinins,

and possibly nitric oxide (NO) also increases in response to low renal

perfusion pressure. Autoregulation is also accomplished by tubuloglomerular feedback, in which decreases in solute delivery to the macula

densa (specialized cells within the distal tubule) elicit dilation of the

juxtaposed afferent arteriole in order to maintain glomerular perfusion, a mechanism mediated, in part, by NO. There is a limit, however,

to the ability of these counterregulatory mechanisms to maintain

GFR in the face of systemic hypotension. Even in healthy adults, renal

autoregulation usually fails once the systolic blood pressure falls below

80 mmHg.

A number of factors determine the robustness of the autoregulatory response and the risk of prerenal azotemia. Atherosclerosis,

long-standing hypertension, and older age can lead to hyalinosis and

myointimal hyperplasia, causing structural narrowing of the intrarenal arterioles and impaired capacity for renal afferent vasodilation.

In CKD, renal afferent vasodilation may be operating at maximal

capacity in order to maximize GFR in response to reduced functional

renal mass. Drugs can affect the compensatory changes evoked to

maintain GFR. NSAIDs inhibit renal prostaglandin production,

limiting renal afferent vasodilation. Angiotensin-converting enzyme

(ACE) inhibitors and angiotensin receptor blockers (ARBs) limit

renal efferent vasoconstriction; this effect is particularly pronounced

in patients with bilateral renal artery stenosis or unilateral renal

artery stenosis (in the case of a solitary functioning kidney) because,

as indicated above, efferent arteriolar vasoconstriction is needed

to maintain GFR due to low renal perfusion. The combined use of

NSAIDs with ACE inhibitors or ARBs poses a particularly high risk

for developing prerenal azotemia.

Many individuals with advanced liver disease exhibit a hemodynamic profile that resembles prerenal azotemia in the setting of

total-body volume overload. Systemic vascular resistance is markedly

reduced due to primary arterial vasodilation in the splanchnic circulation, resulting ultimately in activation of vasoconstrictor responses

similar to those seen in hypovolemia. AKI is a common complication

in this setting, and it can be triggered by volume depletion and spontaneous bacterial peritonitis. A particularly poor prognosis is seen in

the case of type 1 hepatorenal syndrome, in which AKI persists despite

volume administration and withholding of diuretics. Type 2 hepatorenal syndrome is a less severe form characterized mainly by refractory

ascites. The hepatorenal syndrome, defined as it is above, is difficult to

distinguish from prerenal azotemia.

■ INTRINSIC AKI

The most common causes of intrinsic AKI are sepsis, ischemia, and

nephrotoxins, both endogenous and exogenous (Fig. 310-3). As

mentioned previously, in many cases, prerenal azotemia advances to

tubular injury. Although often the AKI is attributed to “acute tubular

necrosis,” human biopsy confirmation of tubular necrosis is, in general,

often lacking in cases of sepsis and ischemia; indeed, processes such as

inflammation, apoptosis, and altered regional perfusion may be important contributors pathophysiologically without frank necrosis. There

are other potential causes of AKI in settings such as sepsis, including

drug-induced interstitial nephritis or glomerulonephritis. These and

other causes of intrinsic AKI can be catalogued anatomically according

to the major site of renal parenchymal damage: glomeruli, tubulointerstitium, and vessels.

■ SEPSIS-ASSOCIATED AKI

In the United States, more than 1 million cases of sepsis occur each

year. AKI complicates more than 50% of cases of severe sepsis and

greatly increases the risk of death. Sepsis is also a very important cause

of AKI in the developing world. Decreases in GFR with sepsis can

occur even in the absence of overt hypotension, although many cases

of severe AKI typically occur in the setting of hemodynamic compromise requiring vasopressor support. While there can be tubular injury

associated with AKI in sepsis as manifest by the presence of tubular

debris and casts in the urine, postmortem examinations of kidneys

from individuals with severe sepsis suggest that other factors, perhaps

related to inflammation, mitochondrial dysfunction, and interstitial

edema, must also be considered in the pathophysiology of sepsisinduced AKI.

 Nephrotoxins

Exogenous: Iodinated

contrast, aminoglycosides,

cisplatin, amphotericin B,

PPIs, NSAIDs

Endogenous: Hemolysis,

rhabdomyolysis,

myeloma, intratubular

crystals

Acute kidney injury

Prerenal Intrinsic Postrenal

Glomerular

• Acute

 glomerulo-

 nephritis

Ischemia

Tubules and

interstitium

Sepsis/

Infection

Vascular

• Vasculitis

• Malignant

 hypertension

• TTP-HUS

Hypovolemia

Decreased cardiac output

Decreased effective circulating

volume

• Congestive heart failure

• Liver failure

Impaired renal autoregulation

• NSAIDs

• ACE-I/ARB

• Cyclosporine

Bladder outlet obstruction

Bilateral pelvoureteral

obstruction (or unilateral

obstruction of a solitary

functioning kidney)

FIGURE 310-1 Classification of the major causes of acute kidney injury. ACE-I, angiotensin-converting enzyme inhibitor-I; ARB, angiotensin receptor blocker; NSAIDs,

nonsteroidal anti-inflammatory drugs; PPI, proton pump inhibitors; TTP-HUS, thrombotic thrombocytopenic purpura–hemolytic-uremic syndrome.

2298 PART 9 Disorders of the Kidney and Urinary Tract

The hemodynamic effects of sepsis—arising from generalized arterial vasodilation, mediated in part by cytokines that upregulate the

expression of inducible NO synthase in the vasculature—can lead to a

reduction in GFR. The operative mechanisms may be excessive efferent

arteriole vasodilation, particularly early in the course of sepsis, or renal

vasoconstriction from activation of the sympathetic nervous system,

the renin-angiotensin-aldosterone system, or increased levels of vasopressin or endothelin. Sepsis may lead to endothelial damage, which

results in increased microvascular leukocyte adhesion and migration,

thrombosis, permeability, increased interstitial pressure, reduction in

local flow to tubules, and activation of reactive oxygen species, all of

which may injure renal tubular cells.

AKI can be an important complication of viral infections, such as

hantavirus, dengue virus, or SARS-CoV-2. The pathophysiology of

AKI due to viral infections remains incompletely understood. As an

example, some have reported infection of the kidney with SARS-CoV-2

while others have found less direct involvement. SARS-CoV-2 is associated with a large release of cytokines into the circulation (“cytokine

storm”), which may cause diffuse intrarenal vasoconstriction. Finally,

there is a generalized hypercoagulable state associated with SARSCoV-2 that may contribute to the impairment of intrarenal blood flow.

■ ISCHEMIA-ASSOCIATED AKI

Healthy kidneys receive 20% of the cardiac output and account for

10% of resting oxygen consumption, despite constituting only 0.5% of

the human body mass. The kidneys are also the site of one of the most

hypoxic regions in the body, the renal medulla. The outer medulla is

particularly vulnerable to ischemic damage because of the architecture

of the blood vessels that supply oxygen and nutrients to the tubules.

In the outer medulla enhanced leukocyte-endothelial interactions in

the small vessels lead to inflammation and reduced local blood flow

to the metabolically very active S3 segment of the proximal tubule,

Glomerulus

Tubule

Afferent

arteriole

Arteriolar resistances

Efferent

arteriole

Increased

vasodilatory

prostaglandins

Increased

angiotensin II

Normal perfusion pressure

A B

C D

Decreased perfusion pressure

Normal GFR Normal GFR maintained

Slightly increased

vasodilatory

prostaglandins

Decreased

angiotensin II

Decreased perfusion pressure in the presence of ACE-I or ARB

Low GFR

Decreased

vasodilatory

prostaglandins

Increased

angiotensin II

Decreased perfusion pressure in the presence of NSAIDs

Low GFR

FIGURE 310-2 Intrarenal mechanisms for autoregulation of the glomerular filtration rate (GFR) under decreased perfusion pressure and reduction of the GFR by drugs.

A. Normal conditions and a normal GFR. B. Reduced perfusion pressure within the autoregulatory range. Normal glomerular capillary pressure is maintained by afferent

vasodilatation and efferent vasoconstriction. C. Reduced perfusion pressure with a nonsteroidal anti-inflammatory drug (NSAID). Loss of vasodilatory prostaglandins

increases afferent resistance; this causes the glomerular capillary pressure to drop below normal values and the GFR to decrease. D. Reduced perfusion pressure with

an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin receptor blocker (ARB). Loss of angiotensin II action reduces efferent resistance; this causes the

glomerular capillary pressure to drop below normal values and the GFR to decrease. (From JG Abuelo: Normotensive ischemic acute renal failure. N Engl J Med 357:797,

2007. Copyright © 2007, Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)

2299Acute Kidney Injury CHAPTER 310

Cortex

Medulla

Outer

Inner

Loop of

Henle

Loop of

Henle

Collecting

duct

Thin

descending

limb

Thick

ascending

limb

Thick ascending

limb

Pars recta

Proximal

convoluted

tubule

Proximal

convoluted

tubule

Distal

convoluted

tubule

Pars recta

Cortical

glomerulus

Juxtamedullary

glomerulus Distal

convoluted

tubule

Small vessels

• Glomerulonephritis

• Vasculitis

• TTP/HUS

• DIC

• Atheroemboli

• Malignant HTN

• Calcineurin

inhibitors

• Sepsis

Intratubular

• Endogenous

 • Myeloma proteins

 • Uric acid (tumor

 lysis syndrome)

 • Cellular debris

• Exogenous

 • Acyclovir,

 methotrexate

Large vessels

• Renal artery embolus,

 dissection, vasculitis

• Renal vein thrombosis

• Abdominal compartment

syndrome

Interstitium

• Allergic (PCN, PPIs,

 NSAIDs, rifampin, etc.)

• Infection (severe

pyelonephritis,

Legionella, sepsis)

• Infiltration

(lymphoma, leukemia)

• Inflammatory

(Sjogren’s, tubulointerstitial

nephritis uveitis), sepsis

Tubules

• Toxic ATN

 • Endogenous

 (rhabdomyolysis,

 hemolysis)

 • Exogenous (contrast,

 cisplatin, gentamicin)

• Ischemic ATN

• Sepsis

Intrinsic Renal Failure

FIGURE 310-3 Major causes of intrinsic acute kidney injury. ATN, acute tubular necrosis; DIC, disseminated intravascular coagulation; HTN, hypertension; PCN, penicillin;

PPI, proton pump inhibitors; TINU, tubulointerstitial nephritis-uveitis; TTP/HUS, thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome.

which depends on oxidative metabolism for survival. Mitochondrial

dysfunction due to ischemia and mitochondrial release of reactive

oxygen species also play a role in renal tubular injury. Transient

ischemia alone in a normal kidney is usually not sufficient to cause

severe AKI, as evidenced by the relatively low risk of severe AKI even

after total interruption of renal blood flow during suprarenal aortic

clamping or cardiac arrest. Clinically, AKI more commonly develops

when ischemia occurs in the context of limited renal reserve (e.g.,

CKD or older age) or coexisting insults such as sepsis, vasoactive or

nephrotoxic drugs, rhabdomyolysis, or the systemic inflammatory

states associated with burns and pancreatitis. Prerenal azotemia and

ischemia-associated AKI represent a continuum of the manifestations

of renal hypoperfusion. Persistent preglomerular vasoconstriction may

be a common underlying cause of the reduction in GFR seen in AKI;

implicated factors for vasoconstriction include activation of tubuloglomerular feedback from enhanced delivery of solute to the macula

densa following proximal tubule injury, increased basal vascular tone

and reactivity to vasoconstrictive agents, and decreased vasodilator

responsiveness. Other contributors to low GFR include backleak of filtrate across damaged and denuded tubular epithelium and mechanical

obstruction of tubules from necrotic debris (Fig. 310-4).

Postoperative AKI Ischemia-associated AKI is a serious complication in the postoperative period, especially after major operations

involving significant blood loss and intraoperative hypotension. The

procedures most commonly associated with AKI are cardiac surgery

with cardiopulmonary bypass (particularly for combined valve and

bypass procedures), vascular procedures with aortic cross clamping,

and intraperitoneal procedures. Severe AKI requiring dialysis occurs

in ~1% of cardiac and vascular surgery procedures. The risk of severe

AKI has been less well studied for major intraperitoneal procedures but

appears to be of comparable magnitude. Common risk factors for postoperative AKI include underlying CKD, older age, diabetes mellitus,

congestive heart failure, and emergency procedures. The pathophysiology of AKI following cardiac surgery is multifactorial. Major AKI risk

factors are common in the population undergoing cardiac or vascular

surgery. Over time, more of these surgical procedures are performed

on older patients with comorbidities that predispose them to AKI and

hasten progression of ESKD if they develop AKI. Longer duration of

cardiopulmonary bypass is a risk factor for AKI. In addition to ischemic

injury from sustained hypoperfusion, cardiopulmonary bypass may

cause AKI through a number of mechanisms including extracorporeal

circuit activation of leukocytes and inflammatory processes, hemolysis

2300 PART 9 Disorders of the Kidney and Urinary Tract

along the nephron where filtrate water

is reabsorbed and in the medullary

interstitium, where water flows from

the descending blood vessels into the

concentrated interstitium; this results in

high-concentration exposure of toxins to

tubular, interstitial, and endothelial cells.

Nephrotoxic injury occurs in response to

a number of pharmacologic compounds

with diverse structures, endogenous substances, and environmental exposures.

All structures of the kidney are vulnerable to toxic injury, including the tubules,

interstitium, vasculature, and collecting

system. As with other forms of AKI,

risk factors for nephrotoxicity include

older age, CKD, and prerenal azotemia.

Hypoalbuminemia may increase the risk

of some forms of nephrotoxin-associated

AKI due to increased free circulating

drug concentrations.

Contrast Agents Iodinated contrast

agents used for cardiovascular and computed tomography (CT) imaging are a

cause of AKI. The risk of AKI, or “contrast nephropathy,” is negligible in those

with normal renal function but increases in the setting of CKD, particularly diabetic nephropathy. The most common clinical course of

contrast nephropathy is characterized by a rise in SCr beginning 24–48

h following exposure, peaking within 3–5 days, and resolving within 1

week. More severe, dialysis-requiring AKI is uncommon except in the

setting of significant preexisting CKD, often in association with congestive heart failure or other coexisting causes for ischemia-associated

AKI. Patients with multiple myeloma and/or renal disease are particularly susceptible. Low fractional excretion of sodium (FeNa) and relatively benign urinary sediment without features of tubular necrosis (see

below) are common findings. Contrast nephropathy is thought to occur

from a combination of factors, including (1) hypoxia in the renal outer

medulla due to perturbations in renal microcirculation and occlusion

of small vessels; (2) cytotoxic damage to the tubules directly or via the

generation of oxygen-free radicals, especially because the concentration

of the agent within the tubule is markedly increased; and (3) transient

tubule obstruction with precipitated contrast material. Other diagnostic agents implicated as a cause of AKI are high-dose gadolinium used

for magnetic resonance imaging (MRI) and oral sodium phosphate

solutions used as bowel purgatives. Gadolinium has been associated

with development of nephrogenic systemic fibrosis (NSF) in subjects

with advanced kidney disease, but the majority of these cases were

associated with group I gadolinium-based contrast media, which are

rarely used now in the United States and have been withdrawn from the

market in many other countries. The risk of AKI associated with standard doses of group II gadolinium-based contrast media is very low.

Antibiotics Several antimicrobial agents are commonly associated

with AKI. Vancomycin may be associated with AKI from tubular injury,

particularly when trough levels are high and when used in combination

with other nephrotoxic antibiotics. Vancomycin can also crystalize

in tubules and cause intratubular obstruction. Aminoglycosides and

amphotericin B both cause tubular necrosis. Nonoliguric AKI (i.e.,

with a urine volume >400 mL/day) accompanies 10–30% of courses of

aminoglycoside antibiotics, even when plasma levels are in the therapeutic range. Aminoglycosides are freely filtered across the glomerulus

and then accumulate within the renal cortex, where concentrations

can greatly exceed those of the plasma. AKI typically manifests after

5–7 days of therapy and can present even after the drug has been discontinued. Hypomagnesemia is a common finding.

Amphotericin B causes renal vasoconstriction from an increase in

tubuloglomerular feedback as well as direct tubular toxicity mediated

by reactive oxygen species. Nephrotoxicity from amphotericin B is

Vasoconstriction in response to:

endothelin, adenosine, angiotensin II,

thromboxane A2, leukotrienes,

sympathetic nerve activity

MICROVASCULAR

Pathophysiology of Ischemic Acute Renal Failure

O2 TUBULAR

Vasodilation in response to:

nitric oxide, PGE2, acetylcholine,

bradykinin

Endothelial and vascular smooth

 muscle cell structural damage

Leukocyte-endothelial adhesion,

vascular obstruction, leukocyte

activation, and inflammation

Cytoskeletal breakdown

Inflammatory and

vasoactive mediators

Loss of polarity

Apoptosis and necrosis

Desquamation of viable

 and necrotic cells

Tubular obstruction

Backleak

Glomerular Medullary

Mitochondrial injury

FIGURE 310-4 Interacting microvascular and tubular events contributing to the pathophysiology of ischemic acute

kidney injury. PGE2

, prostaglandin E2

. (Republished with permission of American Society of Nephrology, from Recent

advances in the pathophysiology of ischemic acute renal failure, JV Bonventre, JM Weinberg, 14:2199, 2003; permission

conveyed through Copyright Clearance Center, Inc.)

with resultant pigment nephropathy (see below), and aortic injury with

resultant atheroemboli. AKI from atheroembolic disease, which can also

occur following percutaneous catheterization of the aorta, or spontaneously, is due to cholesterol crystal embolization resulting in partial or

total occlusion of multiple small arteries within the kidney. Over time,

a foreign body reaction can result in intimal proliferation, giant cell

formation, and further narrowing of the vascular lumen, accounting for

the generally subacute (over a period of weeks rather than days) decline

in renal function. In addition, high doses of exogenous vasopressors

and blood-product perfusion increase the risk of AKI. Mortality among

cardiovascular patients who require renal replacement therapy can be

as high as 40–70%. Even with milder forms of post-operative AKI there

is an increased risk of subsequent progression to chronic kidney disease.

Burns and Acute Pancreatitis Extensive fluid losses into the

extravascular compartments of the body frequently accompany severe

burns and acute pancreatitis. AKI is an ominous complication of burns,

affecting 25% of individuals with >10% total body surface area involvement. In addition to severe hypovolemia resulting in decreased cardiac

output and increased neurohormonal activation, burns and acute pancreatitis both lead to dysregulated inflammation and an increased risk of sepsis and acute lung injury, all of which may facilitate the development and

progression of AKI. Individuals undergoing massive fluid resuscitation for

trauma, burns, and acute pancreatitis can also develop abdominal compartment syndrome, where markedly elevated intraabdominal pressures,

usually >20 mmHg, lead to renal vein compression and reduced GFR.

Diseases of the Vasculature Leading to Ischemia These diseases can compromise oxygen and metabolic substrate delivery to

the tubules and glomeruli. Microvascular causes of AKI include the

thrombotic microangiopathies (due to cocaine, certain chemotherapeutic agents, antiphospholipid antibody syndrome, radiation nephritis,

malignant hypertensive nephrosclerosis, thrombotic thrombocytopenic

purpura/hemolytic-uremic syndrome [TTP-HUS]), scleroderma, some

chemotherapeutic agents and atheroembolic disease. Large-vessel diseases associated with AKI include renal artery dissection, thromboembolism, or thrombosis, and renal vein compression or thrombosis. Renal

angiography is the gold standard for direct visualization of the renal

vasculature and is important for the diagnosis of renal artery stenosis,

large vessel vasculitis, fibromuscular disease, or renal vein obstruction.

■ NEPHROTOXIN-ASSOCIATED AKI

The kidney has very high susceptibility to nephrotoxic agents due to

extremely high blood perfusion and concentration of filtered substances

2301Acute Kidney Injury CHAPTER 310

dose and duration dependent. This drug binds to tubular membrane

cholesterol and introduces pores. Clinical features of amphotericin B

nephrotoxicity include polyuria, hypomagnesemia, hypocalcemia, and

nongap metabolic acidosis.

Acyclovir can precipitate in tubules and cause AKI by tubular

obstruction, particularly when given as an intravenous bolus at high

doses (500 mg/m2

) or in the setting of hypovolemia. Foscarnet, pentamidine, tenofovir, and cidofovir are also frequently associated with AKI

due to tubular toxicity. AKI secondary to acute interstitial nephritis

can occur as a consequence of exposure to many antibiotics, including

penicillins, cephalosporins, quinolones, sulfonamides, and rifampin.

Chemotherapeutic Agents Cisplatin and carboplatin are accumulated by proximal tubular cells and cause necrosis and apoptosis.

Intensive hydration regimens have reduced the incidence of cisplatin

nephrotoxicity, but it remains a dose-limiting toxicity. Ifosfamide may

cause hemorrhagic cystitis and tubular toxicity, manifested as type II

renal tubular acidosis (Fanconi syndrome), polyuria, hypokalemia,

and a modest decline in GFR. Antiangiogenesis agents, such as bevacizumab, can cause proteinuria and hypertension via injury to the

glomerular microvasculature (thrombotic microangiopathy). Other

antineoplastic agents such as mitomycin C and gemcitabine may cause

thrombotic microangiopathy with resultant AKI. Immune checkpoint

inhibitors, such as ipilimumab, tremelimumab, nivolumab, and pembrolizumab can cause immune-related adverse events, often manifesting in the kidney as acute interstitial nephritis.

Toxic Ingestions Ethylene glycol, present in automobile antifreeze,

is metabolized to oxalic acid, glycolaldehyde, and glyoxylate, which

may cause AKI through direct tubular injury and tubular obstruction.

Diethylene glycol is an industrial agent that has caused outbreaks of

severe AKI around the world due to adulteration of pharmaceutical

preparations. The metabolite 2-hydroxyethoxyacetic acid (HEAA) is

thought to be responsible for tubular injury. Melamine contamination

of foodstuffs has led to nephrolithiasis and AKI, either through intratubular obstruction or possibly direct tubular toxicity. Aristolochic acid

was found to be the cause of “Chinese herb nephropathy” and “Balkan

nephropathy” due to contamination of medicinal herbs or farming.

The list of environmental toxins is likely to grow and contribute to

a better understanding of previously catalogued “idiopathic” chronic

tubular interstitial disease, a common diagnosis in both the developed

and developing world.

Endogenous Toxins AKI may be caused by a number of endogenous compounds, including myoglobin, hemoglobin, uric acid, and

myeloma light chains. Myoglobin can be released by injured muscle

cells, and hemoglobin can be released during massive hemolysis

leading to pigment nephropathy. Rhabdomyolysis may result from

traumatic crush injuries, muscle ischemia during vascular or orthopedic surgery, compression during coma or immobilization, prolonged

seizure activity, excessive exercise, heat stroke or malignant hyperthermia, infections, metabolic disorders (e.g., hypophosphatemia,

severe hypothyroidism), and myopathies (drug-induced, metabolic,

or inflammatory). Pathogenic factors for AKI due to endogenous

toxins include intrarenal vasoconstriction, direct proximal tubular

toxicity, and mechanical obstruction of the distal nephron lumen when

myoglobin or hemoglobin precipitates with Tamm-Horsfall protein

(uromodulin, the most common protein in urine and produced in the

thick ascending limb of the loop of Henle), a process favored by acidic

urine. Tumor lysis syndrome may follow initiation of cytotoxic therapy

in patients with high-grade lymphomas and acute lymphoblastic leukemia; massive release of uric acid (with serum levels often exceeding

15 mg/dL) leads to precipitation of uric acid in the renal tubules and

AKI (Chap.  75). Other features of tumor lysis syndrome include

hyperkalemia and hyperphosphatemia. The tumor lysis syndrome

can also occasionally occur spontaneously or with treatment for solid

tumors or multiple myeloma. Myeloma light chains can also cause AKI

by glomerular damage and/or direct tubular toxicity and by binding

to Tamm-Horsfall protein to form obstructing intratubular casts.

Hypercalcemia, which can also be seen in multiple myeloma, may

cause AKI by intense renal vasoconstriction and volume depletion.

Other Causes of Acute Tubulointerstitial Disease Leading

to AKI While many of the ischemic and toxic causes of AKI previously described result in tubulointerstitial disease, many drugs are also

associated with the development of an allergic response characterized

by an inflammatory infiltrate and sometimes, peripheral and urinary

eosinophilia. Proton pump inhibitors and NSAIDs are commonly used

drugs that have been associated with acute tubulointerstitial nephritis.

AKI may be also caused by severe infections and infiltrative malignant

or nonmalignant (e.g., sarcoidosis) diseases.

Anticoagulant-Related Nephropathy Excessive anticoagulation with warfarin or other classes of anticoagulants has been reported

to cause AKI through glomerular hemorrhage resulting in the formation of obstructing red blood cell casts within the kidney tubule and

tubular injury.

Glomerulonephritis Diseases involving the glomerular podocytes, mesangial, and/or endothelial cells can lead to AKI by compromising the filtration barrier and blood flow within the renal

circulation. Although glomerulonephritis is a less common (~5%)

cause of AKI, early recognition is particularly important because the

diseases can respond to timely treatment with immunosuppressive

agents or therapeutic plasma exchange, and the treatment may reverse

the AKI and decrease subsequent longer term injury.

■ POSTRENAL AKI

(See also Chap. 319) Postrenal AKI occurs when the normally unidirectional flow of urine is acutely blocked either partially or totally,

leading to increased retrograde hydrostatic pressure and interference

with glomerular filtration. Obstruction to urinary flow may be caused

by functional or structural derangements anywhere from the renal

pelvis to the tip of the urethra (Fig. 310-5). Normal urinary flow rate

does not rule out the presence of partial obstruction, because the GFR

is normally two orders of magnitude higher than the urinary flow rate

and hence a preservation of urine output may be misleading in hiding

the postrenal partial obstruction. For moderate to severe AKI to occur

in individuals with two healthy functional kidneys, obstruction must

affect both kidneys in order to observe large increases in SCr, unless

there is asymmetric kidney function with one chronically diseased,

and the other obstructed. Unilateral obstruction may cause AKI in

the setting of significant underlying CKD or, in rare cases, from reflex

vasospasm of the contralateral kidney. Bladder neck obstruction is a

common cause of postrenal AKI, which impacts both kidneys. This can

be due to prostate disease (benign prostatic hypertrophy or prostate

cancer), neurogenic bladder, or therapy with anticholinergic drugs.

Obstructed Foley catheters can cause postrenal AKI if not recognized

and obstruction relieved. Other causes of lower tract obstruction are

blood clots, calculi, and urethral strictures. Ureteric obstruction can

occur from intraluminal obstruction (e.g., calculi, blood clots, sloughed

renal papillae), infiltration of the ureteric wall (e.g., neoplasia), or

external compression (e.g., retroperitoneal fibrosis, neoplasia, abscess,

or inadvertent surgical damage). The pathophysiology of postrenal

AKI involves hemodynamic alterations triggered by an abrupt increase

in intratubular pressures. An initial period of hyperemia from afferent

arteriolar dilation is followed by intrarenal vasoconstriction from the

generation of angiotensin II, thromboxane A2, and vasopressin, and

a reduction in NO production. Secondary reductions in glomerular

function are due to underperfusion of glomeruli and, possibly, changes

in the glomerular ultrafiltration coefficient.

DIAGNOSTIC EVALUATION (TABLE 310-2)

By current definitions the presence of AKI is defined by an elevation

in the SCr concentration or reduction in urine output. AKI is currently

defined by a rise from baseline of at least 0.3 mg/dL within 48 h or at

least 50% higher than baseline within 1 week, or a reduction in urine

output to <0.5 mL/kg per h for longer than 6 h. As indicated previously,

it is important to recognize that given this definition, some patients

2302 PART 9 Disorders of the Kidney and Urinary Tract

with AKI will not have tubular or glomerular damage (e.g., prerenal

azotemia). The distinction between AKI and CKD is important for

proper diagnosis and treatment. The distinction is straightforward

when a recent baseline SCr concentration is available, but more difficult in the many instances in which the baseline is unknown. In such

cases, clues suggestive of CKD can come from radiologic studies (e.g.,

small, shrunken kidneys with cortical thinning on renal ultrasound, or

evidence of renal osteodystrophy) or laboratory tests such as normocytic anemia in the absence of blood loss or secondary hyperparathyroidism with hyperphosphatemia and hypocalcemia, consistent with

CKD. No set of tests, however, can rule out AKI superimposed on CKD

because AKI is a frequent complication in patients with CKD, further

complicating the distinction. Serial blood tests showing a continued

substantial rise of SCr represent clear evidence of AKI. Once the diagnosis of AKI is established, its cause needs to be determined because

the elevation of SCr or reduction in urine output can be due to a large

number of physiological and pathophysiological processes as described

previously.

■ HISTORY AND PHYSICAL EXAMINATION

The clinical context, careful history taking, and physical examination

often narrow the differential diagnosis for the cause of AKI. Prerenal

azotemia should be suspected in the setting of vomiting, diarrhea,

glycosuria causing polyuria, and several medications including diuretics, NSAIDs, ACE inhibitors, and ARBs. Physical signs of orthostatic

hypotension, tachycardia, reduced jugular venous pressure, decreased

skin turgor, and dry mucous membranes are often present in prerenal azotemia. Congestive heart failure, liver disease, and nephrotic

syndrome can be associated with reductions in renal blood flow and/

or alterations in intrarenal hemodynamics leading to reduced GFR.

Extensive vascular disease raises the possibility of renal artery disease,

especially if kidneys are known to be asymmetric in size. Atheroembolic disease can be associated with livedo reticularis and other signs

of emboli to the legs. The presence of sepsis is an important clue to

causation, although, as described above, the detailed pathophysiology

may be multifactorial.

A history of prostatic disease, nephrolithiasis, or pelvic or paraaortic

malignancy would suggest the possibility of postrenal AKI. Whether or

not symptoms are present early during obstruction of the urinary tract

Kidney

Ureter

Bladder

Urethra

Sphincter

Stones, blood clots,

external compression,

tumor, retroperitoneal

fibrosis

Prostatic enlargement,

blood clots, cancer

Strictures

Obstructed Foley

catheter

Postrenal

FIGURE 310-5 Anatomic sites and causes of obstruction leading to postrenal acute kidney injury.

depends on the location of obstruction. Colicky flank pain radiating

to the groin suggests acute ureteric

obstruction. Nocturia and urinary frequency or hesitancy can be seen in

prostatic disease. Abdominal fullness

and suprapubic pain can accompany

bladder enlargement. Definitive diagnosis of obstruction requires radiologic investigations.

A careful review of all medications

is imperative in the evaluation of an

individual with AKI. Not only are

medications frequently a nephrotoxic

cause of AKI, but doses of administered medications must be adjusted

for reductions in kidney function. In

this regard, it is important to recognize that reductions in true GFR are

not reflected by equations that estimate GFR because those equations

are dependent on SCr and the patient

being in a steady state. With AKI,

changes in SCr will lag behind changes

in filtration rate. Idiosyncratic reactions to a wide variety of medications

can lead to allergic interstitial nephritis, which may be accompanied by

fever, arthralgias, and a pruritic erythematous rash. The absence of systemic

features of hypersensitivity, however, does not exclude the diagnosis

of interstitial nephritis, and a kidney biopsy should be considered for

definitive diagnosis.

AKI accompanied by palpable purpura, pulmonary hemorrhage, or

sinusitis raises the possibility of systemic vasculitis with glomerulonephritis. A history of autoimmune disease, such as systemic lupus erythematosus, should lead to consideration of the possibility that the AKI is

related to worsening of this underlying disease. Pregnancy should lead

to the consideration of preeclampsia as a pathophysiological contributor to the AKI. A tense abdomen should prompt consideration of acute

abdominal compartment syndrome, a diagnosis faciliated by measurement of bladder pressure. Signs and/or symptoms of limb ischemia

may be clues to the diagnosis of rhabdomyolysis.

■ URINE FINDINGS

Complete anuria early in the course of AKI is uncommon except in the

following situations: complete urinary tract obstruction, renal artery

occlusion, overwhelming septic shock, severe ischemia (often with cortical necrosis), or severe proliferative glomerulonephritis or vasculitis.

A reduction in urine output (oliguria, defined as <400 mL/24 h) usually

denotes more severe AKI (i.e., lower GFR) than when urine output is

preserved. Oliguria is associated with worse clinical outcomes in AKI.

Preserved urine output can be seen in nephrogenic diabetes insipidus

characteristic of long-standing urinary tract obstruction, tubulointerstitial disease, or nephrotoxicity from cisplatin or aminoglycosides,

among other causes. Red or brown urine may be seen with or without

gross hematuria; if the color persists in the supernatant after centrifugation, then pigment nephropathy from rhabdomyolysis or hemolysis

should be suspected.

The urinalysis and urine sediment examination are invaluable tools,

but they require clinical correlation because of generally limited sensitivity and specificity (see Fig. 310-6 and Chap. A4). In the absence

of preexisting proteinuria from CKD, AKI from ischemia or nephrotoxins leads to mild proteinuria (<1 g/d). Greater proteinuria in AKI

suggests damage to the glomerular ultrafiltration barrier or excretion

of myeloma light chains; the latter are not detected with conventional

urine dipsticks (which detect albumin) and require the sulfosalicylic

acid test or immunoelectrophoresis. Atheroemboli can cause a variable

degree of proteinuria. Heavy proteinuria (“nephrotic range,” >3.5 g/d)

2303Acute Kidney Injury CHAPTER 310

TABLE 310-2 Major Causes, Clinical Features, and Diagnostic Studies for Prerenal and Intrinsic Acute Kidney Injury

ETIOLOGY CLINICAL FEATURES LABORATORY FEATURES COMMENTS

Prerenal azotemia History of poor fluid intake or fluid loss

(hemorrhage, diarrhea, vomiting, sequestration

into extravascular space); NSAID/ACE-I/ARB;

heart failure; evidence of volume depletion

(tachycardia, absolute or postural hypotension,

low jugular venous pressure, dry mucous

membranes), decreased effective circulatory

volume (cirrhosis, heart failure)

BUN/creatinine ratio above 20, FeNa

<1%, hyaline casts in urine sediment,

urine specific gravity >1.018, urine

osmolality >500 mOsm/kg

Low FeNa, high specific gravity and

osmolality may not be seen in the setting

of CKD, diuretic use; BUN elevation out of

proportion to creatinine may alternatively

indicate upper GI bleed or increased

catabolism. Response to restoration of

hemodynamics is most diagnostic.

Sepsis-associated AKI Sepsis, sepsis syndrome, or septic shock; overt

hypotension not always seen in mild to moderate

AKI

Positive culture from normally sterile

body fluid or other test confirming

infection; urine sediment often contains

granular casts, renal tubular epithelial

cell casts

FeNa may be low (<1%), particularly early in

the course, but is usually >1% with osmolality

<500 mOsm/kg

Ischemia-associated AKI Systemic hypotension, often superimposed upon

sepsis and/or reasons for limited renal reserve

such as older age, CKD

Urine sediment often contains granular

casts, renal tubular epithelial cell casts;

FeNa typically >1%

Nephrotoxin-Associated AKI: Endogenous

Rhabdomyolysis Traumatic crush injuries, seizures, immobilization Elevated myoglobin, creatine kinase;

urine heme positive with few red blood

cells

FeNa may be low (<1%)

Hemolysis Recent blood transfusion with transfusion

reaction

Anemia, elevated LDH, low haptoglobin FeNa may be low (<1%); evaluation for

transfusion reaction

Tumor lysis Recent chemotherapy Hyperphosphatemia, hypocalcemia,

hyperuricemia

Multiple myeloma Age >60 years, constitutional symptoms, bone

pain

Monoclonal spike in urine or serum

electrophoresis; low anion gap; anemia

Bone marrow or renal biopsy can be

diagnostic

Nephrotoxin-Associated AKI: Exogenous

Contrast nephropathy Exposure to iodinated contrast Characteristic course is rise in SCr

within 1–2 d, peak within 3–5 d, recovery

within 7 d

FeNa may be low (<1%)

Tubular injury Aminoglycoside antibiotics, cisplatin, tenofovir,

vancoycin, zoledronate, ethylene glycol,

aristolochic acid, and melamine (to name a few)

Urine sediment often contains granular

casts, renal tubular epithelial cell casts.

FeNa typically >1%.

Can be oliguric or nonoliguric

Other Causes of Intrinsic AKI

Glomerulonephritis/

vasculitis

Variable (Chap. 314) features include skin rash,

arthralgias, sinusitis (AGBM disease), lung

hemorrhage (AGBM, ANCA, lupus), recent skin

infection or pharyngitis (poststreptococcal),

thrombotic microangiopathies including those

related to drugs, such as cocaine, anti-VEGF

agents

ANA, ANCA, AGBM antibody, hepatitis

serologies, cryoglobulins, blood culture,

complement abnormalities, ASO titer

(abnormalities of these tests depending

on etiology)

Kidney biopsy may be necessary

Interstitial nephritis Nondrug-related causes include tubulointerstitial

nephritis-uveitis (TINU) syndrome, Legionella

infection

Eosinophilia, sterile pyuria; often

nonoliguric

Urine eosinophils have limited diagnostic

accuracy; kidney biopsy may be necessary

TTP/HUS Neurologic abnormalities and/or AKI; recent

diarrheal illness; use of calcineurin inhibitors;

pregnancy or postpartum; spontaneous

Schistocytes on peripheral blood

smear, elevated LDH, anemia,

thrombocytopenia

“Typical HUS” refers to AKI with a diarrheal

prodrome, often due to Shiga toxin released

from Escherichia coli or other bacteria;

“atypical HUS” is due to inherited or

acquired complement dysregulation.

“TTP-HUS” refers to sporadic cases in

adults. Diagnosis may involve screening for

ADAMTS13 activity, Shiga toxin–producing

E. coli, genetic evaluation of complement

regulatory proteins, and kidney biopsy.

Atheroembolic disease Recent manipulation of the aorta or other

large vessels; may occur spontaneously or

after anticoagulation; retinal plaques, palpable

purpura, livedo reticularis, GI bleed

Hypocomplementemia, eosinophiluria

(variable), variable amounts of

proteinuria

Skin or kidney biopsy can be diagnostic

Postrenal AKI History of kidney stones, prostate disease,

obstructed bladder catheter, retroperitoneal or

pelvic neoplasm

No specific findings other than AKI; may

have pyuria or hematuria

Imaging with computed tomography or

ultrasound

Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor-I; AGBM, antiglomerular basement membrane; AKI, acute kidney injury; ANA, antinuclear antibody; ANCA,

antineutrophilic cytoplasmic antibody; ARB, angiotensin receptor blocker; ASO, antistreptolysin O; BUN, blood urea nitrogen; CKD, chronic kidney disease; FeNa, fractional

excretion of sodium; GI, gastrointestinal; LDH, lactate dehydrogenase; NSAID, nonsteroidal anti-inflammatory drug; TTP/HUS, thrombotic thrombocytopenic purpura/

hemolytic-uremic syndrome.