EPIDEMIOLOGY

Multivariable models have identified risk factors for the development of AKI,

including older age, higher baseline SCr, underlying CKD, diabetes, chronic

respiratory illness, underlying cardiovascular disease, prior heart surgery,

dehydration resulting in oliguria, acute infection, and exposure to nephrotoxins.

11 The

incidence of community-acquired AKI (development of AKI before hospitalization)

is just 1%; approximately 75% of these admissions result from decreased kidney

blood flow, termed prerenal azotemia. Other less-common causes include obstructive

uropathy (17%) and intrinsic renal disease (11%).

12 Community-acquired AKI can

usually be reversed by correcting the underlying problems of volume status or

obstruction. Hospital-acquired AKI is much more common, and the incidence and

severity vary based on intensive care unit (ICU) or non-ICU setting.

13 The incidence

of AKI in general-medicine patients is approximately 5% to 7%, with the most

common causes being prerenal azotemia, postoperative complications, or

nephrotoxin exposure.

14,15 These patients can experience one or more of these renal

insults throughout their hospitalization. Conversely, ICU-acquired AKI is more

prevalent and severe. Data suggest the incidence of AKI in patients in the ICU

approaches 25%, stemming from multiple risk factors including older age, sepsis,

nephrotoxin exposure, male sex (gender), multi-organ dysfunction, and the need for

mechanical ventilation.

16–18 Severe burns, rhabdomyolysis, chemotherapy, and open

heart surgery are also considered risk factors. The natural history of patients who

develop AKI includes (1) complete recovery of renal function, (2) development of

progressive CKD, (3) increased rate of progression of preexisting CKD, or (4)

irreversible loss of kidney function with dialysis-dependent ESRD.

19 Although many

patients with stage 3 AKI will initially require dialysis, a small percentage will

develop ESRD requiring long-term dialysis.

p. 631

p. 632

Table 29.1

Classification/Staging System for Acute Kidney Injury

Category SCr and GFR Criteria Urine Output Criteria

RIFLE Criteria

Risk Increased SCr × 1.5-fold or GFR decrease >25% <0.5 mL/kg/hour × 6 hour

Injury Increased SCr × 2-fold or GFR decrease >50% <0.5 mL/kg/hour × 12 hour

Failure Increased SCr × 3-fold or GFR decrease >75% or SCr

≥4.0 mg/dL with an acute increase of at least 0.5

mg/dL

<0.3 mL/kg/hour × 24 hour

or anuria × 12 hour

Loss Complete loss of kidney function (RRT) >4 weeks

ESRD RRT >3 months

AKIN Criteria

Stage 1 Increased SCr ≥0.3 mg/dL or × ≥1.5 to 2-fold <0.5 mL/kg/hour × >6 hour

Stage 2 Increased SCr × >2 to 3-fold <0.5 mL/kg/hour × >12 hour

Stage 3 Increased SCr × >3-fold or SCr ≥4 mg/dL with an

acute increase of at least 0.5 mg/dL or need for RRT

<0.3 mL/kg/hour × 24 hour

or anuria × 12 hour

KDIGO Criteria

Stage 1 Increased SCr ≥0.3 mg/dL within 48 hours or increased

SCr × 1.5 to 1.9-fold in 7 days or less

<0.5 mL/kg/hour × 6–12 hour

Stage 2 Increased SCr × 2 to 2.9-fold <0.5 mL/kg/hour × ≥12 hour

Stage 3 Increased SCr × ≥3-fold or SCr ≥4 mg/dL or need for

RRT or eGFR <35 mL/minute/1.73 m

2

<0.3 mL/kg/hour × ≥24 hour or

anuria × ≥12 hour

SCr, serum creatinine; GFR, glomerular filtration rate.

PROGNOSIS

Despite recent advances in dialysis delivery and the development of sophisticated

continuous renal replacement therapy (CRRT), patients with AKI continue to have a

grim prognosis. A mild elevation of SCr in ICU patients is associated with a twofold

increase in the risk of death.

20

Indeed, the occurrence of AKI in critically ill patients

carries at least a 50% mortality rate. Worse yet, the mortality rate increases

correspondingly by 10% with each additional failed organ system. The mortality rate

of AKI has declined minimally during the last 50 years. This slow decline may be

explained in part by three important factors. First, patients are older when they

develop AKI. Second, patients are often afflicted with serious underlying medical

illnesses beyond AKI. Third, the clinical severity status of the patient with AKI is

much higher now than ever before. Before the widespread availability of RRT, the

most common causes of death in patients with AKI were fluid and electrolyte

disorders and advanced uremia. Today, the most common causes of death are sepsis,

cardiovascular disease as a result of heart failure and ischemic heart disease,

malignancy, and withdrawal of life support.

21

CLINICAL COURSE

There are three distinct phases of AKI. The oliguric phase generally occurs over the

course of 1 to 2 days and is characterized by a progressive decrease in urine

production. Urine production of less than 400 mL/day is termed oliguria, and urine

production of less than 50 mL/day is termed anuria. The oliguric stage may last from

days to several weeks. Nonoliguric renal failure (>400 mL/day of urine output)

carries a better prognosis compared with oliguric renal failure, although the exact

reason remains unknown. Similarly, the shorter the duration of oliguria, the higher the

likelihood of successful recovery. This is probably because the renal insults (e.g.,

dehydration, nephrotoxin exposure, postrenal obstruction) in these cases are less

severe. Strict fluid and electrolyte monitoring and management are required during

this phase until renal function normalizes.

After the oliguric phase, a period of increased urine production occurs for several

days; this is called the diuretic phase. This phase signals the initial repair of the

kidney insult. The diuretic phase can result, in part, from a return to normal

glomerular filtration rate (GFR) before tubular reabsorptive capacity has fully

recovered. The elevated osmotic load from uremic toxins and the increased fluid

volume retained during the oliguric phase may also contribute to the diuretic phase.

Despite the increased urine production, patients may remain markedly azotemic for

several days. The increase in urine output may lead to volume depletion and

electrolyte loss if patients are not given adequate replacement therapy. Daily

modifications in the fluid and electrolyte requirements are necessary based on urine

output.

The recovery phase occurs over the course of several weeks to months, depending

on the severity of the patient’s AKI. This phase signals the return to the patient’s

baseline kidney function, normalization of urine production, and the return of the

diluting and concentrating abilities of the kidneys.

PATHOGENESIS

The production and elimination of urine requires three basic physiologic events:

Blood flow to the glomeruli

The formation and processing of ultrafiltrate by the glomeruli and tubular cells

Urine excretion through the ureters, bladder, and urethra

p. 632

p. 633

Many conditions and drugs can alter these physiologic events leading to AKI.

These are classified as prerenal azotemia, and functional, intrinsic, and postrenal

AKI (Table 29-2). It is possible for more than one of these categories to coexist.

22,23

Normal renal function depends on adequate renal perfusion. The kidneys receive

up to 25% of cardiac output, which is greater than 1 L/minute of blood flow. Prerenal

azotemia, the most common form of AKI, occurs when blood flow to the kidneys is

reduced. Major causes include decreased intravascular volume (e.g., hemorrhage or

dehydration [including overdiuresis]), decreased effective circulating volume states

(e.g., cirrhosis or heart failure [HF]), hypotensive events (e.g., shock or medicationrelated hypotension), and renovascular occlusion or vasoconstriction. Because no

structural damage occurs to the kidney parenchyma per se, correcting the underlying

cause rapidly restores GFR. Sustained prerenal conditions can result, however, in

glomerular ischemia causing acute tubular necrosis (ATN).

Table 29-2

Causes of Acute Kidney Injury

Classification Common Clinical Disorders

Prerenal azotemia

Intravascular Volume Depletion

Hemorrhage (surgery, trauma)

Dehydration (gastrointestinal losses, aggressive diuretic administration)

Severe burns

Hypovolemic shock

Sequestration (peritonitis, pancreatitis)

Decreased Effective Circulating Volume

Cirrhosis with ascites

Heart failure

Hypotension, Shock Syndromes

Antihypertensive vasodilating medications

Septic shock

Cardiomyopathy

Increased Renal Vascular Occlusion or Constriction

Bilateral renal artery stenosis

Unilateral renalstenosis in solitary kidney

Renal artery or vein thrombosis (embolism, atherosclerosis)

Vasopressor medications (phenylephrine, norepinephrine)

Functional acute kidney injury Afferent Arteriole Vasoconstrictors

Cyclosporine

Nonsteroidal anti-inflammatory drugs

Efferent Arteriole Vasodilators

Angiotensin-converting enzyme inhibitors

Angiotensin II receptor antagonists

Intrinsic acute kidney injury Glomerular Disorders

Glomerulonephritis

Systemic lupus erythematosus

Malignant hypertension

Vasculitic disorders (Wegener’s granulomatosis)

Acute Tubular Necrosis

Prolonged prerenalstates

Drug induced (iodinated contrast media, cisplatin, aminoglycosides,

amphotericin B, adefovir, cidofovir, tenofovir, HMG CoA reductase inhibitors,

pamidronate, gold salts)

Acute Interstitial Nephritis

Drug induced (penicillins, β-lactam antibiotics, fluoroquinolones, proton pump

inhibitors, NSAIDs, sulfonamides)

Postrenal acute kidney injury Ureter Obstruction (Bilateral or Unilateral in Solitary Kidney)

Malignancy (prostate or cervical cancer)

Benign prostate hypertrophy

Anticholinergic drugs (affect bladder outlet muscles)

Renal calculi

Crystals (i.e., drugs such as methotrexate, acyclovir, indinavir, atazanavir,

sulfonamide antibiotics, and ethylene glycol)

p. 633

p. 634

Figure 29-1 Schematic of renal blood flow. Blood enters the glomerulus via the afferent arteriole. The

intraglomerular hydrostatic pressure leads to ultrafiltration across the glomerulus into the proximal tubule. The

unfiltered blood leaves the glomerulus via the efferent arteriole. In conditions of decreased renal perfusion, efferent

arteriolar vasoconstriction occurs to increase intraglomerular hydrostatic pressure and maintain ultrafiltrate

production. Afferent arteriolar vasodilation also occurs to improve blood flow into the glomerulus.

Functional AKI results when medical conditions or drugs impair glomerular

ultrafiltrate production or intraglomerular hydrostatic pressure as a result of impaired

autoregulation. Blood travels through the afferent arteriole and enters the glomerulus,

where it is filtered, and exits through the efferent arteriole (Fig. 29-1). The afferent

and efferent arterioles work in concert to maintain adequate glomerular capillary

hydrostatic pressure to form ultrafiltrate. Many medications can drastically reduce

intraglomerular hydrostatic pressure and GFR by producing afferent arteriolar

vasoconstriction or efferent arteriolar vasodilation (Fig. 29-2).

Intrinsic AKI can occur at the microvascular level of the nephron, glomeruli, renal

tubules, or interstitium. Vasculitic diseases (e.g., Wegener’s granulomatosis,

cryoglobulinemic vasculitis) involve the small vessels of the kidney.

Glomerulonephritis and systemic lupus erythematosus, although relatively uncommon,

result in glomerular damage. ATN is by far the most common cause of intrinsic AKI.

In fact, the term acute tubular necrosis is often used interchangeably with AKI. ATN

occurs in part because the renal tubules require high oxygen delivery to maintain their

metabolic activity. Consequently, any condition that causes ischemia to the tubules

(e.g., hypotension, decreased blood flow) can induce ATN. Moreover, the tubules

may be exposed to exceedingly high concentrations of nephrotoxic drugs (e.g.,

aminoglycosides). Interstitial nephritis or inflammation within the renal parenchyma

is most often associated with drug administration (e.g., penicillins).

Figure 29-2 Drugs that alter renal hemodynamics by causing afferent arteriole vasoconstriction or efferent

arteriole vasodilation. ACEIs, angiotensin-converting enzyme inhibitors; ARBs, angiotensin II receptor blockers;

CCBs, calcium-channel blockers; COX-2, cyclo-oxygenase-2; NSAIDs, nonsteroidal anti-inflammatory drugs.

p. 634

p. 635