REVIEW

Acute Kidney Injury: New Concepts in Definition, Diagnosis,

Pathophysiology, and Treatment
Michael R. Lattanzio, DO
Nelson P. Kopyt, DO

Acute kidney injury (AKI) is increasingly recognized in all of death.4 These findings highlight the importance of prompt
fields of medical practice. Unfortunately, this syndrome has diagnosis and treatment of this ubiquitous condition.
been plagued by inconsistent definitions, simplistic patho- The present review describes the most current concepts
physiologic schemas, and insensitive diagnostic tools. Recent regarding the definition, diagnosis, pathophysiology, and
advances in defining AKI, understanding its pathophysi- treatment of AKI.
ology, and improving the diagnostic accuracy of the testing
tools available eventually will impact disease management Definition
and clinical outcomes. Prompt recognition and treatment of A uniform and precise operational definition of AKI (for-
AKI remain the cornerstone of clinical management for this merly acute renal failure [ARF]) has remained somewhat elu-
high-mortality, high-cost syndrome. The authors provide sive.5 However, a recent proposal by the Acute Kidney
the most recent updates in the definition, diagnosis, patho- Injury Network6 appears to have gained clinical acceptance.
physiology, and treatment options for patients with AKI, In that initiative, the group6 outlined two options for mea-
providing a stepwise approach to clinical evaluation for use suring the abrupt (⭐48 hour) reduction of kidney function
in all fields of medical practice. that signifies AKI:
J Am Osteopath Assoc. 2009;109:13-19
▫ increased serum creatinine levels (absolute, ⭓0.3mg/dL;
percentage, ⭓50%; or 1.5-fold from baseline), or

A cute kidney injury (AKI) is commonly encountered in the

hospital and outpatient settings and is associated with
a high rate of mortality. Despite improvements to our under-
▫ oliguria (⬍0.5mL/kg/h for more than 6 hours)

The term AKI is intended to emphasize the reversible nature

standing of its pathogenesis, many aspects of AKI remain of most renal insults. The term ARF is now generally reserved
subject to debate and incongruity. to describe the condition of patients who sustain kidney injury
Acute kidney injury has been documented in up to 7% of that necessitates renal replacement therapy (RRT) (ie, any
hospitalized patients on the basis of several single-center method of conventional or intermittent dialysis).
reports.1,2 In addition to demonstrating a potent, independent Medical understanding of AKI was augmented by the
effect on mortality,3 AKI is associated with a significantly RIFLE criteria.7-9 The acronym RIFLE defines AKI with three
increased length of hospital stay and high financial costs across grades of increasing severity (Risk, Injury, Failure) and outlines
a broad spectrum of conditions. two outcome variables (Loss and End-stage). This system,
In fact, Chertow et al4 found an increase of serum creati- much like that of the Acute Kidney Injury Network,6 describes
nine levels greater than or equal to 2.0 mg/dL was associated the severity of renal dysfunction on the basis of increase in
with an almost $34,000 mean unadjusted increase in total hos- serum creatinine levels and decline in urine output (Figure 1).
pital costs. In addition, a serum creatinine rise of 0.5 mg/dL or The RIFLE criteria has been validated in clinical settings
more correlated with a more than sixfold increase in the odds for predicting patient outcomes.10 Hoste et al11 observed that
the three grades described in the RIFLE criteria—risk, injury,
and failure—were associated with inpatient mortality rates
of 8.8%, 11.4%, and 26.3%, respectively.
It is anticipated that these more precise and universal
From the University of Maryland Medical Center in Baltimore (Dr Lattanzio) definitions of AKI will aid clinicians in rapid recognition of at-
and Nephrology Hypertension Associates of the Lehigh Valley in Easton, Pa risk patients.
(Dr Kopyt).
Address correspondence to Michael R. Lattanzio, DO, 22 S Greene St
N3W 143, Department of Nephrology, Baltimore, MD 21201-1544. New Biomarkers
E-mail: [email protected] And yet, serum creatinine levels demonstrate poor sensitivity
and specificity in this setting, slowing recognition and thera-
Submitted September 10, 2007; revision received April 23, 2008; accepted
May 1, 2008. peutic management of AKI. However, several other biomarkers

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Figure 1. The RIFLE (Risk, Injury, Failure, Loss,

Increase in Glomerular Reduced Urine Output End-stage) criteria for acute kidney injury,7-9
Class Filtration Rate by Symptom Duration which defines this syndrome based on
glomerular filtration rate (ie, serum creati-
 Severity nine increase) and weight-dependent urine
▫ Risk 1.5-fold ⬍0.5 mL/kg/h for 6 h output criteria. *A threefold increase in serum
▫ Injury twofold ⬍0.5 mL/kg/h for 12 h creatinine or a serum creatinine level
▫ Failure threefold* ⬍0.3 mL/kg/h for 24 h† ⭓4.0mg/dL with an acute rise ⬎0.5 mg/dL
 Outcome indicates renal failure. †Likewise, anuria for
▫ Loss—Persistent acute kidney injury with complete loss of function for more than 4 wk 12 hours indicates renal failure.
▫ End-stage—End-stage kidney disease for more than 3 mo

have shown promise in assisting physicians detect decrements Pathophysiology

in renal function. The mechanisms involved in the etiology of AKI are as follows:
Cystatin C is a cysteine protease inhibitor that is released
at a constant rate by all nucleated cells.12 It is freely filtered by ▫ endothelial injury from vascular perturbations
the glomerulus and is completely reabsorbed, not secreted, ▫ direct effect of nephrotoxins
by the tubules.12 Studies13,14 have shown cystatin C to be at least ▫ abolishment of renal autoregulation
as good as serum creatinine in estimating GFR in chronic ▫ formation of inflammatory mediators (Figure 2)
kidney disease (CKD)—and probably a better estimator of
GFR in AKI. Necrosis and apoptosis of tubular cells lead to tubular obstruc-
Neutrophil gelatinase–associated lipocalin,15 kidney injury tion, which contributes to the reduction of GFR.18 In addition,
molecule-116, and interleukin 1817 have likewise shown promise elevated intracellular calcium levels from tubular damage cause
for representing the “troponin-like” molecule of AKI. If vali- a series of cellular-level alterations that culminate in increased
dated, these molecules will offer substantial advantages over tubuloglomerular feedback, and thus, diminished GFR.18
serum creatinine in the early detection of AKI. Vascular compromise causes increased cytosolic calcium,
If renal injury can be diagnosed sooner in its etiologic elevated endothelial injury markers, and production of inflam-
process, therapeutic interventions can be instituted more matory mediators (eg, tumor necrosis factor ␣, interleukin 18,
promptly, thereby improving secondary disease prevention. intercellular adhesion molecule 1), which result in reduced GFR.18

Renal ischemia

Vascular effects

Increased cytosolic Ca2+ ↑Inflammatory mediators

in afferent arterioles (TNF-⬀, IL-18)
of the glomerulus
↑Endothelial
injury Endothelial
ICAM-1 and P-selectin

Increased sensitivity to
vasoconstrictor and ↑Neutrophil adhesion
renal nerve stimulation; ↓NO derived ↑ET ↓PGs
impaired autoregulation from eNOS
↑Oxygen radicals

↓GFR

Figure 2. Mechanisms of acute kidney injury: a molecular viewpoint. Cascade of events involved in the pathophysiology of acute kidney
injury. (Copyright 2004 by American Society for Clinical Investigation. Reproduced with permission of American Society for Clinical Inves-
tigation. J Clin Invest. 2004;114:8.18)

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These pathophysiologic mechanisms are perpetuated by Conversely, a urine osmolality of less than 400 mOsm/L,
a persistent imbalance between the mediators of vasocon- high urine sodium (ie, ⬎40 mEq/L), and urine sediment with
striction and -dilatation that result in intrarenal vasoconstric- muddy brown or granular casts suggests tubular injury.
tion and, eventually, ischemia. The vasoconstrictors include Renal ultrasonography aids in ruling out postrenal eti-
angiotensin II, endothelin, thromboxane, and adenosine. The ology of AKI.
vasodilators include prostaglandin I2 and endothelial-derived
nitric oxide. Causes
High levels of vasoconstrictors and low levels of vasodila- Once a diagnosis of AKI has been established, it is important
tors cause continued hypoxia and cell damage or cell death. to stratify the patient’s condition by etiology (ie, prerenal,
Endothelial-derived nitric oxide is under investigation as a renal, or postrenal). Stratification is important because rec-
potential therapeutic option to help break this cycle of ommended therapeutic models are tailored to these categories.
ischemia.19
Continued research into the pathophysiology of AKI may Prerenal
yield potential targets in the clinical management of this syn- Prerenal AKI is secondary to underperfusion of otherwise
drome. normal, functioning kidneys. The hallmark of prerenal AKI is
rapid reversibility. Prerenal kidney injury can result from
Diagnostic Evaluation volume depletion that is the result of renal or extrarenal losses,
Multiple serum and urinary laboratory values or indices can fluid sequestration, or inadequate perfusion pressures sec-
help physicians distinguish among prerenal, renal, and ondary to heart failure, cirrhosis, or sepsis.
postrenal causes of AKI (Figure 3). For patients with prerenal AKI, urinalysis is typically
The fraction of filtered sodium (FeNa) that is excreted in bland or with hyaline casts, urine sodium is low (ie, ⬍1%), and
the urine serves as a useful tool in assessing the tubular integrity urine osmolality is high.
of a functioning nephron, primarily in an oliguric state. A Brisk correction of kidney injury with volume repletion
FeNa (urine sodium ⫻ plasma creatinine ⫼ plasma sodium ⫻ supports a prerenal etiology. Conversely, kidney injury refrac-
urine creatinine) level of less than 1% has a diagnostic accuracy tory to fluid administration suggests an intrinsic renal process.
of approximately 80% for prerenal azotemia.18 Other conditions
associated with FeNa levels of less than 1% include sodium- Renal
avid states (eg, congestive heart failure, cirrhosis, nephrosis), The causes of intrinsic renal disease can be categorized by
contrast-induced nephropathy, rhabdomyolysis, and severe anatomy: tubular, interstitial, glomerular, and vascular. Micro-
glomerulonephritis (glomerular nephritis). scopic analysis of the urine is integral to localizing the site of
In addition, a patient’s FeNa level may be misleading (ie, nephron damage.
inappropriately elevated) in the setting of CKD, diuretic use, Tubular damage usually results in muddy brown, gran-
and glycosuria. The calculated fractional excretion of urea ular casts. Interstitial damage can result in white blood cell
(FeUrea) can function as a surrogate for FeNa when patients cast formation. Microscopic analysis of glomerular—and to a
have received diuretic therapy. lesser extent microvascular—damage reveals red blood cell
An FeUrea level of less than 35% suggests prerenal eti- (RBC) casts and dysmorphic RBCs.
ology. A urine osmolality higher than 500 mOsm/L, a blood
urea nitrogen to creatinine ratio greater than 20 to 1, urine  Tubule—Acute tubular necrosis (ATN) results from pro-
sodium less than 20 mEq/L, and bland urine sediment all longed exposure to a prerenal milieu (ie, ischemic) or from
support a diagnosis of prerenal azotemia. direct toxin damage (ie, nephrotoxic). The list of nephrotoxic
agents is broad and ever-expanding (Figure 4).
The classic course of “self-limited” ATN is a steady rise in
Indices Prerenal Renal serum creatinine levels (injury stage), followed by stabilization
(plateau stage), and an eventual decline in those measures
Blood urea nitrogen (recovery stage) during 7 to 21 days. This pattern correlates with
to creatinine ratio ⬎20 ⬍20 the injury and death of tubular cells, their regeneration, and,
Fraction of filtered sodium, % ⬍1 ⬎2 eventually, recovery of renal tubule function.
Fractional excretion of urea, % ⬍35 ⬎35 It should be noted, however, that fluctuations in serum cre-
Urine osmolality, mOsm/L ⬎500 ⬍400 atinine levels are dependent on many variables (eg, severity
Urine sediment, cast type bland, hyaline granular
and duration of initial renal insult, time to improve the injurious
Urine sodium, mEq/L ⬍20 ⬎40
environment, degree of underlying kidney reserve) and there-
fore cannot be expected in all cases of ATN.
Figure 3. General guidelines for differentiating the etiology of acute Microscopic evidence of granular casts and supportive
kidney injury (ie, prerenal vs renal) using laboratory studies. urinary indices—all within the appropriate clinical setting—

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▫ cryoglobulin
Acyclovir ▫ erythrocyte sedimentation rate
Aminoglycosides ▫ hepatitis panel (ie, specifically for hepatitis B and C)
Amphotericin B
Benzoylmethyl ecgonine (cocaine) Delineating glomerulonephritis based on complement levels
Cisplatin may have diagnostic utility (Figure 5).
Cyclosporine
Proteinuria (ie, ⬎3 g per day), hypercholesterolemia,
Foscarnet sodium
edema, hypoalbuminemia, and fatty casts support a diagnosis
Highly active antiretroviral therapy
Intravenous immunoglobulin therapy of nephrotic syndrome.
Medical contrast media (eg, hyperosmolar radiocontrast media) The differential diagnosis of nephrotic syndrome is broad,
Nonsteroidal anti-inflammatory drugs but consists of primary conditions (eg, minimal change disease,
Penicillin membranous disease, focal segmental glomerulosclerosis
Tacrolimus [FSGS]) and secondary conditions (eg, rheumatologic, amy-
loidosis, diabetes).
Figure 4. Nephrotoxic agents. A renal biopsy may be warranted in cases that are sug-
gestive of glomerular disease of unexplained etiology. Nephrol-
ogist consultation can aid in the diagnosis and treatment of
these relatively uncommon clinical entities.
remain the best way to diagnose ATN. Imediate discontinua-
tion of nephrotoxic agents and restoration of adequate hemo-  Vasculature—Acute kidney injury secondary to vascular
dynamics are paramount in the prevention and management compromise can be difficult to diagnosis. Endovascular manip-
of ATN. ulation followed by AKI raises the possibility of atheroem-
bolic renal disease. Embolic phenomenon, livedo reticularis,
 Interstitium—Acute interstitial nephritis (AIN) is classically hypocomplementemia, and eosinophiluria may help clini-
heralded by depressed renal function in the setting of fever, cians establish the diagnosis. Microvascular compromise from
rash, leukocytosis, and eosinophiluria. White blood cell casts small to medium-sized vasculitides, including the pulmonary-
are occasionally seen on urine microscopy. Acute interstitial renal syndromes, requires consideration in the appropriate
nephritis is usually drug induced, though certain infections and clinical setting.
neoplastic disorders have also been associated with this con- The constellation of reduced renal function, fever, mental
dition.
It should be emphasized that eosinophiluria is a nonspe-
cific test for which positive results are achieved in about 50% Complement Levels
of confirmed cases.
 Low
Other causes of eosinophiluria are prostatitis, rapidly pro-
▫ Cryoglobulinemia
gressive glomerulonephritis, and atheroembolic renal disease.
▫ Hepatitis B or C–related renal disease
The primary therapeutic option for patients with AIN is ▫ Lupus nephritis
to remove the offending agent, if possible. High-dose corti- ▫ Membranoproliferative glomerulonephritis
costeroids have variable success rates among patients with ▫ Postinfectious glomerulonephritis
AIN.20 ▫ Subacute bacterial endocarditis

 Glomerulus—Red blood cell casts, proteinuria, or both sug-  Normal* or High

▫ Antiglomerular basement membrane disease†
gest the presence of glomerular disease. Hematuria, RBC casts,
▫ Fibrillary glomerulonephritis
hypertension, and mild proteinuria suggest a nephritic process
▫ Henoch-Schönlein purpura
(ie, acute glomerulonephritis). ▫ IgA nephropathy
The differential diagnosis for glomerulonephritides ▫ Rapidly progressive glomerulonephritis
includes primary, infectious, and rheumatologic or vasculitic ▫ Wegener’s granulomatosis
conditions. A standard work-up for a patient with presumed
glomerulonephritis includes (but is not limited to):
Figure 5. Categorization of acute renal disease based on comple-
ment levels. Differentiating acute glomerulonephritis by comple-
▫ antineutrophilic cytoplasmic antibody ment levels can aid in diagnosis. *Primary nephrotic syndromes (eg,
▫ antinuclear antibody test minimal change disease, membranous disease, focal segmental
▫ antistreptolysin O glomerulosclerosis) generally have normal complement levels.
▫ complement levels †Antiglomerular basement membrane disease is also known as Good-
▫ c-reactive protein pasture’s syndrome.

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status change, anemia, and thrombocytopenia raises the pos- Less blood pressure variation with continuous modes of
sibility of thrombotic thrombocytopenia purpura, an hemodialysis suggest that it may be a better treatment option
uncommon, yet serious, form of microvascular renal disease. for hemodynamically unstable patients with ARF.30 To date,
however, no data has supported improved survival with con-
Postrenal tinuous RRT (eg, continuous veno-venous hemodiafiltration)
Approximately 10% of AKI cases are the result of postrenal as opposed to traditional intermittent RRT.
causes. Urinary tract obstructions may occur within (eg, stones,
tumors) or outside (eg, tumors, retroperitoneal fibrosis) the  Hepatorenal syndrome (HRS)—Patients with cirrhosis and
urinary system. ascites often demonstrate a particular form of kidney injury that
Ultrasonography has a sensitivity and specificity of up to is secondary to renal vasoconstriction. Two types of HRS have
95% for detecting such obstructions. In most cases, the treat- been described.
ment of postrenal azotemia involves the prompt surgical res- Type 1 is characterized by a rapid and progressive impair-
olution of urinary obstructions (eg, Foley catheter). ment of renal function as defined by a doubling of serum cre-
atinine to a level greater than 2.5 mg/dL during 14 days.31
Special Scenarios Type 1 HRS is associated with very low survival expectancy;
 Contrast-induced nephropathy (CIN)—The third leading median survival time is 14 days.31
cause of AKI in the hospital setting, this condition is defined by Type 2, by contrast, is a less severe form of HRS and por-
an increase in serum creatinine levels that is 25% or higher (0.5 tends a less grave prognosis. In certain patients, triggers like
mg/dL) within 72 hours of contrast media administration.21 spontaneous bacterial peritonitis or acute gastrointestinal
Given the escalating number of procedures and diag- bleeding can be identified.
nostic studies that require the use of contrast media, a larger The diagnostic criteria for HRS include abrupt rise in
percentage of the population is now at risk of CIN. serum creatinine levels (⬎1.5mg/dL), absence of other con-
Associated risk factors for CIN include older age, dia- ditions (eg, sepsis, CHF), refractoriness to isotonic saline chal-
betes, underlying chronic CKD, multiple myeloma, and volume lenge, and minimal proteinuria.
depletion. The treatment of HRS can include trials with midodrine
Vasomotor alterations and free radical formation are two hydrochloride tablets and injectible octreotide; however, ortho-
of the current theories as to how radiocontrast media induces topic liver transplantation currently remains the best thera-
renal failure. The use of hyperosmolar radiocontrast media peutic option.
has been associated with a higher incidence of CIN.22
Briguori et al23 observed reduced risk of CIN in a mod-  Human immunodeficiency virus (HIV)—The prevalence of
erately high-risk patient population using a sodium bicar- renal disease is increasing among the HIV-infected popula-
bonate infusion and N-acetylcysteine concomitantly for pro- tion,32,33 likely reflecting increases in renal disease in the gen-
phylaxis. Conversely, a more recent retrospective study24 eral population from diabetes34 and hypertension,35 clustering
showed an increased incidence of CIN when sodium bicar- of HIV cases among African Americans,36 and toxicities of
bonate was used for prophylaxis. highly active antiretroviral therapy (HAART).37
Clearly, the most appropriate agents for CIN prophylaxis In addition to typical causes of AKI, the differential diag-
remain subject to considerable controversy. The use of hypo- nosis for this syndrome in the HIV-infected population includes
to iso-osmolar radiocontrast agents in limited volumes, pre- the following options among other, less common conditions:
hydration (normal saline or bicarbonate-containing solutions), HIV-associated nephropathy, HAART-related renal disease,
and temporary discontinuation of ACE inhibitors, angiotensin thrombotic thrombocytopenic purpura, FSGS, and membra-
receptor blockers, and diuretics are general principles of CIN noproliferative glomerulonephritis.
prophylaxis. Nephropathy associated with HIV infection is a rapidly
progressing (ie, weeks to months) nephrotic form of kidney dis-
 Sepsis—Acute kidney injury occurs in approximately 19% ease associated with poorly controlled HIV infection. It occurs
of patients with moderate sepsis, 23% with severe sepsis, and almost exclusively in patients of African descent.38
51% with septic shock when blood cultures are positive.25,26 The A rapidly increasing serum creatinine level, hyperten-
combination of AKI and sepsis is associated with a 70% mor- sion, and nephrotic-range proteinuria in the setting of a
tality rate, as compared to a mortality rate of 45% among detectable viral load are generally observed. A “collapsing”
patients with AKI alone.27 variant of FSGS on renal biopsy confirms the diagnosis.
Basic science research is uncovering the role that nitric Highly active antiretroviral therapy is the best method of pre-
oxide synthases, cytokines, chemokines, and adhesion vention and treatment—in addition to blockade of the renin-
molecules play in AKI when it is associated with sepsis. The angiotensin-aldosterone system with angiotensin-converting
use of early goal-directed therapy in sepsis appears to reduce enzyme inhibitors, angiotensin receptor blockade, or both.
mortality rates among patients with AKI.28,29 Beside viral-mediated injury, AKI secondary to medica-

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tions should be excluded. Tenofovir disoproxil fumarate has some syndrome.

been associated with ATN and Fanconi’s syndrome. Indinavir Future research into the mechanisms and pathophysi-
sulfate is associated with a crystalline-induced kidney injury. ology of AKI will elucidate the pathways of this complex dis-
Finally, renal disease resulting from concomitant hepatitis B and ease process.
C infections should be excluded in all HIV patients. As the clinical management of AKI remains largely sup-
portive, the importance of primary disease prevention is clear.
 Nephrogenic systemic fibrosis (NSF)—An emerging scle-
romyxedematous condition can occur in patients with dimin- Acknowledgments
ished renal function after gadolinium exposure. First reported We thank the Research Department of Lehigh Valley Hospital in
in 1997, incidence rates of NSF are increasing.39 Allentown, Pa, for their assistance in compiling material for this
This condition causes dramatic skin changes similar to review article. In particular, we acknowledge the efforts of Dana M.
scleroderma. In addition, multisystem organ fibrosis has been Wentzel, RN, MSHSA, CCRC.
reported.40 Nephrogenic systemic fibrosis carries a high risk of
death once systemic involvement supervenes. References
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Lattanzio and Kopyt • Review JAOA • Vol 109 • No 1 • January 2009 • 19

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