Etiology and Diagnosis of Prerenal Disease and Acute Tubular Necrosis in Acute Kidney Injury in Adults - UpToDate

10/16/23, 5:42 PM Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults
injury in adults - UpToDate
Etiology and diagnosis of prerenal disease and acute

tubular necrosis in acute kidney injury in adults
AUTHORS: Mark D Okusa, MD, Daphne Knicely, MD, MEHP
SECTION EDITOR: Paul M Palevsky, MD
DEPUTY EDITOR: Eric N Taylor, MD, MSc, FASN
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2023.

This topic last updated: Nov 11, 2022.
INTRODUCTION AND DEFINITION
Acute kidney injury (AKI), previously called acute renal failure (ARF), is a common clinical
problem [1-7]. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice
Guidelines for Acute Kidney Injury defined AKI as one or more of three criteria [1]. The first
two were a rise in serum creatinine of at least 0.3 mg/dL (26.5 micromol/L) over a 48-hour
period and/or ≥1.5 times the baseline value within the seven previous days [1].
The third criterion was a urine volume ≤0.5 mL/kg per hour for six hours. However, in a 70 kg
adult male, this would represent a urine volume as high as 210 mL in six hours, which, if
maintained, would be 840 mL/day. Many healthy individuals could meet this criterion if they
had limited fluid intake. Thus, the authors and reviewers of this topic do not agree with
making a diagnosis of AKI based solely upon the urine volume.
Other definitions and severity staging of AKI have also been proposed. These issues are
discussed in detail elsewhere. (See "Definition and staging criteria of acute kidney injury in
adults".)
The two major causes of AKI that occur in the hospital are prerenal disease and acute tubular
necrosis (ATN). Together, they account for approximately 65 to 75 percent of cases of AKI. (See
'Frequency of prerenal disease and acute tubular necrosis as a cause of AKI' below.)
This topic will review the pathophysiology, etiology, clinical presentation, and evaluation and
diagnosis of prerenal disease and ATN as a cause of AKI. The diagnostic approach to patients
with acute or chronic kidney disease (CKD), the possible prevention and management of ATN,
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10/16/23, 5:42 PM Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults - UpToDate
and kidney and patient outcomes after ATN are discussed elsewhere. (See "Diagnostic
approach to adult patients with subacute kidney injury in an outpatient setting" and "Possible
prevention and therapy of ischemic acute tubular necrosis" and "Kidney and patient outcomes
after acute kidney injury in adults".)
PATHOPHYSIOLOGY
AKI is characterized by an abrupt decrease in glomerular filtration rate (GFR). The etiology can
be classified into prerenal, intrinsic renal, and postrenal causes. (See "Diagnostic approach to
adult patients with subacute kidney injury in an outpatient setting", section on 'Major causes
and pathogenesis of kidney disease'.)
Prerenal disease — Decreased GFR due to prerenal disease occurs in two settings [8] (see
'Causes of prerenal disease' below):
● When kidney ischemia is part of a generalized decrease in tissue perfusion

● When there is selective kidney ischemia
Systemic hypoperfusion is initially sensed by cardiac and arterial receptors that respond to
changes in pressure (or stretch). When the mean arterial pressure is reduced, due to a
reduction in either cardiac output or systemic vascular resistance, activation of these
receptors increases sympathetic neural tone and the release of both renin (leading to the
generation of angiotensin II) and antidiuretic hormone. The ensuing arteriolar and venular
constriction and stimulation of cardiac function return the systemic blood pressure and
cardiac output toward normal. The arteriolar vasoconstriction occurs primarily in the renal,
splanchnic, and musculocutaneous circulations, resulting in the relative preservation of blood
flow to the heart and brain.
Although these are appropriate systemic responses, renal vasoconstriction can diminish renal
blood flow and GFR, which is flow dependent. In addition, if the compensatory systemic
responses are incomplete, persistent reductions in cardiac output and/or arterial pressure can
contribute to the decline in GFR.
A common cause of prerenal disease is true volume depletion, which includes hypovolemia
caused by dehydration, hemorrhage, or renal (diuretics) or gastrointestinal (vomiting,
diarrhea) fluid loss. Kidney perfusion can also be reduced in edematous states such as heart
failure and cirrhosis due to myocardial dysfunction and splanchnic venous pooling and
systemic vasodilation, respectively. (See 'Causes of prerenal disease' below.)
With all of these processes that cause prerenal disease, the GFR is diminished because of
decreased renal blood flow. The glomeruli, kidney tubules, and interstitium are intact. The
appropriate treatment is to increase kidney perfusion, as with volume repletion in patients
with true volume depletion. (See "Maintenance and replacement fluid therapy in adults",
section on 'Replacement fluid therapy' and "Treatment of severe hypovolemia or hypovolemic
shock in adults".)
By contrast to prerenal disease, in sepsis-associated AKI, high cardiac output may increase
renal blood flow, yet GFR may be reduced. This is likely due to a decrease in afferent and, to a
greater extent, in efferent arteriolar tone and a decrease in overall arteriolar resistance. This
decrease in arteriolar tone eventually leads to a decline in the intraglomerular pressure, and
thereby, in GFR. In an animal model of experimental hyperdynamic septic AKI, infusion of
angiotensin II (which would increase arteriolar tone) led to decreased renal blood flow,
increased urine output, and increased creatinine clearance [9,10].
Acute tubular necrosis — Prolonged and/or severe ischemia can lead to ATN. This can result
in histologic changes, including necrosis, with denuding of the epithelium and occlusion of the
tubular lumen by casts and cell debris. Postischemic (also called ischemic) ATN is discussed in
detail separately. (See "Pathogenesis and etiology of ischemic acute tubular necrosis".)
Any of the processes associated with prerenal disease can cause ATN, but kidney damage
most commonly occurs in patients with hypotension, particularly in the settings of surgery,
sepsis, or obstetrical complications. The other major causes of ATN include a variety of
nephrotoxins that directly damage renal tubules via a number of different mechanisms [11].
(See 'Causes of acute tubular necrosis' below.)
Although kidney ischemia is the most common cause of ATN, the sensitivity of individual
patients to a decrease in kidney perfusion is variable. In some patients, a few minutes of
hypotension is sufficient to induce ATN, whereas others are able to tolerate hours of kidney
ischemia without structural damage to the kidney, displaying the findings of prerenal disease,
such as a normal urinalysis and a low fractional excretion of sodium (FENa) (see 'Evaluation
and diagnosis' below). Such patients can eventually develop ATN if kidney perfusion is not
improved.
ETIOLOGY
Both prerenal disease and ATN can occur in a variety of settings. In addition, prerenal disease,
if severe, is a common cause of ATN.
Causes of prerenal disease — Prerenal disease may result from the following:
● True volume depletion – Volume depletion may be caused by gastrointestinal disease

(vomiting, diarrhea, bleeding), renal losses (diuretics, glucose osmotic diuresis), skin or
respiratory losses (insensible losses, sweat, burns), and third space sequestration (crush
injury or skeletal fracture). (See "Etiology, clinical manifestations, and diagnosis of
volume depletion in adults", section on 'Etiology'.)
● Hypotension – Severely decreased blood pressure can result from shock (hypovolemic,
myocardial, or septic) and posttreatment of severe hypertension.
● Edematous states – Heart failure and cirrhosis can result in marked reductions in kidney
perfusion that parallel the severity of the underlying disease. The respective mechanisms
are decreased cardiac output in heart failure and splanchnic venous pooling and
systemic vasodilation in cirrhosis. (See "Cardiorenal syndrome: Definition, prevalence,
diagnosis, and pathophysiology" and "Hepatorenal syndrome", section on
'Pathogenesis'.)
Nephrotic syndrome, mostly in adults with minimal change disease, can also lead to AKI.
Decreased kidney perfusion, reduced glomerular permeability, and excessive diuresis are
among the mechanisms that may contribute to AKI. (See "Acute kidney injury (AKI) in
minimal change disease and other forms of nephrotic syndrome".)
● Selective kidney ischemia – Bilateral renal artery stenosis or unilateral stenosis in a

solitary functioning kidney is frequently made worse by treatment with angiotensin-
converting enzyme inhibitors, angiotensin II receptor blockers, or direct renin inhibitors.
(See "Renal effects of ACE inhibitors in hypertension", section on 'Renovascular
hypertension'.)
● Drugs affecting glomerular hemodynamics – Drugs that affect glomerular

hemodynamics can reduce the glomerular filtration rate (GFR) by lowering the
intraglomerular pressure that drives this process. This can occur by decreasing either
afferent (preglomerular) arteriolar dilatation (eg, with nonsteroidal antiinflammatory
drugs or calcineurin inhibitors) or efferent (postglomerular) arteriolar constriction (eg,
with angiotensin-converting enzyme inhibitors or angiotensin II blockers).
The effect of nonsteroidal antiinflammatory drugs is primarily seen in patients with underlying
kidney hypoperfusion due to true volume depletion, heart failure, or cirrhosis, in which
prostaglandin synthesis within or near the glomerulus is increased by vasoconstrictors such
as angiotensin II and norepinephrine and vasodilator prostaglandins help preserve kidney
reperfusion and glomerular filtration. The effect of angiotensin inhibitors is also seen in these
settings since angiotensin II helps maintain the intraglomerular pressure and GFR by
increasing efferent arteriolar resistance. The mechanism with calcineurin inhibitors is less
clear. The supporting data are discussed in detail elsewhere. (See "NSAIDs: Acute kidney
injury", section on 'Mechanism of acute kidney injury' and "Major side effects of angiotensin-
converting enzyme inhibitors and angiotensin II receptor blockers", section on 'Reduction in
GFR'.)
Causes of acute tubular necrosis — There are three major causes of ATN: kidney ischemia,
sepsis, and nephrotoxins.
Kidney ischemia — All causes of severe prerenal disease, particularly if accompanied by

hypotension, surgery, and/or sepsis, can cause postischemic (also called ischemic) ATN. For
reasons that are not well understood, ATN is an unusual complication of heart failure, and it is
not clear if prolonged kidney ischemia alone can lead to ATN in patients with cirrhosis in the
absence of some other risk factor (eg, hypotension due to bleeding or aminoglycoside
therapy). (See "Hepatorenal syndrome", section on 'Acute tubular necrosis' and "Pathogenesis
and etiology of ischemic acute tubular necrosis".)
Sepsis — Sepsis-induced ATN is often associated with prerenal factors such as decreased
kidney perfusion and systemic hypotension. However, as discussed above, in sepsis-associated
high cardiac output failure, an increase in kidney perfusion pressure may be observed [9,10].
Generally, these prerenal factors, when severe and sustained, lead to ATN. Other factors can
also contribute, including release of cytokines and activation of neutrophils by cytokines. (See
"Pathogenesis and etiology of ischemic acute tubular necrosis", section on 'Sepsis'.)
Nephrotoxins — A number of drugs and exogenous and endogenous toxins can cause ATN
[11]. These include:
● Vancomycin ─ The risk of AKI may be increased when vancomycin is combined with
piperacillin-tazobactam [12].
● Aminoglycosides. (See "Manifestations of and risk factors for aminoglycoside

nephrotoxicity".)
● Heme pigments. (See "Clinical features and diagnosis of heme pigment-induced acute
kidney injury".)
● Cisplatin. (See "Cisplatin nephrotoxicity".)
● Radiocontrast media. (See "Contrast-associated and contrast-induced acute kidney

injury: Clinical features, diagnosis, and management".)
● Pentamidine. (See "Overview of kidney disease in patients with HIV", section on

'Medication nephrotoxicity'.)
● Foscarnet. (See "Foscarnet: An overview", section on 'Renal insufficiency'.)
● Cidofovir. (See "Cidofovir: An overview", section on 'Toxicity'.)
● Tenofovir [13-15].
● Intravenous immunoglobulin, mostly in products containing sucrose, which is thought to

be taken up by tubular cells, leading to cell swelling and tubular obstruction. (See
"Intravenous immune globulin: Adverse effects", section on 'Complications affecting the
kidney'.)
● Mannitol, primarily in patients treated with more than 200 to 300 g/day. (See
"Complications of mannitol therapy", section on 'Acute kidney injury'.)
● Hetastarch (also called hydroxyethyl starch), a hyperoncotic colloid used for fluid
resuscitation in intensive care units [16-21].
● Synthetic cannabinoids (also called SPICE, K2) [22,23]. (See "Synthetic cannabinoids:
Acute intoxication".)
● mTOR inhibitors, such as everolimus and temsirolimus, when used in high doses, such as
for treatment of renal cell carcinoma, breast cancer, and other cancers [24,25].
FREQUENCY OF PRERENAL DISEASE AND ACUTE TUBULAR NECROSIS AS A

CAUSE OF AKI
AKI, as defined by the RIFLE criteria, has been observed in 9 percent of hospitalized patients
[26] and in more than 50 percent of patients in the intensive care unit [27]. (See "Definition
and staging criteria of acute kidney injury in adults".)
Approximately 65 to 75 percent of cases of AKI in the hospital are due to either prerenal
disease or ATN [28-31]. A report from Madrid, for example, evaluated all 748 cases of AKI at 13
tertiary hospital centers [29]. The most frequent causes were:
● ATN – 45 percent
● Prerenal disease – 21 percent

● Acute on chronic kidney failure – 13 percent (mostly due to ATN or prerenal disease)
● Urinary tract obstruction – 10 percent
● Glomerulonephritis or vasculitis – 4 percent
● Acute interstitial nephritis – 2 percent
● Atheroemboli – 1 percent
Another study based upon data from the Program to Improve Care in Acute Renal Disease
(PICARD) examined the etiology of AKI in 618 critically ill patients in intensive care units in five
medical centers in the United States [31]. The most common causes were postischemic ATN
(primarily due to sepsis or hypotension and accounting for 50 percent of cases), prerenal
disease (hypovolemia, hemorrhage, heart failure, shock, hepatorenal syndrome),
nephrotoxicity (radiocontrast media and rhabdomyolysis were the most common),
cardiovascular disease (heart failure, shock), liver disease (hepatorenal syndrome), and
multifactorial etiologies.
EVALUATION AND DIAGNOSIS
The initial step in the evaluation of patients with AKI is a careful history and physical
examination. When appropriate, prerenal disease must be distinguished from postischemic
ATN. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient
setting".)
History and physical examination — The history and physical examination frequently
identify events and/or disease processes that result in decreased tissue perfusion that can
lead to prerenal disease or postischemic ATN:
● The history may reveal a cause of decreased tissue perfusion (eg, vomiting, diarrhea,
bleeding, or sepsis). In addition, in hospitalized patients, a close examination of the
clinical setting may help identify the underlying cause of AKI (eg, hypotension, sepsis,
intraoperative events, aminoglycoside therapy, or the administration of radiocontrast
media, particularly in patients at increased risk). (See "Manifestations of and risk factors
for aminoglycoside nephrotoxicity" and "Contrast-associated and contrast-induced acute
kidney injury: Clinical features, diagnosis, and management".)
● Among patients who develop AKI in the hospital, the day of onset can be determined if
the serum creatinine concentration has been measured daily. Suppose, for example, that
a patient has had a stable serum creatinine concentration, which began to rise
progressively on day 5. In such a patient, there must have been some insult on day 4 (eg,
hypotension, radiocontrast media) or a cumulative insult that has become clinically
apparent (eg, aminoglycoside therapy). Careful perusal of the patient's chart may identify
the probable cause.
● Findings on physical examination may suggest hypovolemia, such as otherwise

unexplained tachycardia, dry mucous membranes, decreased skin turgor, cool
extremities, supine and/or orthostatic hypotension, and, particularly in older adults,
sunken eyes. (See "Etiology, clinical manifestations, and diagnosis of volume depletion in
adults", section on 'Clinical manifestations'.)
● Heart failure and cirrhosis can result in edema, ascites, and other signs of specific organ
dysfunction. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis",
section on 'Clinical manifestations' and "Heart failure: Clinical manifestations and
diagnosis in adults", section on 'Clinical presentation'.)
● Abdominal distension leading to intra-abdominal hypertension and abdominal

compartment syndrome may be a complication of abdominal surgery. The mechanisms
responsible for decreased kidney perfusion are discussed elsewhere. (See "Abdominal
compartment syndrome in adults", section on 'Renal'.)
Distinction of prerenal disease from acute tubular necrosis — Distinguishing ATN from
prerenal disease should be considered in patients who have a suggestive history and physical
examination (as described in the preceding section) and no evidence for another cause of AKI
such as aminoglycoside therapy; glomerulonephritis (which is typically associated with
hematuria and dysmorphic red cells ( picture 1 and picture 2) with or without red cell
casts ( picture 3) and variable degrees of proteinuria); acute interstitial nephritis (which is
often drug induced and typically associated with pyuria with or without white cell casts
( picture 4 and picture 5 and picture 6) or hematuria, but not red cell casts); and
urinary tract obstruction (which is diagnosed by imaging studies). (See "Clinical manifestations
and diagnosis of acute interstitial nephritis", section on 'Laboratory and radiographic findings'
and "Glomerular disease: Evaluation and differential diagnosis in adults" and "Clinical
manifestations and diagnosis of urinary tract obstruction (UTO) and hydronephrosis".)
There are three major diagnostic approaches that, in the appropriate clinical setting, are used
to distinguish prerenal disease from ATN and from other causes of AKI [32-36]:
● Urinalysis and urine microscopy.
● Fractional excretion of sodium (FENa) and, to a lesser degree, the urine sodium
concentration. The fractional excretion of urea may be helpful in patients being treated
with diuretics [37].
● Response to fluid repletion in patients who have evidence of volume depletion, which is
the gold standard for the diagnosis of prerenal disease. This does not apply to prerenal
disease due to heart failure (cardiorenal syndrome) or cirrhosis (hepatorenal syndrome).
Some patients have an intermediate syndrome, with features of both prerenal disease and
ATN. The relative contribution of ATN can be assessed by evaluating the response to fluid
repletion. (See 'Response to fluid repletion' below.)
Other parameters or tools that may be helpful in selected patients include:
● Blood urea nitrogen (BUN)/serum creatinine ratio.
● Rate of rise of serum creatinine concentration.
● Urine osmolality.
● Urine volume.
● Bedside ultrasound measurements of the inferior vena cava [38].
In patients with prerenal AKI due to cardiorenal syndrome or abdominal compartment

syndrome, definitive diagnosis should be made with cardiac functional evaluation (eg, cardiac
echo, invasive hemodynamic monitoring) or transduced bladder pressure, respectively. (See
"Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology", section on
'Diagnosis' and "Abdominal compartment syndrome in adults", section on 'Clinical
presentation' and "Abdominal compartment syndrome in adults", section on 'Measurement of
intra-abdominal pressure'.)
Urinalysis — The urinalysis with sediment examination by urine microscopy is normal or

near normal in prerenal disease unless it is superimposed on another cause of kidney disease.
Hyaline and/or fine granular casts may be seen, but these are not an abnormal finding. In
comparison, the classic urinalysis in ATN reveals muddy brown granular, epithelial cell casts,
and free renal tubular epithelial cells ( picture 7A-B). Ischemic or toxic injury to the tubular
epithelial cells can lead to cell sloughing into the tubular lumen due either to cell death or to
defective cell-to-cell or cell-to-basement membrane adhesion. (See "Pathogenesis and etiology
of ischemic acute tubular necrosis" and "Urinalysis in the diagnosis of kidney disease".)
However, the absence of these urinary findings does not exclude ATN, and their presence
does not always establish the diagnosis of ATN, as illustrated by the following examples:
● Cell sloughing and cast formation are less prominent in patients with less severe disease
and nonoliguric ATN, a setting in which the urinalysis may be relatively normal [39].
● Marked hyperbilirubinemia alone can, via an uncertain mechanism, lead to the

formation of granular and epithelial cell casts in the absence of overt tubular injury [40].
In this setting, the urinalysis does not distinguish between prerenal disease and ATN. In
contrast, marked hyperbilirubinemia does not impair sodium reabsorption; thus,
measurement of the FENa and the urine sodium concentration remains useful. In one
study, patients with higher urinary bilirubin levels had large numbers of granular casts
and renal tubular epithelial cells on urine sediment, regardless of the presence of AKI
[41].
The value of urinalysis in distinguishing between ATN and prerenal disease was examined in a
study that utilized a scoring system based upon the number of granular casts and renal
tubular epithelial cells [35]. There were two major findings:
● Among patients with a high pretest probability of ATN, the presence of any number of
casts or renal tubular epithelial cells had a very high positive predictive value and low
negative predictive value for a final diagnosis of ATN.
● Among patients with a low pretest probability of ATN (ie, initial diagnosis of prerenal
disease), the absence of casts or renal tubular epithelial cells had a negative predictive
value for ATN of 91 percent.
Fractional excretion of sodium and urine sodium concentration — The urine-sodium

concentration is widely used in patients with suspected volume depletion. In the absence of a
sodium-wasting state, the urine-sodium concentration in hypovolemic states should be less
than 20 mEq/L and may be as low as 1 mEq/L in laboratories able to detect such a low level
(see "Etiology, clinical manifestations, and diagnosis of volume depletion in adults", section on
'Urine sodium concentration'). However, for the reasons described in the following discussion,
measurement of the FENa is the preferred test for distinguishing prerenal disease from ATN
as the cause of AKI.
The urine-sodium concentration tends to be low in prerenal disease (less than 20 mEq/L) in an
appropriate attempt to conserve sodium and high in ATN (more than 40 to 50 mEq/L) due, in
part, to impaired tubular function induced by the tubular injury [32]. However, frequent
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overlap occurs due to variations in water reabsorption, which can affect the urine-sodium
concentration without affecting total sodium excretion. As examples:
● A patient with prerenal disease who is highly water avid due to increased secretion of
antidiuretic hormone may have a higher than expected urine sodium concentration,
despite a low rate of sodium excretion.
● Conversely, decreased water reabsorption in ATN due to impaired concentrating ability

can lower the urine sodium concentration by dilution.
The FENa, which includes the urine-sodium concentration, is the better test in patients with
AKI since it only measures sodium handling (the fraction of the filtered sodium load that is
excreted). It is not affected by changes in urine output, since the urine volume is not included
in the formula.
The filtered sodium load can be determined from the product of the glomerular filtration rate
(GFR, as estimated from the creatinine clearance) and the serum sodium concentration (SNa).
Sodium excretion is equal to the product of the urine sodium concentration (UNa) and the
urine volume (V). Thus:
UNa x V
FENa, percent = —————————————————— x 100
SNa x [(UCr x V) ÷ SCr]
Where UNa and SNa are the urine and serum sodium concentrations, UCr and SCr are the
urine and serum creatinine concentrations, and [(UCr x V) ÷ SCr] represents the creatinine
clearance. This equation can be simplified since the urine flow rate (V) terms cancel out,
allowing the FENa to be estimated from simultaneously obtained serum and urine specimens
without measuring the urine volume [2]:
UNa x SCr
FENa, percent = ——————— x 100
SNa x UCr
Calculators for the FENa are available using either standard units (calculator 1) or SI units
(calculator 2).
Among patients with AKI, the FENa is typically less than 1 percent in prerenal disease
(indicative of sodium retention) and above 2 percent in ATN [42].
Limitations of the fractional excretion of sodium — There are several limitations to

the use of FENa in distinguishing prerenal disease from ATN as the cause of AKI. This issue is
discussed in detail elsewhere, but a few examples will be provided here. (See "Fractional
excretion of sodium, urea, and other molecules in acute kidney injury", section on 'Limitations
of fractional excretion of sodium'.)
● The FENa may remain below 1 percent when ATN is superimposed upon a chronic
prerenal disease such as cirrhosis or heart failure, or in a minority of patients with
nonoliguric postischemic (ischemic) ATN who may have persistent kidney ischemia and
less severe ATN.
● A FENa below 1 percent is not unique to prerenal disease, since it can occur with other
causes of AKI that are associated with a low GFR and relatively intact tubular function.
These include acute glomerulonephritis, vasculitis, rhabdomyolysis, and contrast-
induced nephropathy.
● Patients with AKI are often treated with diuretics, which, if effective, can raise the FENa,
even in patients with prerenal disease. Potential alternative in such patients, which have
been less well studied than FENa, include the fractional excretion of molecules such as
urea, lithium, and uric acid that are primarily reabsorbed and, with uric acid, secreted in
the proximal tubule, which is proximal to the sites of action of loop diuretics (loop of
Henle) or thiazide diuretics (distal tubule). (See "Fractional excretion of sodium, urea, and
other molecules in acute kidney injury", section on 'Fractional excretion of other
molecules'.)
● The FENa defining sodium retention varies with the filtered sodium load: below 1
percent when the filtered sodium load is low due to the marked reduction in GFR in AKI
and progressively lower as the filtered sodium load increases, reaching a value of less
than 0.1 percent when the GFR is normal. If, for example, the normal GFR is 180 L/day
(125 mL/min) and the normal plasma water sodium concentration is 150 mEq/L, then the
daily filtered sodium load will be 27,000 mEq/L. In a patient with prerenal disease, urine
sodium excretion can be reduced to less than 27 mEq/day, which represents a FENa
below 0.1 percent, if a normal GFR is maintained.
Response to fluid repletion — The gold standard for the distinction between prerenal
disease secondary to volume depletion and postischemic or nephrotoxic ATN is the response
to fluid repletion. If sufficient fluid is given to reverse any signs of volume depletion (eg,
hypotension, cool extremities, low FENa and urine-sodium concentration), return of the serum
creatinine to the previous baseline within 24 to 72 hours is considered to represent correction

of prerenal disease, whereas persistent AKI is considered to represent ATN.
Although prerenal disease and postischemic ATN are usually discrete entities, some patients
have an intermediate presentation, with overlap between features of both prerenal disease
(eg, low FENa) and ATN, such as coarse granular casts and/or renal tubular epithelial cells on
urine microscopy [35,36,43] and urinary biomarkers of renal tubular injury [44]. (See
'Urinalysis' above and 'Investigational biomarkers' below.)
In contrast to the prompt recovery to baseline kidney function following volume repletion in
pure prerenal disease, patients with prerenal disease who also have features of ATN may have
delayed recovery to baseline kidney function after fluid repletion [43]. This may reflect a
pattern of patchy tubular injury (accounting for the urine manifestations and delayed
recovery) interspersed among normal functioning nephrons [45].
Unless contraindicated, a trial of intravenous fluid therapy is warranted in patients with a

clinical history consistent with fluid loss (such as vomiting, diarrhea, or bleeding) and a
physical examination consistent with hypovolemia (such as otherwise unexplained
tachycardia, decreased skin turgor, cool extremities, and/or supine or orthostatic
hypotension). In contrast, fluid administration is not warranted and may be harmful (eg, fluid
overload and pulmonary congestion) in critically ill patients with AKI who do not have a history
or physical or laboratory findings suggestive of hypovolemia [45,46].
Fluid infusion to reverse prerenal disease is generally not performed in patients with obvious
volume overload, as in heart failure or cirrhosis, particularly in patients with pulmonary
vascular congestion. However, there are some settings in which fluid repletion may be
considered, particularly in patients with cirrhosis and ascites who do not have peripheral
edema. In the presence of peripheral edema, the edema fluid can be rapidly mobilized with
fluid loss (as with diuretic therapy), which will minimize the degree of intravascular volume
depletion ( figure 1) [47]. In contrast, in patients with ascites but no edema, the ascites fluid
can only be slowly mobilized (300 to 500 mL/day). Thus, fluid loss, as with excessive diuretic
therapy, can lead to plasma volume depletion ( figure 1) and elevations in BUN and serum
creatinine. The supportive data are presented elsewhere. (See "Ascites in adults with cirrhosis:
Initial therapy", section on 'Rate of fluid removal'.)
Fluid repletion is typically initiated with intravenous isotonic saline. The rate of fluid repletion
varies with the severity of the hypovolemia:
● Patients with severe hypovolemia or hypovolemic shock are typically treated with an
initial infusion of one to two liters of isotonic fluid (ie, isotonic saline or a balanced
crystalloid solution) given as rapidly as possible. The rate of further fluid repletion is
governed by the blood pressure response and other clinical signs such as peripheral
perfusion, mental status, and urine output. Patients with persistent hypotension are
continued at the initial rapid rate, as long as there are no signs of volume overload or
some other cause of hypotension (eg, sepsis).
● Patients with mild-to-moderate hypovolemia are treated with isotonic fluid at a slower
rate. The goal of therapy, volume repletion, requires that the rate of fluid administration
be greater than the rate of ongoing fluid losses. One regimen that has been used is a
fluid administration rate that is 50 to 100 mL/hour above ongoing fluid losses. These
include insensible losses (usually 30 to 50 mL/hour) plus any other fluid losses (eg,
gastrointestinal losses). (See "Maintenance and replacement fluid therapy in adults",
section on 'Replacement fluid therapy'.)
● The choice of replacement fluid may be influenced by concurrent abnormalities in serum

sodium or potassium or the presence of metabolic acidosis. Potassium or bicarbonate
may be added in patients who have hypokalemia or metabolic acidosis, respectively,
while patients who are hypernatremic may be treated with one-half isotonic saline at two
times the rate of isotonic saline therapy, respectively, to achieve the same degree of
sodium repletion while also treating the hypernatremia. The choice of initial replacement
fluid in hypernatremic patients is dependent upon the degree of hypernatremia. Careful
monitoring of the rate of correction of the hypernatremia is important, with the
composition and/or the rate of administration of the replacement fluid being adjusted
accordingly. (See "Clinical manifestations and treatment of hypokalemia in adults",
section on 'Treatment' and "Approach to the adult with metabolic acidosis", section on
'Overview of therapy' and "Bicarbonate therapy in lactic acidosis" and "Treatment of
hypernatremia in adults".)
● The type of replacement fluid may influence outcomes and lower the risk of AKI. Some
but not all studies suggest that balanced crystalloid solutions (eg, lactated Ringer's
lactate, Plasma Lyte, Hartman solution) are associated with reduced risk compared with
normal saline. This topic is covered extensively elsewhere. (See "Treatment of severe
hypovolemia or hypovolemic shock in adults".)
The following responses to fluid repletion are compatible with prerenal disease: restoration of
adequate urine flow, improvement in kidney function, and a rise in urine-sodium
concentration, which, if it is an isolated finding, can also reflect progression of prerenal
disease to ATN. If the urine output does not increase, kidney function fails to improve with the
restoration of intravascular volume, and prerenal disease is still suspected, invasive
monitoring may be required to adequately assess the patient's volume status and help guide
further therapy. (See "Maintenance and replacement fluid therapy in adults", section on
'Replacement fluid therapy' and "Treatment of severe hypovolemia or hypovolemic shock in
adults".)
Other tests that may be helpful
Blood urea nitrogen/serum creatinine ratio — The BUN/serum creatinine ratio is

normal at 10 to 15:1 in ATN (measured in mg/dL) but is often greater than 20:1 in prerenal
disease due to the increase in the passive reabsorption of urea that follows the enhanced
proximal reabsorption of sodium and water [32]. Thus, a high ratio suggests prerenal disease
as long as other causes of a high ratio are not present. Other causes include gastrointestinal
bleeding, which disproportionately increases the BUN, or loss of muscle mass in a chronically
ill individual, which lowers creatinine [48]. (See "Etiology, clinical manifestations, and diagnosis
of volume depletion in adults", section on 'Elevation of the BUN and serum creatinine
concentration'.)
However, this ratio cannot reliably distinguish prerenal AKI from ATN [49].
Rate of rise of serum creatinine concentration — The serum creatinine concentration

tends to rise progressively and usually at a daily rate greater than 0.3 to 0.5 mg/dL (26 to 44
micromol/L) per day in patients with ATN. A slower rate of rise with periodic downward
fluctuations (due to variations in kidney perfusion) is suggestive of prerenal disease.
Urine osmolality — Loss of concentrating ability is an early and almost universal finding
in ATN, with the urine osmolality being below 450 mosmol/kg in almost all cases and usually
below 350 mosmol/kg [32]. In contrast, a urine osmolality above 500 mosmol/kg is highly
suggestive of prerenal disease since it reflects both the hypovolemic stimulus to the secretion
of antidiuretic hormone and the maintenance of normal tubular function [32]. However, lower
values similar to those in ATN may be seen in prerenal disease and are therefore of little
diagnostic help.
Urine volume — The urine volume is typically, but not always, low (oliguria) in prerenal
disease due to appropriate increases in both sodium and water reabsorption, which limits
further fluid loss. One exception is effective diuretic therapy, which will acutely raise the urine
volume while the diuretic is acting.
In comparison, patients with ATN may be either oliguric or nonoliguric. (See "Nonoliguric
versus oliguric acute kidney injury".)
Investigational biomarkers — Although measurement of the serum creatinine

concentration is widely used for the detection of AKI, it does not permit early diagnosis of
ATN, since tubular injury precedes a significant rise in serum creatinine. Investigational
biomarkers have been evaluated in patients with possible ATN in an attempt to detect tubular
injury at an earlier stage. None have been approved for clinical use in the United States. (See
"Investigational biomarkers and the evaluation of acute kidney injury".)
Limitations with underlying kidney disease — None of the above criteria for the diagnosis
of prerenal disease may be present in a patient with underlying kidney disease. In this setting,
the ability to conserve sodium and the ability to concentrate the urine are often impaired, and
the urinalysis may be abnormal, reflecting the primary disorder. As a result, a cautious trial of
fluids may be given (independent of the urinary findings) if it is suspected from the history
and physical examination that an acute rise in the serum creatinine concentration may be due
to volume depletion. (See "Etiology, clinical manifestations, and diagnosis of volume depletion
in adults", section on 'Clinical manifestations'.)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Acute kidney injury in
adults".)
SUMMARY AND RECOMMENDATIONS
● Pathogenesis – The two major causes of acute kidney injury (AKI) developing in the
hospital are prerenal disease and acute tubular necrosis (ATN). Decreased kidney
function due to prerenal disease occurs when kidney ischemia is part of a generalized
decrease in tissue perfusion and when there is selective kidney ischemia. ATN can occur
with prolonged and/or severe ischemia. This can result in histologic changes, including
necrosis. (See 'Introduction and definition' above and 'Pathophysiology' above.)
● Etiology – Both prerenal disease and ATN can occur in a variety of settings. Prerenal
disease may result from true volume depletion, hypotension, edematous states, and
selective kidney ischemia, while ATN is principally due to all the causes of severe prerenal
disease, particularly hypotension, sepsis, and nephrotoxins. (See 'Etiology' above.)
● Evaluation – A careful history and physical examination can frequently identify events
and/or disease processes that underlie prerenal disease or ATN, suggesting the
underlying diagnosis. (See 'Evaluation and diagnosis' above.)
In addition to a careful history and physical examination, the initial evaluation to

distinguish ATN from prerenal disease includes a number of laboratory measurements,
close examination of the urine, and (if not contraindicated) fluid repletion. The principal
diagnostic measures are urinalysis, response to fluid repletion, and fractional excretion
of sodium (FENa). These three measures are used in combination with the clinical setting
to help diagnose the underlying disorder. (See 'Evaluation and diagnosis' above.)
● Diagnosis
• Urinalysis – The urinalysis is normal or near normal in prerenal disease; hyaline casts
may be seen, but these are not an abnormal finding. In comparison, the classic
urinalysis in ATN reveals muddy brown granular, epithelial cell casts, and free
epithelial cells. However, the absence of these urinary findings does not exclude ATN.
(See 'Urinalysis' above.)
• Fluid challenge (if appropriate) – The patient with a clinical history consistent with
fluid loss, a physical examination consistent with hypovolemia (hypotension and
tachycardia), and/or oliguria should be administered intravenous fluid therapy, unless
contraindicated. This fluid challenge attempts to correct the fluid deficit and optimize
kidney perfusion. (See 'Response to fluid repletion' above.)
• Other tests – The FENa is typically less than 1 percent in prerenal disease (indicative of
the sodium retention) and above 2 percent in ATN. There are conditions in which this
distinction is not accurate, such as ATN superimposed upon a chronic prerenal state
such as cirrhosis, a setting in which the FENa may remain below 1 percent. (See
"Fractional excretion of sodium, urea, and other molecules in acute kidney injury".)
The serum creatinine is widely used in diagnosing the presence of AKI. However, since
it is a suboptimal biomarker for this process, different urinary and serum proteins
have been intensively investigated. Although there are promising candidate
biomarkers, only one is approved by Food and Drug Administration (FDA) in the
United States but not implemented in many medical centers. (See 'Investigational
biomarkers' above.)
ACKNOWLEDGMENT
The UpToDate editorial staff acknowledges Uta Erdbruegger, MD, who contributed to earlier
versions of this topic review.
Use of UpToDate is subject to the Terms of Use.
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10/16/23, 5:42 PM Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults

injury in adults - UpToDate

Etiology and diagnosis of prerenal disease and acute

Literature review current through: Sep 2023.

INTRODUCTION AND DEFINITION

● When kidney ischemia is part of a generalized decrease in tissue perfusion

● True volume depletion – Volume depletion may be caused by gastrointestinal disease

● Selective kidney ischemia – Bilateral renal artery stenosis or unilateral stenosis in a

● Drugs affecting glomerular hemodynamics – Drugs that affect glomerular

Kidney ischemia — All causes of severe prerenal disease, particularly if accompanied by

● Aminoglycosides. (See "Manifestations of and risk factors for aminoglycoside

● Cisplatin. (See "Cisplatin nephrotoxicity".)

● Radiocontrast media. (See "Contrast-associated and contrast-induced acute kidney

● Pentamidine. (See "Overview of kidney disease in patients with HIV", section on

● Foscarnet. (See "Foscarnet: An overview", section on 'Renal insufficiency'.)

● Cidofovir. (See "Cidofovir: An overview", section on 'Toxicity'.)

● Intravenous immunoglobulin, mostly in products containing sucrose, which is thought to

FREQUENCY OF PRERENAL DISEASE AND ACUTE TUBULAR NECROSIS AS A

● Prerenal disease – 21 percent

EVALUATION AND DIAGNOSIS

● Findings on physical examination may suggest hypovolemia, such as otherwise

● Abdominal distension leading to intra-abdominal hypertension and abdominal

● Urinalysis and urine microscopy.

Other parameters or tools that may be helpful in selected patients include:

● Blood urea nitrogen (BUN)/serum creatinine ratio.

● Rate of rise of serum creatinine concentration.

● Bedside ultrasound measurements of the inferior vena cava [38].

In patients with prerenal AKI due to cardiorenal syndrome or abdominal compartment

Urinalysis — The urinalysis with sediment examination by urine microscopy is normal or

● Marked hyperbilirubinemia alone can, via an uncertain mechanism, lead to the

Fractional excretion of sodium and urine sodium concentration — The urine-sodium

● Conversely, decreased water reabsorption in ATN due to impaired concentrating ability

Limitations of the fractional excretion of sodium — There are several limitations to

creatinine to the previous baseline within 24 to 72 hours is considered to represent correction

Unless contraindicated, a trial of intravenous fluid therapy is warranted in patients with a

● The choice of replacement fluid may be influenced by concurrent abnormalities in serum

Other tests that may be helpful

Blood urea nitrogen/serum creatinine ratio — The BUN/serum creatinine ratio is

Rate of rise of serum creatinine concentration — The serum creatinine concentration

Investigational biomarkers — Although measurement of the serum creatinine

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

underlying diagnosis. (See 'Evaluation and diagnosis' above.)

In addition to a careful history and physical examination, the initial evaluation to

Use of UpToDate is subject to the Terms of Use.

10. Wan L, Langenberg C, Bellomo R, May CN. Angiotensin II in experimental hyperdynamic

Children. JAMA Pediatr 2017; 171:e173219.

21. Boussekey N, Darmon R, Langlois J, et al. Resuscitation with low volume

29. Liaño F, Pascual J. Epidemiology of acute renal failure: a prospective, multicenter,

49. Manoeuvrier G, Bach-Ngohou K, Batard E, et al. Diagnostic performance of serum blood

Topic 7216 Version 42.0

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