Critical Care Nephrology

and Acute Kidney Injury

Low-Flow Acute Kidney Injury

The Pathophysiology of Prerenal Azotemia, Abdominal Compartment
Syndrome, and Obstructive Uropathy

Bruce A. Molitoris

Abstract
AKI is a syndrome, not a disease. It results from many different primary and/or secondary etiologies and is
often multifactorial, especially in the hospitalized patient. This review discusses the pathophysiology of three Division of Nephrology,
Department of
etiologies that cause AKI, those being kidney hypoperfusion, abdominal compartment syndrome, and urinary
Medicine, Indiana
tract obstruction. The pathophysiology of these three causes of AKI differs but is overlapping. They all lead to University School of
a low urine flow rate and low urine sodium initially. In all three cases, with early recognition and correction Medicine, Indianapolis,
of the underlying process, the resulting functional AKI can be rapidly reversed. However, with continued Indiana, and
duration and/or increased severity, cell injury occurs within the kidney, resulting in structural AKI and a Department of
Anatomy, Cell Biology
longer and more severe disease state with increased morbidity and mortality. This is why early recognition and Integrative
and reversal are critical. Physiology, Indiana
CJASN 17: 1039–1049, 2022. doi: https://doi.org/10.2215/CJN.15341121 University School of
Medicine, Indianapolis,
Indiana
Introduction their severity and/or duration increase, can lead to
AKI is a heterogeneous syndrome defined by the Correspondence:
intrinsic AKI secondary to cellular injury. This results
Dr. Bruce A. Molitoris,
rapid (hours to days) decline in the GFR resulting in in subsequent organ dysfunction and, finally, overt 6452 South Himalaya
serious morbidity, mortality, and increased hospital organ failure, causing increased morbidity and mor- Court, Centennial, CO
costs (1–3). AKI is defined by the retention of the met- tality (Figure 1). Intrinsic or “structural” AKI occurs 80016. Email:
abolic waste product, creatinine, and/or a reduction when there is cellular injury, and it is diagnosed by bmolitor@iu.edu
in urine production, and it is associated with altera- positive urinary cell injury biomarkers. Structural AKI
tions in fluid, electrolyte, and acid-base homeostasis can occur without a measured increase in serum creat-
(2). AKI is often multifactorial, resulting from a large inine as creatinine is an insensitive marker of GFR
group of etiologies and pathophysiologic mechanisms, reductions, especially in patients with normal or near-
and it can be primary or secondary to a systemic pro- normal baseline GFR (4–6). There are two main rea-
cess. For diagnostic purposes, AKI is classically sons for this insensitivity. First, kidneys have a reserve
divided into prerenal, intrarenal (intrinsic), and post- capacity, like the heart, that is called into action dur-
renal (extrinsic) etiologies. These processes include ing stress situations. In a person with normal kidney
hypoperfusion of the kidney, termed prerenal azote- function, this reserve can be up to 50% of the baseline
mia, with the reduction in GFR resulting from GFR. When GFR is lost during injury, this reserve
reduced kidney perfusion without parenchymal kicks in and “hides” the loss in baseline GFR. As base-
injury. Intrinsic causes include processes inducing line GFR is lost, as in CKD, the amount of GFR com-
glomerular, interstitial, tubular, or endothelial cell pensation available from kidney reserve decreases,
injury. Postrenal AKI results from partial or complete reducing the likelihood of subclinical AKI. The second
obstruction of venous outflow or urinary flow. reason has to do with the exponential nature of GFR
A rapid diagnosis of AKI is critically important for versus serum creatinine contributing to its insen-
several causes of AKI, termed “functional” AKI, as sitivity at normal GFRs and hypersensitivity at low
effective therapy can result in rapid reversal by correc- GFRs (5).
tion of the underlying pathophysiologic process. Patients with positive urinary biomarkers and no
These processes include hypoperfusion of the kidney, change in serum creatinine are referred to as having
reductions in venous outflow from the kidney, and “subclinical AKI” as there is known tubular cell injury
obstruction of urine flow. I have termed these three but the serum creatinine definition for clinical AKI is
processes low-flow AKI as they result from a primary not met. Clinical outcomes in this group of patients
pathophysiologic mechanism of low arterial, venous, are poorer than in patients with prerenal azotemia but
or urinary flow, respectively. The resulting AKI is rap- without positive urinary cell injury biomarkers (7,8).
idly reversible if diagnosed early; it occurs from The use of urinary biomarkers has mostly been lim-
events external to the kidney and results initially in a ited to research studies as the lack of an effective ther-
low urinary sodium. In all three conditions, sepsis can apeutic agent for AKI has made the rapid diagnosis
be a contributing factor. These etiologies of AKI, as of AKI without therapeutic consequences. Also, the

www.cjasn.org Vol 17 July, 2022 Copyright © 2022 by the American Society of Nephrology 1039
1040 CJASN

Prerenal azotemia
(Functional AKI)
sCr ( GFR)
Urine output
(–) Urinary cell injury biomarkers

Increased
Normal
risk
B

Acute tubular necrosis

(Structural AKI)
(+) Urinary cell injury biomarkers
(±) sCr

Figure 1. | Acute kidney injury divided into prerenal azotemia (functional AKI) and acute tubular necrosis (structural AKI) on the basis
of serum creatinine (sCr) and urinary biomarkers. Prerenal azotemia has negative urinary cell injury biomarkers, whereas acute tubular
necrosis has positive urinary cell injury biomarkers, indicating proximal tubule cell injury or dysfunction. (A) An image of normal human
cortex, and prerenal azotemia appears the same. Courtesy of Jim Hasbargen. (B) A human kidney biopsy specimen 24 hours after injury.
Note the flattened proximal tubule cells and shed brush border membrane in the lumen. The peritubular capillaries are filled with white
blood cells and rouleauxs, and a mitotic cell is visible. Reprinted from ref. 67, with permission.

urinary biomarker studies are population studies, and
there is wide overlap in individual values, making their
use difficult. In some centers, urinary biomarkers are used
to separate patients into high-risk and lower-risk patient
care areas. The utility of this has not been established. As
the extent of injury progresses, serum creatinine rises fur-
ther, and clinical outcomes deteriorate. The one clinical
area where clinically utility may be important is in drug
nephrotoxicity, where early detection could limit injury.
Prerenal AKI
Prerenal azotemia, also known as functional AKI, results
from many different pathophysiologic processes (Table 1)
and is the most common cause of AKI, accounting for up
to 50% of all AKI cases (9–11). Prerenal azotemia is diag-
nosed by an elevation of serum creatinine or low urine
flow rate without positive urinary cell injury biomarkers.
Kidney hypoperfusion results from reductions in the effec-
tive arterial blood volume, the volume of blood effectively
perfusing the body organs with or without true vascular or
total body volume depletion (Figure 2). True intravascular
hypovolemia results from a loss of blood volume through
hemorrhage, gastrointestinal volume losses, renal volume
losses, and third spacing. Hypoperfusion of the kidney also
results from disease processes with normal or even
increased vascular volume status but reduced effective
arterial blood volume. These include cardiogenic shock,
septic shock, cirrhosis, pancreatitis, and abdominal com-
partment syndrome. If kidney perfusion is restored,
prerenal azotemia reverses rapidly within 24 hours
because, by definition, the integrity of the kidney paren-
chyma has remained intact. However, severe and/or pro-
longed hypoperfusion can result in tubular epithelial cell
injury, leading to intrinsic (structural) AKI. The spectrum
of injury and the importance of a rapid diagnosis and
reversal of the underlying process are shown in Figure 1.
Prerenal azotemia has also been divided into volume
responsive and volume nonresponsive. The former is easy
to comprehend, whereas the latter is less straightforward.
In volume-nonresponsive forms, additional intravenous
volume is of no help in restoring kidney perfusion and
function. Disease processes such as congestive heart failure,
hepatorenal syndrome, abdominal compartment syn-
drome, and sepsis may not respond to intravenous fluids
as markedly reduced cardiac output or decreased systemic
vascular resistance prevents improved kidney perfusion
(Table 1).
Reductions in effective arterial blood volume lead to acti-
vation of aortic and cardiac baroreceptors and initiate a
cascade of neural and humoral responses in an attempt to
minimize any reduction in renal blood flow and GFR
(Figure 3). Activation of the sympathetic nervous system
increases production of catecholamines, especially norepi-
nephrine. Sympathetic activation has ionotropic and
chronotropic effects on the heart, stimulates systemic vaso-
constriction in musculocutaneous and splanchnic circula-
tions, inhibits salt loss through sweat, and stimulates
thirst, resulting in retention of salt and water. Increased
release of antidiuretic hormone mediates additional systemic
CJASN 17: 1039–1049, July, 2022
Table 1. Causes of prerenal AKI
Different Pathophysiologic Mechanisms of Kidney
Hypoperfusion
Intravascular volume depletion
Hemorrhage—trauma, surgery, postpartum, gastrointestinal
Gastrointestinal losses—diarrhea, vomiting, NG loss
Kidney losses—diuretics, osmotic diuresis, diabetes
insipidus
Skin and mucous membrane losses—burns, hyperthermia
Nephrotic syndrome
Cirrhosis
Capillary leak
Reduced cardiac output
Cardiogenic shock
Pericardial diseases—restrictive/constrictive/tamponade
Congestive heart failure
Valvular diseases
Pulmonary diseases—pulmonary hypertension, pulmonary
embolism
Reduced systemic vascular resistance
Sepsis
Hepatorenal syndrome
Anaphylaxis
Renal vasoconstriction
Early sepsis
Hepatorenal syndrome
Acute hypercalcemia
Drugs—norepinephrine, vasopressin, nonsteroidals,
renin-angiotensin system inhibitors
Calcineurin inhibitors
Iodinated contrast agents
Increased intra-abdominal pressure and/or reduced
venous flow
Abdominal compartment syndrome
Venous outflow obstruction
NG, nasogastric.
vasoconstriction, water retention, and urea reabsorption.
Angiotensin II also causes systemic arteriole vasoconstric-
tion to preserve BP.
Concomitantly, there are various compensatory mecha-
nisms within the kidney to compensate for the reductions
in renal blood flow in an attempt to preserve glomerular
perfusion and filtration (Figure 3) (12). Autoregulation,
activated by stretch receptors in afferent arterioles in
response to reduced perfusion pressure, causes vasodila-
tion to increase renal blood flow. Autoregulation functions
well until a mean systemic arterial BP of 70 mm Hg. Below
this, the glomerular ultrafiltration pressure and GFR
decline. Production of prostaglandins, kallikrein, and
kinins by the kidneys as well as nitric oxide is increased,
contributing to the vasodilation (13,14). Increased prosta-
glandin synthesis results in afferent arteriole vasodilation,
and inhibition of this response by nonsteroidal anti-
inflammatory drugs decreases afferent arteriole vasodila-
tion, resulting in a lack of compensation in renal blood
flow and GFR. Intrarenal angiotensin II activity is increased
by activation of the renin-angiotensin-aldosterone system.
It minimizes GFR reductions by maintaining glomerular
hydrostatic pressure by preferentially increasing efferent
arteriolar resistance. Renin-angiotensin system blockade,
by angiotensin-converting enzyme inhibitors, angiotensin
receptor blockers, or direct renin inhibitors, reduces intrare-
nal angiotensin II effects, minimizing efferent arteriole tone
Low-Flow Acute Kidney Injury, Molitoris 1041
and leading to reductions in glomerular hydrostatic pres-
sure and GFR. Thus, this homeostatic protective GFR
mechanism in patients with severe reductions in effective
arterial blood volume is lost, and GFR is reduced.
Tubular glomerular feedback is another regulatory path-
way important in controlling glomerular perfusion. A
reduction in distal tubule delivery of Na and Cl, as would
be seen in prerenal azotemia, is sensed by the Na/K/2Cl
cotransporter and leads to reductions in adenosine and ATP
release by macula densa cells of the juxtaglomerular appara-
tus. This results in relaxation of afferent arteriole tone,
increasing glomerular flow. Sodium reabsorption by proxi-
mal tubules results from increased angiotensin II by activat-
ing the sodium-hydrogen exchangers. This leads to reduced
distal sodium delivery and activation of the Na/K/2Cl
exchanger, mediating increased glomerular flow (15). In
intrinsic AKI with proximal tubule dysfunction, reduced
proximal tubule Na reabsorption results in high distal deliv-
ery of Na and Cl, mediating increased macula densa afferent
arteriole contraction and reductions in glomerular blood
flow and GFR. This also occurs with both the acute and
chronic use of sodium glucose transport inhibitors as Na
and Cl delivery to the macula densa increases with reduced
proximal tubule reabsorption of glucose (16).
Clinical risk factors for developing prerenal azotemia at
lesser levels of hypotension include renovascular disease,
hypertensive nephrosclerosis, diabetic kidney disease, and
older age and CKD (10,11). Prerenal azotemia also predis-
poses patients to developing AKI in clinical situations, such
as exposure to radiocontrast, other nephrotoxins such as
cisplatin and aminoglycoside antibiotics, general anesthe-
sia, and surgery. Therefore, it is clinically important to
consider the possibility of prerenal azotemia promptly and
initiate effective treatment to reverse this condition, mini-
mizing the potential for ischemic acute tubular necrosis
and/or nephrotoxic AKI. Also, in patients who develop
intrinsic AKI, it is essential to first replete the intravascular
volume to avoid worsening intrinsic AKI from continued
hypoperfusion of the kidney. This is often overlooked,
especially in patients with baseline CKD when the clinician
is worried about volume overload and the potential need
for dialysis to remove fluid (17).
Prerenal azotemia, with its rapid recovery of GFR, has
always been considered a clinically insignificant event fol-
lowing resolution. Is this true, or are we missing important
underlying issues, such as reductions in total GFR and base-
line GFR plus kidney reserve, that cannot be detected simply
using serum creatinine? The numerous risk factors shown in
Figure 2 and listed above all indicate a delicate situation with
enhanced likelihood of recurrence. Because serum creatinine
is so insensitive to reductions in GFR, are we missing reduc-
tions in GFR with each prerenal event? An important con-
tributor to this possibility is the kidney reserve component of
total GFR (4,5,18,19). The kidney, like the heart, has reserve
functional capacity, kidney reserve, to increase GFR during
stress and following protein ingestion. Early studies
highlighted the importance of kidney reserve and showed
that it is lost with loss of baseline GFR but not in a predict-
able way (5,20,21). Thus, two patients could have the same
baseline GFR and differ in the amount of kidney reserve and
therefore total GFR. The patient with the lower kidney
reserve would likely progress faster to advanced kidney
1042 CJASN

Intravascular volume
Oncotic pressure Intake Central venous return
Hypoalbuminuria Loss Pulmonary disease
Synthesis Hemorrhage Abdominal pressure
Loss GI Positive pressure ventilation
Kidney

Interstitial
Systemic factors

fluid

Systemic inflammation
Vascular permeability Blood volume
Vasodilation

Cardiac output
Systemic vascular Effective arterial
Congestive heart failure
resistance blood volume
Vasoconstricting drugs

Renal vasoconstriction
Serum Ca++
Intrarenal factors

NSAIDs Prostaglandins Kidney perfusion Drugs

Afferent arteriole dilation Catecholamines
Calcineurin
Renal artery stenosis

ACE or ARB

Angiostensin II GFR

Efferent arteriole constriction

Figure 2. | Pathophysiology of prerenal azotemia. Numerous systemic and intrarenal factors predispose to the development of prerenal azo-
temia. Systemic factors lead to a reduced blood volume, resulting in a reduced effective arterial blood volume. This is the effective blood vol-
ume circulating through organs. A reduced systemic vascular resistance or a decreased cardiac output, even in the setting of normal or
increased blood volume, can lead to hypoperfusion of the kidneys. Intrinsic factors within the kidney can also result in hypoperfusion, includ-
ing that inhibition of prostaglandin synthesis by nonsteroidal anti-inflammatory drugs results in afferent arteriole vasoconstriction. Also, a
reduction in efferent arteriole due to renin-angiotensin system inhibition (angiotensin-converting enzyme inhibitors, angiotensis receptor
blockers, and renin inhibitors) can result in normal to increased perfusion but a reduced GFR due to a reduced pressure gradient for filtration.
Finally, renal artery stenosis, vasoconstrictive drugs, and hypercalcemia can cause renal vasoconstriction and hypoperfusion. ACE, angioten-
sin-converting enzyme; ARB, angiotensin II receptor blocker; GI, gastrointestinal; NSAIDs, nonsteroidal anti-inflammatory drugs.

failure, all other things being equal, as the patient’s total GFR
is lower (5). The importance of quantifying an individual’s
total GFR to show loss of GFR without apparent change in
baseline serum creatinine had been previously postulated
and has now been shown in clinical studies (7,8,22).
Debate of the clinical importance and existence of prere-
nal azotemia without tubular cell injury has occurred. In
one study, some, but not all, urinary biomarkers were posi-
tive in patients with “prerenal azotemia.” However, the
definition of prerenal azotemia included patients recover-
ing to baseline serum creatinine for up to 48 hours, not the
usual definition of 24 hours (23). This well may have
included patients with mild intrinsic AKI.
Abdominal Compartment Syndrome
Abdominal compartment syndrome occurs when the
intra-abdominal pressure is high enough to result in any
abdominal organ dysfunction. The kidney is a primary tar-
get of abdominal compartment syndrome as it is so depen-
dent on high blood flow, and AKI from this syndrome is
primarily mediated by reductions in renal blood flow,
CJASN 17: 1039–1049, July, 2022 Low-Flow Acute Kidney Injury, Molitoris 1043

Kidney hypoperfusion
Sympathetic response Intrarenal response

Sympathetic response
Catecholamines Afferent Efferent
arteriole arteriole
Heart rate
Effective arterial Vasoconstriction
blood volume ADH release
Vasoconstriction MD
Angiotensin II
Vasoconstriction RBF

Neurohormonal
activation Intrarenal response

Na
Angiotensin II H2O
EA resistance
Aldosterone
Distal tubular Na
reabsorption
Proximal tubule
Na reabsorption
ADH
Water reabsorption

RBF
GFR
Plasma volume

Autoregulation and GFR

RBF

60 80 100 120 140 160

MAP

Figure 3. | Systemic and intrarenal compensatory mechanisms respond to a reduced effective arterial blood volume. Systemic and intrare-
nal neurohormonal activation occurs to counteract systemic and kidney hypoperfusion in a compensatory fashion in an attempt to normalize
renal blood flow (RBF) and GFR. Catecholamines increase heart rate and vasoconstriction to increase BP, antidiuretic hormone (ADH) release
increases to induce vasoconstriction, and angiotensin II production also causes vasoconstriction. This results in an increase in cardiac output and
BP. Within the kidney, macula densa (MD)–mediated angiotensin II release increases efferent arteriole resistance, leading to stabilization of filtra-
tion pressure and GFR, and production of aldosterone, resulting in higher sodium (Na) reabsorption to increase plasma volume. ADH also
increases water reabsorption to increase plasma volume in conjunction with the increased Na reabsorption. This results in an increase in plasma
volume and maintenance of GFR. The lower graph shows autoregulation of RBF and GFR mediated by the intrarenal measures in response to
reduced RBF. Autoregulation of RBF and GFR occurs between a mean arterial pressure (MAP) of 70 and 140 mm Hg. EA, efferent arteriole.

resulting in prerenal azotemia. The normal intra-abdominal
pressure is approximately 6 mm Hg, is dependent on body
mass, and can reach as high as 10–15 mm Hg chronically in
morbidly obese individuals without causing abdominal
compartment syndrome (24,25). Therefore, the level of
intra-abdominal pressure cannot be used for a strict defini-
tion for abdominal compartment syndrome. However, if
the intra-abdominal pressure is ,10 mm Hg, abdominal
compartment syndrome does not exist, whereas if it is .25
mm Hg, abdominal compartment syndrome is highly likely
(Figure 4) (26,27). This wide range of possible pressures
resulting in abdominal compartment syndrome is due to a
number of associated variables that will be discussed later.
Abdominal compartment syndrome is classified as either
primary if resulting from an intrabdominal process or sec-
ondary if resulting from a process outside of the abdomen.
1044 CJASN

30

25

IAP (mm Hg) 20

15

10

0
Normal IAH ACS research ACS
(6–10 mm Hg) (12 mm Hg) definition definite
(20 mm Hg) (25 mm Hg)

Figure 4. | The spectrum of intra-abdominal pressure (IAP) and abdominal compartment syndrome (ACS) as intra-abdominal pressure
rises. Normal IAP is about 6 mm Hg. Intra-abdominal hypertension (IAH) occurs when IAP reaches 12 mm Hg. ACS occurs when the IAP
is elevated and there are signs of any abdominal organ hypoperfusion. This can occur at any pressure above 12 mm Hg but is more likely
as IAP increases to 20 mm Hg. The research definition of ACS is IAP of 20 mm Hg, even without signs of organ hypoperfusion. Above IAP
level of 25 mm Hg, ACS is almost always present.

The etiology of abdominal compartment syndrome
includes a wide range of both medical and surgical condi-
tions that often occur only after large amounts of volume
administration and/or intra-abdominal hemorrhage (28).
These causes include shock from sepsis, trauma, burns, pan-
creatitis, or liver transplantation, resulting in abdominal third
spacing; massive ascites; and intra-abdominal bleeding
resulting from a ruptured abdominal aortic aneurysm, pelvic
fracture, or retroperitoneal bleed (24,28–32). The incidence of
abdominal compartment syndrome is related to the extent of
the underlying disease process and the requirement for mas-
sive volume administration for control of mean arterial pres-
sure (24,33,34). Both the total volume and the rate of volume
administration have been shown to be critical factors in the
development of abdominal compartment syndrome (35).
Other individual clinical factors include abdominal wall
compliance and the mean arterial pressure. This latter factor
determines the abdominal perfusion pressure, the dif-
ference between mean arterial pressure and intra-abdominal
pressure, and maintaining it above 60 mm Hg has been
shown to improve outcomes (24,35,36). Many other clinical
risk factors associated with abdominal compartment syn-
drome have been identified and relate to reducing abdominal
compliance, such as pneumonia; mechanical ventilation
with positive end expiratory pressure; abdominal surgery;
increased intra-abdominal contents, such as ascites, preg-
nancy, or morbid obesity; and increased capillary leak syn-
drome as occurs in abdominal infections, acute pancreatitis,
trauma, sepsis, and burns (24,34–36).
Intra-abdominal hypertension is the term used to
describe intra-abdominal pressure $12 mm Hg (37). It is
graded one to four according to the measured pressure
and from hyperacute to chronic according to the rate of
development (Table 2). With more rapid development of
intra-abdominal hypertension, the abdominal wall is less
compliant, resulting in a higher rate of rise in intra-
abdominal pressure and the likelihood of abdominal
compartment syndrome occurring. For clinical trials, an

Table 2. Intra-abdominal hypertension classification

Grades of Intra-Abdominal Hypertension Pressures, mm Hg Development Time Examples
I 12–15 Hyperacute Seconds Cough
II 16–20 Acute Hours Hemorrhage
III 21–25 Subacute Days Pancreatitis
IV $25 Chronic Months Ascites
Years Morbid obesity
CJASN 17: 1039–1049, July, 2022 Low-Flow Acute Kidney Injury, Molitoris 1045

Initiating event Total body fluid third Elevated intra-abdominal Vena cava
capillary permeability. spacing/edema pressure compression
Aggressive fluid administration

Intestines: IAH compromises intestinal

blood flow resulting in ischemia,
Brain: IAH directly Lung: IAP limits diaphragm edema, and injury
contributes to ICP movement, raising intrathoracic
elevation pressure

MAP mm Hg
EDEMA

IAH >15–20 mm Hg, capillary

IAP blood flow leading to anaerobic
metabolism, increased cytokine
production, and capillary leak.
At IAP –20 mm Hg, venous
return to the heart is impaired,
reducing cardiac output
CVP mm Hg

Heart: CVP and PCWP
are artificially elevated by
IAH, making them difficult
to interpret
Kidneys: Increased venous outflow Vena cava compression: IAP greater
pressure leads to reduced arterial than 12 mm Hg results in reduced
perfusion and urine production, resulting blood flow to the heart (preload)
in the inability to mobilize fluids and
increased rates of kidney insufficiency/failure.
Also, angiotensin II, renin, and
aldosterone lead to Na+ reabsorption

Multisystem organ Reduced blood Reduced blood flow

Reduced cardiac output
dysfunction/failure flow to organs to heart (preload)

Figure 5. | The complex multiorgan pathophysiology of abdominal compartment syndrome. Following an initiating event that leads to
inflammation and increased capillary permeability, especially if associated with aggressive volume administration, intra-abdominal pres-
sure (IAP) increases, resulting in intra-abdominal hypertension (IAH) at 12 mm Hg. Above this level, there is diaphragm elevation, resulting
in increased intrathoracic pressure, abdominal venous pressure, central venous pressure (CVP), and pulmonary capillary wedge pressure
(PCWP), all leading to a reduction in right ventricular function and lower extremity edema. Cerebral blood flow is also reduced by an
increase in intracranial pressure (ICP) due to the high thoracic pressure. The high IAP also reduces venous return to the heart by increasing
venous pressure within the abdomen, leading to reduced renal and inferior vena cava flows. This leads to a reduction in cardiac output,
reducing renal blood flow. Gastrointestinal capillary perfusion is reduced, leading to tissue ischemia, cytokine production, and increased
capillary permeability. Within the kidney, this results in a prerenal state as shown in Figure 2, with reductions in GFR and increases in
renin, angiotensin II, and aldosterone. MAP, mean arterial pressure; Na, sodium. Adapted from LearnPICU (http://www.learnpicu.com/gi/
abdominal-compartment-syndrome), with permission.

intra-abdominal pressure of .20 mm Hg is used to define
abdominal compartment syndrome when associated with
new organ dysfunction (37).
The clinical signs of abdominal compartment syndrome
include reduced urine output, increased airway pressure,
and a tense abdomen. These signs and symptoms are nonspe-
cific, making surveillance and diagnosis difficult. For this rea-
son, measurement of intra-abdominal pressure has become a
necessary and reliable method. Although direct measurement
of intra-abdominal pressure is possible, the preferred tech-
nique is to measure intrabladder pressure. This correlates
highly with intra-abdominal pressure and is currently the
preferred technique as it is simple, reliable, reproducible, and
low cost and has minimal complications (38). The technique
involves draining the bladder with a foley, instilling 25 ml of
normal saline, and measuring the pressure in the mid axillary
line, in millimeters of mercury, with the patient in the supine
position. Pressure can be measured using a monometer or
transducer intermittently or continuously (38).
The pathophysiology of abdominal compartment syndrome
includes all intra-abdominal organs, and its consequences
reach outside the abdomen to affect cardiac, pulmonary, and
central nervous system function (Figure 5). Many of these
extra-abdominal effects result in part from the pathophysiol-
ogy of AKI during abdominal compartment syndrome.
Increasing intra-abdominal hypertension reduces cardiac func-
tion in several ways. First, the increase in intra-abdominal
pressure reduces inferior vena cava venous return and pro-
motes lower extremity edema (38,39), resulting in a reduced
plasma volume. Second, it reduces right ventricular compli-
ance and contractility via an elevation of the diaphragm (39).
Furthermore, it can also increase central venous pressure and
pulmonary capillary pressure, both further reducing right ven-
tricular output and thus cardiac output (40). In ventilated
patients, positive end expiratory pressure further reduces car-
diac output (41). The elevated central venous pressure leads to
higher intracranial pressure and reduced cerebral blood flow
(42). Therefore, the pathophysiology of AKI from abdominal
compartment syndrome is multidimensional, primarily
involving increased renal venous resistance and a reduction in
cardiac output, both leading to reduced kidney perfusion and
a prerenal state (Figure 6).
1046 CJASN

Angiotensin II
Thromboxine
TNF
Afferent Efferent Normal
arteriole arteriole
B
RBF

RBF
GFR
P Tubular injury Urethral obstruction
Fibrosis
Lymphangiogenesis
C

Urethral obstruction

Figure 6. | The pathophysiology of urinary tract obstruction causing AKI seen using two-photon microscopy. Urinary tract obstruction
results in increased pressure within the collecting system. This increased pressure is transmitted in a retrograde fashion, resulting in high
tubule luminal pressure. This high luminal pressure reduces the difference between tubular and glomerular filtration pressure, leading to
reduced single-nephron and total GFR. Thereafter, angiotensin II and thromboxane A2 increase further, dramatically reducing renal blood
flow (RBF) by afferent and efferent arteriole vasoconstriction. TNF is released, and fibrosis is initiated rapidly. Although glomerular filtra-
tion still occurs at a low level, there is no net filtration as it cannot reach the urine. The lymphatic system increases to handle the increased
interstitial accumulation of fluid following filtration. (A) A intravital two-photon image of the outer cortex of a Munich Wistar rat that has
surface glomeruli. The glomerular capillaries are easily seen within Bowman’s space; nuclei are labeled in blue with an intravital nuclear
dye, and the S1 portion of the proximal tubule is labeled. Blood flow through the glomerular capillaries is rapid as shown by long streak-
ing RBCs appearing as dark lines as they do not take up the red intravascular dye. (B) The cortex of a Munich Wistar Fromter rat after 6
weeks of unilateral obstruction. Within the glomerular capillaries, many WBCs can be seen, RBCs move very slowly as RBF has been
reduced to about 20% of normal, and most of the capillary space is filled with plasma and rouleauxs (rlx). The peritubular capillaries also
have increased white blood cells and numerous rouleauxs, leading to reduced flow, ischemia and cortical tubular injury, and destruction.
(C) The abnormal tubular structures. Not shown is the rapidly increasing fibrosis leading to nonreversible loss of kidney function. abPT,
abnormal proximal tubule; alb, filtered albumin; P, pressure; RBC, red blood cell; S1, S1 segment of proximal tubule; vr, vascular rarefac-
tion; WBC, white blood cell. Scale bars shown in A and B are 30 mm and in C 50 mm.

Abdominal compartment syndrome is also a syndrome often indicated to relieve the high intra-abdominal pressure
requiring input and care from multiple medical specialties and, thus, reverse the overall pathophysiologic process
(43,44). Mortality usually ranges from 25% to 50%, but with- (43,44). Finally, abdominal compartment syndrome is often a
out treatment, it can reach 90% (44). Opening the abdomen is silent disease, especially in the intensive care setting (35). It
CJASN 17: 1039–1049, July, 2022
Table 3. Etiology of obstructive AKI by site
Anatomic Locations and Etiologies of Urinary Tract
Obstuction
Kidney pelvis
Kidney stones, papillary necrosis
Ureter
Bilateral obstruction (patients with CKD, unilateral
obstruction with solitary kidney)
Kidney stones, cancer, retroperitoneal fibrosis, severe
benign prostatic hypertrophy, neurogenic bladder,
stenosis, abscess, ureteral valves
Posterior to bladder
Benign prostatic hypertrophy, cancer, clots
Extrinsic to urinary system
Abdominal and pelvic malignancies, aortic aneurism,
pelvic fractures, atrophic vaginitis, vulvovaginitis,
pelvic organ prolapse
requires consideration in multiple clinical settings, surveil-
lance, and verification measurement of intra-abdominal pres-
sure via the bladder using the modified Kron technique
(35,45).
Obstructive Uropathy and AKI
Obstructive uropathy is a frequent cause of AKI, account-
ing for up to 10% of all AKI cases (46) in the general popula-
tion and an even higher percentage in the elderly (46,47). The
wide variety of causes of obstructive uropathy, both within
and outside of the urinary track, are shown in Table 3.
Obstructive uropathy differs from acute urinary retention in
that it is a more severe form and associated with reduced kid-
ney function. Acute urinary retention has an expanded list of
causes, including many drugs that will not be discussed here.
It is important to recognize acute urinary retention as it can
be a presenting symptom and deteriorate into obstructive
uropathy. The degree of injury resulting from obstructive
uropathy depends on the extent of the obstruction and its
duration. Most of the information regarding obstructive urop-
athy comes from different observations made in complete
acute obstructive uropathy. This is also true of the postob-
structive phase following release of the complete obstruction.
Obstructive uropathy is initiated by a buildup of pressure
within the collecting system that is transferred in a retrograde
fashion to Bowman’s space of the glomerulus. The increased
pressure results in decreased net glomerular filtration pres-
sure across the glomerular capillary wall due to Starling
forces (48–50). In the early phase of acute obstructive urop-
athy (the first 2–3 hours), total renal blood flow actually
increases due to enhanced local vasodilatory prostaglandin
synthesis (51), and then returns to baseline within 5 hours
mediated by the myogenic changes in the afferent artery.
Over the first 24 hours, intrarenal production of thromboxane
A2 and angiotensin II leads to reductions in intraglomerular
blood flow (48,49,51) by causing vasoconstriction of afferent
and efferent arterioles. The overall glomerular surface area for
filtration is also reduced from mesangial contraction, resulting
in a further decrease in glomerular filtration (49). After 24–48
hours, renal blood flow decreases up to 60% as a result of the
increase of thromboxane A2 (52) and increased intrarenal
pressure. Glomerular filtration decreases even more than
renal blood flow, up to an 80% reduction (48,53). Thereafter,
Low-Flow Acute Kidney Injury, Molitoris 1047
the hemodynamic changes remain unchanged in unilateral
obstruction with reduced renal blood flow, glomerular
plasma flow, tubular pressure, and GFR. Bilateral obstruc-
tion only differs from unilateral obstruction in that glomeru-
lar plasma flow and glomerular capillary pressure return to
normal. Interestingly but unexplained, in unilateral obstruc-
tion, the predominant site of glomerular vasoconstriction is
the afferent arteriole, and in bilateral obstruction, it is the
efferent arteriole. The central role of angiotensin II can be
demonstrated by the ability of angiotensin-converting
enzyme and other renin-angiotensin system inhibitors
to minimize the decline in renal plasma flow and GFR
(54). The increased level of angiotensin II also stimulates
secretion of TNF-a, resulting in fibrosis and tubular cell
apoptosis.
With continued obstruction, there is proximal tubule cell
injury, including apical membrane shedding, cell injury,
and apoptosis. Although there is an early increase in proxi-
mal tubule Na and H2O reabsorption, this is short lived,
and Na and H2O reabsorption falls. This is accompanied
by renal arteriole and microvascular rarefaction and further
reductions in renal blood flow (55). More distal aspects of
the nephron basically shut down transport activities with
reductions in Na, H2O, Ca, and Mg reabsorption; Na-K-H
exchange; and ammonia synthesis and excretion. Hyper-
chloremic metabolic acidosis occurs as renal acidification is
reduced by the inability to excrete ammonium, potassium,
and hydrogen, resulting in a distal renal tubular acidosis
with hyperkalemia (56,57). This is in large part due to aldo-
sterone deficiency, leading to a reduction in epithelial volt-
age and the inability to excrete K and H and reabsorb Na.
Interestingly, even with complete obstruction and no
urine flow, glomerular filtration continues. Proximal tubule
Na and H2O reabsorption actually increases early on,
resulting in net fluid removal, and later, decreases. In addi-
tion, the lymphatics increase movement of interstitial fluid
out of the kidney, lessening the intrarenal pressure result-
ing from obstruction. This does not result in net glomerular
filtration as the filtered material is completely reabsorbed,
and so, there is no net loss of filtered material.
Studies in rodents have shown complete unilateral ure-
teral obstruction results in progressive reduction in renal
blood flow and GFR, tubular injury with cell death, severe
interstitial fibrosis, cortical destruction, and atrophy result-
ing in glomeruli rising to the surface (58,59). Because mice
after the age of 4 weeks very rarely have surface glomeruli,
this approach has been used to study glomerular processes
in normal and transgenic mice with micropuncture or
intravital microscopy (60). After 6–12 weeks of complete
unilateral ureteral obstruction, numerous glomeruli are
seen at the surface due to cortical atrophy. Unfortunately,
these are highly inflamed glomeruli with dysfunctional or
nonfunctioning tubules attached (58–61). Total separation
of tubules from glomeruli has also been seen, leading to
atubular glomeruli (61,62).
Release of the obstruction results in a reversal of the
events described above. The rate of reversal depends on
the severity and duration of the obstruction, with a pro-
longed obstruction resulting in a slow and only partial
recovery. In a dog model of unilateral ureteral obstruction
for 7 days, maximal recovery of GFR took 2–4 weeks and
was only two thirds of baseline values. If the obstruction
1048 CJASN
was left in place for 1 month, the final GFR was only one
fifth of preobstruction levels (63).
Release in patients with severe bilateral obstruction can
result in a postobstructive diuresis. This is rare and requires
bilateral obstruction or obstruction of a solitary kidney.
There can be massive release of water and solutes secondary
to reduced tubular absorptive capacity (46,64) and lost con-
centrating ability, resulting in nephrogenic diabetes insipidus
(65). This is due to a lack of response to antidiuretic hormone
and an inner medullary gradient that has been reduced.
Aquaporin-2 has been found to be reduced in collecting duct
principal cells following either unilateral ureteral obstruction
or bilateral obstruction (66). This postobstructive diuresis can
result in hypovolemia and hypernatremia. However, the
diuresis, especially the later phase, can also be secondary to
accumulated solute and water occurring during the obstruc-
tive period and/or too aggressive volume repletion postre-
lease of the obstruction.
In summary, the pathophysiology of three forms of revers-
ible AKI resulting from factors external to the kidney is dis-
cussed. Although AKI is a syndrome and often multifacto-
rial, these three forms result in low urine flow and low urine
sodium and have overlapping pathophysiologic events. Both
systemic and intrarenal neurohormonal events mediate
systemic and local adaptive responses that become patho-
logic and fail with continued stresses placed on the body
and kidney. All three lead to intrinsic AKI in an intensity-
and duration-mediated fashion, making rapid diagnosis and
treatment critical.
Disclosures
B.A. Molitoris reports consultancy agreements with Akebia, AM
Pharma, Astellas, CSL Behring, FAST BioMedical, Ionis, Janssen,
Rayze Bio, Seagan, and Tamarix; ownership interest in FAST Bio-
Medical; research funding from FAST BioMedical, Ionis, National
Institutes of Health (NIH) research grants, Razebio, and Segen; pat-
ents and inventions with FAST BioMedical for GFR and plasma vol-
ume measurement, Indiana University for C1 and C2 gentamicin
and soluble thrombomodulin, and the Veterans Administration for
small interfering ribonucleic acids (siRNA) for CKD; and serving as
a scientific advisor or member of Akebia scientific advisory board,
AM Pharma data safety and monitoring board, CSL Behring data
safety and monitoring board, FAST BioMedical, Ionisdata safety and
monitoring board, and NIH study section.
Funding
This work was supported by National Institute of Health National
Institute of Diabetes and Digestive and Kidney Diseases grant DK
091623 and National Institute of Health grant DK079312.
Author Contributions
B.A. Molitoris wrote the original draft and reviewed and edited
the manuscript.
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