AKI Associated with Acute Pancreatitis

Tareq I. Nassar and Wajeh Y. Qunibi

Abstract
Acute pancreatitis is a common disorder of the pancreas. It is the most frequent gastrointestinal cause for
hospitalization and one of the leading causes of in-hospital deaths. Its severity ranges from mild self-limited disease
to severe acute necrotizing pancreatitis characterized by systemic complications and multiorgan failure. Severe
acute pancreatitis develops in about 20% of patients with acute pancreatitis and may be associated with Division of
multiorgan failure (respiratory, cardiovascular, and kidney). AKI is a frequent complication of severe acute Nephrology,
pancreatitis and develops late in the course of the disease, usually after the failure of other organs. It carries a Department of
Medicine, University
very poor prognosis, particularly if kidney replacement therapy is required, with mortality rates exceeding 75%.
of Texas Health at San
The exact pathophysiology of AKI in acute pancreatitis remains unclear but appears to result from initial Antonio, San Antonio,
volume depletion followed by complex vascular and humoral factors. Here, we provide an overview of the Texas
epidemiology, pathogenesis, causes, and management of AKI in patients with severe acute pancreatitis.
CJASN 14: 1106–1115, 2019. doi: https://doi.org/10.2215/CJN.13191118 Correspondence:
Dr. Tareq I. Nassar,
Division of
Nephrology,
Introduction studies clearly needed to determine the actual in- Department of
Acute pancreatitis is an inflammatory condition asso- cidence and prognosis of AKI in acute pancreatitis. Medicine, University
ciated with a high complication rate and an increased AKI develops late in the course of acute pancrea- of Texas Health at San
Antonio, 7703 Floyd
risk of death. The diagnosis can be made by history, titis, usually after failure of other organs (4,5). Re- Curl Drive, San
physical examination, and results of diagnostic tests markably, the kidney was the first organ to fail in only Antonio, TX 78229-
(Table 1) (1). The revised Atlanta criteria classified acute 8.9% of patients with AKI, and only a minority of 3900. Email:
pancreatitis according to type, severity, and phase of the patients develop isolated AKI (4,5,9). Retrospective NassarT@uthscsa.edu
disease (Table 2) (1). Imaging plays an important role in studies reported risk factors for AKI in acute pancre-
the diagnosis and staging of acute pancreatitis, estab- atitis but not the need for kidney replacement ther-
lishing the cause and identifying its complications. apy (KRT) (3–6). Li et al. reported history of kidney
Contrast-enhanced computed tomography is the most disease, hypoxemia, and abdominal compartment
useful imaging technique especially when performed syndrome as risk factors (6), whereas Devani et al.
after 72 hours to assess the extent of the disease (1,2). found older age, male gender, sepsis, respiratory
The severe form of acute pancreatitis is associated failure, intensive care unit admission, and history of
with multiorgan failure and poor outcome. AKI has CKD to increase risk for AKI (3). Of these, abdominal
long been recognized as a common and important compartment is likely the only modifiable risk factor.
complication of acute pancreatitis. Unfortunately, The mortality rate of patients with AKI and acute
there has been scarce information about this entity pancreatitis varied between 25% and 75% (5,7). How-
in the literature. In this review, we will provide an ever, Devani et al. found a three-fold fall in mortality
overview of epidemiology, pathophysiology, and rate among patients with AKI over the past decade (3).
management of AKI in patients with acute pancrea-
titis.
Pathophysiology
The pathophysiology of AKI in acute pancreatitis is not
Epidemiology and Outcome well studied. However, a key pathophysiologic process
The prevalence of AKI in acute pancreatitis is not involves premature activation of pancreatic enzymes
well documented (Table 3) (3–8). Previous studies within the acinar cells. This leads to autodigestion of the
highlighted the high prevalence of AKI in acute pancreas and surrounding tissues, triggering a cascade of
pancreatitis and its dismal prognosis. Most of these events that contribute to AKI (Figure 1) (10). Release into
were limited by small samples and retrospective the systemic circulation of activated enzymes and pro-
design. However, in a comprehensive, retrospective, teases may cause endothelial damage leading to extrav-
observational study utilizing the National Inpatient asation of fluids from the vascular space, hypovolemia,
Sample, Devani et al. reported an overall AKI prev- hypotension, increased abdominal pressure, intense kid-
alence of 7.9% among 3,466,493 patients hospitalized ney vasoconstriction, hypercoagulability, and fibrin de-
with acute pancreatitis (3). The mortality rate among position in the glomeruli. Moreover, acinar injury from
AKI subgroup was significantly higher (8.8% in AKI autodigestion stimulates cytokine release and production
group versus 0.7% in non-AKI; P,0.01). Prospective of oxygen free radicals (Figure 2) (11–13).

1106 Copyright © 2019 by the American Society of Nephrology www.cjasn.org Vol 14 July, 2019
CJASN 14: 1106–1115, July, 2019 AKI in Acute Pancreatitis, Nassar and Qunibi 1107

Table 1. Diagnostic criteria of acute pancreatitis

Diagnosis of acute pancreatitis is established by the presence of two of the following three features:

Abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, epigastric pain often radiating to the back).
Serum lipase activity (or amylase activity) at least three times greater than the upper limit of normal.
Characteristic findings of acute pancreatitis on contrast-enhanced computed tomography and less commonly magnetic resonance
imaging or transabdominal ultrasonography

Reprinted from reference 1, with permission.

Hypovolemia chymotrypsin, bradykinin, histamine, and prostaglandin E,

Hypovolemia plays a critical role in causing AKI early
during acute pancreatitis. This was first documented in dogs
with experimental acute pancreatitis (11). At 4 hours after bile
infusion and the development of pancreatitis, GFR fell by
40% and the plasma volume by 26% compared with the
control group. There were no morphologic abnormalities in
kidney biopsies, but the decline in GFR was prevented by
plasma infusion. However, at 24 hours, kidney failure
became unresponsive to further volume expansion. Remark-
ably, these results were reproduced by the infusion of
trypsin, chymotrypsin, elastase, and phospholipase A2
(PLA2) into normal dogs. The authors speculated that
released enzymes caused increased vascular permeability
and leakage of protein-rich fluid into the interstitial com-
partment, leading to hypovolemia. In similar experiments in
dogs, there was a rapid accumulation of ascites, increased
hematocrit level, and decreased arterial pressure, suggesting
hypovolemia (12). These experiments demonstrated the role
for hypovolemia in AKI, at least in the initial 24 hours after
the onset of acute pancreatitis (Figure 2).
Role of Toxic Substances Released from the Necrotic
Pancreas
Substances released from the necrotic pancreas were
implicated in the pathogenesis of AKI. These include trypsin,
as well as endotoxins and bacteria (11,12). Ofstad et al. (14)
reported that histamine release in the pancreatic exudate of
dogs with experimental acute pancreatitis caused increased
vascular permeability, hypovolemia, and hypotension. In
patients with acute pancreatitis and AKI, urine output
improved by peritoneal lavage, suggesting that dialysis
may remove substances that contributed to AKI (15). To
investigate this further, Satake et al. (12) collected ascitic fluid
from experimental dogs with acute pancreatitis and injected
10 ml intravenously in healthy dogs. The dogs developed
transient hypotension that was not caused by hypovolemia
as evidenced by lack of changes in hematocrit level. There
was a significant decrease in kidney blood flow, GFR, urine
output, and an increase in kidney vascular resistance, even
after hypotension resolved. Kidney vasoconstriction was also
documented in patients with acute pancreatitis despite
adequate extracellular volume, suggesting increased sympa-
thetic activity (16). Thus, although hypotension and hypo-
volemia may be the initial culprits in causing AKI early
during acute pancreatitis, toxic substances in the pancreatic
exudate may subsequently contribute to AKI.
Inflammation
Cytokines may contribute to the pathogenesis of AKI.
TNF-a acts directly on glomeruli and tubular capillaries,

Table 2. The 2012 revision of the Atlanta classification of acute pancreatitis in adults

Types

Interstitial edematous pancreatitis

Acute necrotizing pancreatitis
Severity
Mild
Most common form (up to 80% of cases)
Absence of organ failure
Absence of local or systemic complications
Usually resolves in the first week
Moderately severe
Presence of transient organ failure ,48 h
Local complications may be present
Severe
About 20% of cases
Persistent organ failure for .48 h
Local complications include peripancreatic fluid collections, pancreatic and peripancreatic necrosis (sterile or infected), pseudocyst and walled-
off necrosis (sterile or infected)
Poor outcome
Phases
Early: usually lasts for 1 wk
Late: may follow a protracted course from weeks to months

Reprinted from reference 1, with permission.

 1108
CJASN
Table 3. Prevalence and outcomes of AKI in acute pancreatitis in previous studies

No. of
% of Mortality in Patients
First Author/ Patients with % of ICU % of Patients with AKI
Year Patients Definition of AKI with Acute Pancreatitis Scoring System
Country Acute Admissions who Received KRT
with AKI and AKI
Pancreatitis

Tran/ 1993 267 44 16 Cr. 3.2 mg/dl or a 26% (11/42), all died 81% (34/42) hospital Ranson score (161.2 in non-
Netherlands (4) two-fold creatinine rise in mortality AKI, 3.961.5 in AKI)
patients with CKD
Kes/Croatia (5) 1996 563 35 14 NA 62% (49/79), 95.9% died 74.7% (59/79) overall Ranson score
mortality (1.160.7 in non-AKI,
3.861.4 in AKI)
Li/China (6) 2010 228 NA 18.4a Urine output ,400 ml/d or NA 66.6% (28/42) overall APACHE II score
Cr .2 mg/dl mortality (9.6564.40 in non-AKI,
11.7165.60 in AKI)
Lin/Taiwan (7) 2011 1734 100 15.0 On the basis of NA 23.8% (62/261) ICU NA
ICD-9-CM codes mortality
Zhou/China (8) 2015 414 100 69.3 Absolute increase of serum 53.3% (153/287), 58.1% 44.9% (128.8/287) ICU APACHE II score 1767.9
Cr .0.3 mg/dl or 50% died mortality
increase
Devani/United 2018 3,466,493 NA 7.9 On the basis of ICD-9-CM NA 8.8% (24,099/ NA
States (3) codes 273,852.9) inpatient
mortality

Overall mortality indicates that authors did not specify time or location of death. ICU, intensive care unit; KRT, kidney replacement therapy; Cr, serum creatinine; NA, not available;
APACHE II, Acute Physiology and Chronic Health Evaluation II; ICD-9-CM, International Classification of Disease, ninth revision, Clinical Modification.
a
Denotes incidence. All studies are retrospective in nature.
CJASN 14: 1106–1115, July, 2019 AKI in Acute Pancreatitis, Nassar and Qunibi 1109

Figure 1. | Premature activation of pancreatic enzymes within the acinar cells leads to autodigestion of the pancreas and release of
enzymes and proteases which trigger a cascade of events that contribute to the pathogenesis of AKI.

leading to ischemia and tubular necrosis. It also stimulates
release of other cytokines, such as IL-1b, IL-8, and IL-6,
which act on endothelial cells leading to kidney ischemia,
thrombosis, and release of oxygen free radicals (13). A
study of 60 patients with acute pancreatitis found high
levels of IL-6 and IL-8 in patients who developed AKI (17).
PLA2 rapidly deposited in proximal tubular cells of rats
with experimental acute pancreatitis, causing tubular necro-
sis. A prospective study of 31 patients with acute pancreatitis
found a positive correlation between serum PLA2 activity, as
measured early during acute pancreatitis, and urinary N-
acetyl-b-glucosaminidase–to–creatinine ratio, suggesting
that PLA2 may hydrolyze tubular epithelial cell membrane
and contribute to AKI (18). PLA2 also increases vascular
permeability and generation of AA, which produces throm-
boxane. This potent vasoconstrictor and platelet aggregation
promoter leads to microthrombi and vascular occlusion. This
may be complicated by an increase in platelet-activating
factor, which induces platelet activation, aggregation and
generation of inflammatory mediators (13).

Figure 2. | AKI in severe acute pancreatitis usually results from volume depletion due to extravasation of fluids from the vascular space
followed by complex interactions between inflammatory, vascular and humoral factors.
1110 CJASN
Inflammatory mediators may increase mucosal perme-
ability leading to translocation of endotoxin and bacteria
from the colon. Endotoxins contribute to the development
of AKI by increasing endothelin level, which causes
vasoconstriction, decreased kidney blood flow, and tubular
necrosis (19). Also, oxygen free radicals may react with
proteins and enzymes, leading to lipid peroxidation of the
cell and organellar membranes, protein denaturation and
increased capillary permeability, ischemia, and direct
kidney cell membrane injury (13).
Finally, apoptotic cell death may also play a role in AKI. A
Japanese group detected DNA fragmentation in Madin–
Darby canine kidney cells exposed to pancreatitis-associated
ascitic fluid. They also found nuclear and DNA fragmenta-
tion in Wister rat kidneys after intraperitoneal injection of
pancreatitis-associated ascitic fluid, indicating that ascitic
fluid contains factor(s) that induce apoptosis (20).
Vascular Effects of Acute Pancreatitis
Increased kidney vascular resistance was demonstrated
in dogs with experimental acute pancreatitis (21). Werner
et al. found an increase in kidney vascular resistance in 11
patients with acute pancreatitis. All patients became
hypertensive indirectly implicating a vasopressor sub-
stance release (16). Patients with acute pancreatitis had
six-fold higher plasma renin values than normal, which
could be attributed to hypovolemia (22). However, plasma
trypsin and kallikrein activate prorenin to renin, which in
turn increases angiotensin II levels, leading to increased
kidney vascular resistance, decreased effective kidney
blood flow, and decline in GFR (22,23).
Abdominal Compartment Syndrome
Abdominal compartment syndrome develops when intra-
abdominal pressure increases to .20 mm Hg (24,25). Patients
with severe acute pancreatitis are at risk of developing
abdominal compartment syndrome because of increased
intra-abdominal contents by ileus, ascites, and intra-ab-
dominal bleeding. Moreover, interstitial fluid accumula-
tion due to increased capillary permeability and
endothelial damage from volume administration, acidosis,
sepsis, transfusion, coagulopathy, as well as reduced
abdominal wall compliance due to edema, may play a role
(24,25). The mechanism of intra-abdominal hypertension
induced AKI is not clear, but intra-abdominal hypertension
may compress and compromise the kidney blood flow in
both the arterial and venous vasculature, leading to de-
creased perfusion pressure, increased venous pressure,
decreased venous blood flow, and increased kidney
parenchymal pressure. This results in decreased glomer-
ular filtration pressure, and impaired microvascular func-
tion and oxygen delivery, and precipitates ischemic kidney
injury.
Causes of AKI
The causes of AKI are speculative according to the
above-proposed pathophysiology. Hypovolemia and sep-
sis can lead to prekidney AKI, acute tubular necrosis and,
rarely, bilateral kidney cortical necrosis (26). As mentioned
above, intra-abdominal hypertension is very common in
patients with acute pancreatitis and can lead to kidney
impairment. AKI also can result from associated diseases
such as autoimmune disease, hemolytic-uremic syndrome,
or thrombotic thrombocytopenic purpura, as well as from
drugs causing acute pancreatitis and AKI, but this in-
formation is limited and on the basis of a few case reports
published in the literature. Unfortunately, patients with
acute pancreatitis and AKI are usually critically ill, and as a
result, a kidney biopsy is rarely performed.
Management
Management of AKI in severe acute pancreatitis involves
intravenous fluid administration, avoidance of nephrotoxic
agents, the minimizing intra-abdominal pressure, and
providing KRT when indicated. The routine use of pro-
phylactic antibiotic is not recommended unless there is
evidence of active infection. If antibiotic is given, nephro-
toxic ones should be avoided (Figure 3) (2,10). Similarly,
not all patients with acute pancreatitis need to undergo
contrast-enhanced computed tomography particularly
those with mild pancreatitis and those who improve
rapidly to reduce the risk of contrast nephrotoxicity.
Magnetic resonance imaging can be an alternative as it
has excellent soft tissue contrast, but gadolinium admin-
istration has been implicated in the development of
nephrogenic systemic fibrosis. Abdominal ultrasound has
little value in the diagnosis of pancreatitis or its compli-
cations, but can be useful in detecting gallstones or biliary
duct stones (1,2).
Diagnosis of AKI is currently according to the Kidney
Disease Improving Global Outcomes criteria. However,
recent studies have suggested that biomarkers of kidney
injury, such as urine concentrations of neutrophil gelati-
nase-associated lipocalin, kidney injury molecule 1, IL-18,
angiopoietin 2, and procalcitonin, may help in earlier
diagnosis of AKI (27,28). Procalcitonin level was superior
to other inflammatory mediators in predicting AKI in
patients with acute pancreatitis and in identifying patients
at risk of worsening kidney function (28). Currently, there
are no data to indicate that these biomarkers perform better
in AKI associated with acute pancreatitis than other types
of AKI. Further research will be required before biomarkers
can be used to predict the onset of AKI and to guide its
early management.
Fluid Management
An essential initial step in the management is the
administration of ample intravenous fluids. Few human
studies evaluated the optimal type, rate, duration, com-
plications, and outcomes of fluid administration in acute
pancreatitis (2). Although some clinical trials have shown a
clear benefit of aggressive hydration, others reported that
aggressive hydration might be associated with increased
morbidity and mortality (2). The American College of
Gastroenterology recommends that early aggressive in-
travenous hydration is most beneficial in the first 12–24
hours, but does have a little benefit beyond this time (2).
The goal of fluid resuscitation is to improve the mean
arterial pressure, central venous pressure, and urine out-
put. Patients with severe hypovolemia may initially re-
quire 500–1000 ml of fluids per hour, whereas those with
CJASN 14: 1106–1115, July, 2019 AKI in Acute Pancreatitis, Nassar and Qunibi 1111

Figure 3. | Management of AKI in acute pancreatitis requires a multidisciplinary approach that begins in the emergency department. This
involves providing supportive care, close monitoring of kidney function and treatment of pancreatitis related complications. Escalation of
therapy to a higher level of care, providing KRT and surgical treatment might be required if the initial therapy fails. CRRT, continuous RRT;
ICU, intensive care unit; IV, intravenous; NSAIDs, nonsteroidal anti-inflammatory drugs.

less severe volume depletion may require 300–500 ml per
hour (10). However, infusion rate should be reduced in
patients with heart failure, liver cirrhosis, and oliguric/
anuric AKI. Fluid balance is commonly positive in criti-
cally ill patients with AKI and should be avoided as it can
lead to increased morbidity and mortality due to pulmo-
nary edema, tissues hypoxia, increased need for mechan-
ical ventilation, and cardiac dysfunction (29). In these
patients, loop diuretics can be considered.
In a retrospective study of 99 patients with severe acute
pancreatitis in Sweden, patients who received 4000 ml or more
of fluids during the first 24 hours developed significantly higher
respiratory complications rates (66% versus 53%; P,0.001), and
admission to intensive care units was also more common
compared with patients who received ,4000 ml (47% versus
20%; P,0.001), but there was no difference in patients’
outcomes (30). Aggressive volume resuscitation ($7.5 L within
6 hours from hospital admission) was also found to be an
independent predictor of developing abdominal compartment
syndrome (31). Another study of 179 patients with moderately
severe acute pancreatitis showed that aggressive fluid resusci-
tation ($4 L) was associated with increased incidence of
AKI compared the nonaggressive group (53.12% versus
25.64%; P50.008), and longer AKI lasting time (P50.04) (32).
By contrast, a recent four-center retrospective cohort study of
1010 patients with acute pancreatitis divided fluid adminis-
tered from arrival to the emergency room to 4 hours after
diagnosis of acute pancreatitis into tertiles: nonaggressive
(,500 ml), moderate (500–1000 ml), and aggressive (.1000 ml).
Compared with the nonaggressive fluid group, the moderate
and aggressive resuscitations were associated with lower
rates of complications and invasive interventions (33). Thus,
although adequate intravenous fluid administration in the
first 24 hours is indicated, excessive fluid administration
beyond this period may be harmful and should be avoided.
It is unclear what type of fluids is most beneficial for
patients with acute pancreatitis. Observational studies re-
ported that chloride-rich solutions are associated with a
higher risk of AKI and the need for KRT than balanced
solutions (34). In a retrospective study of 145 patients with
moderately severe and severe acute pancreatitis, hyperchlor-
emia was associated with an increased incidence of AKI. On
multivariable analysis, the increase in serum chloride was
independently associated with AKI (odds ratio, 1.32; 95%
confidence interval, 1.00 to 1.74; P=0.04). The authors
suggested that chloride-rich solutions decreased kidney
blood flow and GFR via tubuloglomerular feedback activa-
tion (35). However, randomized, controlled trials have not
demonstrated the superiority of balanced solutions over
chloride-rich solutions (36). The American College of Gas-
troenterology and International Association of Pancreatology
(IAP)/American Pancreatic Association (APA) guidelines
suggest that lactated Ringer solution might be the preferred
fluid replacement (2,37). In a prospective, multicenter,
randomized study, Wu et al.(38) reported that lactated
Ringer solution reduces systemic inflammation compared
with saline in patients with acute pancreatitis. Although it
is unlikely that lactated Ringer solution, which contains 4 mEq/L
of potassium, will cause hyperkalemia, we recommend close
monitoring of serum potassium level.
 1112
Table 4. Blood purification modalities in patients with severe acute pancreatitis

CJASN
No. of Patients
First Author/
Study Design (Year) with Acute Blood Purification Modality Outcomes
Country
Pancreatitis

Oda/Japan (40) Prospective observational (2005) 17 Continuous hemodiafiltration Intra-abdominal pressure and IL-6 were significantly lower
after 24 h of continuous hemodiafiltration initiation
Jiang/China (41) Randomized controlled (2005) 37 Low-volume versus high-volume High-volume CVVH and early CVVH improved
CVVH, early versus late CVVH hemodynamics and survival in patients with acute
pancreatitis more than low-volume CVVH and late
CVVH
High-volume CVVH and early CVVH decreased serum
concentrations of TNF-a, IL-1b, and IL-6 more efficiently
than low-volume CVVH and late CVVH
Chen/China (42) Prospective observational (2007) 20 CVVH The APACHE II score improved significantly after
CVVH with improvement in endothelial dysfunction
Zhang/China (43) Randomized controlled (2010) 63 CVVH versus standard CVVH improved APACHE II score and SOFA score
medical therapy significantly, and effectively improved gut barrier
dysfunction
Gong/China (44) Prospective nonrandomized (2010) 12 High-volume CVVH versus standard High-volume CVVH significantly reduced plasma
medical therapy inflammatory cytokines concentrations including those
of IFN-g, TNF-a, IL-1, IL-2, IL-5, and IL-13. Peripheral
CD41 and CD81 T cells, monocyte count, and HLA-DR
expression increased significantly only in the high-
volume CVVH group
Yang/China (45) Randomized controlled (2010) 51 Combined CVVH and peritoneal Inflammatory cytokines (IL-6, IL-8, and TNF-a) decreased
dialysis versus traditional therapy significantly at days 1 and 2 compared with control group
The APACHE II score of the combined CVVH and
peritoneal dialysis significantly decreased compared
with the control group
Zhu/China (46) Prospective nonrandomized (2011) 75 High-volume CVVH versus The 28-d survival rate was higher in patients who accepted
conventional treatment high-volume CVVH, especially in those without AKI.
After 72 h of therapy, patients who accepted high-volume
CVVH had significantly better APACHE II scores
Chu/China (47) Randomized controlled (2013) 30 Pulse high-volume hemofiltration The levels of IL-6, IL-10, and TNF-a decreased in the pulse
versus CVVH high-volume hemofiltration group more significantly
than the control group
Pulse high-volume hemofiltration group was superior to
the control group in APACHE II score, C-reactive
protein, SOFA score, and SAPS II score
Guo/China (48) Prospective nonrandomized (2014) 61 High-volume CVVH versus optimal High-volume CVVH was associated with a significant
standard therapy reduction in the incidence of kidney failure, infected
pancreatic necrosis, length of hospitalization, mortality,
as well as duration of kidney, respiratory, and hepatic
failure
APACHE II score, C-reactive protein, and IL-6 levels
were significantly reduced by high-volume CVVH on
days 1, 3, and 7
CJASN 14: 1106–1115, July, 2019 AKI in Acute Pancreatitis, Nassar and Qunibi 1113

Nutrition

procalcitonin and TNF-a decreased in the high-volume

The paradigm has shifted dramatically over the past

CVVH, continuous venovenous hemofiltration; APACHE II, Acute Physiology and Chronic Health Evaluation II; SOFA, Sequential Organ Failure Assessment; SAPS II, Simplified Acute
decade, with new evidence suggesting that early enteral

CVVH more effective in decreasing intra-abdominal

feeding is beneficial in acute pancreatitis. Delayed feeding for
The levels of IL-4, IL-6, IL-8, and IL-10, as well as

CVVH group more than in the control group .24 hours is associated with higher rates of infected
peripancreatic necrosis, multiple organ failure, and necrotiz-
ing pancreatitis (2). It was hypothesized that enteral nutrition
protects the mucosal barrier of the gut and reduces bacterial
translocation. Parenteral nutrition should be avoided unless
pressure and blood level of IL-8
Outcomes

the enteral route is not possible. To our knowledge, there are

no studies that specifically examined the nutritional needs of
patients with AKI and acute pancreatitis.

Monitoring Intra-Abdominal Pressure

Close monitoring of intra-abdominal pressure is es-
sential in all patients with acute pancreatitis. This can
be measured directly by an intraperitoneal catheter, or
indirectly by gastric or urinary bladder pressure. However,
transduction of bladder pressure remains the gold standard
(24). Percutaneous drainage of ascites or continuous hemo-
diafiltration may decrease intra-abdominal pressure, but some
patients require decompressive laparotomy, particularly in
CVVH versus conventional treatment

patients with intra-abdominal pressure .25 mm Hg (25).

High-volume CVVH versus CVVH
Blood Purification Modality

The Working Group IAP/APA Acute Pancreatitis Guide-

lines to decrease intra-abdominal pressure in acute pancre-
atitis recommend: (1) nasogastric drainage, prokinetics, rectal
tubes, and if necessary, endoscopic decompression; (2)
volume resuscitation on demand, if volume overloaded
either ultrafiltration or diuretics can be used; and (3) adequate
analgesia and sedation to decrease abdominal muscle tone,
and if necessary, neuromuscular blockade (37).

KRT
Indications and timing of KRT in patients with AKI after
acute pancreatitis are not different from those of other
critically ill patients with AKI. Urgent indications for KRT
No. of Patients

include severe hyperkalemia, severe metabolic acidosis

Pancreatitis
with Acute

(pH,7.1) and pulmonary edema unresponsive to diuretic

86

25

therapy, irrespective of kidney function. The timing of

elective initiation of KRT is debatable. A randomized,
controlled trial failed to show a significant difference in the
90 days mortality between early and late initiation groups
(39). The patient’s hemodynamic status usually dictates the
Prospective nonrandomized (2017)

choice of KRT modality. Intermittent hemodialysis, ex-

tended daily dialysis, or slow low-efficiency daily dialysis
Randomized controlled (2017)
Study Design (Year)

are reserved for hemodynamically stable patients, whereas

continuous RRT (CRRT) is preferred in hemodynamically
unstable patients. A few clinical trials have specifically
examined the benefits of one modality of KRT over the
other in these patients. A possible advantage of CRRT is its
ability to decrease serum cytokine levels (Table 4).
However, a low-intensity CVVH may not be adequate
because of the large amount of circulating inflammatory
mediators in patients with severe acute pancreatitis. In this
Table 4. (Continued)

regard, limited data suggest that high-volume CVVH,

particularly when started early, may be more effective
Physiology Score II.

(Table 4). However, the evidence so far is not strong

First Author/

Liu/China (49)

Xu/China (50)

enough to recommend its routine use for such patients.

Country

Research Needs and Conclusions

AKI is a frequent complication of acute pancreatitis and
usually develops after the failure of other organs. It carries a
1114 CJASN
poor prognosis, particularly if KRT is required. There is a need
for prospective studies to establish the true incidence and risk
factors for AKI in acute pancreatitis. The exact pathophysiol-
ogy of AKI remains unclear, but appears to result from initial
hypovolemia followed by complex interactions between in-
flammatory, vascular, and humoral factors. More studies are
clearly needed particularly on the nephrotoxic potential of
toxic substances released from the necrotic pancreas and
inflammatory cytokines. There is also a lack of human biopsy
studies in this condition because most patients are acutely ill.
Prospective clinical studies that examine the impact of various
therapeutic modalities on patients’ outcomes, including type
and volume of intravenous fluid resuscitation, nutritional
support, and KRT, are needed.
Acknowledgments
The authors would like to thank Dr. W. Brian Reeves and
Dr. Kumar Sharma for reviewing the manuscript.
Disclosures
Dr. Nassar and Dr. Qunibi have nothing to disclose.
References
1. Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr
MG, Tsiotos GG, Vege SS; Acute Pancreatitis Classification
Working Group: Classification of acute pancreatitis--2012: Re-
vision of the Atlanta classification and definitions by international
consensus. Gut 62: 102–111, 2013
2. Tenner S, Baillie J, DeWitt J, Vege SS, American College of
Gastroenterology. American college of gastroenterology guide-
line: Management of acute pancreatitis. Am J Gastroenterol 108:
1400–1415; 1416, 2013
3. Devani K, Charilaou P, Radadiya D, Brahmbhatt B, Young M,
Reddy C: Acute pancreatitis: Trends in outcomes and the role of
acute kidney injury in mortality- A propensity-matched analysis.
Pancreatology 18: 870–877, 2018
4. Tran DD, Oe PL, de Fijter CW, van der Meulen J, Cuesta MA: Acute
renal failure in patients with acute pancreatitis: Prevalence, risk
factors, and outcome. Nephrol Dial Transplant 8: 1079–1084, 1993
5. Kes P, Vucicevic Z, Ratkovic-Gusic I, Fotivec A: Acute renal failure
complicating severe acute pancreatitis. Ren Fail 18: 621–628, 1996
6. Li H, Qian Z, Liu Z, Liu X, Han X, Kang H: Risk factors and outcome
of acute renal failure in patients with severe acute pancreatitis. J
Crit Care 25: 225–229, 2010
7. Lin HY, Lai JI, Lai YC, Lin PC, Chang SC, Tang GJ: Acute renal
failure in severe pancreatitis: A population-based study. Ups J Med
Sci 116: 155–159, 2011
8. Zhou J, Li Y, Tang Y, Liu F, Yu S, Zhang L, Zeng X, Zhao Y, Fu P:
Effect of acute kidney injury on mortality and hospital stay in
patient with severe acute pancreatitis. Nephrology (Carlton) 20:
485–491, 2015
9. Gougol A, Dugum M, Dudekula A, Greer P, Slivka A, Whitcomb
DC, Yadav D, Papachristou GI: Clinical outcomes of isolated renal
failure compared to other forms of organ failure in patients with
severe acute pancreatitis. World J Gastroenterol 23: 5431–5437,
2017
10. Pandol SJ, Saluja AK, Imrie CW, Banks PA: Acute pancreatitis:
Bench to the bedside. Gastroenterology 132: 1127–1151, 2007
11. Levy M, Geller R, Hymovitch S: Renal failure in dogs with ex-
perimental acute pancreatitis: Role of hypovolemia. Am J Physiol
251: F969–F977, 1986
12. Satake K, Kanazawa G, Hiura A, Nishiwaki H, Ha SS, Chung YS,
Umeyama K, Yukimura T: Renal function in experimentally in-
duced acute pancreatitis in dogs: How it is affected by the
nephrotoxic substance in pancreatic exudate from ascitic fluid.
Jpn J Surg 21: 88–95, 1991
13. Zhang XP, Wang L, Zhou YF: The pathogenic mechanism of severe
acute pancreatitis complicated with renal injury: A review of
current knowledge. Dig Dis Sci 53: 297–306, 2008
14. Ofstad E, Amundsen E, Hagen PO: Experimental acute pancre-
atitis in dogs. II. Histamine release induced by pancreatic exu-
date. Scand J Gastroenterol 4: 75–79, 1969
15. Wall AJ: Peritoneal dialysis in the treatment of severe acute
pancreatitis. Med J Aust 2: 281–283, 1965
16. Werner MH, Hayes DF, Lucas CE, Rosenberg IK: Renal vaso-
constriction in association with acute pancreatitis. Am J Surg 127:
185–190, 1974
17. Malmstrøm ML, Hansen MB, Andersen AM, Ersbøll AK, Nielsen
OH, Jørgensen LN, Novovic S: Cytokines and organ failure in
acute pancreatitis: Inflammatory response in acute pancreatitis.
Pancreas 41: 271–277, 2012
18. Grönroos JM, Hietaranta AJ, Nevalainen TJ: Renal tubular cell
injury and serum phospholipase A2 activity in acute pancreatitis.
Br J Surg 79: 800–801, 1992
19. Bose SM, Verma GR, Mazumdar A, Giridhar M, Ganguly NK:
Significance of serum endotoxin and antiendotoxin antibody
levels in predicting the severity of acute pancreatitis. Surg Today
32: 602–607, 2002
20. Takeyama Y: Significance of apoptotic cell death in systemic
complications with severe acute pancreatitis. J Gastroenterol 40:
1–10, 2005
21. Nishiwaki H, Ko I, Hiura A, Ha SS, Satake K, Sowa M: Renal
microcirculation in experimental acute pancreatitis of dogs. Ren
Fail 15: 27–31, 1993
22. Greenstein RJ, Krakoff LR, Felton K: Activation of the renin system
in acute pancreatitis. Am J Med 82: 401–404, 1987
23. Uehara S, Honjyo K, Furukawa S, Hirayama A, Sakamoto W: Role
of the kallikrein-kinin system in human pancreatitis. Adv Exp Med
Biol 247B: 643–648, 1989
24. Patel DM, Connor MJ Jr: Intra-abdominal hypertension and ab-
dominal compartment syndrome: An underappreciated cause of
acute kidney injury. Adv Chronic Kidney Dis 23: 160–166, 2016
25. De Waele JJ, De Laet I, Kirkpatrick AW, Hoste E: Intra-abdominal
hypertension and abdominal compartment syndrome. Am J
Kidney Dis 57: 159–169, 2011
26. Goffin EJ, Coche EE, Lambert MJ: The case: Acute renal failure
following necroticohemorrhagic pancreatitis. Kidney Int 74:
975–976, 2008
27. Sporek M, Dumnicka P, Gala-Bladzinska A, Ceranowicz P,
Warzecha Z, Dembinski A, Stepien E, Walocha J, Drozdz R,
Kuzniewski M, Kusnierz-Cabala B: Angiopoietin-2 is an early
indicator of acute pancreatic-renal syndrome in patients with
acute pancreatitis. Mediators Inflamm 2016: 5780903, 2016
28. Huang HL, Nie X, Cai B, Tang JT, He Y, Miao Q, Song HL, Luo TX,
Gao BX, Wang LL, Li GX: Procalcitonin levels predict acute
kidney injury and prognosis in acute pancreatitis: A prospective
study. PLoS One 8: e82250, 2013
29. Schrier RW: Fluid administration in critically ill patients with
acute kidney injury. Clin J Am Soc Nephrol 5: 733–739, 2010
30. Eckerwall G, Olin H, Andersson B, Andersson R: Fluid re-
suscitation and nutritional support during severe acute pancre-
atitis in the past: What have we learned and how can we do better?
Clin Nutr 25: 497–504, 2006
31. Balogh Z, McKinley BA, Holcomb JB, Miller CC, Cocanour CS,
Kozar RA, Valdivia A, Ware DN, Moore FA: Both primary and
secondary abdominal compartment syndrome can be predicted
early and are harbingers of multiple organ failure. J Trauma 54:
848–859, discussion 859–861, 2003
32. Ye B, Mao W, Chen Y, Tong Z, Li G, Zhou J, Ke L, Li W: Aggressive
resuscitation is associated with the development of acute kidney
injury in acute pancreatitis. Dig Dis Sci 64: 544–552, 2019
33. Singh VK, Gardner TB, Papachristou GI, Rey-Riveiro M, Faghih M,
Koutroumpakis E, Afghani E, Acevedo-Piedra NG, Seth N, Sinha
A, Quesada-Vázquez N, Moya-Hoyo N, Sánchez-Marin C,
Martı́nez J, Lluı́s F, Whitcomb DC, Zapater P, de-Madaria E: An
international multicenter study of early intravenous fluid ad-
ministration and outcome in acute pancreatitis. United European
Gastroenterol J 5: 491–498, 2017
34. Yunos NM, Bellomo R, Glassford N, Sutcliffe H, Lam Q, Bailey M:
Chloride-liberal vs. chloride-restrictive intravenous fluid ad-
ministration and acute kidney injury: An extended analysis. In-
tensive Care Med 41: 257–264, 2015
35. Mao W, Wu J, Zhang H, Zhou J, Ye B, Li G, Gao L, Li X, Ke L, Tong Z,
Li W, Li J: Increase in serum chloride and chloride exposure are
CJASN 14: 1106–1115, July, 2019
associated with acute kidney injury in moderately severe and
severe acute pancreatitis patients. Pancreatology 19: 136–142,
2019
36. Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur
C, McGuinness S, Mehrtens J, Myburgh J, Psirides A, Reddy S,
Bellomo R; SPLIT Investigators; ANZICS CTG: Effect of a buffered
crystalloid solution vs saline on acute kidney injury among pa-
tients in the intensive care unit: The SPLIT randomized clinical
trial. JAMA 314: 1701–1710, 2015
37. Working Group IAP/APA Acute Pancreatitis Guidelines: IAP/APA
evidence-based guidelines for the management of acute pan-
creatitis. Pancreatology 13[Suppl 2]: e1–e15, 2013
38. Wu BU, Hwang JQ, Gardner TH, Repas K, Delee R, Yu S, Smith B,
Banks PA, Conwell DL: Lactated Ringer’s solution reduces
systemic inflammation compared with saline in patients with
acute pancreatitis. Clin Gastroenterol Hepatol 9: 710–717.e1,
2011
39. Barbar SD, Clere-Jehl R, Bourredjem A, Hernu R, Montini F,
Bruyère R, Lebert C, Bohé J, Badie J, Eraldi JP, Rigaud JP, Levy B,
Siami S, Louis G, Bouadma L, Constantin JM, Mercier E, Klouche
K, du Cheyron D, Piton G, Annane D, Jaber S, van der Linden T,
Blasco G, Mira JP, Schwebel C, Chimot L, Guiot P, Nay MA,
Meziani F, Helms J, Roger C, Louart B, Trusson R, Dargent A,
Binquet C, Quenot JP; IDEAL-ICU Trial Investigators and the
CRICS TRIGGERSEP Network: Timing of renal-replacement
therapy in patients with acute kidney injury and sepsis. N Engl J
Med 379: 1431–1442, 2018
40. Oda S, Hirasawa H, Shiga H, Matsuda K, Nakamura M, Watanabe
E, Moriguchi T: Management of intra-abdominal hypertension in
patients with severe acute pancreatitis with continuous hemo-
diafiltration using a polymethyl methacrylate membrane hemo-
filter. Ther Apher Dial 9: 355–361, 2005
41. Jiang HL, Xue WJ, Li DQ, Yin AP, Xin X, Li CM, Gao JL: Influence
of continuous veno-venous hemofiltration on the course of
acute pancreatitis. World J Gastroenterol 11: 4815–4821,
2005
AKI in Acute Pancreatitis, Nassar and Qunibi 1115
42. Chen ZH, Liu ZH, Yu C, Ji DX, Li LS: Endothelial dysfunction in
patients with severe acute pancreatitis: Improved by continuous
blood purification therapy. Int J Artif Organs 30: 393–400, 2007
43. Zhang J, Yuan C, Hua G, Tong R, Luo X, Ying Z: Early gut barrier
dysfunction in patients with severe acute pancreatitis: Attenuated
by continuous blood purification treatment. Int J Artif Organs 33:
706–715, 2010
44. Gong D, Zhang P, Ji D, Chen Z, Li W, Li J, Li L, Liu Z: Improvement
of immune dysfunction in patients with severe acute pancreatitis
by high-volume hemofiltration: A preliminary report. Int J Artif
Organs 33: 22–29, 2010
45. Yang C, Guanghua F, Wei Z, Zhong J, Penghui J, Xin F, Xiping Z:
Combination of hemofiltration and peritoneal dialysis in the
treatment of severe acute pancreatitis. Pancreas 39: 16–19, 2010
46. Zhu Y, Yuan J, Zhang P, Hu X, He Q, Han F, Chen J: Adjunctive
continuous high-volume hemofiltration in patients with acute
severe pancreatitis: A prospective nonrandomized study. Pan-
creas 40: 109–113, 2011
47. Chu LP, Zhou JJ, Yu YF, Huang Y, Dong WX: Clinical effects of pulse
high-volume hemofiltration on severe acute pancreatitis com-
plicated with multiple organ dysfunction syndrome. Ther Apher
Dial 17: 78–83, 2013
48. Guo J, Huang W, Yang XN, Jin T, Altaf K, Javed MA, Lin ZQ, Huang
ZW, Xue P, Johnstone M, Sutton R, Xia Q: Short-term continuous
high-volume hemofiltration on clinical outcomes of severe acute
pancreatitis. Pancreas 43: 250–254, 2014
49. Liu C, Li M, Cao S, Wang J, Huang X, Zhong W: Effects of
HV-CRRT on PCT, TNF-a, IL-4, IL-6, IL-8 and IL-10 in patients
with pancreatitis complicated by acute renal failure. Exp Ther
Med 14: 3093–3097, 2017
50. Xu J, Cui Y, Tian X: Early continuous veno-venous hemofiltration is
effective in decreasing intra-abdominal pressure and serum in-
terleukin-8 level in severe acute pancreatitis patients with ab-
dominal compartment syndrome. Blood Purif 44: 276–282, 2017
Published online ahead of print. Publication date available at
www.cjasn.org.