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Septic acute kidney injury (SAKI)

Article in JOURNAL OF PEDIATRIC CRITICAL CARE · April 2018

DOI: 10.21304/2018.0502.00370

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 DOI-10.21304/2018.0502.00370

Symposium
Septic Acute Kidney Injury (SAKI)
Vinayak Patki*
*Chief, Advanced Pediatric Critical Care Centre & Head, Dept of Pediatrics, Wanless Hospital, Miraj, 416101,
Maharashtra, India
Received: 01-Apr-18/Accepted: 14-Apr-18/Published online: 30-Apr-18
ABSTRACT
Acute kidney injury (AKI) is a common and potentially fatal complication of sepsis. Septic acute kidney injury (SAKI)
remains an important challenge in critical care medicine. SAKI has a complex pathophysiology than previously
anticipated. The pathophysiologic mechanisms of sepsis-induced AKI are different from non-septic AKI. Sepsis-
induced systemic inflammation triggers protective mechanisms within the nephron, affecting tubular and glomerular
functions. A varying degree of kidney impairment can be expected, from a small decrease in GFR to complete shutdown
and permanent dysfunction, depending on the severity of the inflammatory response. It is likely that progression of
septic AKI can be prevented by avoiding hypotension, fluid overload, and venous congestion. There is no specific
therapy for septic AKI at present. Even though novel drugs and blood purification techniques for sepsis-induced AKI
are being tested, supportive care to prevent further kidney insults is likely to allow kidney structure and function to
more easily recover once the septic state has resolved.
Key Words: Sepsis, Acute kidney injury, Septic acute kidney injury, Prevention, Treatment

Introduction hold promise for further improvement.

Both sepsis and acute kidney injury (AKI) are diseases
of major concern in critically ill patients. AKI usually
complicates severe sepsis. In approximately 50% of
cases of acute kidney injury (AKI) among critically
ill patients is triggered by Severe sepsis. The overall
incidence of septic AKI (SAKI) among all intensive
care unit (ICU) admissions ranges between 15 and 20
% 1. The incidence of AKI is as high as 16% to 25% ,
even in patients with less severe infections.2 Depending
on severity, SAKI is associated with mortality rates of
up to 50% to 60% 3 .The characteristic of Septic AKI
is a rapid and often profound decline in the kidneys’
ability to filter blood and eliminate nitrogen waste
products, which usually evolves over hours to days
after the onset of sepsis. Early control of infection
and supportive care, with vasopressors, intravenous
fluids and renal replacement therapy (RRT) seem to
be logical and are likely to allow favorably outcomes
among patients with septic AKI. Here some important
developments in our understanding of pathogenesis,
prevention and treatment of SAKI are reviewed,
which have contributed to this improved prognosis or
Correspondence:
Dr.Vinayak Patki, MB,DNB,FCCP,FIAP.
Chief, Advanced Pediatric Critical Care Centre & Head, Dept of
Pediatrics, Wanless Hospital, Miraj, 416101,Maharashtra,India.
Phone:+919822119314, E-Mail-patkivinayak@gmail.com
Pathophysiology of SAKI
The pathophysiology of SAKI is much more complex
than previously anticipated. Renal dysfunction is
not only a result from hypoperfusion alone but also
ensues to a large extent from renal inflammation and
tubular responses to various sepsis mediators. In many
patients, AKI occurs without overt signs of global
renal hypoperfusion and SAKI has been described
in the presence of normal or even increased renal
blood flow 4. This is the reason why only correction
of hemodynamic parameters often fails to prevent
SAKI. The pathophysiology of SAKI is no longer
based on an ischemia/reperfusion paradigm but rather
it is an aggregate of inflammation, microcirculatory
dysfunction, perfusion deficit, bio-energetic reactions,
and tubular cell adaptation to injury.5
Cellular Adaptation in SAKI
The adaptive mechanisms are triggered by the
immune response to infections affecting the kidneys’
tubular, vascular and glomerular functions. Invading
pathogens release molecules, known as pathogen-
associated molecular patterns (PAMPs), like
lipopolysaccharide, lipoteichoic acid, or DNA, into
the blood. Additionally, cellular injury and disruption
release intracellular contents, the so-called damage-
associated molecular patterns (DAMPs). The pattern

Vol. 5 - No.2 Mar-Apr. 2018 30 JOURNAL OF PEDIATRIC CRITICAL CARE

SYMPOSIUM
recognition receptors, such as Toll-like receptors, on
immune cells recognize the PAMPs and DAMPs.6
The immune cells release cytokines, chemokines
and reactive oxygen (ROS) and nitrogen (RNS)
species in response to this activation. The systemic
inflammatory response is triggered by PAMPs from
invading microorganisms and by DAMPs from
damaged cells. Inflammatory mediators, ROS and
RNS, are released by the activated neutrophils, which
cause kidney tubular cell stress and injury. Tubules
adapt to cellular stress by conserving energy through
G1 cell cycle arrest. Mislocation of Na1/K1-adenosine
triphosphatase prevents energy consuming NaCl
reuptake. Recruitment of glomerular shunt pathways
shunt toxin-rich blood away from the kidneys to
protect the tubules from further harm. (Figure 1)7
Figure 1 : Pathophysiology of SAKI7
A major portion of cardiac output (approximately
one- fifth) is received by the kidneys and they filter
large plasma volumes every hour. The tubules in
septic patients are therefore likely to be continuously
exposed to DAMPs, PAMPs, ROS, and RNS,
either through blood or via its filtrate in the tubular
lumen. Logically, this toxic milieu poses a threat to
the nephrons and cellular stress or injury could be
expected. But histologic evidence of cell injury is
remarkably scarce even in the presence of complete
loss of kidney function in sepsis.8,9 These observations
suggest that important adaptive mechanisms may be
at work, which, at least partly, can protect the kidneys
until the septic state has resolved.
Glomerular Hemodynamics in SAKI
A decreased GFR is the major functional event of
Vol. 5 - No.2 Mar-Apr. 2018
Septic Acute Kidney Injury (SAKI)
septic AKI. Low GFR is a protective mechanism
which guards against further insults by decreased
filtration of toxins such as DAMPs and PAMPs,
which limits further tubular cell toxin exposure and
stress. It also means lower energy consumption,
because less sodium chloride is filtered and needs to
be reabsorbed. Despite normal or increased global
renal blood flow during septic AKI, GFR some-times
ceases completely. There are vascular pathways
bypassing the glomerular capillaries (glomerular
shunt pathways) which provide another possible
explanation to the loss of GFR in sepsis. Recruitment
of such shunt pathways may be an important defense
mechanism blunting the kidneys’ exposure to
PAMPs, DAMPs, ROS, and RNS.9-10 Raised central
venous pressure (CVP) with renal venous congestion
and renal interstitial edema may lead to the onset and
maintenance of sepsis-induced kidney dysfunction.11
Management of SAKI
Systemic Blood Pressure
Arterial hypotension is a frequent complication of
severe infections which contributes to the development
and progression of AKI . The optimal blood pressure
target needed to prevent kidney damage and/or delay
mortality in individual patients is not yet determined.
However, in a recent multicenter, randomized
controlled trial (RCT), the SEPSISPAM trial (MAP
80–85 vs 65–70 mm Hg ) found no significant
difference in 90-day mortality between the high-
target and the low-target group. An important and
logical result of the findings of SEPSISPAM is that
norepinephrine infusion at higher doses is safe from
a renal point of view, not contraindicated in septic
patients with AKI, and possibly beneficial to GFR
preservation in selected patients.12
Fluid Management and Central Venous Pressure
The mainstay of treatment of septic shock is to give
intravenous fluids, vasopressors and inotropes guided
by physiologic endpoints. Even though such early
goal-directed therapy is recommended in the Surviving
Sepsis Campaign guidelines, its benefits are still to be
proved.13 In fact, in two recent large multicenter RCTs,
early goal- directed therapy did not reduce mortality
or prevent RRT requirements in patients with early
septic shock.14-15 Moreover, fluid resuscitation does
not reverse hemodynamic instability in a significant
31 JOURNAL OF PEDIATRIC CRITICAL CARE
SYMPOSIUM
proportion of critically ill patients.16 When fluid
therapy does improve physiologic parameters, the
effect is transient and repeated fluid boluses are
required to maintain the effect. Thus, unnecessary and
repeated fluid administration leads to gradual fluid
retention over days. Observational studies show that
fluid accumulation is associated with development
and progression of AKI and increased mortality in
AKI patients.17 This association is particularly strong
when CVP increases beyond 12 mm Hg. The role of
venous congestion in the pathogenesis of AKI is thus
supported.18
Vasopressor Therapy
Vasopressors can restore blood pressure reliably
in most septic patients. This contrasts with fluid
therapy. However, optimal timing and choice of
vasopressor therapy is uncertain. In the Vasopressin
and Septic Shock Trial (VASST), administration of
low- dose vasopressin (0.01–0.03 U/min) instead of
norepinephrine did not decrease mortality in patients
with septic shock.19 However, a secondary analysis of
the VASST showed attenuated progression of AKI
and decreased need for RRT in vasopressin treated
patients.20 Terlipressin, a vasopressin analog with
greater selectivity for the vasopressin 1 receptor,
prevented renal function worsening, compared with
placebo, in patients with the hepatorenal syndrome,
which has many common pathophysiologic features
with sepsis-induced AKI. The benefits of terlipressin
in septic shock patients need to be confirmed in future
RCTs.21
Red Blood Cell Transfusion
Septic AKI patients treated with RRT are prone
to anemia and hence to receive RBC transfusions.
First, the frequent blood sampling needed to monitor
electrolyte balance during RRT contributes to low
hemoglobin levels. Second, both filter clotting and
increased bleeding risk owing to circuit anticoagulation
are recognized complications during RRT. Third,
AKI is associated with disturbed red cell production
because of an altered response to erythropoietin.
Also, many AKI patients have chronic kidney disease
with associated chronic anemia. Lastly, fluid overload
is common in AKI and might dilute hemoglobin.
In the Surviving Sepsis Campaign guidelines, a
restrictive RBC transfusion strategy, targeting a
Vol. 5 - No.2 Mar-Apr. 2018
Septic Acute Kidney Injury (SAKI)
hemoglobin of 70 g/L, is recommended and results
from observational studies show that RBC transfusion
in response to the anemia of critical illness is
associated with increased morbidity and mortality. A
recent RCT therefore explored the safety of targeting
a hemoglobin level of 70 g/L compared with 90 g/L
in 998 patients with septic shock, of which 12%
were treated with RRT at baseline.22 No differences
in mortality, ischemic events, or further RRT
requirements were found. Thus, a hemoglobin target
just above 70 g/L seems to be safe and appropriate.
Renal Replacement Therapy
Continuous RRT (CRRT) rather than intermittent
RRT or extended daily hemofiltration is preferred in
AKI patients with severe sepsis. Although differences
in survival are negligible when comparing these
modalities, the rate of renal recovery is better with
CRRT, most probably due to the lower rate of
hypotensive episodes and better fluid homeostasis
achieved with CRRT.23 In contrast, optimal timing of
CRRT initiation relative to the onset and severity of
septic AKI as well as the optimal intensity of such
therapy remains uncertain. In a secondary analysis
of the Randomized Evaluation of Normal versus
Augmented Level (RENAL) replacement therapy
study, where 50% of patients had severe sepsis, the
time between a doubling of serum creatinine and
CRRT start had no impact on mortality. Also, early
CRRT, started before conventional criteria were
met, failed to improve outcomes in patients with
severe sepsis. In contrast, others suggest that there
is improvement in survival when CRRT has been
initiated before fluid overload has evolved.24 A CRRT
intensity of 20 to 25 mL/kg per hour is recommended
for critically ill AKI patients. Based on large RCTs,
higher intensities do not offer additional survival
benefit in general patients in the intensive care unit.24-
25
Yet, high-volume hemofiltration (65– 70 mL/kg/h)
has been suggested in patients with septic shock. 25
Future Therapies
Alkaline phosphatase
The molecular mechanisms involved in the sepsis-
induced inflammatory response are potential targets
for future therapies. Alkaline phosphatase blunts the
inflammatory response by detoxifying endotoxin, and
by attenuating RNS production. Intravenous injection
32 JOURNAL OF PEDIATRIC CRITICAL CARE
SYMPOSIUM
of alkaline phosphatase in patients with early septic
AKI significantly improved creatinine clearance with
a trend towards a reduced need for RRT. No large
RCT has yet explored its efficacy in septic humans.26
Acetylsalicylic acid (aspirin)
Several proinflammatory pathways involved in sepsis
induced organ damage are triggered by activated
platelets. Acetylsalicylic acid (aspirin) interferes with
several of these pathways by stimulating the synthesis
of anti-inflammatory molecules such as lipoxins,
resolvins, and protectins. Observational data suggest
that aspirin treatment before or during intensive care
unit admission is associated independently with lower
mortality. Animal studies also confirm an aspirin-
induced resolvin mediated attenuation of AKI during
endotoxemia.27,28
Antihistone antibodies
Like other DAMPs, histones (nuclear gene-regulating
proteins) are released by necroptotic cells. These
activate the immune system and promote sepsis-
induced organ injury. Activated protein C, which
degrades extracellular histones, was an unsuccessful
therapy for sepsis owing to lack of efficacy in a large
RCT. Antihistone antibodies were recently shown
to prevent death and AKI in a septic mouse model.29
Their role as therapeutic agents in human septic AKI
is yet to be determined.
Polymyxin B hemoperfusion
Removal (adsorption) of circulating endotoxin by
polymyxin B hemoperfusion in patients with severe
abdominal sepsis improved hemodynamics, organ
function, and survival significantly as shown in a
recent, small RCT. An ongoing phase 3 trial, including
650 patients with septic shock and elevated endotoxin
levels, will provide more robust evidence on the
potential benefits of polymyxin B hemoperfusion on
clinical outcomes.30
Prevention of SAKI
Fluid Resuscitation
The old “credo” stating that fluid harms the lung
but benefits the kidney should be revised. Liberal
fluid administration is of key importance to optimize
systemic hemodynamics in patients with SAKI. But
there is an ongoing controversy about efficacy, nature,
extent and duration of fluid therapy in septic shock.31
Vol. 5 - No.2 Mar-Apr. 2018
Septic Acute Kidney Injury (SAKI)
In fact, ICU physicians are faced with a “double-
edged” fluid dilemma. An optimal fluid management
would be to ensue a stepwise and smooth transition
from initial unrestricted fluid administration (positive
fluid balance) over a state of equilibrium (steady-state
fluid balance) to appropriate fluid removal (negative
fluid balance).32
Balanced crystalloids versus isotonic salt solutions
Balanced crystalloid perfusions (e.g., Ringer’s lactate,
Plasmalyte®) are associated with less occurrence of
AKI than isotonic salt solutions. The latter contain a
too high chloride load which is thought to be harmful
for the kidney by inducing vasoconstriction in the
renal vascular bed. It was independently associated
with increased morbidity and mortality. But recent
RCTs were not able to prove their efficacy.33,34
Early use of continuous RRT (CRRT)
Fluid overload definitely increases kidney edema
and enhances severity and irreversibility of SAKI.
Therefore, timely use of CRRT in case of fluid
overload that is poorly responding or refractory to
diuretics might be a reasonable approach to attenuate
or control SAKI.35
Differentiating transient (functional) SAKI from
structural SAKI
Urine biochemistry
SAKI may present either as a functional or structural
entity. The difference is clinically relevant since
functional SAKI can be reversed completely by early
adequate treatment whereas structural kidney damage
will mostly require RRT. However, discriminating
functional from structural SAKI at the bedside,
remains challenging. Low fractional excretions
of sodium (FENa) and urea (FEUrea) are highly
prevalent during the initial phase of sepsis. Oliguria is
an earlier sign of impending SAKI than the increase
in serum creatinine. It is assumed that high FENa
and low FEUrea values are associated with intrinsic
SAKI whereas high values of both FENa and FEUrea
occur with transient or functional SAKI. However, a
definite discriminative power of these urinary indices
has not been established. They are also less specific
than currently tested biomarkers of SAKI and less
accurate for differentiating transient from persistent
AKI and SAKI from non-SAKI 36
33 JOURNAL OF PEDIATRIC CRITICAL CARE
SYMPOSIUM
Biomarkers
Among various biomarker assays, neutrophil
gelatinase- associated lipocalin, urine insulin-like
growth factor-binding protein 7, and tissue inhibitor
of metalloproteinases- 2 are the most promising. They
cannot be advocated for routine guidance of therapy
because of their limited availability.37
Oliguria vs creatinine
Oliguria is an earlier sign of impending SAKI than
the increase in serum creatinine. Macedo et al.
reported that oliguric episodes occurred frequently
in ICU patients and allowed to identify more AKI
as compared to serum creatinine. 38 In contrast, other
investigators found a poor specificity of oliguria 39 To
date, no biological or laboratory marker can be put
forward that reliably distinguishes functional from
structural SAKI.
Conclusion
In conclusion, the old belief that sepsis-induced AKI is
initiated by renal ischemia because of macrovascular
dysfunction has been questioned, because AKI can
also develop in the presence of normal or increased
renal blood flow. The simultaneous occurrence of
renal inflammation and microvascular dysfunction
exacerbates the adaptive response of tubular epithelial
cells to injurious signals. In addition, the initiation
and development of sepsis-induced AKI through
the nitric oxide pathway, leukocyte adhesion, ROS,
and inflammation due to endothelial cell injury is
also important. Targeting tubular epithelial cells
and components of the microcirculation may be an
effective strategy in preventing and/or treating sepsis-
induced AKI.
Acknowledgement : Dr. Rinaldo Bellomo, MD, FRACP,
FCICM, Dept. of Intesive Care, Austin Hospital, Victoria, Australia
Source of Funding - Nil
Conflict of Interest - Nil
References:
1. Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure
in critically ill patients: a multinational, multicenter study.
JAMA 2005; 294(7):813–8.
2. Bagshaw SM, George C, Bellomo R, ANZICS Database
Management Committee. Early acute kidney injury and
sepsis: a multicentre evaluation .Crit Care 2008;12:R47.
3. Bagshaw SM, Uchino S, Bellomo R, Morimatsu H, Morgera
Vol. 5 - No.2 Mar-Apr. 2018
Septic Acute Kidney Injury (SAKI)
S, Schetz M et al. Beginning and Ending Supportive Therapy
for the kidney (BEST Kidney). Septic acute kidney injury in
critically ill patients: clinical characteristics and outcomes.
Clin J Am Soc Nephrol 2007;2:431–9.
4. Honore PM, Jacobs R, Joannes-Boyau O, De Regt J, Boer
W, De Waele E, et al. Septic AKI in ICU patients. Diagnosis,
pathophysiology, and treatment type, dosing, and timing: a
comprehensive review of recent and future developments.
Ann Intensive Care. 2011;1:32.
5. Gomez H, Ince C, De Backer D, Pickkers P, Payen D,
Hotchkiss J, et al. A unified theory of sepsis-induced acute
kidney injury: inflammation, microcirculatory dysfunction,
bioenergetics, and the tubular cell adaptation to injury. Shock
2014;41:3–11.
6. Zhang Q, Raoof M, Chen Y, et al. Circulating mitochondrial
DAMPs cause inflammatory responses to injury. Nature
2010;464(7285):104–7.
7. Mårtensson J, Bellomo R. Sepsis Induced Acute Kidney
Injury. Crit Care Clin 2015;31: 649-60
8. Lerolle N, Nochy D, Guerot E, et al. Histopathology of septic
shock induced acute kidney injury: apoptosis and leukocytic
infiltration. Intensive Care Med 2010; 36(3):471–8.
9. Langenberg C, Bagshaw SM, May CN, et al. The
histopathology of septic acute kidney injury: a systematic
review. Crit Care 2008;12(2):R38.
10. Calzavacca P, May CN, Bellomo R. Glomerular
haemodynamics the renal sympathetic nervous system and
sepsis-induced acute kidney injury. Nephrol Dial Transplant
2014;29(12):2178–84.
11. Prowle JR, Kirwan CJ, Bellomo R. Fluid management for the
prevention and attenuation of acute kidney injury. Nat Rev
Nephrol 2014;10(1):37–47.
12. Legrand M, Dupuis C, Simon C, et al. Association between
systemic hemodynamics and septic acute kidney injury in
critically ill patients: a retrospective observational study. Crit
Care 2013;17(6):R278.
13. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid
bolus in African children with severe infection. N Engl J
Med 2011;364(26):2483–95.
14. Yealy DM, Kellum JA, Huang DT, et al. A randomized trial
of protocol-based care for early septic shock. N Engl J Med
2014;370(18):1683–93.
15. Peake SL, Delaney A, Bailey M, et al. Goal-directed
resuscitation for patients with early septic shock. N. Engl. J
Med 2014;371(16):1496–506.
16. Bihari S, Prakash S, Bersten AD. Post resuscitation fluid
boluses in severe sepsis or septic shock: prevalence and
efficacy (price study). Shock 2013;40(1):28–34
17. Grams ME, Estrella MM, Coresh J, et al. Fluid balance,
diuretic use, and mortality in acute kidney injury. Clin J Am
Soc Nephrol 2011;6(5):966–73.
18. Boyd JH, Forbes J, Nakada TA, et al. Fluid resuscitation in
septic shock: a pos- itive fluid balance and elevated central
venous pressure are associated with increased mortality. Crit
Care Med 2011;39(2):259–65.
19. Russell JA, Walley KR, Singer J, et al. Vasopressin versus
34 JOURNAL OF PEDIATRIC CRITICAL CARE
 SYMPOSIUM
norepinephrine infusion in patients with septic shock. N
Engl J Med 2008;358(9):877–87.
20. Gordon AC, Russell JA, Walley KR, et al. The effects
of vasopressin on acute kid- ney injury in septic shock.
Intensive Care Med 2010;36(1):83–91.
21. Sanyal AJ, Boyer T, Garcia-Tsao G, et al. A randomized,
prospective, double- blind, placebo-controlled trial
of terlipressin for type 1 hepatorenal syndrome.
Gastroenterology 2008;134(5):1360–8.
22. Holst LB, Haase N, Wetterslev J, et al. Lower versus higher
hemoglobin threshold for transfusion in septic shock. N Engl
J Med 2014;371(15):1381–91.
23. Wald R, Shariff SZ, Adhikari NK, et al. The association
between renal replacement therapy modality and long-term
outcomes among critically ill adults with acute kidney injury:
a retrospective cohort study. Crit Care Med 2014;42(4):868–
77.
24. Bellomo R, Cass A, Cole L, et al. Intensity of continuous
renal-replacement ther- apy in critically ill patients. N Engl
J Med 2009;361(17):1627–38.
25. Palevsky PM, Zhang JH, O’Connor TZ, et al. Intensity
of renal support in critically ill patients with acute kidney
injury. N Engl J Med 2008;359(1):7–20.
26. Peters E, van Elsas A, Heemskerk S, et al. Alkaline
phosphatase as a treat- ment of sepsis-associated acute
kidney injury. J Pharmacol Exp Ther 2013; 344(1):2–7.
27. Akinosoglou K, Alexopoulos D. Use of antiplatelet
agents in sepsis: a glimpse into the future. Thromb Res
2014;133(2):131–8.
28. Chen J, Shetty S, Zhang P, et al. Aspirin-triggered resolvin
D1 down-regulates inflammatory responses and protects
against endotoxin-induced acute kidney injury. Toxicol Appl
Pharmacol 2014;277(2):118–23.
29. Xu J, Zhang X, Pelayo R, et al. Extracellular histones are major
mediators of death in sepsis. Nat Med 2009;15(11):1318–21.
30. Klein DJ, Foster D, Schorr CA, et al. The EUPHRATES
trial (Evaluating the Use of Polymyxin B Hemoperfusion
How to cite this article:
Patki V. Septic Acute Kidney Injury (SAKI). J Pediatr Crit Care 2018;5(2):30-35.
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Septic Acute Kidney Injury (SAKI)
in a Randomized controlled trial of Adults Treated for
Endotoxemia and Septic shock): study protocol for a
randomized controlled trial. Trials 2014;15:218
31. Prowle JR, Bellomo R. Fluid administration and the kidney.
Curr Opin Crit Care 2013;4:308–14.
32. Goldstein SL. Fluid management in acute kidney injury. J
Intensive Care Med. 2014;29:183–9.
33. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M.
Association between a chloride-liberal vs chloride-restrictive
intravenous fluid administration strategy and kidney injury in
critically ill adults. JAMA 2012;308:1566–72.
34. Zhang Z, Xu X, Fan H, Li D, Deng H. Higher serum
chloride concentrations are associated with acute kidney
injury in unselected critically ill patients. BMC Nephrol.
2013;28(14):235.
35. Payen D, de Pont AC, Sakr Y, Spies C, Reinhart K, Vincent
JL. Sepsis Occurrence in Acutely Ill Patients (SOAP)
Investigators. A positive fluid balance is associated with a
worse outcome in patients with acute renal failure. Crit Care.
2008;12:R74.
36. Pons B, Lautrette A, Oziel J, Dellamonica J, Vermesch R,
Ezingeard E, et al. Diagnostic accuracy of early urinary
index changes in differentiating transient from persistent
acute kidney injury in critically ill patients: multicenter
cohort study. Crit Care. 2013;17:R56.
37. Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw
SM, Bell M, et al.Discovery and validation of cell cycle
arrest biomarkers in human acute kidney injury. Crit Care.
2013;17: R 25.
38. Macedo E, Malhotra R, Claure-Del Granado R, Fedullo P,
Mehta RL. Defining urine output criterion for acute kidney
injury in critically ill patients. Nephrol Dial Transplant.
2011;26:509–15.
39. Legrand M, Jacquemod A, Gayat E, Collet C, Giraudeaux
V, Launay JM, et al. Failure of renal biomarkers to predict
worsening renal function in high-risk patients presenting
with oliguria. Intensive Care Med. 2015;41:68–76.
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