Clinical Queries: Nephrology 5 (2016) 16–20

Contents lists available at ScienceDirect

Clinical Queries: Nephrology

journal homepage: www.elsevier.com/locate/cqn

Review

Management of acute kidney injury in sepsis

B Karthikeyan, R Sharma *
Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

A R T I C L E I N F O A B S T R A C T

Article history: Acute kidney injury and multiorgan dysfunction due to sepsis and septic shock increase the morbidity
Received 11 April 2016 and mortality among critically ill patients. It remains an important challenge in critically ill patients. In
Accepted 19 April 2016 this review, management of septic AKI in terms of prevention, medical therapies, and extracorporeal
Available online 12 May 2016
therapies is discussed. Stabilizing the hemodynamic parameters by fluid resuscitation and inotropic
support are important strategies to prevent acute kidney injury in the initial stages. Controversies exist
Keywords: in the timing of initiating renal replacement therapy although some studies showed improved outcomes
Sepsis
with early initiation. The recommended dose of renal replacement therapy (25 ml/kg/hr) had not shown
Acute kidney injury
Continuous renal replacement therapy
to be associated with improved survival in randomized studies. The clinical benefit of other therapies,
Hemoadsorption like hemoadsorption, and alkaline phosphatase use is still uncertain. Mesenchymal stem cell therapies
are in phase I trials.
ß 2016 Published by Elsevier, a division of Reed Elsevier India, Pvt. Ltd.

1. Background
Multiorgan failure due to sepsis and septic shock is one of the
most common causes of increase in mortality and morbidity in
critically ill patients. The development of new onset organ failure
in intensive units is associated with increase in mortality.1 Acute
kidney injury due to sepsis develops in critically ill patients as a
part of multiorgan dysfunction and is associated with significant
increase in morbidity and mortality. It also increases the cost of
intensive unit care stay. The overall incidence of sepsis-associated
acute kidney injury in intensive unit admission is reported to be
15–20%.2 In some of the studies, the incidence of septic AKI
approaches to around 50%.3,4 Mortality also increases with
development of sepsis-associated acute kidney injury. The IVOIRE
study had shown 90-day mortality rate of 50% in sepsis-associated
acute kidney injury patients.5
The main management of septic acute kidney injury revolves
around treating the underlying sepsis with appropriate antibiotics
and supporting the organs till the sepsis is managed. So, the acute
kidney injury in sepsis is managed by achieving adequate
hemodynamic status by intravenous fluids or inotropic support
and then if needed by extracorporeal blood purification. In this
* Corresponding author at: Department of Nephrology, Sanjay Gandhi Post
Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, India.
Tel.: +91 9415026762.
E-mail address: rksharma@sgpgi.ac.in (R Sharma).
review, we will discuss about the preventive and treatment aspects
of sepsis-associated acute kidney injury.
2. Preventive strategies
2.1. Fluid resuscitation
The main initial strategies in the management of septic shock
and septic acute kidney injury are maintaining the hemodynamic
parameters by either fluid therapy or by inotropes. Acute kidney
injury due to sepsis is due to regional hypoperfusion of kidney
leading to ischemia-reperfusion damage and is also related due to
the effect of toxins and cytokines. Renal tissue can be further
damaged by the use of nephrotoxic drugs, use of contrast agents,
and associated comorbidities with the patient.
Improving the hemodynamic status of the patient will lead to
improvement in renal perfusion. In patients with sepsis and septic
shock, fluid should be administered liberally after evaluating the
cardiac status and it should be stopped when cardiac output
reaches normal value. Fluid therapy can act as a double-edged
weapon because excessive fluid administration can have negative
effects on organ function. The timing of stopping fluid therapy and
starting renal replacement therapy is an area of controversy.
Hence, the optimal fluid management is step-wise transition from
initial unrestricted fluid administration to maintain neutral fluid
balance to appropriate fluid removal when required.6
The surviving sepsis campaign guidelines mention that fluid
resuscitation should be given in septic shock patients to maintain

http://dx.doi.org/10.1016/j.cqn.2016.04.006
2211-9477/ß 2016 Published by Elsevier, a division of Reed Elsevier India, Pvt. Ltd.
 B Karthikeyan, R Sharma / Clinical Queries: Nephrology 5 (2016) 16–20
central venous pressure of 8–12 mmHg and mean arterial pressure
of more than 65 mmHg.7
The early goal directed therapy (EGDT) for sepsis recommends
starting fluids, vasopressors, and blood products to maintain
central venous oxygen saturation of more than 70%.8 This has been
proved to improve survival in a cohort of sepsis with multiorgan
failure patients. But recent studies did not show mortality benefit
with this approach leading to controversies in fluid administration.
Three main randomized studies (ARISE, ProMISe, and ProCESS) did
not show survival benefit with EGDT approach.9–11 In a retrospec-
tive study done by Kelm et al., fluid administration leading to fluid
overload was associated with increased use of fluid-related
medical interventions and mortality.12
2.2. Crystalloids versus colloids
To improve the hemodynamic status in septic AKI patients
during the initial period, both crystalloids and colloid solution
were used. But recent evidence suggests that crystalloid solutions
rather than colloids should be used for initial resuscitation of
patients with septic AKI,13,14 the reason being the increased risk of
osmotic nephrosis by colloid solutions.15
In crystalloids, balanced solutions (ringer lactate and plasma-
lyte) should be preferred over the isotonic solutions as the latter
contains high chloride content, which produces vasoconstriction
and is detrimental to the renal tissue.16,17 This has been shown in
some studies that isotonic solution was associated with increased
morbidity and mortality. However, a recent, large randomized
study (SPLIT) did not find any significant difference in incidence of
AKI when comparing the two solutions. So, the superiority of
balanced crystalloids yet remains to be proven.18
2.3. Albumin
The use of albumin infusion for resuscitation in septic shock
patients had been studied in SAFE study.19 This study and another
meta-analysis showed that use of albumin was associated with
lower mortality compared to other crystalloids.20 In another
recently published ALBIOS trial, mortality benefit with the use of
albumin was not established.21 In post-hoc analysis of this study, a
subgroup of septic patients treated with albumin and crystalloid
infusion had lower 90-day mortality compared to patients who
were treated with crystalloids alone. Despite this, the use of
albumin as resuscitation fluid is still under debate.
2.4. Use of inotropes
Inotropes are needed to maintain effective renal perfusion. In
septic patients, noradrenaline seems to be the drug of choice.22
Vasopressin is another drug that can be used in septic shock
patients. Although mortality did not differ much between the use
of these two inotropes, a post-hoc analysis of a trial done by Russell
et al. found that in patients who developed milder forms of acute
kidney injury, vasopressin use is associated with lesser progression
to severe AKI than with noradrenaline.23 In some studies, it was
found that vasopressin use was associated with lesser progression
to stage 1 AKI but not to severe stages.24
There is no definite evidence supporting or opposing the
strategies for prevention of AKI in sepsis. To standardize treatment
and optimize the timing, AKI should be diagnosed and monitored
according to AKIN and KDIGO criteria.
2.5. Monitoring of progression
Recognizing AKI early and to determine the need for RRT can be
done by various criteria that have been proposed to diagnose AKI.
17
The RIFLE, AKIN, and KDIGO criteria are used to diagnose acute
kidney injury.25,26 But recent trial did not confirm improved
outcomes by early diagnosis using these criteria.27
Oliguria is a useful earlier sign than serum creatinine in
monitoring the progression in septic acute kidney injury.28
Biomarkers like NGAL (neutrophil gelatinase-associated lipocal-
cin), tissue inhibitor of metalloproteinases, and urine insulin-like
growth factor are useful in diagnosis of septic acute kidney
injury.29,30 But because of limited availability, these could not be
used in routine clinical practice.31
2.6. Fluid overload and septic AKI
Positive fluid balance is associated with increased risk of
development and progression of AKI.32 The kidney tissue is
affected by congestion and rise in renal venous pressure, which
leads to reduction in blood flow and glomerular filtration. In a
multicentre observational study done by Teixeira et al., in
601 critically ill patients, positive fluid balance and lower urine
volume with AKI were associated with significant risk of 28-day
mortality.33 Many observational studies mention that net positive
fluid balance is associated with increased risk of progression of AKI
and mortality.34–36 So removing fluid by either diuretic therapy or
by extracorporeal therapy is essential to improve the beneficial
effect of treatment of sepsis.
2.7. Diuretic therapy in sepsis and septic shock
Diuretic therapy is mainly used to increase the urine output and
to maintain the neutral balance in fluid overload patients. Loop
diuretics that act on medullary thick ascending limb of loop of
Henle is the diuretic of choice. Theoretically, loop diuretics reduce
the oxygen demand, maintain net fluid balance and acid–base
homeostasis, and it should be helpful in reducing the severity of
septic AKI. But most of the studies did not mention renal recovery
and mortality benefit with diuretics.37,38 Controversy still exists
whether diuretic therapy improves outcomes in AKI with
sepsis.35,39
The use of diuretics in absence of hypervolemia is associated
with increased mortality and it should not be encouraged.40
Low-dose continuous diuretic infusion is found to be better in
improving the urine output and reducing the BNP levels.41 Diuretic
resistance and adverse effects, such as metabolic disturbances, can
occur with the use of diuretics. The main strategies while using
loop diuretics is avoiding braking phenomenon and limiting its use
to reduce side effects and resistance.
Use of fenoldapam in critically ill patients who are at risk of AKI
was associated with reduction in degree of subsequent renal
dysfunction.42 But results of recent studies using fenoldapam had
created controversy in using it in critically ill patients.43 However,
larger randomized trials are needed to evaluate the benefit of this
drug in sepsis and septic shock.
3. Extracorporeal therapies
3.1. Indication and timing of RRT
If the medical therapy fails to maintain the fluid status,
electrolyte, and acid–base balance, then renal replacement therapy
should be initiated. Initiating renal replacement therapy aids the
clinician in maintaining the fluid balance while providing adequate
nutrition support through parenteral nutrition. It also helps to
correct metabolic abnormalities associated with sepsis and
decreased organ perfusion.
Early initiation of RRT is crucial and is found to be associated
with better outcome in some studies. Delay in initiating the RRT is
18 B Karthikeyan, R Sharma / Clinical Queries: Nephrology 5 (2016) 16–20
associated with poor outcomes and increase in mortality.44
Traditional parameters like serum urea, serum creatinine con-
centrations, urine output, and progression of renal injury are taken
into consideration for initiating the renal replacement therapy.45,46
A meta-analysis of fifteen studies done by Karvellas et al. found
that early initiation of RRT was associated with decreased
mortality.47 In a recent study by FINNAKI group, it was observed
that early initiation of RRT for conventional indication was
associated with better outcome and lower mortality.48 Three
randomized studies are underway evaluating the timing of RRT in
critically ill patients.49–51 But the studies had significant hetero-
geneity and bias. So early initiation of RRT in critically ill septic AKI
patients may have beneficial effects on outcome and survival but
data are insufficient to confirm it.
3.2. Choice of RRT
Both continuous (CRRT) and intermittent RRT (IHD) can be
initiated in septic AKI patients. Most of the trials done showed
equivalent benefit with both therapies in terms of mortality and
renal recovery.52–54 Intermittent therapies cannot be used in
hemodynamically unstable patients and continuous therapies
require heparin for anticoagulation. Therefore, most of the
clinicians decide the choice of RRT based on hemodynamic status,
bleeding risk, and metabolic parameters. There is a need for large
randomized control study comparing the outcomes of continuous
and intermittent therapies to clear the controversy.
3.3. Dosing of RRT
The optimal dose of RRT in sepsis-induced AKI patients is
uncertain. Two large multicentric trials evaluated the optimal dose
of RRT on the outcome of critically ill patients. The RENAL55
(Randomized Evaluation of Normal versus Augmented Level) renal
replacement therapy study compared the continuous venovenous
hemodiafiltration dose of 25 ml/kg/hr with 40 ml/kg/hr.
The ATN (Veteran Affairs/Acute renal failure Trial Network
study) compared the CVVHDF dose of 20 ml/kg/hr or thrice weekly
hemodialysis with CVVHDF dose of 35 ml/kg/hr or daily intermit-
tent dialysis.56 Both studies found that increasing the intensity of
RRT dose did not turn into survival advantage or renal recovery. A
post-hoc analysis of these patients in ATN study group showed
tendency toward reduced mortality with the use of higher CRRT
dose. But till now, there is no strong evidence favoring higher dose
of RRT in sepsis-induced acute kidney injury patients.
While performing continuous therapies, possibility of under-
dialysis due to technical reasons can occur. Hence, the delivered
dose of CRRT is always less than the prescribed dose. As
underdialysis in critically ill patients is found to be harmful, CRRT
should be prescribed in slightly higher dose to target prescribed
dose of 25–30 ml/kg/hr. This has been by shown by Dose Response
Multicentre collaborative initiative (DOReMi) study.57
CRRT is sometimes used in septic patients without acute kidney
injury. This is based on the principle that hemofiltration will
remove the systemic inflammatory mediators like cytokines. But
results of the studies were conflicting.58,59 At present, hemofiltra-
tion or any other forms of continuous therapies are not
recommended in sepsis patient without acute kidney injury. A
systematic meta-analysis found that high-dose RRT was not
associated with any mortality benefit in sepsis-induced AKI
patients.60
3.4. High-volume hemofiltration
High-volume hemofiltration has been used in sepsis to remove
the inflammatory cytokines. There is lack of success with HVHF
due to technical difficulties and so high cut-off hemofilters are
used in some studies. These high cut-off filters have great
efficiency in removing middle and larger molecules but there is
need of expertise to use these filters.61
3.5. Antimicrobial dosing in CRRT
Continuous therapies alter the pharmacokinetic and pharmco-
dynamic properties of several antimicrobial drugs. Hence, these
drugs require dose adjustment during the use of continuous
therapies.62 As antibiotics are the cornerstone in management of
sepsis, underdosing during CRRT poses real problem of treatment
resistance. The recommended dosage of some of the commonly
used antimicrobials is summarized in Table 1.
3.6. Hemoadsorption in sepsis
Hemoadsorption is a technique where adsorbents are used to
attract solutes through hydrophobic, ionic, hydrogen, and van der
Walls interactions. The adsorbents used are mainly nonspecific like
charcoal and resins, which has high adsorbing capacity. The solutes
are separated according to the size and ability to penetrate the
sorbent material. But its use has been restricted due to poor
biocompatibility. Recently, newer resins with biocompatible outer
layer have solved the problem associated with biocompatibility.63
This leads to use of hemoadsorption technique, an ideal interven-
tion in sepsis.
In septic patients, polymyxin bound to polystyrene fibers is
used as a hemoprefusion technique to clear the endotoxin.64 The
rationale behind the use of this antibiotic polymyxin is that it binds
lipopolysaccharide and endotoxin of outer membrane of gram-
negative bacteria and disturbs the sepsis cascade.
The first controlled small multicentre study of using polymyxin
B hemoperfusion was done in sepsis and septic shock patients
following intraabdominal surgery. This study showed significant
differences in hemodynamics in treated patients compared with
controls and also the need for CRRT is reduced in treated group. But
it did not find significant difference in level of endotoxin and
interleukin-6 between the two groups.
Another large randomized control study EUPHAS (Early Use Of
Polymyxin Hemoperfusion In Abdominal Sepsis) evaluated the use
of polymyxin hemoperfusion in sepsis patients following emer-
gency intraabdominal surgeries.65 In this study, the patients were
randomized to receive either conventional therapy plus polymyxin
hemoperfusion (2 sessions) or conventional therapy alone. This
study found that polymyxin hemoperfusion use was associated
with reduction in vasopressor requirement, increase in mean
arterial pressure, improvement in PaO2/FiO2 ratio, and improve-
ment in SOFA scores. Polymyxin group had lower 28-day mortality
compared to conventional therapy. But there were various
limitation of this trial that the investigators did not measure the
endotoxin level during the study period to conclusively prove that
endotoxin removal by polymyxin was associated with improve-
ment in outcomes. Furthermore, this study failed to make definite
conclusion due to small number of patients.
Table 1
Antimicrobial dose recommendation during CRRT.
Antimicrobials Loading dose Maintenance dose
Meropenem 2g 2 g thrice daily
Piperacillin–tazobactam 4.5 g 4.5 g four times a day
Vancomycin 35 mg/kg 30 mg/kg
Teicoplanin 15 mg/kg 600 mg once daily
Colistin 9 MU 4.5 MU thrice daily
Cefepime 2 g thrice daily
Linezolid 600 mg thrice daily
 B Karthikeyan, R Sharma / Clinical Queries: Nephrology 5 (2016) 16–20
Another new technique to remove inflammatory mediators in
sepsis is by CFPA (plasma filtration coupled with adsorption). This
technique enhances the removal of soluble mediators and
improves the hemodynamic parameters in sepsis and septic shock
patients. In a small noncontrolled study, CPFA was associated with
reduction in noradrenaline dose requirement and improvement in
mean arterial pressure.66
Even though the study by Cantaluppi et al.67 showed that the
adsorption of inflammatory mediators had lead to reduced
apoptosis and reduction in altered polarity of tubular cells, the
effectiveness of this strategy in vivo remains doubtful. Until further
evidence is available, the use of these procedures cannot be
recommended in clinical practice.
3.7. Other recent medical therapies
In a randomized phase 1 trial, it was found that recombinant
alkaline phosphatase could prevent and reverse some cases of
sepsis-associated acute kidney injury.68 The proposed mechanism
of action is through dephosphorylation of lipopolysaccharide and
adenosine triphosphate (ATP), which in turn reduces renal
inflammation. Phase II trial results are awaited to know further
use of alkaline phosphatase in sepsis.
Mesenchymal stem cell use in sepsis has been evaluated in
preclinical experimental models and had shown beneficial
results.69
4. Conclusion
Sepsis-associated acute kidney injury increases the mortality
and morbidity in critically ill patients. Prevention of AKI in sepsis
should be initiated with fluid resuscitation, stabilizing hemody-
namic parameters, using broad-spectrum antibiotics, and avoiding
nephrotoxic agents. Crystalloids are preferred than colloids for
initial fluid resuscitation. Controversy exists in the timing, dose,
and type of renal replacement therapy. But early initiation of RRT is
advocated by many clinicians for maintaining fluid balance.
Continuous therapies are better for hemodynamically unstable
patients. Data on newer pharmacological therapies and hemoad-
sorption are inadequate to use them in clinical practice. Future
studies should evaluate the timing, dose, and choice of RRT. Studies
are needed in area of novel biomarkers to diagnose early and to
monitor the progression of acute kidney injury and pharmacologi-
cal therapies in sepsis.
Conflicts of interest
The authors have none to declare.
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