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CJASN ePress. Published on October 25, 2017 as doi: 10.2215/CJN.07310717
Kidney Case
Attending Rounds
Sepsis-Associated AKI
J.R. Prowle
Clin J Am Soc Nephrol ▪: ccc–ccc, 2017. doi:
Sepsis remains the most important cause of AKI in
the intensive care unit (ICU) with 15%–20% of patients
with sepsis-associated AKI (SA-AKI) prescribed RRT
(1). In addition to association with short term mortality,
AKI is also linked to the later development of CKD,
ESRD, and long-term increased risk of death (2). In
ICUs, abdominal infections are the commonest association of SA-AKI (3). However, in instances where AKI
develops in the context of sepsis, other risk-factors often
coexist (3), complicating assessment and management.
Despite its importance, treatment recommendations for
SA-AKI (4) and AKI in general (5,6) are not sophisticated, emphasizing prompt and effective treatment of
underlying infection, avoidance of secondary kidney
injury, and optimization of systemic hemodynamics.
There is, therefore, continued reliance on clinical experience to guide bedside management.
Clinical Case
A 65-year-old man is brought to hospital with a
2-day history of nausea, vomiting, and abdominal pain.
Past medical history includes ischemic heart disease,
type 2 diabetes with microalbuminuria, hypercholesterolemia, and hypertension. Medication includes
Ramipril, Clopidogrel, Amlodipine, Bisoprolol, Atorvastatin, and Metformin. He is sweaty, tachycardic
(heart rate 115), and has cool peripheries. His central
temperature is 38.2°C, BP is 95/55 mm Hg, respiratory rate is 30, and oxygen saturation is 98% on nasal
oxygen. He is disorientated in time and place with a
Glasgow Coma Score of 14 (E4, V4, M6). There is
tenderness in the right upper quadrant with localized
guarding. His partner reports he has not passed urine
that day and he is subsequently catheterized with
residual urine of 120 ml. Arterial blood gases demonstrate pH 7.30, base excess 212 mmol/L, lactate
5.5 mmol/L, partial pressure of oxygen 120 mm Hg,
partial pressure of carbon dioxide 30 mm Hg, sodium
130 mmol/L, chloride 104 mmol/L, glucose 290 mg/dl,
and capillary blood ketones are negative. Following
Surviving Sepsis guidelines (7), 30 ml/kg of intravenous
crystalloid is rapidly administered, blood cultures obtained, and intravenous piperacillin-tazobactam is administered. Systolic BP remains ,100 mm Hg. In view of
his abdominal signs and lactic acidosis, a CT scan of the
abdomen with contrast is performed revealing dilated Vol ▪ ▪▪▪, 2017
extra- and intrahepatic bile ducts and multiple stones
in thick-walled gall bladder. First serum creatinine is
2.3 mg/dl (outpatient baseline 1.1) and potassium is
5.1 mmol/L. Urine output is 15 ml in the first 2 hours
and repeat lactate is 4.5 mmol/L. He is referred to
gastroenterology for management of his obstructive
cholangitis and critical care for ongoing supportive
Initial Management Considerations
Sepsis definitions have recently been simplified
and refined (8), and sepsis is now defined as “lifethreatening organ dysfunction caused by a dysregulated host response to infection.” In this patient there
is suspected biliary infection and the presence of
sepsis, with associated risk of prolonged ICU stay or
death in hospital, which can identified by virtue of a
quick-Sequential Organ Failure Assessment screening score of $2 of 3 (alteration in mental status,
systolic BP ,100 mm Hg/vasopressor requirement,
and respiratory rate $22/min) (8). Furthermore, the
patient has septic shock (8), defined by having sepsis
syndrome together with persisting hypotension requiring vasopressors after volume resuscitation or a
lactate level .2 mmol/L: a group where hospital
mortality is .40%. Finally, he has stage 2 AKI by
the Kidney Disease Improving Global Outcomes
(KDIGO) classification of creatinine criteria (5) and
has been significantly oliguric (likely stage 2–3 by
urine criteria). Importantly, in the context of acutely
rising creatinine, any assessment of AKI severity on the
basis of a creatinine measurement at a single point in
time could underestimate the true extent of decline in
kidney function. In this context, AKI is likely both a
marker of disease severity and a direct contributor to
adverse outcomes, through adverse effects of AKI on
homeostasis and distant organ function.
This life-threatening illness requires two-pronged
management: source control of sepsis (drainage of the
obstructive biliary system and antibiotics), accompanied in parallel by intensive monitoring and
multiorgan support in the ICU (Figure 1). Etiology
of kidney dysfunction is likely to be sepsis, but
contributions from medications, hypovolemia, poor
cardiac response, and loss of kidney reserve in early
diabetic nephropathy (baseline CKD stage 2–3) are all
plausible contributors. Radiologic contrast exposure
Adult Critical Care
Unit and Department
of Renal Medicine and
Transplantation, The
Royal London
Hospital, Barts Health
National Health
Service Trust, London,
United Kingdom; and
Critical Care and
Medicine Research
Group, William
Harvey Research
Institute, Queen Mary
University of London,
London, United
Dr. John R. Prowle,
Adult Critical Care
Unit, Royal London
Hospital, Whitechapel
Road, London E1 1BB,
United Kingdom.
Email: j.prowle@
Copyright © 2017 by the American Society of Nephrology
Clinical Journal of the American Society of Nephrology
Figure 1. | Parallel and sequential steps in the management of sepsis-associated AKI. Successful management of sepsis and its complications
requires both adequate treatment of underlying infection in parallel with provision of good supportive critical care, and escalation to artificial
organ-support, including RRT, when clinically indicated. Treatment of infection-induced critical illness concludes with follow-up to detect longterm consequences of acute organ injury, such as development of CKD after AKI. ICU, intensive care unit.
occurred after onset of AKI, but could contribute to AKI
progression; however, the best diagnostic imaging should in
general be obtained to allow definitive treatment of a lifethreatening underlying condition (6). Similarly, although
exposure to nephrotoxic antibiotics should be minimized,
this can be outweighed by the need to cover the likely
underlying infection, especially when prevalence of
community-acquired, multidrug-resistant gram-negative
bacteria is high. Importantly, early, appropriate antibiotics
with source-control have been shown to lower risk of AKI
(9) and speed AKI recovery (10). In this case, best management of SA-AKI (5) is encompassed within good ICU care of
septic shock: resuscitation guided by invasive hemodynamic monitoring and mechanical organ support if clinically indicated. Nephrotoxins should be avoided, but not if
essential for management of the underlying condition. Drug
dosing should be modified in the context of kidney
dysfunction, but, because loading doses are dependent on
volume of distribution, this may not apply in the first 24
During resuscitation, it is critical to balance the need to
restore normal hemodynamics while minimizing the adverse effects of fluid overload. In general, need for fluid
resuscitation is predicated on both the presence of inadequate cardiac output for good tissue perfusion and a
significant, sustained increase in stroke volume with
filling. In numerous studies in critical illness, absolute and
relative change in central venous pressure have not been
shown to reliably predict cardiac response to fluid challenges or to improve outcomes, and central venous
pressure targets are no longer recommended in the
treatment of septic shock (7). Similarly, no improvement
in kidney outcomes occurred with early goal-directed
therapy in three major sepsis studies (4), suggesting any
role of cardiac output monitoring is more to indicate that
fluid is not required as to drive ongoing fluid-loading.
Importantly, fluid overload has been consistently associated with worse outcomes in the context of established
AKI (11), and a recent pilot study has suggested that
more restrictive resuscitation in early septic shock may be
Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2017
associated with better kidney outcomes (12). In addition,
most cases of human SA-AKI occur with hyperdynamic,
vasodilatory shock, where inflammation rather than global
kidney ischemia drive pathogenesis (13). Thus, after initial
bolus, further fluids may be given if hypotension and
shock is ongoing; however, once .2–3 L has been administered, measurement of cardiac fluid-responsiveness is
essential to avoid unnecessary, potentially harmful therapy. Finally, fluid composition continues to be controversial; undoubtedly, hydroxyethyl starches should be
avoided in the context of sepsis, but the relative merits of
colloids in the form of albumin and buffered versus unbuffered crystalloid solutions remain debated, without
definitive evidence.
Given these concerns, vasopressors are the mainstay of
refractory hypotension management in the complex setting of SA-AKI. Norepinephrine remains the international
drug of choice; early use of vasopressin in septic shock
was not associated with improved primary kidney outcomes in a randomized trial, but there was potential
benefit in lesser need for RRT and no apparent harm (14).
BP targets may be individualized: in a subgroup analysis
of a large trial (15), mean arterial BP (MAP) target of
.80 mm Hg was associated with less RRT in patients with
preexisting hypertension; however, because there was no
survival benefit, if higher targets are adopted, they should
be reviewed if vasopressor requirement is high, or RRT is
Clinical Progress
The patient is admitted to the ICU, and an additional
2 L of crystalloid is administered together with boluses
of ephedrine while arterial and central venous lines are
inserted with a calibrated pulse-contour cardiac output
monitor. He becomes increasingly agitated and hypoxic,
requiring intubation and ventilation. Cardiac index is 2.9
L/min per 1.73 m2 and norepinephrine is commenced,
initially targeting a MAP of $75 mm Hg on the basis of
prior history of hypertension. Fluid challenge demonstrates no increment in stroke volume and further fluids
are not administered. Piperacillin-tazobactam was given at
4.5 g three times daily in the first 24 hours. A radiologically
guided percutaneous transhepatic biliary drain is requested
for source control of presumed biliary sepsis. Over the
next 6 hours, norepinephrine at 0.5 mg/kg per minute is
required to achieve the MAP target, and 0.02 U/min of
vasopressin is added; however, urine output remains 5–10
ml/h and lactate 3 mmol/L. The MAP target is therefore
revised to 60 mm Hg due to high vasopressor requirement
and lack of diuresis response to a higher MAP target. After
return from interventional radiology, an evaluation is
made regarding ongoing management. The presence of
persistent oliguria after initial resuscitation faces clinicians with a choice between watchful waiting, addition
of diuretics to manage fluid balance, or direct institution of
Indications for RRT
Classically, RRT is indicated for severe refractory uremia,
hyperkalemia, acidosis, or fluid overload causing organ
Sepsis-Associated AKI, Prowle
impairment. Organ support should be given in anticipation of immediate threat to life. Thus, in critical illness,
RRT is usually instituted on clinical judgement rather than
on absolute indications. Two recent studies have examined KDIGO AKI criteria for the initiation of RRT in the
ICU: a single center study suggesting benefit from commencing at stage 2 versus stage 3 AKI in a predominantly
surgical population (16), and a larger trial with predominantly SA-AKI showing no benefit from initiation at stage
3 AKI versus conventional criteria (17). The problematic
aspect of these studies and ongoing RRT-timing studies is
that AKI diagnosis on the basis of an isolated measurement creatinine doesn’t accurately reflect underlying GFR
when creatinine is rising due to lack of steady-state.
Furthermore, during critical illness and sepsis, creatinine
generation decreases rapidly so that, in two patients with
similarly decreased kidney function, creatinine is likely to
rise more slowly in the sicker patient. Urine output may
be a better guide because oliguria-anuria implies a very
low-level kidney function and predisposes to progressive
fluid overload. Thus, consensus AKI diagnostic criteria,
designed to categorize complete patient episodes by peak
creatinine or maximal oliguria, may not be the best guide
to dynamic decision making about RRT in real-time.
On assessment, our patient had urine output ,0.5 ml/kg
per hour for at least 9 hours, with repeat creatinine
2.6 mg/dl, urea 30 mg/dl, pH 7.31 (after sodium bicarbonate), and potassium 5.4 mmol/L. Although he is not
difficult to mechanically ventilate, cumulative fluid balance
since admission is now 17 L after peri-procedural fluid
therapy. He remains on high doses of vasopressor, lactate is
3.1 mmol/L, and cardiac index is 3.5 L/min per 1.73 m2,
consistent with vasodilatory shock with limited cardiac
reserve. Level of lactic acidosis does not suggest Metformin toxicity requiring RRT in isolation. Although no
absolute RRT indication is present and AKI based on
creatinine and charted urine output is only stage 2, the
likely clinical course seems clear. Importantly, in the context of refractory oliguria, progressive fluid overload is
probable, with its multiple adverse associations. A diagnostic challenge with diuretics might have been considered in a less acutely unwell patient; however, for this
patient RRT was deemed clinically indicated and was not
further delayed. Postdilution continuous veno-veno hemofiltration was commenced at a dose of 25 ml/kg per
hour using citrate anticoagulation. Initially, net fluid removal was not attempted, with ultrafiltration adjusted to
actively control on-going fluid balance and minimize
further fluid sequestration (18).
Subsequent Progress
Over the next 3 days, clinical condition stabilizes and
accumulated fluid overload is progressively resolved with
continuous RRT. Sensitive Klebsiella pneumoniae is grown
from blood. RRT is discontinued on day 7; however, recovery
for critical illness is prolonged. At hospital discharge (day 60)
creatinine is low-normal at 0.65 mg/dl. Importantly,
after prolonged hospitalization serum creatinine may
be a poor indicator of kidney recovery and overall prognosis (19). Thus, follow-up measurement of renal function
forms the final stage in AKI management (20).
Clinical Journal of the American Society of Nephrology
Dr. Prowle reports receiving speaker fees and travel from Baxter
Inc. and Nikkiso Europe GmbH and serves as a consultant for
Nikkiso Europe GmbH.
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