NEWS & VIEWS

DECADE IN REVIEWACUTE KIDNEY INJURY

Acute kidney injurya decade

ofprogress
Rinaldo Bellomo

The past decade has seen developments in several aspects of acute

kidney injury (AKI), including the discovery of an array of biomarkers,
assessment of the optimal dose intensity for renal replacement therapy,
and the impact of fluid administration. Furthermore, AKI has emerged as
an important risk factor for chronic kidney disease.
Clinical research dedicated to understanding, diagnosing, and treating acute kidney
injury (AKI)a term that, by consensus, has
now substituted the previously used acute
renal failurehas increased markedly over
the past 10years. The number of research
papers on this topic has doubled during the
past decade, and during this period several
trends have evolved. One key development
has been the discovery and testing of biomarkers for early AKI. Heralded by the first
publication of the predictive value of neutrophil gelatinase associated lipocalin (NGAL)
in paediatric cardiac surgery,1 biomarker
discovery and testing for the early indication and prognosis of AKI has undergone
a remarkable degree of exploration. More
than a dozen candidate biomarkers with
variable predictive value have now been
identified in urine and blood, with typical
values for the area under the receiver operating characteristic (AUROC) curve ranging
between 0.65 and 0.85 (Figure1). NGAL
has been the most investigated biomarker
so far, with mixed results and some serious
u TIMP-2
IGFBP-7
u TIMP-2
u IGFBP-7

Biomarker

u NGAL
p Cys C
u KIM-1
p NGAL
u IL-18
u pi-GST
u L-FABP

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8

AUROC

concerns regarding assay reproducibility

together with the growing understanding
that NGAL probably represents a family of
molecules of different origin and with different epitopes. The most recent and more
systematically studied biomarker discovery
relates to the so-called cell cycle arrest biomarkers, which have now been assessed in
several large cohorts and have achieved consistent AUROC values of ~0.8 (Figure1).2
Although now FDA approved, the value of
cell cycle arrest biomarkers in clinical practice remains unclear and is hampered by the
absence of specific linked therapies.
Irrespective of the possibility of early
diagnosis, some patients develop severe
AKI and are deemed to require renal
replacement therapy (RRT), raising the
issue of optimal dose intensity. After some
initial small and single institution studies
that produced promising results, two large
multicentre trials (one in the USA3 and the
other in Australia and New Zealand4) tested
whether increasing the intensity of RRT
from an effluent flow of 2025ml/kg per
hour in continuous modes or from intermittent dialysis, to 3540ml/kg per hour or
Figure 1 | Histogram summarizing the
estimated AUROC for 12 biomarkers used to
predict early AKI. The predictive value of each
biomarker for AKI stage 2 or 3 (according to
the Kidney Disease: Improving Global
Outcomes in Acute Kidney Injury working group
guidelines) was assessed within 12h of urine
or blood sampling. Data obtained from the
Sapphire study2 under the Creative Commons
agreement. Kashani, K. et al. Crit. Care 17,
R25 (2013). Abbreviations: AKI,acute kidney
injury; AUROC, area under receiver operating
characteristic; p, plasma; u, urinary.

daily dialysis would increase survival. Both

studies were identical in demonstrating a
lack of effect on survival, thus establishing
a worldwide standard of care in relation to
RRT dose.
The epidemic of chronic kidney disease
(CKD), chronic heart failure, acute decompensated heart failure, and AKI prompted
consideration of the complex interactions
between cardiac and renal function, kidney
heart cross talk, and the clinical syndromes
that can ensue to be conceptualized as
cardiorenal syndromes. The initial definition, description, and proposed mechanisms
by which acute disease of each organ could
affect the other has spawned important
reinvestigations and greater understanding of applied pharmacology in this field.5
Importantly, and together with other studies,
the concept of cardiorenal syndrome has
shifted the focus of management in patients
with AKI from the administration of fluids
to rescue the failing kidney, to a greater
understanding and concern that fluid
administration might have little beneficial
effect on renal function and could impose
a substantial contribution to positive fluid
balance. A positive fluid balance might,
in turn, cause renal oedema, delay renal
recovery, injure vital organs, and increase
mortalityan effect seen most strikingly in
children with severe AKI.6
Faced with such varied practice patterns,
the utility of several definitions of AKI,
and uncertainty with regard to how best to
manage patients with developing or established AKI, a large group of experts were
funded to develop a detailed framework of
reference for the definition, diagnosis, prevention, and treatment of AKI. The Kidney
Disease: Improving Global Outcomes in
Acute Kidney Injury working group delivered an analysis of all literature in this field
and generated a global definition for this syndrome, which represents the most comprehensive body of references and information
associated with this condition to date.7
Simultaneously, and published in the
same year, intensive care investigators
tackled the possible effect of fluid choice on
renal outcomes in critically ill patients. Two
large multicentre double-blind randomized trials compared the most commonly
administered artificial colloid solution in

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the world for fluid resuscitation (hydroxyethyl starch [HES]) and compared it with
saline. In a study of patients with severe
sepsis, the Scandinavian Critical Care Trials
Group found that fluid resuscitation with
HES increased mortality and the incidence
of AKI, including severe AKI requiring
RRT.8 Concordant with such findings, the
Australian and New Zealand Intensive Care
Society Clinical Trials Group investigated
a broad cohort of all patients in intensive
care treated with fluid bolus therapy and
also found that the administration of HES
increased the need for RRT.9 These studies
have established beyond doubt that HES is a
nephrotoxin and has led to a major decrease
in its use in developed countries.
Finally, the impact of AKI on the longterm outcome of patients both from a
general and renal point of view has become
a focus of active investigation after a seminal
study of ~4,000 patients identified a clear
association (a threefold increase in risk)
between an episode of AKI requiring dialysis and the subsequent need for chronic
dialysis despite initial recovery. 10 Other
studies have since confirmed this associ
ation. Whether these findings relate to the
possibility that patients who develop AKI
have characteristics that make them more
likely to develop CKD or represent a specific deleterious effect of AKI on renal function is unclear. These data have confirmed,
however, that patients with AKI require

specific medical attention and represent a

new at-risk population for CKD.
In summary, we have made notable
strides in understanding the pathology and
improving outcomes in AKI over the past
decade. We have identified new biomarkers that could prove useful in the future,
defined a standard dose for RRT, recognized
the adverse consequences of overzealous
fluid therapy on the kidney as well as the
patient, defined the need to develop focused
interventions to modulate the cross-effect of
simultaneous acute losses of kidney function and cardiac function, developed a set
of practice guidelines that provide a baseline reference point definition and approach
to AKI management for future reference,
clearly demonstrated the nephrotoxiciy of
HES and, finally, have shown that AKI is
a major risk factor for CKD. Despite these
advances that have undoubtedly decreased
patient harm, we remain deeply ignorant
of the molecular mechanisms responsible
for the development of AKI in humans and
have not yet devised a single specific and
effective therapy to prevent, treat, or attenuate AKI. Much remains to be done in this
field before notable improvements can be
made to patient outcomes.
Australian and New Zealand Intensive Care
Research Centre (ANZICRC), Monash
University, Commercial Road, Melbourne,
VIC3181, Australia.
rinaldo.bellomo@austin.org.au

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doi:10.1038/nrneurol.2015.147
Published online 15 September 2015
Competing interests
R.B. has received grants from Baxter and honoraria
from Gambro and B. Braun.
1.

Mishra, J. etal. Neutrophil gelatinaseassociated lipocalin (NGAL) as a biomarker for

acute renal injury after cardiac surgery. Lancet
365, 12311238 (2005).
2. Kashani, K. etal. Discovery and validation of
cell cycle arrest biomarkers in human acute
kidney injury. Crit. Care 17, R25 (2013).
3. VA/NIH Acute Renal Failure Trial Network.
Intensity of renal support in critically ill patients
with acute kidney injury. N.Engl. J.Med. 359,
720 (2005).
4. The RENAL Replacement Therapy Study
Investigators. Intensity of continuous renal
replacement therapy in critically ill patients.
N.Engl. J.Med. 361, 16271638 (2009).
5. Ronco, C. etal. Cardiorenal syndrome.
J.Am. Coll. Cardiol. 52, 15271539 (2008).
6. Sutherland, S.M. etal. Fluid overload and
mortality in children receiving continuous
renalreplacement therapy: the prospective
pediatric continuous renal replacement therapy
registry. Am. J.Kidney Dis. 55, 316325
(2010).
7. KDIGO working group. KDIGO clinical practice
guidelines for acute kidney injury. Kidney Int.
Suppl. 2, 1136 (2012).
8. Perner, A. etal. Hydroxyethyl starch 130/0.42
versus Ringers acetate in severe sepsis.
N.Engl. J.Med. 367, 124134 (2012).
9. Myburgh, J.A. etal. Hydroxyethyl starch or
saline for fluid resuscitation in intensive care.
N.Engl. J.Med. 367, 19011911 (2012).
10. Wald. R. etal. Chronic dialysis and death
among survivors of acute kidney injury
requiringdialysis. JAMA 302, 11791185
(2009).

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