Intensive Care Med

https://doi.org/10.1007/s00134-022-06946-0

LASTING LEGACY IN INTENSIVE CARE MEDICINE

Acute kidney injury

Marlies Ostermann1* , Rajit K. Basu2 and Ravindra L. Mehta3

© 2022 Springer-Verlag GmbH Germany, part of Springer Nature

The understanding of acute kidney injury (AKI) has Different nephrotoxic triggers elicit divergent responses
evolved from the perception of a single disease to a within the kidney at genetic, molecular, cellular and
multi-factorial syndrome with a complex and varying functional level, resulting in distinct patterns of injury
pathophysiology and prognosis. Before 2004, more than [5]. For instance, volume depletion leads to activation
50 different definitions of AKI (or ‘acute renal failure’) of metabolic pathways consistent with starvation (such
were in use and the reported incidences, prevalences as gluconeogenesis, lipid metabolism) as well as anti-
and outcomes were very variable. The publication of the inflammatory molecules and predominantly affects the
‘Risk, Injury, Failure, Loss, and End-stage kidney disease’ inner medulla. In contrast, ischaemia stimulates genes
(RIFLE) criteria in 2004, followed by the AKI Network related to inflammatory, coagulation and epithelial repair
(AKIN) classification in 2007, and the current AKI Kid- pathways with most changes seen in the outer medulla.
ney Disease Improving Global Outcomes (KDIGO) con- Despite a similar SCr rise, there is often little overlap
sensus classification in 2012 [1] have facilitated epide- of activated genes between different AKI models. The
miological studies showing a high prevalence of AKI specific characteristics of different nephron segments,
worldwide, a link between AKI severity and outcomes, a including heterogeneity in metabolic pathways and abil-
high risk of short- and long-term complications, includ- ity to activate cellular defence mechanisms account, at
ing chronic kidney disease (CKD) and major economic least in part, for the variable regional susceptibility of
consequences [2, 3] (Fig. 1). tubular cells to injurious stimuli. The patterns of injury
AKI diagnosis and staging currently rely on a rise in are impacted further by associated comorbidities and
serum creatinine (SCr) and/or decrease in urine output components of clinical management. Research in sep-
without consideration of the various aetiologies, sites and sis-associated AKI presents another apt example of the
severity of injury, timing and course of disease and the evolution in knowledge [6]. Once simplified into a bipar-
response to therapy [4]. To compensate for these limita- tite model of ‘ischemia to the glomerulus’ and ‘tubular
tions, descriptors are often added, for instance, ‘subclini- necrosis’, it has expanded into a sepsis ‘portfolio’ of injury,
cal AKI’ (tubular injury without a SCr rise or with a SCr inclusive of (but not limited to): (a) glomerular capil-
rise not meeting AKI criteria), ‘transient, sustained or lary vasomotor instability, (b) microcirculatory dysfunc-
persistent AKI’ (based on the duration of SCr elevation), tion, (c) mitochondrial dysregulation, (d) inflammasome
‘community’ or ‘hospital acquired’ AKI, and ‘recovered perturbations from endocrine and paracrine cytokine
AKI’ (SCr decrease after peak). However, there are no mediators, (e) disruption in pathogen-associated molec-
agreed definitions for these terms [4]. ular activity receptors, (f ) tubular injury; (g) interstitial
inflammation; (h) aberrant autophagy and efferocytosis
Mechanisms contributing to AKI of important repair molecules, and (i) impact of associ-
Our contemporary understanding of the mechanisms ated comorbidities and clinical strategies used to mitigate
involved in AKI appreciates the heterogeneity of disease. the insult (i.e. fluids and catecholamines). An important
revelation of clinical and experimental studies is the asso-
ciation between AKI and new-onset CKD [3, 7]. Mala-
*Correspondence: [email protected] daptive repair and interactions between injured proximal
1
Department of Critical Care, King’s College London, Guy’s & St Thomas’ tubular cells and fibroblasts appear to play a role. These
NHS Foundation Hospital, London SE1 7EH, UK
Full author information is available at the end of the article
insights have improved our understanding and offer tar-
gets for potential future therapies.
 First description First RCT
First ADQI
of ARF by investigating Introduction of
consensus RIFLE criteria
Baywaters and timing of RRT in term AKI
meeting23
Beal Critical Care21

1941 2000 2002 2003 2004

EARLYARF trial19
AKIN - First biomarker KDIGO AKI
guided RCT in
AKI

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

NIH Precision
AKI - EPI study16 AWARE study18
Medicine project
25th ADQI
KDIGO AKD
consensus
First RCT meeting24
0by25 Global
investigating AKI AWAKEN study17
Snapshot study20
e-alerts22

2015 2016 2017 2019 2020 2021

Metabolomic & transcriptomic studies in AKI Discovery of new kidney biomarkers Development
of new imaging techniques Investigation of AKI e-alerts & digital tools

Fig. 1 Chronological evolution of AKI research. AKI acute kidney injury, ARF acute renal failure, AKD acute kidney disease,
KIN acute kidney injury network, RIFLE Risk–Injury–Failure–Loss–End-stage, RCT​randomised controlled trial, RRT​ renal
replacement therapy, KDIGO Kidney Disease Improving Global Outcomes, NIH National Institutes of Health

Emerging trends AKI subphenotypes

Biomarker‑based characterisation Subphenotyping identifies subgroups of patients with
The discovery of kidney damage biomarkers (e.g. NGAL, different biological mechanisms, treatment responses or
KIM-1, IL-18, TIMP-2, IGFBP7 and CCL14) and alterna- prognosis [10]. Using latent class analysis of clinical and
tive functional markers (e.g. Cystatin C and Proenkepha- biomarker data from the first 48 h in intensive care unit
lin) has provided insight into the potential aetiology, (ICU), Bhatraju et al. analysed 1800 patients of whom
pathophysiology and prognosis of AKI [8]. For instance, 794 had AKI [11]. They identified two independent pop-
evidence from about 4,000 patients revealed that 15–20% ulations: Subphenotype 1 was characterised by a low
had elevated NGAL levels without a SCr rise. This was ratio of angiopoietin (Ang) 2/Ang1 and soluble tumour
associated with a two-to-threefold increased risk of death necrosis factor receptor (sTNFR) 1 and signified a hypo-
or need for renal replacement therapy (RRT) compared inflammatory state. Mortality was lower compared to
to patients without a SCr or NGAL rise [9]. subphenotype 2 which had high Ang2/Ang1 ratios and
higher sTNFR-1 and represented a hyper-inflammatory
state with increased vascular permeability. These find-
ings were replicated in 800 patients enrolled in a different
sepsis trial showing that mortality and dialysis need were new therapies and reno-protective strategies, supported
higher in patients with subphenotype 2. Similarly, a post by tools to measure kidney function more accurately and
hoc analysis of the Finnish Acute Kidney Injury (FiN- in real time. AKI alerts and machine learning models in
NAKI) study of patients with sepsis-associated AKI iden- electronic health records should improve earlier identi-
tified two subphenotypes with subphenotype 2 having fication of patients while the availability of telemedicine,
elevated levels of inflammatory and endothelial markers, digital health tools and improved awareness of the dis-
lower short-term recovery and a higher 90-day mortality ease can support follow-up of patients even in remote
[12]. The identification of these different subphenotypes settings.
underpins the change in our perception of AKI as a ‘sin-
gle disease’ to AKI being a complex syndrome (Supple- Supplementary Information
The online version contains supplementary material available at https://​doi.​
mentary Fig. 1). org/​10.​1007/​s00134-​022-​06946-0.

AKI across the lifespan

Author details
Neonatal and paediatric AKI have emerged as impor- 1
Department of Critical Care, King’s College London, Guy’s & St Thomas’ NHS
tant paradigms of critical care nephrology. Multi-centre Foundation Hospital, London SE1 7EH, UK. 2 Ann & Robert Lurie Children’s
studies including the AWARE and AWAKEN study have Hospital of Chicago, Northwestern University, Chicago, IL, USA. 3 University
of California, San Diego Health Sciences, San Diego, CA, USA.
revealed unique, discernible AKI phenotypes in children
different from adults [13–15] (Fig. 1). Even though AKI Declarations
demonstrates a synergism with adult comorbidities on
Conflicts of interest
patient outcome, AKI in children with both unique co- MO, RKB and RLM report no conflict of interest related to the content of the
morbid conditions (e.g. inborn errors of metabolism) manuscript.
and in those without any medical history demonstrates
the independent contribution of AKI with host outcome.
Further, the effects of premature birth on kidney matura- Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in
tion and the impact of a single AKI episode during kidney published maps and institutional affiliations.
development on short- and long-term outcomes remain
incompletely understood. Finally, the influence of sex, Received: 16 October 2022 Accepted: 28 November 2022
nutrition and biological development (growth) through-
out childhood and puberty on the risk and prognosis of
AKI has yet to be fully characterised [14]. The kindle of
injury which may start in the neonatal period of life can References
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