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34 Acute Kidney Disease 401
Fig. 34.1 Graph depicting some of the many hypothetical patient trajectories of GFR through
windows for diagnosis and staging of AKI, AKD, and CKD
these also capture AKD without antecedent AKI representing a relatively acute
progressive decline in kidney function where the rate of decrease is insufficient to
trigger AKI criteria within any 7-day window. Finally, when the 90-day window of
AKD elapses, there is not a smooth transition to CKD status as a patient with AKD
might lack CKD criteria as the estimated GFR was above 60 without proteinuria,
while conversely a patient without AKD based on the ratio between their cu
rrent and
baseline creatinine might still newly fulfil CKD criteria based on absolute eGFR or
presence of proteinuria. While the AKD concept was very much needed to complete
the classification of patients’ kidney health, it was difficult to apply clinically. In
recognition of this, the Kidney Disease: Improving Global Outcomes (KDIGO)
organization held a consensus conference aimed at “harmonizing acute and chronic
kidney disease definition and classification.” In these
deliberations, the definitions of
AKI and CKD retained by the AKD concept broadened to encompass “abnormalities
of kidney function and/or structure with implications for health and with a duration
of <3 months, ” mirroring the CKD definition but over a less rather than more than
3-month timescale. The definitions of these three disease entities draw on the
distinctions between the timing and persistence of renal disease as well as structural
and functional criteria (Table
34.2). T
no kidney disease (NKD) as a decline in GFR below the 60 ml/min/1.73 m
his means that AKD may arise in a patient with
2
which
has not yet persisted for 3 months or the new development of pathological proteinuria. Alternatively AKD may represent a rapid and substantial (sub)acute decline in
kidney function on a background of prior CKD that may eventually become CKD
402 G. Azzopardi and J. Prowle
Table 34.2 KDIGO definition of kidney diseases and disorders
NKD
AKI AKD CKD
Duration Within 7 days ≤3 months >3 months
Functional
criteria
Structural
criteria
Table adapted
report of a Kidney Disease: Improving Global Outcomes (KDIGO) Consensus Conference” [
AKI acute kidney injury, AKD acute kidney disease, CKD chronic kidney disease, NKD no kidney
disease
Increase in serum creati-
nine >50% within
7 days or increase in
serum creatinine by
0.3
mg/dl (26.5 €umol/
L) within
oliguria for ≥6h
Not defined Marker of kidney damage
from “Harmonizing acute and chronic kidney disease definition and classification:
2 days or
AKI or eGFR <
min/1.73
in GFR ≥35% or increase
in serum creatinine by
>50%
And/or And/or And
(proteinuria)
2
or decrease
m
60 ml/
GFR
<60 ml/
min/1.73 m
Marker of
kidney
damage
(proteinuria)
(no kidney
disease)
GFR
>60 ml/
2
min/
1.73 m
No
markers of
kidney
damage
2
10]
progression at 90 days or might potentially reverse back to baseline. In either
situation, severity of AKD is represented by current level of kidney function
and/or indication of structural damage in terms of proteinuria providing much better
harmonization with CKD definitions and better reflecting actual clinical practice.
Within this concept, episodes of AKI may exist to trigger an episode of AKD, occur
within an episode of AKD, or, in the case of transient AKI, may repr
esent the entire
AKD episode. Alternately AKD may exist without AKI, in fact particularly in
patients with CKD who experience a stochastic stepwise decline in kidney function.
As such, AKD presents an acute abnormality of kidney structure and function, while
AKI represents a rapid temporal change in creatinine or urine output—indicative of
an acute injury or physiological upset. Outcomes from AKD signify a stabilization of
kidney function to a new chronic baseline (to
enable CKD staging); however, some
patients with progressive CKD may be stuck in a cycle of recurrent AKD episodes as
their kidney function progressively declines toward requirement of chronic dialysis
or death. Thus, one of the key objectives of AKD management is to thus stabilize
kidney function and prevent future decline—as such, AKD presents clinicians with a
window of opportunity within the continuum of kidney disease to prevent further
kidney damage and alter the
long-term outcomes for patients. Finally, it is useful to
contrast the outcomes of AKD and development or not of CKD at a 90-day time
point to the Major Adverse Kidney Events (MAKE) definition [11]. MAKE has been
developed as a clinical trial endpoint and represents a composite of death, a need for
ongoing kidney replacement therapy, or a stated decline in kidney function from
baseline at a given time point after the exposure or injury of interest (most often
90 days). The importance of the last criterion is based partly on epidemiological
34 Acute Kidney Disease 403
evidence that a significant decline in kidney function over a short time is strongly
linked to eventual death or need for long-term dialysis [12], a decline of GFR or 25%
or 33% below baseline being the threshold commonly incorporated into MAKE. As
such, many AKD patients who persist to 90 days will meet MAKE criteria, and some
but not all of these will also then meet CKD criteria. Thus, MAKE is an overlapping
concept with AKD and CKD, not intended for day to day clinical use but as a robust
and meaningful clinical trial outcome. Clinicals should be aware of these different
definitions for different contexts, particularl
trials into everyday practice.
y when applying evidence from clinical
Clinical Course of AKD Within the ICU
AKI is a common feature of up to 50% of critical care admissions. While many
patients present with impaired kidney function without a recent baseline to properly
stage AKI, this does not preclude AKD classification based on assessment of
absolute kidney function. Indeed, in some databases, AKD has been found to be
almost three times more common than AKI with an increased risk of progression to
CKD and dialysis requirement [
represent first presentations with established CKD or progression of previous diagnosed CKD. Conversely, recovery from AKI within 48 h of its onset has been
associated with improved outcomes compared to AKI persisting beyon d this period.
Within the ICU, persistent severe AKI (stage 2 AKI persisting or progressing over a
72-h period) occurs in about 25% of patients who develop stage 2 AKI and is
strongly linked to mortality, morbidity, and non-recovery of kidney function
[
. P
14]
ersistent severe AKI therefore represents a distinct but allied concept to
AKD, as a patient following an adverse course of AKI likely results in a lengthy
duration of AKD, eventually leading to CKD or death.
Within the
tubular injury secondary to sepsis, surgery and trauma, low cardiac output states, and
drug-related nephrotoxicity [1, 15]. The spectrum of persistent AKD within the ICU
encompasses these causes of AKI in their most severe forms but is enriched in
patients with premorbid kidney dysfunction who are less likely to experience rapid
kidney recovery. Kidney biopsies are rarely performed in critical care; however,
1 study of 77 patients with AKI showed that up to 50% of patients had a specific
alternative diagnosis to classical acute tubular necrosis or less sever tubular injury
[
While there are significant selection biases in patients undergoing biopsies,
16].
these findings do underline the advice that specific renal diagnoses should be
considered when the severity and/or persistence of kidney dysfunction is out of
context with other aspects of their critical illness or when indicators of structural
kidney injury such as significant proteinuria or hematuria are present. One recent
study to date examined kidney biopsies of patients outside of the ICU that met AKI
and AKD criteria. They found that acute tubulointerstitial nephritis, cellular crescentic glomerulonephritis, and acute thrombot ic microangiopathy were more
intensive care unit (ICU), the most common causes of AKI are acute
13], probably because many of these presentations
404 G. Azzopardi and J. Prowle
common in patients with AKD without AKI than those with AKI alone suggesting
particular attention should be paid to the diagnosis of patients with subacute presentations with AKD as specific treatments are available for many underlying
conditions [
is the result of severe multifactorial kidney injury; in these patients, further research
is needed to advance the understanding of underlying phenotypes of kidney failure
or recovery to prognosticate kidney outcomes and enable targeted intervention.
17]. Nevertheless, the large majority of AKD in the intensive care unit
Prediction, Diagnosis, and Classification of AKD
A major challenge to the diagnosis and staging of AKI, AKD, and CKD during and
after critical illness is the reliance on comparison to a premorbid creatinine baseline
and/or the use of estimated GFR equations calibrated to a stable outpatient population. This usage neglects the fact that critically unwell patients are at substantial risk
of catabolism, muscle wasting [18], and subsequently low creatinine generation,
causing systematic overestimation of eGFR and making comparison of incident
creatinine to premorbid baseline inapplicable [19, 20]. Critically ill patients are
estimated to lose around 2% of muscle mass per day in ICU [21], so that by the
time clinicians are considering persistent AKI and AKD during prolonged ICU
admission, decrease in creatinine generation may be substantial precluding the
detection of significant AKD in a majority of at risk patients at ICU discharge
[20, 21]. Importantly, creatinine generation will also be decreased by dietary
changes, liver dysfunction, and mitochondrial bioenergetic changes in creatine
phosphorylation, so that reduced production may precede and be in excess of
overt reduction in muscle mass. It should be noted however that the eGFR formulae,
developed in an outpatient CKD population, do reflect a higher underlying prevalence of sarcopenia in patients with advanced CKD; thus, lower measures of eGFRcreatinine may be relatively more accurate, while apparently normal values may be
substantial overestimates. Measured GFR, urinary creatinine clearance, or other
serum biomarkers of GFR, such as cystatin-C or pro-encephalin, may be more
reflective of true GFR in the critical care population [20, 22]. Thus, the choice of
measure of kidney function for the detection and classification of AKD during and
after critical illness should be made judiciously, and alternatives to sole use of serum
creatinine sough where available. Also, additional context from measurement of
serum urea and presence of proteinuria can be used to develop a better picture of
likely underlying kidney health.
Within the
critical illness during AKI episodes. The furosemide stress test (FST) is a diagno stic
challenge currently utilized in critical care to identify those at risk of AKI progression and those who might require renal replacement therapy. It tests kidney tubular
function in terms of secretion and response to a standardized dose of intravenous
furosemide. Poor response to the furosemide stress test has been shown to be
predictive of developing stage 3 AKI in ICU patients [
ICU, it would be useful to predict AKD duration and severity earlier in
23, 24].
The FST might
34 Acute Kidney Disease 405
also be useful in predicting the progression of renal disease and renal recovery
during AKD as well as providing guidan ce on the immediate clinical course.
The presence and persisten
sure to perform in critical care patients. Further studies of proteinuria (and other
biomarkers) during the AKD time period are warranted to enable us to use this
information to predict and prognosticate the outcomes of patients with AKD as while
huge volumes of data exist relating chronic proteinuria to outcomes in CKD, its
significance during the acute period and its relationship to long-term prognosis are
less well quantified.
Currently, there is no predictive or prognostic biomarker specifically for the
development and recovery of AKD. However, candidate biomarkers predictive of
persistence, recovery, and worsening of kidney disease may provide some insight
into the course of AKD. For example, urinary C-C motif chemokine ligand
14 (CCL14), a chemokine potentially involved in monocyte activation and fibrotic
response to injury, has been identified a promising predictive biomarker for persistent and severe AKI in critically ill patients with early stage 2–3 AKI [25]. Furthermore, persistent elevation of CCL-14 was associated with continued risk of
persistent severe AKI [26]. This makes CCL-14 an attractive biomarker of underlying severity of parenchymal kidney injury and expected medium term prognosis.
Similarly, soluble urokinase plasminogen activator receptor (suPAR), an innate
immune-derived molecule implicated in inflammatory organ damage, has been
shown to predict CKD progression, AKI incidence during acute illnesses, and risk
of progression to severe AKI requiring kidney replacement therapy in sepsis
[27, 28]. Another biomarker of CKD is urinary dickkopf-3 (DKK-3) a marker of
chronic renal tubular stress measured preoperative before cardiac surgery. DKK-3
has been shown not just to associate with AKI risk but also AKI recovery and
subsequent kidney function loss at 90 days—providing anothe r candidate biomarker
not just of AKI risk but AKD and CKD risk which is quantifiable prior to a planned
insult.
ce of proteinuria is a relatively straightforward mea-
Management of AKD in Critical Care and Beyond
Once AKD is identified, further management draws on the principles underlying
both AKI and CKD management. If a specific cause of intrinsic renal disease is
identified, such as vasculitis, this should be treated in collaboration with specialist
nephrology teams. When kidney disease results as a consequence of another chronic
disease such as cardiac (Type 1 cardiorenal syndrome) or liver disease (hepatorenal
syndrome), management should be focused toward treating the underlying condition
if possible. However, the majority of AKD in the critical care unit will have a
multifactorial cause of kidney damage, meaning that management will be focused on
reducing the risk of progression and preserving residual kidney function. This
includes but is not limited to stopping or avoiding potentially harmful medications,
406 G. Azzopardi and J. Prowle
restoring and maintaining an appropriate fluid balance, and treating potential triggers
such as sepsis.
Particularly pertinent to
critical care is careful attention around the use of medications such as aminoglycosides, ß-lactams, and other potentially harmful drugs and
their metabolites. Factors to consider include renal metabolism, excretion, and
potential for further nephrotoxicity or kidney injury. These will vary during each
phase of kidney injury, recovery, or non-recovery. Creatinine-based equations may
not be the optimal method of estimating GFR to guide drug dosing, due to loss of
muscle mass, and other biomarkers such as cystatin-C may be more appropriate
measures during this time point.
Consideration should also be applied to identify when to restart medications such
as angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor
blockers (ARBs) if they have been stopped. Traditionally, these have been considered “nephrotoxic”; however, there is evidence that while these may be reducing
GFR, they may not be inflicting kidney injury. A secondary analysis of the Veteran
Affairs Nephropathy in Diabetes (VA NEPHRON-D) study showed that sequential
renin-angiotensin system (RAS) blockade with ACE-I and ARBs increased the risk
of developing AKI; however, they were less likely to die within 30 days of
developing AKI and were more likely to recover kidney function within 25% of
their baseline serum creatinine [29]. A multicenter ICU study showed that the
prescription of ACE-I at ICU discharge was associated with a lower 1-year mortality
rate in patients who experienced AKI [
30]. The use of ACE-I and ARBs in AKD has
not been studied, and there are both potential harms and benefits associated with
their use during this period which needs further investigation.
Preserving residual kidney function and preventing the consequences of kidney
disease should be considered in all AKD patients surviving their acute illness. This
includes management of blood pressure, reducing proteinuria, and addressing the
future risk of cardiovascular disease. Two recent advances in this area include the
use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors and mineralocorticoid
antagonists, targeted at preventing the progression of kidney disease. DAPA-CKD
showed a reduction in the progression of CKD, the development of ESKD, or death
from a renal or cardiovascular cause was lower in patients with an eGFR of
25–75 ml/min/1.73 m
who were on dapagliflozin [
empagliflozin led to a lower risk of progression of CKD in patients with an eGFR
between 20 and 45 ml/min/1.73 m
2
1.73 m
with an ACR of >200 mg/g [32]. Recent guidelines [33] have seen the
2
and albumin/creatinine ratio (ACR) of 200–5000 mg/g
Similarly, EMPA-Kidney showed that
31].
2
and those with an eGFR >45– 90 ml/min/
introduction of finerenone, a mineralocorticoid antagonist, for the treatment of
patients with CKD stage 3–4 and type 2 diabetes following the FIDELIO-DKD
trial. Here they showed that finerenone was associated with a reduction in kidney
failure, progression of CKD, and death from a renal cause in patients with an eGFR
of 25–60 ml/min/1.73 m
min/1.73 m
2
and an ACR of 300–5000 mg/g [34]. It is unknown whether these
2
and an ACR of 30–<300 mg/g or an eGFR of 25–75 ml/
interventions would have the same effect if started earlier in the disease process
during AKD before CKD is formally diagnosed, but recognition of the risk of
34 Acute Kidney Disease 407
developing future CKD would certainly highlight these patients as those who may
potentially benefit in the future. Importantly, while SGLT-2 inhibitors cause a stepdown in GFR when commenced, this is then associated with a lower risk of CKD
progression over time. Similarly, despite initial concerns, chronic use of SGLT-2
inhibitors has been associated with a lower incidence of AKI during follow-up. More
complex pharmacological management after AKD will however dema
to monitor and adjust this treatment, a challenge in many care environments where
routine nephrology follow-up is only available to patients with advanced kidney
disease after critical illness.
AKI and ICU admission have
negative impact on physical, emotional, and mental health [35, 36]. The “po stintensive care syndrome” (PICS) is now a relatively well-recognized consequence
of ICU admission and includes worsening physical and mental health and the
development of neurocognitive disorders. Although studies are small, patient education and knowledge surrounding AKI and its impact on future health is poor,
particularly as its presentation is often asymptomatic in the early stages
[37, 38]. CKD and ESKD are also linked with depression and anxiety [39]. It is
therefore not unreasonable to predict that these associations will be present in those
with AKD. AKD, therefore, presents a further time period where holistic care,
involving patient education, multidisciplinary therapies, and mental health interventions, may have an impact on not just kidney health but on the future of long-term
mental health and well-being of patients.
Some of the interventions discussed may not be appropriate to initiate within
critical care, or as an inpatient, so ensuring appropriate follow-up is in place prior to
discharge enables these interventions to be considered. Timing for follow-up is
another area which lacks consensus—KDIGO AKI guidance suggests evaluation
for kidney disease 3 months after AKI [40]. One study has looked at nephrology
follow-up after AKI in patients meeting AKD criteria, where they found that those
who received nephrology aftercare had improved survival and cardiovascular outcomes [41]. Large-scale application of this may not be practical given the potentially
increasing numbers of patients with AKD. Careful selection of patients who will
benefit the most will need to be considered, and close communication and working
with primary care physicians will be essential. ICU follow-up is an evolving area
within critical care, and we may play an important role in assessing and protecting
kidney health during this time. We know that current follow-up practices post-AKI
are variable and therefore the ADQI consensus report suggests a proportional model
for follow-up related to baseline risk factors and severity of AKD [9].
both been associated with an increased risk of a
nd a process
Conclusions and Future Directions
AKD is a novel concept which expands on the current definitions of kidney disease,
joining CKD and encompassing AKI. It lies within a time frame that is particularly
applicable to many patients experiencing persistent critical illness, who are already
408 G. Azzopardi and J. Prowle
among those at highest risk of adverse long-term health outcomes. There are many
unanswered questions and research opportunities within AKD. Importantly wider
education promotion of the terminology and definitions is required. However, better
identification of patients with acute worsening of their kidney health presents us with
an opportunity to positively impact and alter the long-term outcomes for those who
may otherwise go unrecognized until they have develope
d advanced CKD. Specific
areas of investigation relevant to the intensivist are the prediction of the development
of AKD, diagnosing reversible causes of AKD, preventing secondary kidney injury,
and initiating a multifaceted management and follow-up plan for the patient with
AKD disch arged from ICU. Improving care will be a complex task; however, in
recent years, care of CKD in the community has been revolutionized by a series of
new inte rventions providing great optim
ism that we may be able to transfer some of
this success to patient with AKI and AKD.
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