Acute Kidney Disease to

C h ro n i c K i d n e y D i s e a s e
a, b
Javier A. Neyra, MD, MSCS *, Lakhmir S. Chawla, MD

KEYWORDS
 Acute kidney injury  AKI  Acute kidney disease  AKD  Chronic kidney disease
 CKD  Kidney recovery

KEY POINTS
 Acute kidney injury (AKI) and chronic kidney disease (CKD) are common interconnected
syndromes that represent a public health problem. AKI and CKD predispose to each other
in a vicious circle and may exert negative impacts independently or synergistically.
 The term AKD has emerged and is defined as the post-AKI status of acute or subacute
kidney damage/dysfunction manifested by persistence of AKI stage 1 or greater (Kidney
Disease: Improving Global Outcomes criteria) beyond 7 to 90 days after the initial AKI
diagnosis. If criteria of AKI persist beyond 90 days, it is considered incident or progressive
CKD according to baseline kidney function.
 Pathways of maladaptive repair predisposing to inflammation and fibrosis leading to CKD
have been identified and include cell cycle arrest, endothelial injury followed by capillary
regression and rarefaction, mitochondrial dysfunction, fibroblast/macrophage-aberrant
differentiation and function, and the immune response with imbalance of more proinflam-
matory injury and less anti-inflammatory repair.
 Limited clinical data exist with regard to AKD epidemiology. Studies published after AKD
was formally defined have limited generalizability as they represent heterogeneous pop-
ulations with distinct timeframes of observation to define AKD. At least 1 of 4 AKI survivors
developed AKD by 90 days of follow-up.
 Useful risk-stratification tools to predict risk of AKD and its prognosis are needed. Timely
kidney-protective approaches centered in aspects such as fluid management, exposure
to nephrotoxic agents, and follow-up care may have a big impact in AKD management
and outcomes.

a
Department of Internal Medicine, Division of Nephrology, Bone and Mineral Metabolism,
University of Kentucky Medical Center, 800 Rose Street, MN668, Lexington, KY 40536, USA;
b
Department of Medicine, Veterans Affairs Medical Center, 3350 La Jolla Village Drive, San
Diego, CA 92161, USA
* Corresponding author.
E-mail address: javier.neyra@uky.edu

Crit Care Clin 37 (2021) 453–474

https://doi.org/10.1016/j.ccc.2020.11.013 criticalcare.theclinics.com
0749-0704/21/ª 2020 Elsevier Inc. All rights reserved.
454 Neyra & Chawla

INTRODUCTION

Chronic kidney disease (CKD) represents an enormous public health problem due to
its high prevalence, economic impact, and strong association with morbidity and mor-
tality.1–3 Acute kidney injury (AKI) is a common complication during hospitalization that
occurs in approximately 1 of 5 hospitalized patients and in 1 of 2 critically ill patients in
the intensive care unit (ICU).4–6 These 2 clinical syndromes are interconnected, as sur-
vivors of AKI have increased risk of CKD and end-stage kidney disease (ESKD),7,8 as
well as cardiovascular disease.9–14 Conversely, patients with underlying CKD have an
increased risk of AKI, so that AKI and CKD predispose to each other in a vicious circle
and may exert negative impacts independently or synergistically.4,15–17
The heterogeneity in AKI definitions from different etiologies and practice variations
for AKI diagnosis and management precluded, for many years, the development of
robust epidemiologic data that clearly delineated the interplay between AKI and
CKD. To overcome these barriers, the Kidney Disease: Improving Global Outcomes
(KDIGO) Clinical Practice Guidelines emerged to standardize criteria for AKI diag-
nosis and management.18 Although the main goals of promoting early AKI recogni-
tion and standardizing AKI diagnosis were fulfilled, the period of transition from
AKI to CKD (also known as acute kidney disease [AKD]) was poorly defined and
seldom characterized in clinical practice. In this context, the Acute Disease Quality
Initiative (ADQI) 16 Workgroup proposed a consensus and more practical definition
of AKD to promote its widespread application in clinical research and direct patient
care.19
In this article, we review the AKD definition and the challenges of its recognition,
emerging epidemiologic data of AKD, key pathophysiological concepts of the AKI-
to-AKD-to-CKD interplay, and important aspects of AKD management for reducing
the burden of CKD.

EPIDEMIOLOGY OF CHRONIC KIDNEY DISEASE

CKD is a major public health problem that affects more than 20 million individuals in
the United States (w15% of the US population) and carries devastating human and
economic burden.1 CKD is a major cause of disproportionate morbidity and mortality,
ranking as the ninth leading cause of death in the United States.2 The financial cost of
CKD care accounts for 20% of total Medicare spending with the most costly care
related to ESKD.3 Therefore, there is an urgent need to identify public health interven-
tions that can mitigate the incidence and progression of CKD.
To mitigate the burden of CKD and its devastating complications, such as cardio-
vascular disease and death, identification of modifiable risk factors for development
and progression of CKD is necessary. A critical contributor to the prevalence of
CKD is AKI, which increases the risk of development of CKD by as much as 10-
fold, and strongly associates with cardiovascular disease, poor health-related quality
of life, rehospitalizations, and death.4,8–11,20–24

EPIDEMIOLOGY OF ACUTE KIDNEY INJURY

AKI affects up to 20% of hospitalized patients and up to 50% of patients admitted to

the ICU.4–6 The incidence of AKI is growing by 10% per year,25–27 whereas the
morbidity and mortality associated with its occurrence remain exceedingly high.28,29
AKI is associated with increased length of ICU and hospital stay, and disproportionate
increased resource utilization and health care costs.30 Furthermore, complications af-
ter an episode of AKI are also common and include cardiovascular disease,9–13
 Acute Kidney Disease to CKD 455

hypertension,14 and the development or progression of CKD or ESKD.7,23,24 Estimates

of 10-fold higher risk of CKD and 3-fold higher risk of ESKD following an episode of AKI
have been determined from multiple observational studies.7,8 Importantly, ESKD due
to AKI carries higher 6-month mortality risk than ESKD related to other causes.31
Therefore, early AKI recognition and risk-stratification are needed for implementation
of timely interventions that can mitigate further kidney damage and complications of
AKI.32
Survivors of AKI, especially those with severe AKI, are at high risk for developing
CKD, and this is compounded by concerns of inequitable access to health care or
inadequate postdischarge processes of health care.33 This is particularly important
because survivors of AKI frequently experience recurrence of AKI and rehospitaliza-
tions at rates of up to 25% and 50% within a year after discharge, respectively.34
Hence, improving care following AKI has been recognized as critical to reducing
AKI to CKD transition and CKD progression and importantly, to improving patient-
centered quality-of-life outcomes.35
There is a bidirectional interplay between AKI and CKD and recognized risk factors
of kidney disease, such as age, diabetes, hypertension, and proteinuria beget both
conditions.14,36,37 Therefore, there was a dire need to systematically differentiate pa-
tients with ongoing acute kidney pathology versus those in the recovery phase of
AKI, specifically in the period of 7 to 90 days following AKI diagnosis. This context
nurtured the concept of AKD, which was formally proposed and defined by the
ADQI Workgroup 16 in 2017.19 This new concept is critically important, as AKD rep-
resents a period in which tailored interventions both in inpatient and outpatient set-
tings can be potentially instituted to favorably alter the natural history of kidney
disease (Fig. 1).

Fig. 1. Conceptual interplay and epidemiology of AKI, AKD, and CKD. The incidence of AKI
in hospitalized patients is approximately 20% and AKD occurs in 1 of 4 survivors of AKI by
90-days post-AKI onset, albeit epidemiologic data of AKD are still limited. It is estimated
that 1 of 3 patients surviving an episode of AKI may develop incident or progressive CKD
within the subsequent 2 to 5 years. An important consequence of AKI is cardiovascular dis-
ease, which carries a great burden of morbidity and mortality in these patients. CVD, cardio-
vascular disease.
456 Neyra & Chawla

ACUTE KIDNEY DISEASE AFTER ACUTE KIDNEY INJURY

Definition of Acute Kidney Injury
The KDIGO Clinical Practice Guideline defined AKI as an absolute increase in serum
creatinine (SCr) by 0.3 mg/dL (26.5 mmol/L) within 48 hours; or a relative increase in
SCr 1.5 times baseline within 7 days; or urine volume less than 0.5 mL/kg per hour
for 6 hours.18 However, one should recognize that despite the urine volume criterion
is known to be informative of AKI incidence and prognosis38 and is now more
commonly used and monitored in clinical practice given the recognition of the detri-
mental effects of fluid overload,39–41 it has seldom been examined in observational
studies of AKI. Therefore, the epidemiology and characterization of AKI are mostly
based on SCr changes over time.

Duration of Acute Kidney Injury

Rapidly reversible episodes of AKI within 48 hours of onset are epidemiologically
distinct from those that last more than 48 hours for the association with short-term
and long-term mortality. This has been demonstrated in observational studies
including postoperative and critically ill patients with AKI.42–45 Therefore, the terms
“transient AKI” and “persistent AKI” are used for describing episodes of AKI of dura-
tion of less than and more than 48 hours, respectively.19 Further, a minimum sustained
AKI reversal for a period of 48 hours has been suggested by consensus for evaluation
of recurrent or de novo AKI episodes. One should exert caution when interpreting
these recommendations, as urine output data may be inaccurate in patients without
urinary catheters and SCr is susceptible to specific clinical conditions such as sepsis,
sarcopenia, and fluid overload/change in volume of distribution,46–49 which can
acutely affect SCr interpretation as a surrogate of kidney function.
The early recognition of “persistent AKI” may facilitate further evaluation of AKI eti-
ology and interventions that can halt progression of kidney injury and its associated
complications, including dependence on renal replacement therapy (RRT) and short-
term and long-term mortality.50,51 Importantly, many multimodal tools have been
evaluated to identify patients at risk of “persistent AKI” over the past years, but stan-
dardized or fully validated risk-stratification tools are not yet available for clinical
application.19 The ability to combine pragmatic and readily available functional
testing (eg, furosemide stress test),52 kidney biomarkers of injury,53,54 dysfunction55
and repair,56,57 functional imaging testing,58 and novel methods of interrogation of
“big data” (eg, machine learning)59,60 shows promise, although challenges with
reproducibility and access to external validation hinder applicability into clinical
practice.

Assessment of Kidney Function

Iterative monitoring of kidney function is needed in hospitalized patients with AKI,
particularly those patients in whom AKI persists for more than 48 hours. When assess-
ing kidney function, it is important to consider that measurement of glomerular filtra-
tion rate (GFR) with inulin or iohexol, which yield high accuracy, is not practical for
use in acute settings. Furthermore, estimation of GFR with equations routinely used
in “steady-state” outpatient settings such as Modification of Diet in Renal Disease
and Chronic Kidney Disease–Epidemiology Collaboration are not validated for use
in acute settings of dynamic change in kidney function, particularly in the ICU.61 There-
fore, short-timed urine collection for measurement of creatinine clearance is a valid
surrogate of kidney function, although overestimation of kidney function due to tubular
secretion of creatinine limits its accuracy.62 Alternative calculations of GFR based on
 Acute Kidney Disease to CKD 457

volume of distribution and creatinine kinetics have shown promise in not “steady
state” situations but further validation in larger studies is needed.63–65 Measurement
of GFR can be also obtained with optical fluorescence approaches using novel mini-
mally invasive or noninvasive techniques that can quantify kidney function, indepen-
dent of serum or urinary measurements.66,67 Although these approaches hold
promise to more comprehensively determine kidney function by measures of baseline
and total GFR (whereas total GFR minus baseline GFR estimates renal reserve), repro-
ducibility and validation in human studies are necessary.

Definition of Acute Kidney Disease

In an effort to provide more conceptual background to the AKI-to-CKD interaction,
the 2012 KDIGO-AKI workgroup proposed the term “acute kidney disease” to define
any acute condition that acutely decreases kidney function. The proposed term
encompassed AKI, an absolute estimated GFR (eGFR) less than 60 mL/min per
1.73 m2 or a decrease in eGFR by more than 35%, an increase in SCr of more
than 50%, or any kidney damage lasting less than 3 months.18 The ADQI 16 Work-
group further refined this definition by adding a staging criteria and proposing AKD to
be defined as the post-AKI status of acute or subacute kidney damage/dysfunction
manifested by persistence of AKI stage 1 or greater (KDIGO criteria) beyond 7 to
90 days after the initial AKI diagnosis. If criteria of AKI persist beyond 90 days, it
is considered incident or progressive CKD according to baseline kidney function
(see Fig. 1). It is important to note that the ADQI 16 Workgroup determined the
period of AKD beyond 7 to 90 days after a known AKI initiating event. Patients
with community-acquired AKI, those transferred from other facilities, or those with
unmeasured baseline kidney function may have an ambiguous timeline of the initial
AKI event and therefore the precise AKI, AKD, or CKD status of these patients
may be difficult to ascertain. Hence, clinical rationale is highly recommended when
diagnosing AKD in the inpatient setting.19 Among survivors of the inciting AKI events,
the period of AKD includes multiple outcomes that should be clearly differentiated
and defined to guide tailored management and mitigate the burden of post-AKI com-
plications. These outcomes include (1) recovery, ( 2) recurrence of AKI, and (3)
persistence or progression of AKD.

Recovery
Recovery of AKD is defined as a reduction in peak AKI stage (KDIGO criteria) within 7
and 90 days after the initial AKI diagnosis. Understanding the caveats of isolated use
of KDIGO criteria, additional information from trajectories of SCr,68,69 real-time mea-
surement of GFR, kidney biomarkers of injury/repair, and functional assessment of
kidney function/reserve could assist in phenotyping the presence and degree of re-
covery of AKD.32 The concept of defining recovery involves the quantification of the
loss of baseline kidney function and the status of current residual kidney function
and reserve, which conveys important prognostic information to risk-stratify patients.

Recurrent acute kidney injury

In cases in which AKI has resolved, meaning kidney function has returned back to
baseline level for at least 48 hours, the incidence of a new episode of AKI (KDIGO
criteria) within the period of AKD will be considered recurrent AKI.19

Persistence or progression of acute kidney disease

In cases in which AKI has not resolved, meaning kidney function has not returned back
to baseline level, AKD may persist or worsen based on KDIGO criteria of AKI.
458 Neyra & Chawla

Subclinical Acute Kidney Injury and Acute Kidney Disease

An important consideration when examining AKD is the presence of subclinical AKI,
which is not detected by traditional KDIGO criteria of AKI but with histologic, imaging,
or biomarker evidence of kidney damage or dysfunction not included in current KDIGO
definition of AKI.70 Furthermore, subclinical AKD after AKI is also possible and
detected when SCr remains above baseline but without reaching the threshold estab-
lished by KDIGO to define persistence of AKI criteria. Observational studies have
shown that patients who achieved a recovery SCr that remains 15% to 49% above
baseline levels still carry an increased mortality risk than those with complete recovery
to baseline levels.71 The standardization of measurements of ongoing injury, status of
kidney repair and/or regeneration or indicators of loss of glomerular or tubular reserve
is needed to further characterize subclinical AKD.
Acute Kidney Disease Staging Criteria
Table 1 outlines proposed AKD staging criteria according to consensus by the ADQI
16 Workgroup.19 The proposed definition can facilitate better phenotyping of AKI and
AKD beyond initial AKI KDIGO diagnosis and staging, which can outline the natural
course of kidney disease and assist the implementation of tailored surveillance and in-
terventions (eg, follow-up care) that can mitigate progression of AKI to AKD and its
detrimental complications. However, the proposed AKD definition and staging needs
additional validation in large epidemiologic studies.

PATHOPHYSIOLOGY OF KIDNEY REPAIR AND REGENERATION

The transition from AKD to CKD is complex, as there are important a priori consider-
ations. First, CKD is a strong risk factor for AKI, therefore an AKI event in a patient with
preexisting CKD may serve to accelerate the underlying CKD in a different manner
than incident de novo AKI in a patient who was previously healthy. Second, the type

Table 1
Proposed staging criteria of AKD

AKD
Stage Definition Diagnosis
Stage 0 0A: Absence of criteria for B or C but In addition to examination of SCr,
susceptible to post-AKI biomarkers/imaging studies (still
complications under investigation) or clinical
0B: Ongoing injury, repair/ characteristics such as new-onset
regeneration, or loss of glomerular/ proteinuria, worsened proteinuria
tubular reserve from baseline, new-onset
0C: SCr <1.5 times baseline but not hypertension, or worsening
back to baseline levels hypertension can be used for
0B 1 C assessment of ongoing injury or loss
of renal reserve
Stage 1 SCr 1.5–1.9 times baseline SCr levels
Stage 2 SCr 2.0–2.9 times baseline SCr levels
Stage 3 SCr 3.0 times baseline or increase in SCr levels and need for renal
SCr to 353.6 mmol/L (4.0 mg/dL)a replacement therapy
or ongoing need for renal
replacement therapy

Abbreviations: AKD, acute kidney disease; AKI, acute kidney injury; SCR, serum creatinine.
a
If baseline SCr is <353.6 mmol/L (<4.0 mg/dL) and an episode of AKI has occurred.
 Acute Kidney Disease to CKD 459

of injury (eg, ischemic vs nephrotoxic) may have important impacts on the AKI-to-
AKD-to-CKD transition. Third, host factors related to preexisting chronic conditions,
risk factors for CKD development, and genetic factors may all play important roles.
Nonetheless, the main pathophysiologic pathways that have been identified in pre-
clinical and supporting clinical investigations suggest broad “themes” of injury (eg,
AKI) that then lead to dysregulated or maladaptive repair and impaired recovery
that propagate the transition to incident or progressive CKD.72
In general, AKI most commonly targets tubular cells, and although the kidney tissue
and proximal tubular cells in particular have prodigious capacity for repair and regen-
eration, most studies identified maladaptive repair processes and impaired recovery
as a key driver of the transition to a fibrotic phenotype and ensuing CKD.73 Proximal
tubular cells depend on mitochondrial b-oxidation for source of ATP due to limited
glycolytic activity and have the ability to differentiate and proliferate following injury.73
Surviving and adjacent intact tubular epithelial cells are key contributors to the repair
capacity of the kidney after AKI.74,75 Resident fibroblasts crosstalk with tubular epithe-
lial cells, migrate, and may promote tubular regeneration in early stages of injury.76
However, maladaptive multimodal repair processes ensue in response to distinct
microenvironment conditions leading to inflammation and fibrosis.72 The key path-
ways of maladaptive repair leading to fibrosis and inflammation that have been iden-
tified are as follows (Fig. 2): (1) tubular cell cycle arrest (G2/M phase of cell cycle)77; (2)
aberrant reactivation of developmental pathways78,79; (3) endothelial injury followed
by peritubular capillary regression and rarefaction80; (4) mitochondrial dysfunction
leading to excess of reactive oxygen species81; (5) phagocyte (fibroblast, macro-
phage) dysfunctional differentiation and migration73; and (6) dysfunctional immune

Fig. 2. Pathobiology of maladaptive repair following AKI that leads to CKD. The key path-
ways of maladaptive repair leading to fibrosis and inflammation that have been identified
are (1) tubular cell cycle arrest (G2/M phase of cell cycle); (2) aberrant reactivation of devel-
opmental pathways; (3) endothelial injury followed by pericyte detachment from peritubu-
lar capillary vessels leading to capillary regression and rarefaction; (4) mitochondrial
dysfunction leading to excess of reactive oxygen species; (5) phagocyte (fibroblast, macro-
phage) dysfunctional differentiation and migration; and (6) dysfunctional immune response
with imbalance of more proinflammatory injury and less anti-inflammatory repair.
460 Neyra & Chawla

response with imbalance of more proinflammatory injury and less anti-inflammatory

repair.82–84

EPIDEMIOLOGY OF ACUTE KIDNEY DISEASE

Since the ADQI 16 Workgroup consensus to redefine AKD, several observational

studies examining epidemiology of AKD in different study populations have been pub-
lished. A summary of these studies is presented in Table 2.85–92 Multiple important as-
pects should be noted when reviewing these observational data, such as (1) the
patient populations represented in these studies are mostly single-center and very
heterogeneous, limiting generalizability; (2) the timeframe of observation of AKD inci-
dence is sometimes a continuous period within 7 to 90 days following AKI or a cross-
sectional observation within this time period, typically at 30 or 90 days following AKI,
and therefore time-to-event is highly variable and the incidence of AKD ranges from
w5% to w50%; (3) the diagnosis of AKD is dependent on SCr measures performed
under routine clinical care, which is currently not standardized for AKI survivors; (4)
some studies evaluated AKD following an AKI event detected by the KDIGO-AKI defi-
nition but others evaluated AKD in patients without a clinical diagnosis of AKI under the
premise that subclinical AKI is common and not detected by the KDIGO-AKI definition,
particularly in critical care settings; (5) most studies evaluated outcomes of mortality
and kidney recovery associated with AKD but non–kidney-related outcomes of cardio-
vascular health, processes of post-AKI care, or patient-centered quality-of-life out-
comes have not been yet comprehensively evaluated in AKI survivors to further
define AKD epidemiology; and (6) the identification of clinical parameters associated
with AKD is limited by selection bias and lack of external validation in the represented
studies, therefore robust and potentially useful risk-stratification models of AKD are
not yet available.
Most recent studies have adopted the proposed AKD definition by the ADQI 16
Workgroup,85–88 whereas others have used variants of these consensus criteria to
adapt to the specific study populations or limitations of data availability or both.89–92
One important observation is the seldom use of urine output criterion to define AKI
or evaluate kidney function within the 7-day to 90-day period post-AKI, which has
shown relevance for diagnosis and prognosis of AKI, particularly in ICU settings.38
Only the study by Peerapornratana and colleagues85 used both SCr and urine output
criteria for defining AKI and transition to AKD post-AKI in a specific group of critically ill
septic patients. As a result of distinct study populations and definitions, the incidence
of AKD has been variably reported in observational studies: critically ill septic patients
(26.9%),85 cardiac surgery patients (w5% to 47.6%),86,87,90,92 patients on extracorpo-
real membrane oxygenation (ECMO) support (44.6%),88 hematopoietic stem cell
transplantation (HSCT) patients (15.7%),91 and 32.5% in-hospital survivors of AKI fol-
lowed in specialized clinics.89 Albeit this is expected fluctuation in the observed inci-
dence of AKD, it should be recognized as a frequent outcome following AKI in different
clinical settings.
Another frequent observation in these studies is the association of AKD with scarce
kidney recovery at hospital discharge in critically ill septic patients,85 and the consis-
tent association of AKD with short-term and long-term mortality outcome, particularly
in patients who underwent cardiac surgery or received ECMO.86–88,92 These studies
generally exhibited a graded association between level of AKD and future risk of mor-
tality. In addition, cardiac surgery patients transitioning from AKI to AKD exhibited
lower chances of kidney recovery at 90 days and higher risk of further deterioration
of kidney function up to 2 years following cardiac surgery, reflecting the association
Table 2
Observational studies of AKD published after consensus definition by the ADQI 16 Workgroup

Incidence
Study Population Definition of AKD of AKD Outcomes Comments
Peerapornratana 1341 pts with septic shock AKI KDIGO (SCr/UOP) 1  26.9% 9.3% of AKD pts recovered  Male sex, black race, and
et al,85 2020 *19.9% died first 7 d more than 7–90d from kidney function at CKD were more frequent
AKI onset discharge in AKD pts
 TIMP-2*IGFBP7, NGAL,
KIM-1, L-FABP not useful
to predict AKD
Chen et al,86 2020 269 pts in the coronary care AKI KDIGO (SCr) 1  more 47.6% Mortality risk at 5 y  Age, hemoglobin,
unit than 7–90 d from AKI correlated with AKD ejection fraction, serum
*4.8% hospital mortality onset stages, particularly AKD IL-18 associated with
1–3 AKD
Matsuura 3605 pts post cardiac AKI KDIGO (SCr) 1  more 11.2% AKD / 90-d mortality  Renal recovery at
et al,87 2020 surgery than 7–90 d from AKI (aOR: 63.0, 95% CI: 27.9– 90-d was 54.8% in AKD
onset 180.6) patients
AKD / 50% eGFR decline
at 2-y f/u in survivors
(aOR: 3.56, 95% CI: 2.24–
5.57)
Hsu 168 ECMO pts that AKI KDIGO (SCr) 1  more 44.6% AKD / up to 10-y mortality  Age, initial SOFA score,

Acute Kidney Disease to CKD

et al,88 2020 survived >7 d than 7–90 d from AKI f/u (45.8% died within urine output on day 1 of
onset 90 d) ECMO associated with
Stage 1: aHR 2.58 (95% CI mortality
1.27–5.23)
Stage 2: aHR 2.35 (95% CI
1.10–5.51)
Stage 3: aHR 5.25 (95% CI
2.71–10.16)

(continued on next page)

461
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Table 2

Neyra & Chawla

(continued )
Incidence
Study Population Definition of AKD of AKD Outcomes Comments
Hines 345 AKI survivors AKI KDIGO (SCr) 1 at first 32.5% There was no difference in  Acute exposure to an
et al,89 2020 discharged from the clinic visit after a the rate of AKD in ACEI/ARB during
hospital hospitalization patients discharged vs hospitalization was not
complicated by AKI not discharged on an associated with AKD at
(median: 33 d from ACEI/ARB (12.5 vs 15.0%, the time of first clinic visit
discharge) P 5 .530)
Sun Cho 1190 cardiac surgery pts eGFR 7.2% AKD / CKD at 12 mo (aOR:  Age and preoperative
et al,90 2019 with preserved baseline <60 or ESKD at 90 d after 16.8; 95% CI: 8.2–34.2) albumin level associated
kidney function (eGFR surgery with AKD
60)  Postoperative AKI
increased the risk of AKD
at 90 d, even if it resolved
within 3 d
Mima 108 pts undergoing HSCT AKI KIDGO (SCr) 1 or 15.7% AKD / 100-d mortality  ABO-incompatible HSCT
et al,91 2019 GFR <60 or decrease in AKD vs no AKD mortality and acute GVHD after
GFR by 35% or increase (29.4% vs HSCT were more
in SCr by >50%  <3 mo 20.2, respectively, P 5 .409) frequent in AKD pts
Mizuguchi 2095 cardiac surgery pts Doubling of SCr 2–4 wk 4.4% in Pts with AKD had higher  Stages of AKI predicted
et al,92 2018 *43% with CKD after surgery patients with hospital and 30- AKD in a graded manner
(preoperative eGFR <60) preserved d mortality than those
kidney without AKD, both in
function and patients with and
4.8% in without CKD at baseline
patients
with CKD

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; aHR, adjusted hazard ratio; AKD, acute kidney disease; AKI, acute kidney injury; aOR, adjusted
odds ratio; ARB, angiotensin-II receptor blocker; CKD, chronic kidney disease; CI, confidence interval; ECMO, extracorporeal membrane oxygenation; eGFR, esti-
mated glomerular filtration rate; ESKD, end-stage kidney disease; f/u, follow-up; GVHD, graft vs host disease; HSCT, hematopoietic stem cell transplantation; IL-18,
interleukin 18; KDIGO, Kidney Disease: Improving Global Outcomes; KIM-1, kidney injury molecule-1; L-FABP, liver fatty acid-binding protein; NGAL, neutrophil
gelatinase-associated lipocalin; pts, patients; SCr, serum creatinine; SOFA, Sequential Organ Failure Assessment; TIMP-1*IGFBP7, product of tissue metalloprotei-
nase inhibitor 2 and the insulin growth factor–binding protein 7; UOP, urine output.
 Acute Kidney Disease to CKD 463

between AKD and the risk of CKD.87,90 Despite observational data support that AKI
begets AKD even when accompanied by an apparent complete return of SCr to base-
line level,7,8,93 kidney injury biomarkers measured in the first 24 hours of ICU admis-
sion, such as the product of tissue metalloproteinase inhibitor 2 and the insulin
growth factor–binding protein 7 (TIMP-1*IGFBP7), kidney injury molecule-1 (KIM-1),
neutrophil gelatinase-associated lipocalin (NGAL), and liver fatty acid-binding protein
(L-FABP) were not useful to predict AKD in patients with septic shock.85 Only 1 study
reported that levels of serum interleukin-18 (IL-18) measured close to coronary care
unit admission were associated with subsequent AKD. Limited data using kidney bio-
markers are currently available. Furthermore, time-varying biomarker data may be
more informative that single time-point measurements for recalibrating risk of AKD,
which may be influenced by a myriad of events occurring in the first 7 days of hospital
or ICU admission. In addition, utilization of biomarkers more reflective of kidney repair
and regeneration processes are needed to be able to accurately stratify the individual
risk of AKD in susceptible populations. Among these biomarkers, urinary C–C motif
chemokine ligand 14 (CCL14)56 and urinary klotho57 have shown promise as potential
biomarkers of kidney recovery risk-stratification but further study for validation and
clinical application is needed. Moreover, the combination of tailored panels of kidney
biomarkers of tubular injury or repair with functional tubular testing (eg, furosemide
stress test) hold promise for further evaluation in the context of AKD.52,53
Among summarized studies in Table 2, the most consistent clinical parameter asso-
ciated with AKD was age, whereas other notable parameters inconsistently associ-
ated with AKD in different studies included male gender, black race, prevalent CKD,
hemoglobin levels, left ventricular ejection fraction, Sequential Organ Failure Assess-
ment (SOFA) score, and urine output on day 1 of admission. The use of “big data” with
proper external validation may help reconcile these parameters and underpin others
that can inform risk-stratification tools that can be useful and widely used.32 The
importance of early recognition and risk-stratification of AKD is beyond diagnostic
purposes, as it may assist timely interventions that can mitigate detrimental post-
AKI complications. However, there is a dire need to further define AKD epidemiology
and its clinical course as well as standardize its definition, risk-stratification, and clin-
ical application. Furthermore, the evaluation of processes of health care and patient-
centered outcomes across the trajectory of AKI-to-AKD-to-CKD is fundamental to
ameliorate the burden of kidney and non–kidney-related complications and the overall
health-related quality of life of AKI survivors.94 This is a critical aspect for improving the
care of patients with AKI that has ongoing collaborative research initiatives in the sci-
entific nephrology and critical care community.

MANAGEMENT OF ACUTE KIDNEY DISEASE

The management of AKI has been traditionally supportive based on KDIGO-bundle rec-
ommendations focusing on hemodynamic support and monitoring, optimization of fluid
management and organ perfusion pressure, avoidance of nephrotoxic agents and hy-
perglycemia, tailored diagnostic workup that warrants specific intervention, and timely
RRT initiation when appropriate.18 Although there are no specific widely effective ther-
apies that prevent or drastically ameliorate AKI in clinical practice, timely implementa-
tion of the KDIGO-bundle in high-risk patients, identified with assistance of
biomarkers of kidney injury, significantly attenuated the incidence of postoperative
AKI following cardiac surgery.95,96 Therefore, timely kidney-protective approaches
centered in 3 key aspects, such as fluid management, exposure to nephrotoxic agents,
and follow-up care may have a big impact in AKD management and outcomes.
464 Neyra & Chawla

Fluid Management
The main goal of fluid management is the timely recognition of fluid responsiveness
and type of fluid to be administered during resuscitation and optimization phases of
fluid therapy, while preventing iatrogenic fluid overload during stabilization and dees-
calation phases of fluid therapy.97–99 Fluid overload is a state of impaired homeostasis
characterized by fluid retention, often detrimentally in the interstitial compartment,
caused by either impaired kidney function and/or iatrogenic excessive fluid adminis-
tration. Several observational studies have found fluid overload to be associated
with increased mortality and increased ventilator dependence in critically ill pa-
tients.39,100–105 Interventions to prevent or limit fluid overload include conservative
fluid management after resuscitation, optimal diuretic use, and timely RRT when
appropriate and extracorporeal fluid removal is desired.97,102,105,106 Fluid overload
also has been associated with increased mortality and reduced kidney recovery,
including RRT dependence, in patients with AKI.39–41,102,107,108 Being that fluid ther-
apy is a dynamic target in hospitalized patients with AKI and AKD, particularly in those
critically ill in the ICU, iterative assessment and adjustment in goals of fluid therapy are
required. In this context, a physiologic-based approach to administration of di-
uretics,109,110 as well as patient selection for RRT and timely initiation of RRT are
crucial.111 Evolving evidence from randomized clinical trials suggests that accelerated
initiation of RRT may increase the risk of RRT dependence and RRT-related adverse
events supporting a more conservative strategy of vigilant waiting in critically ill pa-
tients with regard to RRT initiation.112–114 However, individualized risk-stratification
to timely address modifiable risk factors such as fluid overload is recommended while
protocol-based approaches of de-resuscitation are more widely tested. Furthermore,
multiple RRT-specific factors may have an impact on AKI-to-AKD-to-CKD transition
and require further study (eg, hypotension during RRT or the acute impact on nutri-
tional status and early mobilization/rehabilitation).19

Limiting Exposure to Nephrotoxic Agents

The incidence of AKI related to exposure to nephrotoxic agents accounts for approx-
imately 1 of 5 cases of community-acquired AKI in developed countries and approx-
imately 1 of 4 cases of AKI occurring in the ICU.115–117 Importantly, drug-associated
AKI has similar rates of mortality and RRT dependence than AKI resulting from other
etiologies.116 Careful examination of ambulatory and inpatient medication exposure is
necessary when evaluating a patient with AKI and AKD to limit continued exposure if a
plausible and causal temporal relationship is determined.18 The incremental associa-
tion between number of nephrotoxic agents and risk of AKI has been well established
in observational studies,118,119 whereas some combinations affecting renal plasma
flow (eg, diuretics, nonsteroidal anti-inflammatory drugs [NSAIDs] and angiotensin-
converting enzyme inhibitors [ACEI] or angiotensin-II receptor blockers [ARB]) may
be particularly detrimental to the kidneys, particularly when tissue perfusion is already
compromised by hypovolemia, intra-abdominal hypertension, or peripheral vasodila-
tion.120 The exposure to NSAIDs was shown as high as 20% after AKI in one observa-
tional study.121
Time-varying drug dosing according to kidney functional recovery and changes in
volume of distribution and metabolic status are needed during the AKD period.19 It
is important to recognize that medication dosing during AKD has been seldom studied
and is challenging given the difficulties in evaluating kidney functional status in a stan-
dardized and validated fashion. Furthermore, drug-to-drug interactions such as spe-
cific type of macrolide antibiotics (clarithromycin or erythromycin) together with a 3-
 Acute Kidney Disease to CKD 465

hydroxy 3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) for the

risk of rhabdomyolysis-related AKI should be considered, among multiple others.122
The use of ACEI/ARB in the context of AKD is controversial. The traditional
approach is to routinely hold these medications during an AKI episode, but the evi-
dence for this is lacking, particularly in mild to moderate cases without severe hypo-
tension or hyperkalemia.18 Furthermore, questions related to risk-stratification of
patients that can benefit from these drugs and the best timing for reinitiating these
drugs during the period of AKD is unclear.123 Overall, evidence suggests that expo-
sure to an ACEI/ARB may be associated with absent or small risk of AKI that may
be confounded by indication, and mostly functional AKI rather than structural damage
to the kidneys.124,125 Furthermore, a recent study found that acute exposure to an
ACEI/ARB (48 hours) before or during an AKI episode was not associated with
AKD at the time of first postdischarge clinic visit (median follow-up of 33 days from
hospital discharge).89 Another recent population-based study found that survivors
of AKI with exposure to an ACEI/ARB (new or continued use) within 6 months of
discharge had greater 2-year survival. The use of ACEI/ARB within 6 months of
discharge was associated with an increased risk of hospitalization for kidney-
related events (AKI or hyperkalemia), but no increased risk of ESKD or doubling of
SCr during the 2-year follow-up.126 In a different study including critically ill survivors
of AKI, an association between ACEI/ARB prescription and a lower 1-year mortality
rate was described.127 It has also been demonstrated that holding these medications
during a hospitalization may lead to an inadvertent nonresumption after hospitaliza-
tion, therefore depriving patients of important therapy for their chronic conditions,
including the known kidney- and heart-protective effects of these drugs.89 The use/
exposure to ACEI/ARB during AKD constitutes an area of post-AKI intervention that
needs further study to develop evidence-guided approaches.
An example of feasibility of improvement in processes of care for patients with AKD
is the recently published quality improvement initiative (The Nephrotoxic Injury
Negated by Just-in time Action [NINJA]) developed to prevent nephrotoxic drug expo-
sure in hospitalized children.128 This clinical decision support tool continuously
screened high-risk children exposed to multiple nephrotoxic drugs and recommended
providers to obtain daily SCr measurements throughout the identified exposure period
and to consider alternative less nephrotoxic options when possible. Importantly, this
tool dramatically decreased drug-induced AKI in hospitalized children by 23.8% at
a multicenter level.128 The successful implementation of the NINJA program holds
promise for similar interventions in the adult population throughout the spectrum of
heterogeneity of the AKI-to-AKD-to-CKD conundrum.

Follow-up Care
Adequate and accessible postdischarge AKD care is essential for reducing the AKI-to-
CKD transition and CKD progression. It is well recognized that AKI is associated with
incident and progressive CKD, including risk of ESKD,7,8 and is a novel risk factor for
cardiovascular disease.11,13 The exacerbation of traditional risk factors such as hyper-
tension and proteinuria, which frequently occurs after AKI,14,36,37 may partially explain
the observed association, although precise mechanisms and therapeutic targets are
not fully elucidated. Furthermore, incomplete kidney recovery and/or impairment of
kidney functional reserve may render the kidney more susceptible to subsequent in-
sults and recurrent AKI, as demonstrated in observational studies showing exceed-
ingly high rates of rehospitalizations within the first year after discharge.34,35
Furthermore, processes of care are far beyond optimal to address challenges of
timely recognition and management of risk factors for incident or progression of
466 Neyra & Chawla

AKD, limitation of nephrotoxic drug exposure, appropriate initiation or reinitiation of

kidney-protective and heart-protective medications, and evaluation and management
of patient-centered outcomes, such as impairments in cognitive and functional status
and debilitating symptoms hindering health-related quality of life in survivors of AKI.129
Despite that KDIGO guidelines recommend that all survivors of AKI should have their
kidney function evaluated at 3 months after discharge to determine kidney recovery
and progression of kidney disease,18 up to one-third of AKI survivors were shown
not to have a single SCr measurement postdischarge. Similarly, proteinuria was
seldom examined despite being a potentially modifiable risk factor of progressive kid-
ney disease after AKI.37,130 Furthermore, only 8% of veterans who experience AKI
were referred to see a nephrologist after hospitalization in the VA Healthcare System,
despite studies demonstrating that referral may improve outcomes.131
Importantly, poor patient knowledge and awareness of AKI have been demon-
strated in different studies of AKI survivors.132,133 However, patients’ self-perceived
knowledge about AKI significantly increased following a single postdischarge clinic
encounter, which included education about AKI.133 The latter finding highlights poten-
tial interventions tailoring processes of postdischarge care as a way to mitigate the
burden of AKD and its complications, as the quality of care provided to patients
with or at risk for AKD is highly variable and may contribute to poor outcomes. One
option is to develop and implement postdischarge AKI care bundles that can be
applied to high-risk patients by incorporating simple, straightforward processes of
care that can be reproduced and sustained across multiple centers with a wide range
of available logistics and resources, and improve clinical and patient-centered out-
comes beyond that which would be expected when applied individually.134,135 Limited
observational data and, most importantly, absence of interventional studies hinder
evidence-based practices for postdischarge AKI/AKD care but represent a key area
of active research to ameliorate the global burden of kidney disease.

SUMMARY

Both AKI and CKD represent a public health problem due to their high occurrence,
economic impact, and burden of morbidity and mortality. These 2 clinical syndromes
are interconnected. AKI and CKD predispose to each other in a vicious circle and may
exert negative impacts independently or synergistically. In an effort to provide more
conceptual background to the AKI-to-CKD interaction, the term AKD has emerged
and is defined as the post-AKI status of acute or subacute kidney damage/dysfunction
manifested by persistence of AKI stage 1 or greater (KDIGO criteria) beyond 7 to
90 days after the initial AKI diagnosis. If criteria of AKI persist beyond 90 days, it is
considered incident or progressive CKD according to baseline kidney function.
The transition from AKD to CKD is complex, as there are important a priori consid-
erations. First, CKD is a strong risk factor for AKI, therefore an AKI event in a patient
with preexisting CKD may serve to accelerate the underlying CKD in a different
manner than incident de novo AKI in a patient who was previously healthy. Second,
the type of injury (eg, ischemic vs nephrotoxic) may have important impacts on the
AKD-to-CKD transition. Third, host factors related to preexisting chronic conditions,
risk factors for CKD development, and genetic factors may all play important roles.
Pathways of maladaptive repair predisposing to inflammation and fibrosis leading to
CKD have been identified and include cell cycle arrest, endothelial injury followed
by capillary regression and rarefaction, mitochondrial dysfunction, fibroblast/
macrophage-aberrant differentiation and function, and the immune response with
imbalance of more proinflammatory injury and less anti-inflammatory repair.
 Acute Kidney Disease to CKD 467

Limited clinical data exist with regard to AKD epidemiology. Studies published after
AKD was formally defined have limited generalizability, as they represent heteroge-
neous populations with distinct timeframes of observation to determine AKD. Using
current aggregate observational data, at least 1 of 4 AKI survivors developed AKD
by 90 days of follow-up. Useful risk-stratification tools to predict risk of AKD and its
prognosis are needed for bedside management and to test interventions on modifiable
risk factors. Timely kidney-protective approaches centered in aspects, such as fluid
management, exposure to nephrotoxic agents, and follow-up care, may have a big
impact in AKD management and outcomes.

CLINICS CARE POINTS

 AKI and CKD are common interconnected syndromes that represent a public health problem.
 AKD is the persistence of AKI KDIGO stage 1 or greater beyond 7 to 90 days after the initial
AKI diagnosis.
 Multifaceted repair pathways after AKI has been identified but therapeutic interventions to
promote AKI recovery are still limited.
 Risk-classification tools to predict risk of AKD and its prognosis are needed.
 Fluid management, avoidance of nephrotoxins, and follow-up care are important aspects to
mitigate AKI-to-CKD progression.

ACKNOWLEDGMENTS

Dr Neyra is currently supported by grants from NIDDK (R56 DK126930 and P30
DK079337) and NHLBI (R01 HL148448-01 and R21 HL145424-01A1).

DISCLOSURE

The authors have nothing to disclose.

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