mini review
org
Acute kidney injury and chronic kidney disease:
an integrated clinical syndrome
Lakhmir S. Chawla1,2 and Paul L. Kimmel2,3
1
Department of Anesthesiology and Critical Care Medicine, George Washington University Medical Center, Washington,
District of Columbia, USA; 2Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University
Medical Center, Washington, District of Columbia, USA and 3National Institute of Diabetes, Digestive, and Kidney Disorders,
National Institutes of Health, Bethesda, Maryland, USA
The previous conventional wisdom that survivors of acute
kidney injury (AKI) tend to do well and fully recover renal
function appears to be flawed. AKI can cause end-stage renal
disease (ESRD) directly, and increase the risk of developing
incident chronic kidney disease (CKD) and worsening of
underlying CKD. In addition, severity, duration, and
frequency of AKI appear to be important predictors of poor
patient outcomes. CKD is an important risk factor for the
development and ascertainment of AKI. Experimental data
support the clinical observations and the bidirectional nature
of the relationships between AKI and CKD. Reductions in
renal mass and nephron number, vascular insufficiency, cell
cycle disruption, and maladaptive repair mechanisms appear
to be important modulators of progression in patients with
and without coexistent CKD. Distinction between AKI and
CKD may be artificial. Consideration should be given to the
integrated clinical syndrome of diminished GFR, with acute
and chronic stages, where spectrum of disease state and
outcome is determined by host factors, including the balance
of adaptive and maladaptive repair mechanisms over time.
Physicians must provide long-term follow-up to patients with
first episodes of AKI, even if they presented with normal renal
function.
Kidney International (2012) 82, 516524; doi:10.1038/ki.2012.208;
published online 6 June 2012
KEYWORDS: acute kidney injury; acute on chronic; acute renal failure;
chronic kidney disease; progression; risk factor
Correspondence: Lakhmir S. Chawla, Department of Anesthesiology and
Critical Care Medicine, George Washington University Medical Center, 900
23rd Street, NW, RILF, G-105, Washington, District of Columbia, 20037, USA.
E-mail: minkchawla@gmail.com
Received 20 October 2011; revised 13 January 2012; accepted 21
February 2012; published online 6 June 2012
516
http://www.kidney-international.
& 2012 International Society of Nephrology
Acute kidney injury (AKI) is responsible for approximately
2 million deaths annually worldwide.13 AKI is increasingly
common in critically ill patients, and those patients with the
most severe form of AKI, requiring renal replacement
therapy, have a mortality rate of 5080%.3 Over the past 10
years, there has been substantial progress in the field of AKI.
In particular, work on consensus definitions, epidemiologic
and database studies, AKI biomarkers, and the appropriate
dosing of renal replacement therapy has continued at a brisk
pace. The classic teaching regarding patients who survive an
episode of AKI, in particular acute tubular necrosis (ATN),
was that those patients achieved full or nearly full recovery.4
This notion was based on studies that followed survivors of
AKI after hospital discharge.4,5 The most recent comprehen-
sive study of AKI survivors followed 187 patients with ATN
for 10 years.5 The authors concluded that for those who
survived renal function is adequate in most patients.5
However, the notion that most patients with AKI return to
pre-morbid renal function is contradicted by a series of small
but careful clinical studies conducted over 50 years ago.6,7
Good clinical recovery, which is sustained, is the rule was
reported by Lowe6 in his study of 14 selected patients who
survived an episode of oliguria or anuria associated with
ATN. Three patients (of the eight who had the assessment) in
this series, however, had creatinine clearance of o80 ml/min.
Lowe attributed any renal dysfunction to scarring or vascular
damage. Finkenstaedt and Merrill7 reported inulin clearances
of o70 ml/min in 6 of the 16 patients with no evidence of
renal disease before occurrence of acute renal failure (ARF)
1376 months after the episode. They concluded that the
findings demonstrated that an episode of ARF resulted in
more chronic renal damage than would be expected
and that subnormal renal function late in the follow-up
period occurred in the majority of cases studied. They
attributed chronic dysfunction to rupture of basement
membranes with abnormal epithelial regeneration, resulting
in nephron loss.
Up to 2007, however, when the epidemiology of AKI
survivorship was assessed, there was a lack of large longitudinal
studies to assess the effects of AKI on long-term renal function.8
More recently, from 2008 through 2012, multiple observational
Kidney International (2012) 82, 516524
LS Chawla and PL Kimmel: Acute kidney injury and chronic kidney disease
studies assessing unique cohorts of patients, often using large
administrative databases, demonstrated that patients who survive
an episode of AKI have a significant risk for progression to
advanced-stage chronic kidney disease (CKD).914
We review data suggesting that AKI is a cause of CKD and
that prevalent CKD is a cause of incident AKI, and focus on
the interrelationships between these two entities. We review
the potential mechanistic factors underlying links between
AKI and CKD, and offer clinical considerations based on
these observations.
AKI AS A RISK FACTOR FOR INCIDENT CKD
Ishani et al.10 assessed a random sample of Medicare
beneficiaries and found that patients diagnosed with an
episode of AKI were more likely to develop end-stage renal
disease (ESRD) compared with patients without a history of
either AKI or CKD. In their analysis, the risk of developing
ESRD was eightfold higher in those with AKI compared with
patients without a history of AKI or CKD. As this study used
ICD-9 diagnostic codes, it is difficult to determine the
proportion of patients who suffered AKI and then progressed
directly to ESRD compared with patients who suffered AKI,
recovered renal function, and then progressed to ESRD.10
Lo et al.,11 by using a Kaiser Permanente database in
Northern California, retrospectively studied inpatient admis-
sions. Patients with an episode of AKI treated with dialysis were
compared with patients without an episode of AKI. Patients
with a history of ESRD or a preadmission estimated glomerular
filtration rate (eGFR) o45 ml/min per 1.73 m2 were excluded.
In this study, the investigators found that an episode of
dialysis-requiring AKI was associated with a 28-fold increased
risk of developing advanced CKD, and a 2-fold increase in
mortality. As patients who developed ESRD within 30 days
of discharge were excluded from the long-term follow-up of
advanced CKD, these data are consistent with a severe form
of AKI followed by renal recovery and then progression to
advanced-stage CKD.11 It should be noted that some patients
assessed had pre-existing CKD.
Wald et al.13 conducted a population-based cohort study
in Ontario, Canada of AKI patients who required in-hospital
dialysis and survived free of dialysis for at least 30 days after
discharge. These patients were matched with patients without
AKI or dialysis therapy during their index hospitalization.
Patients with AKI requiring dialysis were over three times
more likely to develop ESRD compared with control-matched
patients.
We and colleagues at the Veterans Affairs Medical Center
in Washington, DC assessed a United States Department of
Veterans Affairs database to ascertain long-term renal function
in over 79,000 hospitalized patients with and without AKI.12
A particular focus was on the long-term outcome in patients
with a diagnosis of ATN. Patients hospitalized for acute
myocardial infarction or pneumonia without AKI were desig-
nated as controls. The remaining 5404 hospitalized patients
who comprised the AKI group had diagnostic codes indicat-
ing ARF or ATN. Patients with pre-existing CKD were
Kidney International (2012) 82, 516524
mini review
excluded. Over the 5-year follow-up period, renal function
deteriorated over time in all groups, but with significantly
greater severity in those who had ATN and ARF compared
with controls. Patients with AKI, especially those with ATN,
with pre-existing normal renal function were more likely
than controls to enter stage 4 or 5 CKD. We found that
patients who had an episode of AKI were at high risk for the
development of stage 4 CKD and had reduced survival time
compared with control patients.12
Our studies in AKI survivors identified advanced age, the
presence of diabetes mellitus, and decreased baseline eGFR as
risk factors for the progression to advanced-stage CKD.12,15 In
addition to these risk factors, along with our colleagues, we
recently showed that low serum albumin concentration (SAlb)
is a strong predictor of poor long-term renal outcome.9 The
value of the SAlb as a predictor of CKD progression is not
surprising, because this parameter has been associated with
poor outcomes in both the general population and in a variety
of diseases including ESRD, surgical illness, and acute stroke.1618
Low SAlb levels can be a result of nutrition-related factors
and/or high levels of inflammation.19,20 As several recent
studies have shown that markers of inflammation predict
AKI, it is likely that the relationship between SAlb level and
CKD progression is based on a complex set of factors,
including those related to diet, nutrition, and catabolism, as
well as increased inflammation.15,21
Collectively, these studies underscore the strong associa-
tion between AKI and the future development of CKD.
SEVERITY, DURATION, AND FREQUENCY OF AKI AND CKD
PROGRESSION
More recently, severity of AKI has been linked to CKD
progression in survivors of AKI. Ishani et al.22 assessed patients
who underwent cardiac surgery, and found that the magnitude
of serum creatinine concentration during the postoperative
hospital course was directly linked to progression. This effect
was seen in patients with AKI with previously normal renal
function (de novo AKI), as well as in patients with an episode
of AKI superimposed on CKD (acute on chronic renal
failure).22 The magnitude of increase in serum creatinine after
cardiac surgery was associated in a graded manner with
increased risk of CKD progression and mortality.
This same trend has been demonstrated in patients who
had percutaneous coronary revascularization. James et al.23
showed that patients undergoing percutaneous coronary
revascularization who had AKI were at risk for future develop-
ment of ESRD. Patients with AKIN stage I AKI were over 4
times more likely to develop ESRD, whereas patients with AKIN
stage II/III were over 11 times more likely to develop ESRD.23
We have similarly shown that the severity of AKI is linked
to CKD progression.9 We assessed a cohort of 11,589 patients
with a spectrum of AKI from RIFLE stage R through F.9
Severity of AKI, assessed by peak serum creatinine, was
associated with progression to advanced CKD (Figure 1). In
particular, patients who required dialysis were at much
higher risk for progression to CKD than patients with less
517
mini review LS Chawla and PL Kimmel: Acute kidney injury and chronic kidney disease

a b
3.5 Mean eGFR 15 years post tertile 100
Tertile 1 (n = 767) 90
3.0
Tertile 2 (n = 766) Tertile 1: mean

Mean Scr (mg/dI)

80 eGFR>79.2

Mean eGFR
2.5 Tertile 3 (n = 767)
70
2.0 Tertile 2: mean
60 eGFR 61-79.2
1.5
50
1.0 Tertile 3: mean
40 eGFR<61
0.5 30

re

st

st

st
e

st

st

st

ita
pr

in

po

po

po
po

po

po

rp

sp
ur
ar

Ho

rs
s

rs
D

ye

th

th
ye

th

th

a
a

on

on

ye
on

on

ye

1
1

m
m

5
5

1
1

12
3

12

1
1

3
3
Time Time
9
Figure 1 | Effect of severity of acute kidney injury (AKI) on outcomes. AKI patients who survived for 1 year. (a) Mean eGFR over time
(tertiles). (b) AKI patients who survived for 1 year. Mean serum creatinine (Scr) over time (tertiles). Tertiles were defined based on Scr at 15
years post admission. Error bars show the 95% confidence interval at each time point.

severe AKI.9 Although it is seemingly intuitive that the 1

severity of AKI would be associated with progression to

advanced CKD, these three studies are the first to show this 0.8

link.9,22,23 These findings suggest that when the severity of Proportion surviving

AKI reaches a certain threshold the course of AKI is altered, 0.6

No AKI
(P < 0.0001)
initiating a chronic, progressive disease.
1 AKI
In addition to severity, the duration of AKI has been 0.4 2 AKIs
linked to mortality but not to CKD progression. Coca et al.24
3+AKIs
assessed a large cohort of patients with diabetes mellitus 0.2
undergoing cardiac surgery in the Veterans Administration
system. Both severity and duration of AKI were linked to
0
long-term mortality. However, the duration of AKI was not 0 20 40 60 80 100
linked to CKD progression.24 Consistent with these findings, Months of follow-up from baseline

Brown et al.25 assessed a separate cohort of US Veterans after
cardiac surgery and confirmed that the duration of AKI was
linked to worse long-term survival.
Not surprisingly, patients who sustain multiple episodes of
AKI as compared with a single episode of AKI have higher
likelihoods of CKD progression. Thakar et al.26 have shown,
in a cohort of US Veterans with diabetes, that those who
experienced two or more episodes of AKI were much more
likely to progress to stage 4 CKD than patients who
experienced only one episode of AKI (Figure 2).26
These data are consistent with the hypothesis that for some
patients a single episode of AKI has biologic ramifications
beyond the acute event, engendering an ongoing state that
predisposes to the development of further injury, manifested
differentially in time as worsened AKI (short-term) or the
development or worsening of CKD over longer periods
(Figure 3). Some patients can fully recover from their initial
AKI, but subsets of AKI survivors appear to go on to
experience vicious cycles of intertwined AKI and CKD.26 It is
likely that the severity of renal injury along with other clinical,
treatment, and host risk factors mediate such processes.
AKI AS AN ACCELERANT OF CKD
Hsu et al.27 showed that the incident growth of the ESRD
population exceeded the prevalent CKD population. The
Figure 2 | Effect of acute kidney injury (AKI) frequency on
outcomes.26 Survival to stage 4 chronic kidney disease (CKD) in
no AKI vs. multiple AKI episode groups.
authors hypothesized that physician-related decisions
to start chronic dialysis earlier might account for this
discrepancy. We believe that the more likely explanation is
the marked effect of AKI on the development and progres-
sion of CKD.
CKD has consistently been shown to be a significant risk
factor for the development of AKI.28,29 Probable explanations
include the hemodynamic instability and failure of auto-
regulation30 in CKD patients, the ease of detection of small
changes in GFR when renal function is impaired, and a
predisposition to further injury in patients with diminished
renal function.31,32 These consist of at least susceptibility to
nephrotoxic agents, and the effects of ongoing humoral and
renal pathologic mechanisms in the setting of CKD.
Unfortunately, this risk appears to be bidirectional. Ishani
et al.10 showed that patients with CKD who experienced an
episode of AKI were 41 times more likely to develop ESRD
than patients without kidney disease, whereas patients with
CKD and no episodes of AKI had an 8.4-fold higher risk
compared with patients without kidney disease. The risk of

518 Kidney International (2012) 82, 516524

LS Chawla and PL Kimmel: Acute kidney injury and chronic kidney disease
100%
AKI Repair Chronic
GFR
0 Time
Figure 3 | Theoretical range of outcomes after acute kidney
injury (AKI). The range of possible long-term outcomes after an
episode of AKI comprises the entire spectrum of the glomerular
filtration rate (GFR). The final GFR is determined by the level of
GFR at the time of injury, the severity and duration of the injury,
and responses across several phases over time. It is envisioned
that repair and chronic phases have different and variable time
frames, and different magnitudes of responses. Responses during
repair and chronic phases are determined by the balance of
processes that result in amelioration and worsening of GFR.
developing ESRD was enhanced almost fourfold by the
superimposition of AKI in CKD patients. AKI enhanced the
risk almost 10-fold compared with patients without either
CKD or AKI, and astonishingly was associated with greater
risk of developing ESRD than those identified with CKD in
the Medicare population. Similarly, Hsu et al.33 showed that
patients with an eGFR o45 ml/min per 1.73 m2 who
experienced an episode of dialysis-requiring AKI were at
very high risk for impaired recovery of renal function. In a
population-based cohort in Scotland, Ali et al.1 showed that
only 64% of patients with an episode of acute on chronic
renal failure had full recovery of kidney function.1
In these studies, CKD was defined by an eGFR of
460 ml/min per 1.73 m2. In addition to low baseline eGFR,
patients with CKD as assessed by proteinuria are at increased
risk for AKI. James et al.29 showed in a cohort of over 920,000
patients that the level of proteinuria and diminished baseline
eGFR were independent risk factors for developing AKI.29
The risk of progression to CKD in patients who develop
AKI is not limited to adults but affects children as well.34,35
Large pediatric cohort studies suggest that certain subsets of
children (such as bone marrow transplant patients) are at
high risk for CKD progression. In contrast to adults, children
tend to be less burdened with chronic disease. Thus, the
evidence that AKI in children puts those patients at risk for
CKD suggests processes subsequent to AKI that are integral
to the acute episode, as opposed to simply changes that occur
in an acute on chronic disease paradigm.
Hui-Stickle et al.36 assessed pediatric intensive care unit
patients upon discharge from a tertiary care center. In all,
Kidney International (2012) 82, 516524
mini review
34% had either reduced kidney function or were dialysis
dependent upon discharge.36 The most compelling data
regarding AKI and the risk of CKD in children came from a
long-term follow-up of participants in the aforementioned
study conducted by Askenazi et al.37 They followed up a
cohort of children for 3 to 5 years after an episode of AKI.
Mortality was 79.9%, with the majority of the deaths
occurring within 2 years of the AKI episode. In all, 17 of
29 patients followed up in an outpatient clinic demonstrated
evidence of CKD, manifested by hyperfiltration, reduced
kidney function, hypertension, or microalbuminuria.37
Although this represents a small sample, it is consistent with
animal and adult human studies showing that subsets of
patients who develop AKI are at high risk for developing
CKD and experiencing progression.
These data suggest that for some patients AKI and CKD
likely coexist in an intimate but vicious cycle. This concept is
supported by the fact that CKD was thought to progress in a
linear manner,38 but this is not always the case. Shah and
Levey39 showed that as many as one-third of patients deviated
from their reciprocal creatinine slope. The African American
Study of Kidney Disease and Hypertension study has delinea-
ted several different courses in patients with CKD (personal
communication, Tom Greene). Some of these courses are
consistent with the notion of intermittent episodes of AKI
complicating CKD, with varying levels of repair occurring.
An episode of AKI that results in a decrement in GFR will
necessarily affect the trajectory of GFR change; the course will
ultimately be determined by whether the injury is reversible
(volume-related changes in GFR and filtration fraction) and
by the balance between effective and maladaptive repair
mechanisms (Figure 4). The exact mechanism(s) by which
AKI accelerates/initiates CKD in humans are unknown.
Preclinical data, however, suggest that a variety of mechanisms
may be operative.
MECHANISMS UNDERLYING PROGRESSION OF AKI TO CKD
An important concept for understanding the course of CKD is
that the progression to ESRD occurs via processes that may
be independent of the original pathology of CKD.32,40 Such
concepts were originally proposed for a variety of glomerular
diseases,40 after follow-up studies in patients with post-
streptococcal glomerulonephritis delineated long-term sequelae41
linked to current definitions of CKD, including decrements
in GFR and the persistence of proteinuria, as well as the
development of hypertension. Data from animal models
suggest that kidneys after episodes of injury may be sus-
ceptible to progression to CKD, which is similarly indepen-
dent of the initial cause of AKI. Key constructs regarding CKD
progression are based on findings from the remnant kidney
model in which nephron loss leads to glomerular hypertrophy
in the remaining nephrons.42 Hypothesized mechanisms
underlying CKD progression include effects of systemic and
intrarenal hypertension and hyperfiltration, tubular hyper-
trophy, and hypertension resulting in arteriosclerosis, tubu-
lointerstitial fibrosis, and glomerulosclerosis,4345 as well as
519
mini review LS Chawla and PL Kimmel: Acute kidney injury and chronic kidney disease

c
Normal repair
and regeneration

a b
ATN
Neutrophils and
monocytes
Interstitium
Endothelial
injury d Maladaptive
response
Zones of
hypoxia
Interstitial
fibrosis

Peri-tubular
blood vessels
Cells
and casts
Depleted
blood supply
Cell cycle arrest
Epigenetic changes

Figure 4 | Tubule cross-section. (a) Cross section of normal renal tubule with intact epithelial cells, renal interstitium, and peri-tubular
blood vessels. (b) Cross section of renal tubule with acute tubular necrosis (ATN) with epithelial cell necrosis, intra-tubular cast formation,
endothelial injury of peri-tubular blood vessels, and migration of monocytes and macrophages into renal interstitium. (c) Cross section of
renal tubule after normal repair and regeneration showing restoration of normal renal architecture. (d) Cross section of renal tubule after
severe episode of AKI, resulting in maladaptive repair. Epithelial cells have evidence of cell cycle arrest and epigenetic changes that favor a
fibrosis phenotype. Renal interstitium shows evidence of fibrosis. Post-injury vascular supply is less dense than baseline. The combination
of decreased blood supply and fibrosis leads to zones of hypoxia wherein the combination of decreased vascular supply and fibrosis can
initiate a vicious cycle leading to ongoing fibrosis.

the effects of derangements of the endocrine response and
abnormalities in circulating mediators associated with decre-
ments in renal function. The latter may affect cell structure and
function, as well as physiologic responses. In the case of normal
kidneys after an episode of injury, multiple injury pathways and
maladaptive processes have been identified, which may
contribute to determining the course of renal function after
an initial insult.
Nephron loss and glomerular hypertrophy
The pathophysiology of loss of nephron mass followed by
glomerular hypertrophy has been well described in animal
models.43 After an episode of AKI, it is possible that signi-
ficant permanent loss of nephron mass results in a clinical
state comparable to that of the remnant kidney model. After
subtotal nephrectomy, single-nephron GFR increases via
hyperfiltration and glomerular hypertrophy. Cellular prolif-
eration ensues, ultimately resulting in tubulointerstitial fibrosis
and progressive nephron loss.32 These processes are exacer-
bated by high-salt and high-protein diets.46,47 Increased
tubular workload predisposes nephron segments to fibrosis
and senescence, which can be mitigated by protein and calorie
restriction.47,48
The lessons from animal studies have been successfully
translated into patient-care paradigms. As an example, a
cornerstone of CKD therapy is mitigation of glomerular
hypertrophy and hyperfiltration via hypertension control and
reninangiotensinaldosterone system blockade.
Interstitial inflammation and fibrosis
In human CKD and in the remnant kidney model,
tubulointerstitial fibrosis predominates over glomerulo-
sclerosis.32 As a consequence, human CKD often progresses
without the need for continued glomerular injury.45,4951
Further support of a pro-fibrotic effect in the setting of
reduced renal mass is provided by experiments that show that
the kidneys of animals exposed to ischemiareperfusion (IR)
injury are more predisposed to developing fibrosis if nephron
loss (e.g., unilateral nephrectomy) occurs before injury.52,53
In addition, inflammation after AKI can lead to interstitial
immune cell infiltration followed by interstitial fibrosis.
Inflammation has been shown to be an important feature of
ischemic and septic AKI.15,5456 Animal models of ATN
consistently show an interstitial neutrophil infiltrate during
the acute phase of ATN, often followed by monocytic
lymphocytic infiltration in later stages.32,55,57,58 Monocytes
can exacerbate injury and promote fibrosis.59 The effects of
tubulointerstitial fibrosis are critical, as tubulointerstitial
fibrosis injury scores predict the decline of renal function
better than glomerular injury scores.60,61 Reduced renal
mass impairs recovery of experimental AKI and may
predispose to the development of fibrosis.32 In most models

520 Kidney International (2012) 82, 516524

LS Chawla and PL Kimmel: Acute kidney injury and chronic kidney disease
of experimental AKI, renal tubular regeneration occurs, but
depending on the severity of the initial damage the recovery
is often incomplete. Areas that do not complete full recovery
may develop into focal areas of fibrosis.32,55,62
Both human and animal models link severity and
frequency of AKI with worsening of long-term renal
function.9,22,63 Multiple episodes of IR-induced AKI have
been shown to cause CKD and tubulointerstitial fibrosis in
animal models. Thus, it is conceivable that subclinical
episodes of AKI could both cause and worsen CKD.32 These
data are consistent with the previously cited human data
showing the effect of multiple episodes of AKI to enhance
CKD progression.26
Endothelial injury and vascular rarefaction
Experimental models of AKI demonstrate endothelial
involvement and vascular injury. Tubular repair after injury
tends to be robust, but the vascular restorative capacity after
AKI is more blunted.64 Various different injury models (e.g.,
IR, folate, nitric oxide synthase inhibition, and ureteral
obstruction) all demonstrate diminished vascular density
after injury.6568 The loss of vascular density varies between
30 and 50%.69 The loss of vascular reserve may be one
of the key components of the development of fibrosis
after injury. Injured tissue that has insufficient vascular
supply becomes hypoxic, potentially setting into motion a
self-propagating injury cascade. Rarefaction of capillaries
initiates activation of hypoxia-inducible pathways that can
promote inflammation and downstream fibrosis.32 Thus,
capillary rarefaction in fibrotic foci can be both a cause and
an effect of tissue hypoxia, in turn leading to activation of
hypoxic signaling, inflammation, and activation of factors
enhancing fibrosis.
In experimental models, treatment with angiogenic factors
such as vascular endothelial growth factor-121 ameliorates
vascular dropout and endothelial damage.54 However, these
compounds are only useful in the immediate post-injury
period, and do not improve vascular dropout after AKI when
administered 43 weeks after the insult.32
Cell cycle and maladaptive repair
Normal repair processes involve a host of growth factors and
proliferative and other signaling cascades, which must be
deployed, and function in coordinated, integrated temporal,
and spatial manners. These mechanisms are critical for
appropriate repair and regeneration.70 Cell cycle abnormalities
affect the outcome of AKI. Preclinical studies demonstrate
that p21, a cyclin-dependent kinase, is a critical check-
point effector for induction of the cell cycle.71 In preclinical
models of AKI, p21 antagonism worsens AKI, whereas p21
induction improves outcomes in AKI models.72,73 Cell cycle
dysfunction can have effects at the point of injury and further
downstream during repair. Pathways that affect the cell cycle
can also activate fibroblasts and inflammation. Selected anti-
inflammatory therapies have been shown to decrease the
severity of AKI during its acute phase.32,74 Recently, studies
Kidney International (2012) 82, 516524
mini review
involving the cell cycle of reparative cells have shed light on
such processes.72,73
When AKI is severe, the corresponding tubular injury and
interstitial inflammation are associated with proliferation of
tubular epithelial cells. Yang et al.63 showed that when kidney
damage was accompanied by fibrosis there were large
numbers of proximal tubule epithelial cells arrested in the
G2/M phase of the cell cycle. In contradistinction to prolif-
erating epithelial cells, the arrested cells produced greater
levels of transforming growth factor-b1 and connective tissue
growth factor. These findings suggest that in response to
injury a maladaptive repair process may ensue, causing
fibrosis instead of repair of tubular epithelia. Cell cycle arrest
causes tubular epithelial cells to convert to a phenotype that
promotes the growth and activation of fibroblasts. Interest-
ingly, in this same study, moderate IR injury did not
produce this maladaptive process. Only severe injury with IR
or aristolochic acid activated pro-fibrotic processes. Cell arrest
was mitigated by agents, such as p53 inhibitors, that affect the
cell cycle, and was exacerbated by agents that prolong cell
cycle arrest.63
Animal studies support the notion that fibrosis is ongoing
after AKI. Bechtel et al.69 investigated mechanisms of fibrosis
that were temporally remote from the initiation of kidney
injury. They showed that fibrosis continues owing to a failure
of fibroblasts to return to their resting state. Epigenetic
factors including hypermethylation of RASAL1 gene loci were
involved. Both studies by Yang et al.63 and Bechtel et al.69
implicate the pathologic role of transforming growth factor-b
in promoting fibrosis.63,69
When tubular epithelial cells arrest in the G2/M phase of
the cell cycle, they produce transforming growth factor-b1.
If transforming growth factor-b1 secretion and activation
is sustained, epigenetic changes in fibroblasts may ensue,
which can transform them into tumor-like myofibroblasts
that proliferate in a growth factorindependent manner.74
Altogether, cell cycle arrest and epigenetic changes represent
at least two maladaptive repair mechanisms that appear to
have major roles in determining the post-AKI fibrotic
phenotype. As cell cycle arrest and epigenetic changes appear
to be sequential in nature, they may form pathways amenable
to interruption.63,73,75,76
Identification of patients and risk factors for CKD progression
To help clinicians identify AKI survivors at increased risk for
CKD development and progression, along with our collea-
gues, we developed three multivariable models. The most
accessible (and therefore clinically useful) model is based on
sentinel clinical events (i.e., RIFLE stage, need for dialysis,
baseline eGFR, and sAlb).9 This model performed well,
explaining 11% of the variance in the development of CKD
(area under ROC curve 0.77). We validated this equation in
a separate large cohort of hospitalized Veterans (Po0.001,
c-statisticX0.81). As these end points are accessible and
clinically relevant, clinicians could potentially use such
equations to risk stratify AKI survivors at highest risk for
521
mini review
progression to CKD for therapeutic reasons or for inclusion
in clinical trials.9
In addition to clinical models, novel AKI biomarkers show
promise in improving risk assessment of patients with severe
AKI. Srisawat et al.77 have shown that plasma neutrophil
gelatinaseassociated lipocalin improves the discrimination of
clinical models to predict renal recovery. Future studies
should incorporate plasma and urine biomarkers in risk
assessment strategies to determine the best approach to
identify patients at risk for CKD progression.
Summary
The paradigm of AKI has markedly shifted over the past 5
years. The previous conventional wisdom that survivors of
AKI tend to do well and fully recover renal function, perhaps
based on indistinct recollections of early, limited studies,
appears to be flawed.6,7 AKI can cause ESRD directly,8,10,78
and appears to increase the risk for incident CKD and worsen
underlying CKD.12,22 In addition, severity and frequency of
AKI appear to be important predictors of poorer out-
comes.9,26 Experimental data support the clinical observa-
tions. Mechanistically, renal mass, vascular insufficiency, cell cycle
disruption, and maladaptive repair appear to be important
modulators of outcome, and these pathophysiologic processes
are likely operative in mediating the poor outcomes observed
in the clinical epidemiologic studies reviewed above.
The public health impact of the long-term outcomes of
AKI is significant. The population incidence of AKI is
approximately 2100 per million population.1 Given the
population of the developed world (USA, Canada, Western
Europe, and Australia) of approximately 1 billion, there
will be over 2 million cases of AKI this year, with an expected
1.5 million AKI survivors. Of these patients, approxi-
mately 1520% will progress to advanced-stage CKD within
24 months, resulting in approximately 300,000 cases of
advanced CKD per year. Given the increasing incidence of
AKI in the aging population,8,79,80 the projected incidence is
expected to increase. The National Institute of Diabetes,
Digestive and Kidney Disease supports the Assessment, Serial
Evaluation, and Subsequent Sequelae of Acute Kidney Injury
(ASSESS AKI) study, which evaluates the long-term outcome
of hospitalized patients, with and without CKD, who
experience an episode of AKI, to determine the natural
history of AKI and delineate risk factors for progression and
development of complications, including cardiovascular
disease.81
We propose a new model integrating acute and CKD. The
separation of ARF and CKD into two distinct syndromes as
taught in medical school is not in the best interest of an
integrated approach to the long-term care of patients with
kidney disease. Rather, we propose consideration of the state
of diminution in GFR as a clinical entity, which has
differential initiation and expression in time and along the
spectrum of magnitude of GFR (Figure 3). Phases of disease
include initiation, repair, and long-term outcomes (Figure 3
and/or 4). Differences in timing and severity of injury and the
522
LS Chawla and PL Kimmel: Acute kidney injury and chronic kidney disease
balance of adaptive and maladaptive repair determine
clinically apparent outcomes. The range of change in
response to differential injury and the balance of adaptive
and maladaptive repair in patients with different initial levels
of renal function comprise the entire spectrum of GFR
(Figure 3). Interventions to preserve function and enhance
repair are presumably appropriate at several stages of the
disease. Commonalities and differences in mechanisms
mediating the different courses of long-term outcome must
be delineated and translated into clinical trials and practice
over the next decade.
The giants, such as Lowe and Merrill, on whose shoulders
we stand, were correct, even if their early findings were lost,
misinterpreted, or incorrectly recalled. AKI and CKD
comprise an intertwined clinical entity, a disease of
diminished renal mass resulting in diminished GFR.
Recommendations and future directions
We recommend that hospital survivors of AKI who experience
severe AKI (AKIN stage III) be followed up by a nephrologist
after discharge. Currently, this does not occur. At 30 days after
discharge from the hospital with an episode of AKI, 74.5% of
patients were seen by a primary physician compared with
11.9% and 29.5%, respectively, who were seen by a nephrologist
or a cardiologist.82 Surprisingly, only about one-third of AKI
patients requiring dialysis (AKIN stage III) are seen by a
nephrologist within 30 days of discharge. This increases to
48.6% within 1 year of discharge, which is likely a result of a
rising serum creatinine.82 Overall, a very small fraction of AKI
patients are currently followed up by nephrologists after
hospital discharge.82 To put this into context, an assessment
of the nephrology follow-up of AKI survivors as compared with
the cardiology follow-up of myocardial infarction survivors
reveals a stark difference (11.9% vs. 76%, respectively).31,82 At
the very least, we should continue to see our patients.
Monitoring patients for blood pressure control, the use of
drugs that interfere with the reninangiotensin system, and
avoidance of nephrotoxins may prove critical as public health
measures, which may oppose current secular trends.
DISCLOSURE
All the authors declared no competing interests.
ACKNOWLEDGMENTS
We thank Paul Eggers and Richard Amdur for reviewing the
manuscript.
DISCLAIMER
The views expressed in this article do not necessarily represent the
views of the Department of Health and Human Services, the National
Institutes of Health, the National Institute of Diabetes, Digestive and
Kidney Diseases, or the United States Government.
REFERENCES
1. Ali T, Khan I, Simpson W et al. Incidence and outcomes in acute kidney
injury: a comprehensive population-based study. J Am Soc Nephrol 2007;
18: 12921298.
2. Murugan R, Kellum JA. Acute kidney injury: whats the prognosis? Nat Rev
Nephrol 2011; 7: 209217.
Kidney International (2012) 82, 516524
LS Chawla and PL Kimmel: Acute kidney injury and chronic kidney disease
3. Uchino S, Kellum JA, Bellomo R et al. Acute renal failure in critically ill
patients: a multinational, multicenter study. JAMA 2005; 294: 813818.
4. Kjellstrand CM, Ebben J, Davin T. Time of death, recovery of renal
function, development of chronic renal failure and need for chronic
hemodialysis in patients with acute tubular necrosis. Trans Am Soc Artif
Intern Organs 1981; 27: 4550.
5. Liano F, Felipe C, Tenorio MT et al. Long-term outcome of acute tubular
necrosis: a contribution to its natural history. Kidney Int 2007; 71: 679686.
6. Lowe KG. The late prognosis in acute tubular necrosis; an interim follow-
up report on 14 patients. Lancet 1952: 10861088.
7. Finkenstaedt JT, Merrill JP. Renal function after recovery from acute renal
failure. N Engl J Med 1956; 254: 10231026.
8. Xue JL, Daniels F, Star RA et al. Mortality and advancing to end-stage
renal disease in patients with hospital and non-hospital acquired renal
failure. J Am Soc Nephrol 2007; 15: SA-PO965.
9. Chawla LS, Amdur RL, Amodeo S et al. The severity of acute kidney injury
predicts progression to chronic kidney disease. Kidney Int 2011; 79:
13611369.
10. Ishani A, Xue JL, Himmelfarb J et al. Acute kidney injury increases risk of
ESRD among elderly. J Am Soc Nephrol 2009; 20: 223228.
11. Lo LJ, Go AS, Chertow GM et al. Dialysis-requiring acute renal failure
increases the risk of progressive chronic kidney disease. Kidney Int 2009;
76: 893899.
12. Amdur RL, Chawla LS, Amodeo S et al. Outcomes following diagnosis of
acute renal failure in U.S. veterans: focus on acute tubular necrosis. Kidney
Int 2009; 76: 10891097.
13. Wald R, Quinn RR, Luo J et al. Chronic dialysis and death among survivors
of acute kidney injury requiring dialysis. JAMA 2009; 302: 11791185.
14. Garg AX, Suri RS, Barrowman N et al. Long-term renal prognosis of
diarrhea-associated hemolytic uremic syndrome: a systematic review,
meta-analysis, and meta-regression. JAMA 2003; 290: 13601370.
15. Chawla LS, Seneff MG, Nelson DR et al. Elevated plasma concentrations of
IL-6 and elevated APACHE II score predict acute kidney injury in patients
with severe sepsis. Clin J Am Soc Nephrol 2007; 2: 2230.
16. Engelman DT, Adams DH, Byrne JG et al. Impact of body mass index and
albumin on morbidity and mortality after cardiac surgery. J Thorac
Cardiovasc Surg 1999; 118: 866873.
17. Gariballa SE, Parker SG, Taub N et al. Influence of nutritional status on
clinical outcome after acute stroke. Am J Clin Nutr 1998; 68: 275281.
18. Owen Jr WF, Lew NL, Liu Y et al. The urea reduction ratio and serum
albumin concentration as predictors of mortality in patients undergoing
hemodialysis. N Engl J Med 1993; 329: 10011006.
19. Friedman AN, Fadem SZ. Reassessment of albumin as a nutritional marker
in kidney disease. J Am Soc Nephrol 2010; 21: 223230.
20. Don BR, Kaysen G. Serum albumin: relationship to inflammation and
nutrition. Semin Dial 2004; 17: 432437.
21. Liu KD, Glidden DV, Eisner MD et al. Predictive and pathogenetic value of
plasma biomarkers for acute kidney injury in patients with acute lung
injury. Crit Care Med 2007; 35: 27552761.
22. Ishani A, Nelson D, Clothier B et al. The magnitude of acute serum
creatinine increase after cardiac surgery and the risk of chronic kidney
disease, progression of kidney disease, and death. Arch Intern Med 2011;
171: 226233.
23. James MT, Ghali WA, Knudtson ML et al. Associations between acute
kidney injury and cardiovascular and renal outcomes after coronary
angiography. Circulation 2011; 123: 409416.
24. Coca SG, King Jr JT, Rosenthal RA et al. The duration of postoperative
acute kidney injury is an additional parameter predicting long-term
survival in diabetic veterans. Kidney Int 2010; 78: 926933.
25. Brown JR, Kramer RS, Coca SG et al. Duration of acute kidney injury
impacts long-term survival after cardiac surgery. Ann Thorac Surg 2010;
90: 11421148.
26. Thakar CV, Christianson A, Himmelfarb J et al. Acute kidney injury
episodes and chronic kidney disease risk in diabetes mellitus. Clin J Am
Soc Nephrol 2011; 6: 25672572.
27. Hsu CY, Vittinghoff E, Lin F et al. The incidence of end-stage renal disease
is increasing faster than the prevalence of chronic renal insufficiency. Ann
Intern Med 2004; 141: 95101.
28. Thakar CV, Arrigain S, Worley S et al. A clinical score to predict acute renal
failure after cardiac surgery. J Am Soc Nephrol 2005; 16: 162168.
29. James MT, Hemmelgarn BR, Wiebe N et al. Glomerular filtration rate,
proteinuria, and the incidence and consequences of acute kidney injury:
a cohort study. Lancet 2010; 376: 20962103.
30. Bidani AK, Griffin KA, Williamson G et al. Protective importance of the
myogenic response in the renal circulation. Hypertension 2009; 54:
393398.
Kidney International (2012) 82, 516524
mini review
31. Daugherty SL, Ho PM, Spertus JA et al. Association of early follow-up after
acute myocardial infarction with higher rates of medication use. Arch
Intern Med 2008; 168: 485491 discussion 492.
32. Venkatachalam MA, Griffin KA, Lan R et al. Acute kidney injury: a
springboard for progression in chronic kidney disease. Am J Physiol Renal
Physiol 2010; 298: F1078F1094.
33. Hsu CY, Chertow GM, McCulloch CE et al. Nonrecovery of kidney function
and death after acute on chronic renal failure. Clin J Am Soc Nephrol 2009;
4: 891898.
34. Goldstein SL, Devarajan P. Acute kidney injury in childhood: should we be
worried about progression to CKD? Pediatr Nephrol 2011; 26: 509522.
35. Goldstein SL, Devarajan P. Progression from acute kidney injury to
chronic kidney disease: a pediatric perspective. Adv Chronic Kidney Dis
2008; 15: 278283.
36. Hui-Stickle S, Brewer ED, Goldstein SL. Pediatric ARF epidemiology
at a tertiary care center from 1999 to 2001. Am J Kidney Dis 2005; 45:
96101.
37. Askenazi DJ, Feig DI, Graham NM et al. 35 Year longitudinal follow-up
of pediatric patients after acute renal failure. Kidney Int 2006; 69:
184189.
38. Mitch WE, Walser M, Buffington GA et al. A simple method of estimating
progression of chronic renal failure. Lancet 1976; 2: 13261328.
39. Shah BV, Levey AS. Spontaneous changes in the rate of decline in
reciprocal serum creatinine: errors in predicting the progression of renal
disease from extrapolation of the slope. J Am Soc Nephrol 1992; 2:
11861191.
40. Neugarten J, Feiner HD, Schacht RG et al. Aggravation of experimental
glomerulonephritis by superimposed clip hypertension. Kidney Int 1982;
22: 257263.
41. Baldwin DS. Poststreptococcal glomerulonephritis. A progressive disease?
Am J Med 1977; 62: 111.
42. Ingelfinger JR. Disparities in renal endowment: causes and consequences.
Adv Chronic Kidney Dis 2008; 15: 107114.
43. Hostetter TH. Progression of renal disease and renal hypertrophy. Annu
Rev Physiol 1995; 57: 263278.
44. Hostetter TH, Olson JL, Rennke HG et al. Hyperfiltration in remnant
nephrons: a potentially adverse response to renal ablation. Jam Soc
Nephrol 2001; 12: 13151325.
45. Baldwin DS, Neugarten J. Hypertension and renal diseases. Am J Kidney
Dis 1987; 10: 186191.
46. Shapiro JI, Elkins N, Reiss OK et al. Energy metabolism following reduction
of renal mass. Kidney Int Suppl 1994; 45: S100S105.
47. Nath KA, Croatt AJ, Hostetter TH. Oxygen consumption and oxidant stress
in surviving nephrons. Am J Physiol 1990; 258: F1354F1362.
48. Tapp DC, Wortham WG, Addison JF et al. Food restriction retards
body growth and prevents end-stage renal pathology in remnant
kidneys of rats regardless of protein intake. Lab Invest 1989; 60:
184195.
49. Risdon RA, Sloper JC, De Wardener HE. Relationship between renal
function and histological changes found in renal-biopsy specimens
from patients with persistent glomerular nephritis. Lancet 1968; 2:
363366.
50. Schainuck LI, Striker GE, Cutler RE et al. Structural-functional
correlations in renal disease. II. The correlations. Hum Pathol 1970; 1:
631641.
51. Striker GE, Schainuck LI, Cutler RE et al. Structural-functional correlations
in renal disease. I. A method for assaying and classifying histopathologic
changes in renal disease. Hum Pathol 1970; 1: 615630.
52. Azuma H, Nadeau K, Takada M et al. Cellular and molecular predictors of
chronic renal dysfunction after initial ischemia/reperfusion injury of a
single kidney. Transplantation 1997; 64: 190197.
53. Azuma H, Nadeau K, Takada M et al. Initial ischemia/reperfusion injury
influences late functional and structural changes in the kidney. Transplant
Proc 1997; 29: 15281529.
54. Liu KD, Glidden DV, Eisner MD et al. Predictive and pathogenetic value of
plasma biomarkers for acute kidney injury in patients with acute lung
injury*. Crit Care Med 2007; 35: 27552761.
55. Devarajan P. Update on mechanisms of ischemic acute kidney injury.
J Am Soc Nephrol 2006; 17: 15031520.
56. Leelahavanichkul A, Huang Y, Hu X et al. Chronic kidney disease worsens
sepsis and sepsis-induced acute kidney injury by releasing high mobility
group box protein-1. Kidney Int 2011; 80: 11981211.
57. Bonventre JV, Weinberg JM. Recent advances in the pathophysiology of
ischemic acute renal failure. J Am Soc Nephrol 2003; 14: 21992210.
58. Jang HR, Rabb H. The innate immune response in ischemic acute kidney
injury. Clin Immunol 2009; 130: 4150.
523
mini review
59. Castano AP, Lin SL, Surowy T et al. Serum amyloid P inhibits fibrosis
through Fc gamma R-dependent monocyte-macrophage regulation
in vivo. Sci Transl Med 2009; 1: 5ra13.
60. Nath KA. Tubulointerstitial changes as a major determinant in the
progression of renal damage. Am J Kidney Dis 1992; 20: 117.
61. Bohle A, von Gise H, Mackensen-Haen S et al. The obliteration of the
postglomerular capillaries and its influence upon the function of both
glomeruli and tubuli. Functional interpretation of morphologic findings.
Klinische Wochenschrift 1981; 59: 10431051.
62. Finn WF. Enhanced recovery from postischemic acute renal failure.
Micropuncture studies in the rat. Circ Res 1980; 46: 440448.
63. Yang L, Besschetnova TY, Brooks CR et al. Epithelial cell cycle arrest in G2/
M mediates kidney fibrosis after injury. Nat Med 2010; 16: 535543 531p
following 143.
64. Basile DP, Friedrich JL, Spahic J et al. Impaired endothelial proliferation
and mesenchymal transition contribute to vascular rarefaction
following acute kidney injury. Am J Physiol Renal Physiol 2011; 300:
F721F733.
65. Basile DP, Donohoe D, Roethe K et al. Renal ischemic injury results in
permanent damage to peritubular capillaries and influences long-term
function. Am J Physiol Renal Physiol 2001; 281: F887F899.
66. Yuan HT, Li XZ, Pitera JE et al. Peritubular capillary loss after mouse acute
nephrotoxicity correlates with down-regulation of vascular endothelial
growth factor-A and hypoxia-inducible factor-1 alpha. Am J Pathol 2003;
163: 22892301.
67. O0 Riordan E, Mendelev N, Patschan S et al. Chronic NOS inhibition
actuates endothelial-mesenchymal transformation. Am J Physiol Heart
Circ Physiol 2007; 292: H285H294.
68. Horbelt M, Lee SY, Mang HE et al. Acute and chronic microvascular
alterations in a mouse model of ischemic acute kidney injury. Am J Physiol
Renal Physiol 2007; 293: F688F695.
69. Bechtel W, McGoohan S, Zeisberg EM et al. Methylation determines
fibroblast activation and fibrogenesis in the kidney. Nat Med 2010; 16:
544550.
524
LS Chawla and PL Kimmel: Acute kidney injury and chronic kidney disease
70. Bonventre JV. Dedifferentiation and proliferation of surviving epithelial
cells in acute renal failure. J Am Soc Nephrol 2003; 14Suppl 1: S55S61.
71. Price PM, Safirstein RL, Megyesi J. The cell cycle and acute kidney injury.
Kidney Int 2009; 76: 604613.
72. Hodeify R, Tarcsafalvi A, Megyesi J et al. Cdk2-dependent phosphorylation
of p21 regulates the role of Cdk2 in cisplatin cytotoxicity. Am J Physiol
Renal Physiol 2011; 300: F1171F1179.
73. Megyesi J, Price PM, Tamayo E et al. The lack of a functional p21(WAF1/
CIP1) gene ameliorates progression to chronic renal failure. Proc Natl
Acad Sci USA 1999; 96: 1083010835.
74. Wynn TA. Fibrosis under arrest. Nat Med 2010; 16: 523525.
75. Bechtel W, McGoohan S, Zeisberg EM et al. Methylation determines fibroblast
activation and fibrogenesis in the kidney. Nat Med 2010; 16: 544550.
76. Megyesi J, Udvarhelyi N, Safirstein RL et al. The p53-independent
activation of transcription of p21 WAF1/CIP1/SDI1 after acute renal
failure. Am J Physiol 1996; 271: F1211F1216.
77. Srisawat N, Murugan R, Lee M et al. Plasma neutrophil gelatinase-
associated lipocalin predicts recovery from acute kidney injury following
community-acquired pneumonia. Kidney Int 2011; 80: 545552.
78. Lassnigg A, Schmidlin D, Mouhieddine M et al. Minimal changes
of serum creatinine predict prognosis in patients after cardiothoracic
surgery: a prospective cohort study. J Am Soc Nephrol 2004; 15:
15971605.
79. Chertow GM, Burdick E, Honour M et al. Acute kidney injury, mortality,
length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005;
16: 33653370.
80. Anderson S, Eldadah B, Halter JB et al. Acute kidney injury in older adults.
J Am Soc Nephrol 2011; 22: 2838.
81. Go AS, Parikh CR, Ikizler TA et al. The assessment, serial evaluation, and
subsequent sequelae of acute kidney injury (ASSESS-AKI) study: design
and methods. BMC Nephrol 2010; 11: 22.
82. USRDS Annual Report 2007 Department of Health and Human Services,
NIDDK, United States Renal Data System (USRDS) (NIH publication no
07-3176) 2007; 1: 240241.
Kidney International (2012) 82, 516524
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.