Prevention/Treatment/Rehabilitation: Whats on the Horizon?

Kellum JA, Ronco C, Vincent J-L (eds): Controversies in Acute Kidney Injury.
Contrib Nephrol. Basel, Karger, 2011, vol 174, pp 182190

Acute Kidney Injury Leading to

Chronic Kidney Disease and Long-Term
Outcomes of Acute Kidney Injury:
The Best Opportunity to Mitigate
Acute Kidney Injury?
Lakhmir S. Chawlaa,b
a

Department of Anesthesiology and Critical Care Medicine, and bDivision of Renal Diseases
and Hypertension, Department of Medicine, George Washington University Medical Center,
Washington DC, USA

Abstract
Acute kidney injury (AKI) has been shown to be associated with progression to chronic
kidney disease (CKD). Multiple studies have shown that subsets of AKI survivors are at
high risk for progression to advanced stage CKD and death. Risk factors associated with
AKI survivors progressing to CKD have been identified and include advanced age, diabetes mellitus, decreased baseline glomerular filtration rate, severity of AKI and a low concentration of serum albumin. These risk factors can be utilized to identify those patients at
highest risk for progression. Because progression to CKD in these AKI survivors typically
occurs months after the initial AKI insult, a common injury pathway of CKD progression is
probable, and therapeutic interventions that have been shown to retard CKD progression
are likely to be effective in patients who survive AKI and then progress to CKD. AKI has
many negative impacts across the spectrum of the disease. The 30-day mortality for
patients with AKI is high, hence the preference to target AKI during the initiation phase.
However, this phase is the most difficult point to treat AKI. The maintenance phase of AKI
is longer in duration in comparison to the initiation phase, and thus the logistics are more
amenable to study. However, the mainstay of treatment for the maintenance phase of AKI
(renal replacement therapy) has been tested extensively and increasing the dose of renal
replacement therapy has not been shown to improve outcome. Therefore, the recovery
phase of AKI may represent the best opportunity to intervene in the negative outcomes
Copyright 2011 S. Karger AG, Basel
of AKI.

Acute kidney injury (AKI) is becoming increasingly common in critically ill

patients, and those patients with the most severe form of AKI requiring renal
replacement therapy (RRT) have a mortality of 5080% [1]. Over the past 10
years, there has been substantial progress in the field of AKI. In particular,
consensus definitions, AKI biomarkers and the appropriate dosing of RRT
have been established. Despite these advances, no drug or other therapeutic
intervention currently exists for the treatment of AKI [2].
AKI is a clinical syndrome with a multitude of causes, which contributes
to the complexities in designing therapies [3]. In addition, AKI has distinctive phases of injury (initiation, maintenance and recovery) [4]. While the
consensus definition of AKI (RIFLE/AKIN) does not factor in the cause of
AKI, it is likely that successful treatments for AKI will need to address the
pathophysiologic mechanism of injury, particularly during the initiation
phase [4].
AKI has been shown to be associated with progression to CKD [5
7]. Multiple studies assessing various cohorts of patients have shown that
subsets of AKI survivors are at high risk for progression to advanced stage
CKD [58]. In these studies, subsets of AKI survivors recovered renal function and then progressed to advanced stage CKD. Because the progression to
CKD in these AKI survivors typically occurred months after the initial AKI
insult, a common injury pathway of CKD progression is more probable, and
therapeutic interventions that have been shown to forestall CKD progression
are likely to be effective in patients who survive AKI and then progress to
CKD.
Assessing the current landscape of AKI has shown that it has many negative
impacts across the spectrum of the disease. Because the 30-day mortality for
patients with AKI is 5080%, there is an obvious desire to target AKI during
the initiation phase [1]. However, this phase is the most difficult point to treat
AKI. Despite the current progress in AKI biomarkers, real-time point-of-care
tests for study intervention are not routinely available, except for a few select
academic centers. The time window for intervention during the AKI initiation
phase is short, and since these patients often cannot provide consent for themselves, the logistics of conducting these studies are daunting. These obstacles
are further exacerbated by the fact that the understanding of the pathophysiologic mechanisms for the most common cause of AKI (sepsis-associated AKI,
which contributes to half of all cases) is wanting [1, 9]. Moreover, the associated acute phase mortality of AKI is difficult to dissociate from the underlying
disease.
The maintenance phase of AKI is longer in duration in comparison to the
initiation phase, and thus the logistics are more amenable to study. However, the
mainstay of treatment for the maintenance phase of AKI is RRT, which has been
tested extensively. Two large well-powered prospective trials have shown that
increasing the dose of RRT does not improve outcomes [10, 11]. Therefore, the

Acute Kidney Injury Leading and Chronic Kidney Disease

183

Table 1. Summary of studies indicating association of AKI with progression to CKD

Study

Key findings

Ali [26] 2007

562

AKI-F 51% recover full renal function

ACRF-F 28% recover full renal function

Ishani [6] 2009

233,803

AKI 13 times more likely to develop ESRD

ACRF 41 times more likely to develop ESRD

Hsu [28] 2009

1061

ACRF-F 4263% of hospital survivors progressed to ESRD

Lo [7] 2009

703

AKI-F survivors are 28 times more likely to develop advanced CKD

Amdur [5] 2009

5,404

20% of patients with a diagnosis of ATN progress to CKD4 within 20 months

Wald [8] 2009

3,769

AKI-F survivors are 3 times more likely to develop ESRD

AKI-F = Acute kidney injury RIFLE F; ACRF = acute chronic renal failure; ATN = acute tubular necrosis.

recovery phase of AKI may represent the best opportunity to intervene in the
negative outcomes of AKI.

Acute Kidney Injury as a Cause of Chronic Kidney Disease

Prior to the era of CKD staging, it was generally accepted that patients who
recovered from AKI had good renal outcomes as assessed by a low incidence
of end-stage renal disease (ESRD) [12]. These previous long-term studies were
hampered by different definitions, variable follow-up times, and low overall
numbers. More recently, from 2008 through 2010 (table 1), multiple studies
assessing unique cohorts of patients demonstrated that patients who survive an
episode of AKI have a significant risk for the development of advanced CKD
(stage 4/5) [58].
Ishani et al. [6] assessed a random sample of Medicare beneficiaries and
found that patients who had suffered an episode of AKI were more likely to
develop ESRD than patients who did not have a history of AKI or CKD. In their
analysis, the risk of ESRD was thirteen times higher than patients without a history of AKI or CKD. Because this study utilized diagnostic codes, it is difficult
to determine the proportion of patients who suffered AKI and then progressed
directly to ESRD as compared to patients who suffered AKI, recovered renal
function and then progressed to ESRD [6]. Lo et al. [7], utilizing a database from
the health insurer Kaiser Permanente, retrospectively studied inpatient admissions. Patients who suffered AKI (dialysis-requiring episode of AKI) were compared to patients who did not suffer an episode of AKI. Patients with a history of

184

Chawla

ESRD or a pre-admission estimated glomerular filtration rate <45 ml/min/1.73

m2 were excluded. In this study, the investigators found that an episode of dialysis requiring AKI was associated with a 28-fold increase of developing advanced
CKD and a twofold increase in mortality. Because 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 [7]. Wald et al.
[8] conducted a population-based cohort study of patients in Ontario, Canada
with 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 during their index hospitalization. Patients with AKI
requiring dialysis were over three times more likely to develop ESRD as compared to controlled matched patients.
We assessed a United States Department of Veterans Affairs database to ascertain long-term renal function in over 79,000 hospitalized patients [5]. Within
this cohort, 63,491 patients were hospitalized for acute myocardial infarction or
pneumonia without AKI and designated as controls. Another 5,404 hospitalized
patients, which comprised the AKI group, had diagnostic codes indicating acute
renal failure or acute tubular necrosis. Over the 5-year follow-up period, renal
function deteriorated over time in all groups, but with significantly greater severity in those who had acute renal failure and acute tubular necrosis compared to
controls. Patients with AKI, especially those with acute tubular necrosis, were
more likely than controls to enter stage 4/5 CKD. We found that patients who
had an episode of AKI were at high risk for the development of stage 4 disease
and had a reduced survival time when compared to control patients [5].
In aggregate, these studies underscore the strong association between AKI
and the future development of CKD.

Identification of Patients and Risk Factors for Chronic Kidney Disease

Progression

The above studies in AKI survivors identified advanced age, presence of diabetes mellitus and decreased baseline estimated glomerular filtration rate as risk
factors for the progression to advanced stage CKD. More recently, severity of
AKI has been linked to CKD progression in survivors of AKI. Ishani et al. [13]
assessed patients who underwent cardiac surgery and found that the magnitude
of serum creatinine during the postoperative hospital course was directly linked
to progression. This effect was seen in patients with de novo AKI as well as
in patients with acute on chronic renal failure [13]. Similarly, we have recently
shown that in addition to severity of AKI, a low serum albumin concentration
is a strong predictor of poor long-term renal outcome [14]. The strong predictive value of serum albumin levels as a predictor of CKD progression is not

Acute Kidney Injury Leading and Chronic Kidney Disease

185

surprising because low albumin levels have been associated with poor outcomes
in a variety of diseases including ESRD, surgical illness and acute stroke [15
17]. Low levels of serum albumin can be due to either nutrition-related factors
and/or high levels of inflammation [18]. Given that multiple studies have linked
inflammation to AKI, it is likely that the predictive value of low concentrations
of serum albumin to CKD progression is a composite measure of increased
inflammation [1921].
We assessed a cohort of patients with a spectrum of AKI from RIFLE stages
R through F, and showed that the severity of AKI is associated with progression
to advanced CKD (fig. 1). In particular, we showed that patients who require
dialysis are at much higher risk for progression to CKD than patients with less
severe AKI. The precise mechanism by which AKI causes CKD is unknown.
Preclinical studies suggest several potential mechanisms for how AKI can cause
CKD: acute endothelial injury leading to vascular dropout, nephron loss followed by glomerular hypertrophy or development of fibrosis after sustaining
AKI [22, 23].
In order to help clinicians identify AKI survivors at high-risk for CKD progression, we developed three multivariable models. The most accessible model
is based on sentinel clinical events (RIFLE stage, need for dialysis, etc.) [14].
This model performed well with 11% of the CKD variance explained (area
under ROC curve = 0.77). We validated this equation in a separate large cohort
of hospitalized veterans which resulted in p < 0.001 and c-statistics 0.81, signifying good reproducibility. Because these endpoints are accessible, clinicians
could potentially use this equation to risk stratify AKI survivors who are at the
highest risk for progression to CKD [14].

Interventions during the Recovery Phase of Acute Kidney Injury

Because a primary care provider sees most AKI patients following an AKI episode, these patients are accessible for intervention. At 30 days after AKI discharge, 74.5% have seen a primary physician compared to 11.9 and 29.5%,
respectively, who see a nephrologist or cardiologist [24]. Surprisingly, only
about one third of AKI patients who suffer AKI requiring dialysis see a nephrologist within 30 days of discharge. This increases to 48.6% within 1 year of
discharge, which is likely a result of rising serum creatinine [24]. Overall, a very
small fraction of AKI patients are currently followed by a nephrologist after
an AKI discharge [24]. To put this into context, an assessment of the nephrology follow-up of AKI survivors as compared to the cardiology follow-up of
myocardial infarction survivors reveals a stark difference (11.9 vs. 76%, respectively) [24, 25].
The public health impact of the long-term outcomes of AKI is significant.
The population incidence of AKI is approximately 2,100 pmp [26]. Given

186

Chawla

100

90
Tertile 3: mean eGFR 15 years
post >79.2 (n = 767)

Mean eGFR

80

70
Tertile 2: mean eGFR 15 years
post 6179.2 (n = 766)
60

50
Tertile 1: mean eGFR 15 years
post <61 (n = 767)
40

30
1 year pre

During

13 months
post

312 months
post

15 years
post

Time

3.5

3.0

Mean SC (mg/dl)

2.5

Mean eGFR 15 years

post tertile
Tertile 1 (n = 767)

2.0

Tertile 2 (n = 766)
Tertile 3 (n = 767)
1.5

1.0

0.5
1 year pre

During

13 months 312 months 15 years

post
post
post
Time

Fig. 1. Patients who were still alive 1 year after index hospitalization. a Time vs. mean
estimated glomerular filtration rate (eGFR) in AKI survivors [14]. b Time vs. mean serum
creatinine (SC) in AKI survivors [14].

Acute Kidney Injury Leading and Chronic Kidney Disease

187

the population of the developed world (USA, Canada, Western Europe and
Australia) of approximately 1 billion, this means that there will be over 2 million cases of AKI this year, with an expected 1.5 million AKI survivors. Of these
patients, approximately 1520% will progress to advanced stage CKD within 24
months, resulting in approximately 300,000400,000 cases of advanced CKD
per year. Given the increasing incidence of AKI in the aging population [27], the
numbers above are expected to increase.
In our view, the first interventional study to mitigate the progression of CKD
in AKI survivors should include testing the standard approach that is currently
used to treat CKD patients: blood pressure control, nephrotoxin avoidance and
nutritional intervention. A potential study design would use a risk factor risk
score to identify the patients at highest risk for CKD progression. Those patients
would then be enrolled into a clinical trial during their index hospitalization of
AKI. Patients would be randomized to one of three interventions: intervention
1, standard primary care follow-up at scheduled visits; intervention 2, standard
primary care follow-up, with scheduled nephrology follow-up for blood pressure control, nutritional intervention for sodium and protein diet counseling,
and nephrotoxin avoidance education; and intervention 3, interventions 1 and
2, plus renin-angiotensin-aldosterone system blockade. Other interventions
that could be added or substituted in the above example include HMG Co-A
reductase inhibitors, and antiproliferative agents.

Conclusions

Patients with AKI suffer a high short-term mortality rate and subsets of those
patients who survive are at increased risk for developing CKD. Interventions
targeted during the initiation phase of AKI are the most desirable. However, the
inadequate understanding of the pathophysiologic mechanisms of this phase of
AKI in combination with a paucity of candidate therapeutic agents underlies
the complexities of bringing a successful intervention from the bench to the
bedside.
While the recovery phase of AKI may be less appealing as a point to intervene because of the associated high short-tem mortality of AKI, the advantages
of intervening in the recovery phase of AKI are numerous. The mechanism of
CKD progression is more remote to the initial AKI. Patients at risk can be identified. The pathophysiology of CKD progression is well understood, and similarities between CKD progression and AKI progression to CKD are likely. The
time to progression from AKI to recovery to advanced stage CKD occurs over
months. Because of this longer timeline, incremental dose titration of potential
therapeutic agents can be done more effectively, thereby potentially decreasing
adverse events. Further, AKI survivors currently have no standard of care intervention, and modest interventions could have significant effects.

188

Chawla

In short, intervention at the recovery stage of AKI possesses the important

prerequisites for a successful intervention and this should be a focus for the AKI
research community.

References
1 Uchino S, Kellum JA, Bellomo R, Doig GS,
Morimatsu H, Morgera S, Schetz M, Tan I,
Bouman C, Macedo E, Gibney N, Tolwani A,
Ronco C: Acute renal failure in critically ill
patients: a multinational, multicenter study.
JAMA 2005;294:813818.
2 Bajwa A, Kinsey GR, Okusa MD: Immune
mechanisms and novel pharmacological
therapies of acute kidney injury. Curr Drug
Targets 2009;10:11961204.
3 Himmelfarb J, Joannidis M, Molitoris B,
Schietz M, Okusa MD, Warnock D, Laghi F,
Goldstein SL, Prielipp R, Parikh CR, Pannu
N, Lobo SM, Shah S, DIntini V, Kellum
JA: Evaluation and initial management of
acute kidney injury. Clin J Am Soc Nephrol
2008;3:962967.
4 Cruz DN, Bagshaw SM, Ronco C, Ricci Z:
Acute kidney injury: classification and staging; in Ronco C, Costanzo MR, Bellomo R,
Maisel AS (eds): Fluid Overload: Diagnosis
and Management. Contrib Nephrol. Basel,
Karger, 2010, vol 164, pp 2432.
5 Amdur RL, Chawla LS, Amodeo S, Kimmel
PL, Palant CE: Outcomes following diagnosis of acute renal failure in U.S. veterans:
focus on acute tubular necrosis. Kidney Int
2009;76:10891097.
6 Ishani A, Xue JL, Himmelfarb J, Eggers PW,
Kimmel PL, Molitoris BA, Collins AJ: Acute
kidney injury increases risk of ESRD among
elderly. J Am Soc Nephrol 2009;20:223228.
7 Lo LJ, Go AS, Chertow GM, McCulloch
CE, Fan D, Ordonez JD, Hsu CY: Dialysisrequiring acute renal failure increases the
risk of progressive chronic kidney disease.
Kidney Int 2009;76:893899.
8 Wald R, Quinn RR, Luo J, Li P, Scales DC,
Mamdani MM, Ray JG: Chronic dialysis and
death among survivors of acute kidney injury
requiring dialysis. JAMA 2009;302:1179
1185.

9 Pelte CH, Chawla LS: Novel therapeutic

targets for prevention and therapy of sepsis
associated acute kidney injury. Curr Drug
Targets 2009;10:12051211.
10 Bellomo R, Cass A, Cole L, Finfer S,
Gallagher M, Lo S, McArthur C, McGuinness
S, Myburgh J, Norton R, Scheinkestel C, Su
S: Intensity of continuous renal-replacement
therapy in critically ill patients. N Engl J Med
2009:361:16271638.
11 Palevsky PM, Zhang JH, OConnor TZ,
Chertow GM, Crowley ST, Choudhury D,
Finkel K, Kellum JA, Paganini E, Schein
RM, Smith MW, Swanson KM, Thompson
BT, Vijayan A, Watnick S, Star RA, Peduzzi
P: Intensity of renal support in critically ill
patients with acute kidney injury. N Engl J
Med 2008;359:720.
12 Liano F, Felipe C, Tenorio MT, Rivera M,
Abraira V, Saez-de-Urturi JM, Ocana J,
Fuentes C, Severiano S: Long-term outcome
of acute tubular necrosis: a contribution to its
natural history. Kidney Int 2007;71:679686.
13 Ishani A, Nelson D, Clothier B, Schult T,
Nugent S, Greer N, Slinin Y, Ensrud KE:
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.
14 Chawla LS, Amdur RL, Amodeo S, Kimmel
PL, Palant CE: The severity of acute kidney
injury predicts progression to chronic kidney
disease. Kidney Int 2011; E-pub ahead of
print.
15 Engelman DT, Adams DH, Byrne JG, Aranki
SF, Collins JJ Jr, Couper GS, Allred EN, Cohn
LH, Rizzo RJ: Impact of body mass index
and albumin on morbidity and mortality
after cardiac surgery. J Thorac Cardiovasc
Surg 1999;118:866873.
16 Gariballa SE, Parker SG, Taub N, Castleden
CM: Influence of nutritional status on clinical outcome after acute stroke. Am J Clin
Nutr 1998;68:275281.

Acute Kidney Injury Leading and Chronic Kidney Disease

189

17 Owen WF Jr, Lew NL, Liu Y, Lowrie EG,

Lazarus JM: The urea reduction ratio and
serum albumin concentration as predictors
of mortality in patients undergoing hemodialysis. N Engl J Med 1993:329:10011006.
18 Friedman AN, Fadem SZ: Reassessment of
albumin as a nutritional marker in kidney
disease. J Am Soc Nephrol 2010;21:223230.
19 Chawla LS, Seneff MG, Nelson DR, Williams
M, Levy H, Kimmel PL, Macias WL: 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.
20 Liu KD, Glidden DV, Eisner MD, Parsons PE,
Ware LB, Wheeler A, Korpak A, Thompson
BT, Chertow GM, Matthay MA: Predictive
and pathogenetic value of plasma biomarkers
for acute kidney injury in patients with acute
lung injury*. Crit Care Med 2007, E-pub
ahead of print.
21 Murugan R, Karajala-Subramanyam V, Lee
M, Yende S, Kong L, Carter M, Angus DC,
Kellum JA: Acute kidney injury in nonsevere pneumonia is associated with an
increased immune response and lower survival. Kidney Int 2010;77:527535
22 Sutton TA, Mang HE, Campos SB, Sandoval
RM, Yoder MC, Molitoris BA: Injury of the
renal microvascular endothelium alters barrier function after ischemia. Am J Physiol
Renal Physiol 2003;285:F191F198.

23 Yang L, Besschetnova TY, Brooks CR, Shah

JV, Bonventre JV: Epithelial cell cycle arrest
in G2/M mediates kidney fibrosis after
injury. Nat Med 2010;16:535543, 1p following 143.
24 USRDS. USRDS Annual Report 2009; in
USRDS, Minneapolis, MN, 2009.
25 Daugherty SL, Ho PM, Spertus JA, Jones
PG, Bach RG, Krumholz HM, Peterson ED,
Rumsfeld JS, Masoudi FA: Association of
early follow-up after acute myocardial infarction with higher rates of medication use.
Arch Intern Med 2008;168:485491, discussion 492.
26 Ali T, Khan I, Simpson W, Prescott G,
Townend J, Smith W, Macleod A: Incidence
and outcomes in acute kidney injury: a comprehensive population-based study. J Am Soc
Nephrol 2007;18:12921298.
27 Chertow GM, Burdick E, Honour M,
Bonventre JV, Bates DW: Acute kidney
injury, mortality, length of stay, and costs
in hospitalized patients. J Am Soc Nephrol
2005;16:33653370.
28 Hsu CY, Chertow GM, McCulloch CE,
Fan D, Ordonez JD, Go AS: Clin J Am Soc
Nephrol 2009;4:891898.

Lakhmir S. Chawla, MD
Department of Anesthesiology and Critical Care Medicine
George Washington University Medical Center
900 23rd Street, NW, RILF, G-105, Washington DC, 20037 (USA)
Tel. +1 202 715 4570, E-Mail minkchawla@gmail.com

190

Chawla