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Pediatric acute kidney injury: It’s time for real progress
By Stuart L. Goldstein, M.D.
Fundamental and extensive research effort has been expended in the
area of both pediatric and adult patient acute renal failure in the
past decade. This investigation has spanned the clinical and
translational arenas, focusing on such basic issues as updating
epidemiology, redefining both the definition of, and nomenclature to
classify, acute renal failure as well as searching for markers other
than serum creatinine to identify renal injury before significant
metabolic derangement occurs. Finally, substantial published study
now lends insight into optimal methods for acute renal failure
management and renal replacement therapy provision. The aim of this
article is to provide a description of the state of the art in
pediatric acute renal failure diagnosis and management by
highlighting recent significant clinical and research progress.
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It is likely that a combination of urinary biomarker profiles will
become available to predict patients at risk for developing severe
kidney injury and thus assist in targeting therapies to prevent or
mitigate the degree of renal insult. |
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Acute renal failure vs. acute kidney injury: What’s in a name?
Despite the significant morbidity and mortality associated with
acute renal failure, over 30 definitions exist in the published
literature.[1] Lack of a uniform and multidimensional acute renal
failure classification system has led to the inability to generalize
single study results. Furthermore, since most acute renal failure
definitions are based on a serum creatinine rise, lack of uniform
definition may result in lack of recognition of significant renal
injury and delay in treatment. Chertow and colleagues recently
demonstrated that “small” increases in serum creatinine of 0.3 mg/dL
could be associated with increased patient mortality, even when
outcome is controlled for significant patient comorbidity.[2]
Preliminary data from our center showed a 0.3 mg/dL or greater serum
creatinine rise in 60 pediatric patients with acute decompensated
heart failure; such patients demonstrated a sevenfold increased
mortality risk.[3]
These data argue for a graded acute renal failure classification
system, which can identify patients at risk for developing
significant renal insult and metabolic disturbance. The Acute
Dialysis Quality Initiative (ADQI) (www.adqi.net) recently proposed
[1] a multidimensional system termed the RIFLE criteria (risk,
injury, failure, loss and ESRD) that classify the degree of renal
insult by changes in serum creatinine and/or the duration of
oliguria. ADQI also proposed changing terminology from acute renal
failure to acute kidney injury (AKI) in an effort to focus attention
on early recognition of renal insult and interventions to prevent or
mitigate the effects of significant renal failure. From this point
on, acute kidney injury will be the term employed to describe the
relevant clinical situation previously known as acute renal failure.
RIFLE is an empiric classification system which only recently has
undergone clinical validation. We prospectively studied [4]
critically ill pediatric patients receiving mechanical ventilation
and used pediatric modified RIFLE criteria to describe the pattern
of pediatric AKI and determine if RIFLE provides sufficient
sensitivity and specificity in the clinical setting. The majority of
patients who developed AKI by RIFLE did so in the first seven days
of ICU admission. Failure to reach RIFLE level in the first seven
days of ICU admission resulted in a 98 percent negative predictive
value of developing AKI after seven days.
Urinary AKI biomarkers: The search for the “renal troponin I”
As previously noted, small increases in serum creatinine may reflect
significant renal insult and be associated with significant
morbidity in patients with AKI. Intensive investigation has led to
the identification of several potential urinary biomarkers that may
herald AKI prior to a rise in serum creatinine. Pediatric patients
comprise an important population for study, since they usually do
not have significant comorbidities–hypertension, atherosclerosis and
diabetes–that affect kidneys in adults.
Infants with congenital heart disease undergoing corrective surgery
provide an informative population for study of putative urinary AKI
biomarkers, since the time of renal ischemia (i.e., cardiopulmonary
bypass, CPB) is known and these children can be studied
prospectively for development of AKI. Mishra and colleagues assessed
[5] the incidence of AKI in this population and assayed urine for
appearance of neutrophil gelatinase-associated lipocalin (NGAL) and
found urinary NGAL increased at least fiftyfold and preceded serum
creatinine rise by at least 24 hours in all patients who developed
AKI.
Other urinary biomarkers, including kidney injury molecule –1 (KIM-1)
[6] and urinary IL-18 [7], have been studied in adult patients with
AKI. We are currently assessing these biomarkers in a cohort of 150
ventilated critically pediatric patients at Texas Children's
Hospital, and have found very promising results in which each of the
urinary biomarkers predicts the severity of AKI and precedes AKI in
a majority of patients.
Acute kidney injury treatment: What can we do better now?
While multicenter epidemiological pediatric AKI data do not exist,
single center data from the 1980s report hemolytic uremic syndrome,
other primary renal causes, sepsis and burns as the most prevalent
causes leading to pediatric AKI. [8-10] Most articles from the 1990s
are literature reviews. [11-13]
A recent retrospective AKI review from our center has completely
updated pediatric AKI epidemiology by demonstrating acute tubular
necrosis and nephrotoxic medicines to be the most common ARF cause
cited and that primary kidney disease was cited in only 7 percent of
cases.[14] Thus, the epidemiology of pediatric AKI has changed from
primary kidney diseases to secondary effects of other systemic
illnesses or their treatment.
AKI management should begin prior to consultation of a nephrologist
and provision of renal replacement therapy. Well-designed
prospective randomized study of adult patients at risk for ATN has
called into question the utility of intravenous furosemide or
“renal-dose” dopamine in preventing oliguria. [15, 16] Other recent
study supports the use of fenoldopam, a dopamine alpha-1 agonist to
prevent AKI in certain critically ill adult populations. [17, 18] To
date, no published pediatric study exists with respect to pediatric
AKI.
Recent data from adult patients with septic shock demonstrate that
goal directed fluid therapy using physiologic endpoints could
significantly improve patient survival.[19] Adult patients who
received early goal directed fluid therapy in the emergency center
received more fluid in the emergency center, but received less fluid
and had better survival in the ICU compared to patients who received
standard therapy.
Fluid resuscitation in critically ill children is
essential for patients with acute hypovolemia and septic shock.[20]
The concept that worsening fluid overload is associated with worse
outcome in critically ill pediatric patients who require renal
replacement therapy has been the focus of recent pediatric study.
Both single center data [21-23], including data from Texas
Children's Hospital and a multicenter effort for which I serve as
founder and principal investigator, the Prospective Pediatric
Continuous Renal Replacement Therapy Registry Group (ppCRRT
Registry)[24, 25], demonstrate the worsening fluid overload is an
independent risk factor for mortality, irrespective of severity of
illness by PRISM, in patients who receive CRRT. These data, coupled
with the predilection for early multiorgan system failure and death
in critically ill children [26, 27] with AKI, may argue for early and
aggressive initiation of renal replacement therapy.
The long-term sequelae of pediatric AKI have just been studied.
Askenazi [28] found three- to five-year patient survival of an AKI
episode at Texas Children's Hospital to be 56.8 percent and that a
59 percent of studied patients demonstrated evidence of chronic
kidney injury. As a result, we suggested routine evaluation of all
pediatric AKI survivors for evidence of chronic kidney disease,
hypertension or microalbuminuria.
Pediatric AKI: Where do we go from here?
The exciting developments described above provide an essential
foundation for further study. Acceptance of a multidimensional AKI
classification system such as RIFLE will provide a hard and uniform
outcome endpoint, thereby allowing for generalization across AKI
studies. It is likely that a combination of urinary biomarker
profiles will become available to predict patients at risk for
developing severe kidney injury and thus assist in targeting
therapies to prevent or mitigate the degree of renal insult. Minimal
pediatric data exist to guide medication dosing in patients with
AKI, most of which are extrapolated from adult or in vitro study.
[29] The ppCRRT Registry group plans to study the pharmacokinetics
of various therapeutic agents in children AKI who receive CRRT to
determine optimal dosing strategies based on fluid overload status
and CRRT clearance. Finally, collaborations such as the ppCRRT
Registry Group, ADQI and the proposed Acute Kidney Injury Network
(AKIN, which will include both pediatric and adult patients) are
essential to study fluid, medication, nutrition, and
anti-inflammatory and renal replacement therapy management
strategies in our quest to optimize the care we provide to the
critically ill.
Stuart L. Goldstein, M.D., is medical director of the Renal Dialysis
and Pheresis Unit at Texas Children's Hospital, associate professor
of Pediatrics at Baylor College of Medicine, and the founder and
principal investigator of The Prospective Pediatric Continuous Renal
Replacement Therapy Group in Houston, Texas.
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