In the Literature
Increasing Incidence of Acute Kidney Injury: Also
a Problem in Pregnancy?
Commentary on Mehrabadi A, Liu S, Bartholomew S, et al. Hypertensive disorders of pregnancy and the recent increase in
obstetric acute renal failure in Canada: population based retrospective cohort study. BMJ. 2014;349:g4731.
S everal studies reporting an increased incidence of
acute kidney injury (AKI) over time have
garnered significant recent attention.1-3 Although this
has been observed in samples of the general popula-
tion1,2 and specific subgroups of patients (eg, those
undergoing cardiac surgery4,5), there may be hetero-
geneity across disease groups and the risk may be
changing over time. Amin et al,6 for example, re-
ported that among patients hospitalized across 56 US
centers from 2000 to 2008 with acute myocardial
infarction, the incidence of AKI has decreased.
Prior studies have reported that pregnancy-
associated AKI at the time of delivery has become
more common.7,8 In the pregnant patient, AKI may
be due to decreased renal perfusion or ischemic
acute tubular necrosis from postpartum hemorrhage,
thrombotic microangiopathy (from preeclampsia or
thrombotic thrombocytopenic purpura–hemolytic ure-
mic syndrome), acute fatty liver of pregnancy, acute
pyelonephritis, bilateral renal cortical necrosis, and
bilateral renal obstruction from a gravid uterus.
Because preexisting hypertension is one of the largest
risk factors for preeclampsia, preexisting hypertension
is a significant risk factor for pregnancy-related AKI.
WHAT DOES THIS IMPORTANT STUDY SHOW?
Building on their prior work showing that there has
been an increase in pregnancy-related AKI,7 the recent
British Medical Journal article by Mehrabadi et al9
from the Canadian Perinatal Surveillance System
extended their analyses to 2010 and attempted to find
reasons for this increase. Similar to their prior article,7
the authors analyzed data from the Canadian Institute
for Health Information discharge abstract database,
which captures all in-hospital deliveries in Canada
(except Quebec). Using the International Statistical
Classification of Diseases and Related Health Prob-
lems, Tenth Revision, Canadian version (ICD-10-CA),
AKI was captured with diagnostic codes O90.4
(postpartum acute renal failure), N99.0 (post-
procedural renal failure), N17 (acute renal failure), and
Originally published online January 7, 2015.
Address correspondence to Chi-yuan Hsu, MD, MSc, University
of California, San Francisco, 521 Parnassus Ave, C443, Box 0532,
San Francisco, CA 94143. E-mail: hsuchi@medicine.ucsf.edu
Ó 2015 by the National Kidney Foundation, Inc.
0272-6386
http://dx.doi.org/10.1053/j.ajkd.2014.11.007
650
N19 (unspecified kidney failure). The authors also
relied on ICD-10-CA codes to define other key clinical
variables (eg, postpartum hemorrhage).
Although postpartum hemorrhage and hypertensive
disorders incidence increased between 2003 and 2010,
multivariable analysis showed that these changes did
not explain the observed 61% increase in pregnancy-
related AKI (from 1.66 to 2.68 events/10,000 de-
liveries). The temporal increase in AKI was restricted
to deliveries with hypertensive disorders (adjusted
increase, 95%) and was especially pronounced among
women with gestational hypertension with significant
proteinuria (ie, preeclampsia; adjusted increase,
171%), an interaction discovered by a post hoc anal-
ysis. Based on the data given in the article and their
prior publication,7 there was no change in incidence of
dialysis-requiring AKI during the study period.
The authors posited that changes in preeclampsia
management, including limiting intravenous fluid
administration (to prevent pulmonary edema) and
choice of antihypertensive agents, may have caused
hypovolemia and hypoperfusion, respectively, with
resultant AKI (although pulmonary edema rates did
not change over the study period7,9). They also dis-
cussed a potential role of increased use of nonste-
roidal anti-inflammatory drugs for pain control, but
there was no information provided about medication
use.
HOW DOES THIS STUDY COMPARE WITH
PRIOR STUDIES?
Table 1 summarizes some prior articles reporting
temporal trends in AKI incidence. Comparing find-
ings across studies is not straightforward. In addition
to heterogeneity in disease subtype, population, and
calendar year period, studies also differ by the unit of
disease frequency, which has been expressed as cases
per delivery,7,8 per surgery,4,5 and per hospitaliza-
tion.3,6 Even the population-based studies—in which
the underlying population is used as the denominator
to calculate disease incidence and thus should
be unbiased by variations in the threshold for
hospitalization—varied by whether the numerator is
episodes of AKI2 or number of patients who had one
or more episode of AKI1 because recurrent AKI
within the same individual is possible. A large frac-
tion of the US literature turns out to be based on the
same data source: the Nationwide Inpatient Sample.
To our knowledge, only 2 published articles used
Am J Kidney Dis. 2015;65(5):650-654
 Table 1. Selected Studies of Temporal Trends in AKI Incidence
Am J Kidney Dis. 2015;65(5):650-654

In the Literature
Calculated Annual
Study Population Data Set AKI Definition Calendar Years Incidence Unit Findings Incidence Changea

Xue et al3 (2006) Representative sample Medicare 5% sample ICD-9-CM diagnosis 1992-2001 Per 1,000 AKI increased from 14.6 Increase of w11%
of elderly patients in codes hospital cases/1,000 discharges annually
the US discharges in 1992 to 36.4 cases/
1,000 discharges in 2001
Waikar et al14 (2006) Nationally Nationwide Inpatient ICD-9-CM diagnosis 1988-2002 Per 100,000 AKI incidence increased AKI: increase of
representative sample codes for AKI and people from 61 cases/100,000 w12% annually;
sample of US with ICD-9-CM (general people in 1988 to 288 AKI-D, increase of
hospitalized patients procedure code population) cases/100,000 people in w15% annually
for AKI-D 2002; AKI-D incidence
increased from 4 to 27
cases/100,000 people
CY Hsu et al1 (2007) All patients at least 20 y Kaiser Permanente of Hou et al21 serum 1996-2003 Per 100,000 AKI incidence increased AKI: increase of
old who are members Northern California creatinine change person-y from 322.7 to 522.4 w7% annually;
of an integrated clinical data criteria for ARF; (general cases/100,000 person-y; AKI-D: increase of
health care delivery patients who were population) AKI-D incidence w6% annually
system not on increased from 19.5 to
maintenance 29.5 cases/100,000
dialysis on person-y
admission but
received dialysis
during
hospitalization
were considered
to have AKI-D
Swaninathan et al5 (2007) Nationally Nationwide Inpatient ICD-9-CM diagnosis 1988-2003 Per hospital AKI incidence increased Increase of w11%
representative sample codes for AKI discharge from 1.5% to 7.2% annually
sample of US post-CABG
patients who
underwent CABG
Liu et al7 (2010) All hospital deliveries in Discharge abstract ICD-10-CA 2003-2007 Per 10,000 AKI incidence increased AKI: increase of
Canada (except database, diagnosis codes deliveries from 1.6 cases/10,000 w10% annually;
Quebec) Canadian Institute and CCI deliveries in 2003 to 2.3 AKI-D: no change
for Health procedure codes cases/10,000 deliveries in incidence
Information in 2007, AKI-D incidence
was 0.4 cases/10,000
deliveries in 2003 and
0.4 cases/10,000
deliveries in 2007
(Continued)
651
652

Table 1 (Cont’d). Selected Studies of Temporal Trends in AKI Incidence

Calculated Annual
Study Population Data Set AKI Definition Calendar Years Incidence Unit Findings Incidence Changea

Amin et al6 (2012) Patients admitted with Cerner Corporation’s AKIN11 serum 2000-2008 Per acute MI AKI incidence declined Decrease of w4%
acute MI to 56 Health Facts creatinine change hospitalization from 26.6% in 2000 to annually
hospitals across the database criteria 19.7% in 2008
US
Callaghan et al8 (2012) Nationally Nationwide Inpatient ICD-9-CM 1998-2009 Per 10,000 AKI incidence increased Increase of w6%
representative sample diagnostic codes deliveries from 2.29 cases during annually
sample of US delivery hospitalizations
deliveries and per 10,000 deliveries in
postpartum 1998-1999 to 4.52 cases
hospitalizations during delivery
hospitalizations per
10,000 deliveries in
2008-2009
RK Hsu et al2 (2013) Nationally Nationwide Inpatient ICD-9-CM 2000-2009 Per 1,000,000 AKI-D incidence increased Increase of w10%
representative sample diagnostic and person-y from 222 cases/ annually
sample of US procedure codes (general 1,000,000 person-y in
hospitalized patients for AKI-D population) 2000 to 533 cases/
1,000,000 person-y in
2009
Lenihan et al4 (2013) Nationally Nationwide Inpatient ICD-9 diagnostic 1999-2008 Per hospital AKI incidence increased AKI: increase of
representative sample codes for AKI and discharge for from 4.5% in 1999 to w12% annually;
sample of US procedure codes CABG or 12.8% in 2008, AKI-D AKI-D: increase of
patients who for AKI-D open-heart incidence increased from w12% annually
underwent on-pump valve 0.45% in 1999 to 1.28%
CABG or open- procedure in 2008
chamber valve repair
or replacement
Mehrabadi et al9 (2014) All hospital deliveries in Discharge abstract ICD-10-CA 2003-2010 Per 10,000 AKI incidence increased Increase of w10%
Am J Kidney Dis. 2015;65(5):650-654

Canada (except database, diagnostic codes deliveries from 1.66 cases/10,000 annually

Lunn, Obedin-Maliver, and Hsu

Quebec) Canadian Institute for AKI deliveries in 2003-2004
for Health to 2.68 cases/10,000
Information deliveries in 2009-2010
Abbreviations: AKI, acute kidney injury; AKI-D, dialysis-requiring acute kidney injury; AKIN, Acute Kidney Injury Network; ARF, acute renal failure; CABG, coronary artery bypass grafting;
CCI, Canadian Classification of Health Interventions; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; ICD-10-CA, International Statistical Classification
of Diseases and Related Health Problems, 10th Revision, Canada; MI, myocardial infarction.
a
Incidence calculated from unadjusted rates reported in each publication and assuming a constant rate of change over the study period.
In the Literature
serum creatinine level to define AKI: one showed an
increased incidence2 and one showed a decreased
incidence.6
Studies using analysis of diagnostic codes may
need to be interpreted with caution, especially when
the outcome is non–dialysis-requiring AKI. The
advent of consensus criteria used to diagnose AKI
over the last decade, including the RIFLE (Risk,
Injury, Failure, Loss, End-stage renal disease) criteria
in 200410; the AKI Network (AKIN) criteria in
200711; and KDIGO (Kidney Disease: Improving
Global Outcomes) criteria in 2012,12 have raised
awareness of AKI and emphasized the importance of
small acute increases in serum creatinine levels. The
nomenclature was changed from “acute renal failure”
to “acute kidney injury”13 to draw attention to less
severe degrees of abrupt kidney function decline. In
AKIN and KDIGO, a diagnosis of AKI can be made
based on an absolute serum creatinine level change as
low as 0.3 mg/dL over 48 hours. Thus, it is very likely
that in more recent years, providers have become
more aggressive in testing for and diagnosing AKI,
which will translate into an apparent increase in dis-
ease incidence even in the absence of true changes in
disease frequency.
The issue of “code creep” has been documented
with International Classification of Diseases, Ninth
Revision (ICD-9) codes in the United States. Waikar
et al14 found that using observed acute changes in
inpatient serum creatinine (nadir to peak) as the gold
standard, the sensitivity of ICD-9 codes (584.x)
increased from 17.4% in 1994 to 29.3% in 2002 at 2
academic teaching hospitals. Thus, even without a
true change in disease frequency, the number of cases
coded as AKI would go up by 68% over 8 years (or
almost 8% a year).14
Although we are not aware of studies examining
temporal changes in performance characteristics of
International Statistical Classification of Diseases
and Related Health Problems, Tenth Revision (ICD-
10) AKI codes (such as those used by Mehrabadi
et al9), several studies have documented low sensi-
tivity. In a study of elderly Canadians without chronic
kidney disease who were admitted to the hospital with
AKI between 2003 and 2010 (N 5 9,250), ICD-10
code N17x demonstrated sensitivity of 20.4% and
63.1% for AKIN stage I and RIFLE failure cases,
respectively.15 (Specificity was .96% for both defi-
nitions.) Hence, there is ample opportunity for an
increase in sensitivity over time and similar code
creep concerns (ie, previously not coded AKI coded
in later years). Because RIFLE, AKIN, and KDIGO
are prominent international initiatives, it is likely that
Canadian providers are influenced by them.
Because severe AKI is difficult to miss clinically
and procedure codes are necessary for billing, there is
Am J Kidney Dis. 2015;65(5):650-654
less likelihood of underascertainment of dialysis-
requiring AKI using a combination of diagnostic
and procedure codes. These codes have been reported
to be already .90% sensitive,16 which limits the
degree to which code creep can occur. In this context,
it is interesting to note that there was no change in
dialysis-requiring AKI despite an increase in AKI
overall in obstetrics patients according to 2 analyses
of the Canadian Institute for Health Information
discharge abstract database.7,9
In addition to code creep, there may be increased
measurement of serum creatinine over time such that
mild AKI cases (without other clinical signs such as
oliguria) are detected. Past and current iterations of
Canadian and US guidelines stress the importance of
testing for kidney disease when hypertensive spec-
trum disorders are present or suspected during
pregnancy.17,18 However, in routine practice, serum
creatinine is not measured during pregnancy, labor, or
after delivery except in the context of known co-
morbid conditions for kidney disease (eg, diabetes,
chronic hypertension, and systemic lupus erythema-
tous) or if triggered by signs (eg, hypertension or
oliguria) or symptoms (eg, headache or visual
changes).17,18
Although not fully analyzed in this article, pre-
eclampsia risk factors (eg, advanced maternal age,
diabetes mellitus, multiple births, and heart failure)
were more common in later calendar years. Such
high-risk pregnant women may be more likely to have
more frequent serum creatinine measurements and
thus an increased opportunity for AKI detection (and
subsequent coding). This may explain in part why
increased AKI incidence seemed to be limited to
those hypertensive disorders, especially women with
preeclampsia.
WHAT SHOULD CLINICIANS AND
RESEARCHERS DO?
Notwithstanding potential limitations related to
ascertainment bias (ie, more frequent serum creatinine
testing among women at risk for preeclampsia in
recent years) and code creep bias (ie, cases detected
by serum creatinine changes are more likely to be
assigned a diagnostic code in recent years), this article
by Mehrabadi et al9 should raise awareness among
clinicians about the importance of AKI in modern
obstetrical patients. Overall, there is no doubt that the
pregnant population has become sicker. Diabetic
women, for example, were once advised not to
become pregnant. Now entire clinics are devoted to
their care. Assisted reproductive technology use has
increased19 (this may explain the increase in maternal
age and multiple births reported in this article), and
assisted reproductive technology alone is associated
with increased risk of preeclampsia.20
653

For researchers, there are fundamental knowledge
gaps in our understanding of AKI epidemiology.
More research is urgently needed to quantify accu-
rately the public health burden of AKI.
Mitchell R. Lunn, MD
Juno Obedin-Maliver, MD, MPH
Chi-yuan Hsu, MD, MSc
University of California, San Francisco
San Francisco, California
ACKNOWLEDGEMENTS
We thank Raymond K. Hsu, MD, MAS (University of Cali-
fornia, San Francisco) for discussions.
Support: None.
Financial Disclosure: The authors declare that they have no
relevant financial interests.
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