Research

JAMA Pediatrics | Original Investigation

Acute Kidney Injury in Children With Type 1 Diabetes

Hospitalized for Diabetic Ketoacidosis
Brenden E. Hursh, MD, MHSc, FRCPC; Rebecca Ronsley, MD; Nazrul Islam, MD, MSc, MPH;
Cherry Mammen, MD, MHSc, FRCPC; Constadina Panagiotopoulos, MD, FRCPC

Editorial
IMPORTANCE Acute kidney injury (AKI) in children is associated with poor short-term and Supplemental content
long-term health outcomes; however, the frequency of AKI in children hospitalized for
diabetic ketoacidosis (DKA) has not been previously examined.

OBJECTIVES To determine the proportion of children hospitalized for DKA who develop AKI
and to identify the associated clinical and biochemical markers of AKI.

DESIGN, SETTING, AND PARTICIPANTS This medical record review of all DKA admissions from
September 1, 2008, through December 31, 2013, was conducted at British Columbia
Children’s Hospital, the tertiary pediatric hospital in British Columbia, Canada. Children aged
18 years or younger with type 1 diabetes and DKA and with complete medical records
available for data analysis were included (n = 165). All data collection occurred between
September 8, 2014, and June 26, 2015. Data analysis took place from August 25, 2015, to
June 8, 2016.

MAIN OUTCOMES AND MEASURES Acute kidney injury was defined using Kidney
Disease/Improving Global Outcomes serum creatinine criteria. Multinomial logistic regression
was used to identify potential factors associated with AKI.

RESULTS Of the 165 children hospitalized for DKA, 106 (64.2%) developed AKI (AKI stage 1,
37 [34.9%]; AKI stage 2, 48 [45.3%]; and AKI stage 3, 21 [19.8%]). Two children required
hemodialysis. In the adjusted multinomial logistic regression model, a serum bicarbonate
level less than 10 mEq/L (compared with ⱖ10 mEq/L) was associated with a 5-fold increase in
the odds of severe (stage 2 or 3) AKI (adjusted odds ratio [aOR], 5.22; 95% CI, 1.35-20.22).
Each increase of 5 beats/min in initial heart rate was associated with a 22% increase in the
odds of severe AKI (aOR, 1.22; 95% CI, 1.07-1.39). Initial corrected sodium level of 145 mEq/L
or greater (compared with 135-144 mEq/L) was associated with a 3-fold increase in the odds
of mild (stage 1) AKI (aOR, 3.29; 95% CI, 1.25-8.66). There were no cases of mortality in
patients with or without AKI.

CONCLUSIONS AND RELEVANCE This study is the first to date to document that a high Author Affiliations: Department of
Pediatrics, University of British
proportion of children hospitalized for DKA develop AKI. Acute kidney injury was associated Columbia, Vancouver, British
with markers of volume depletion and severe acidosis. Acute kidney injury is concerning Columbia, Canada (Hursh, Ronsley,
because it is associated with increased morbidity and mortality as well as increased risk of Mammen, Panagiotopoulos);
Endocrinology & Diabetes Unit,
chronic renal disease, a finding that is especially relevant among children who are already at
British Columbia Children’s Hospital,
risk for diabetic nephropathy. Strategies are needed to improve the diagnosis, management, Vancouver, British Columbia, Canada
and follow-up of AKI in children with type 1 diabetes. (Hursh, Ronsley, Panagiotopoulos);
School of Population and Public
Health, University of British
Columbia, Vancouver, British
Columbia, Canada (Islam); Division of
Nephrology, British Columbia
Children’s Hospital, Vancouver,
British Columbia, Canada (Mammen).
Corresponding Author: Constadina
Panagiotopoulos, MD, FRCPC,
Endocrinology & Diabetes Unit,
British Columbia Children’s Hospital,
4480 Oak St, ACB K4-213,
JAMA Pediatr. 2017;171(5):e170020. doi:10.1001/jamapediatrics.2017.0020 Vancouver, BC V6H 3V4, Canada
Published online March 13, 2017. (dpanagiotopoulos@cw.bc.ca).

(Reprinted) 1/7

Copyright 2017 American Medical Association. All rights reserved.

 Research Original Investigation
D
iabetic ketoacidosis (DKA) is a severe complication of
diabetes in children caused by a state of insulin defi-
ciency. It is defined by hyperglycemia, metabolic aci-
dosis, and the production of ketoacids, and hyperglycemia
leads to an osmotic diuresis that causes volume depletion. It
may occur at the initial presentation of newly diagnosed type
1 diabetes, or in a child with preexisting type 1 diabetes in times
of illness or insulin omission. Diabetic ketoacidosis is the lead-
ing cause of hospitalization, morbidity, and mortality in chil-
dren with type 1 diabetes,1-5 and cerebral edema is the most
serious complication that leads to morbidity and mortality.6
To mitigate the risk of cerebral edema, pediatric-specific DKA
protocols have been developed and frequently recommend
conservative fluid administration at presentation. The DKA
protocol at the British Columbia Children’s Hospital (BCCH),
Vancouver, Canada,7 is used provincewide for all pediatric
patients in British Columbia and is noted to be conservative
regarding initial fluid management.8
Acute kidney injury (AKI), previously referred to as acute re-
nal failure, is a common event in hospitalized children and im-
plies a sudden worsening of the kidney’s ability to function. The
clinical manifestations of pediatric AKI range from a mild increase
in serum creatinine to anuric renal failure that requires dialysis.
The most common risk factor for pediatric AKI is prerenal dis-
ease or volume-responsive AKI, which is caused by hypovole-
mia and reduced renal perfusion. If a prerenal insult is severe or
prolonged, the injury can result in structural damage to the re-
nal parenchyma, a condition known as acute tubular necrosis. De-
spite the marked intravascular volume depletion that occurs in
DKA and subsequent cautious fluid-rehydration strategies, AKI
in children with DKA has not been systematically studied. Only
2 case reports9,10 have been published to date indicating that se-
vere kidney injury occurs in the pediatric DKA setting. Murdoch
and colleagues9 reported on 2 girls, aged 13 and 14 years, with
DKA complicated by anuric renal failure requiring dialysis. Both
girls had biopsy evidence of acute tubular necrosis. More re-
cently, Al-Matrafi and colleagues10 reported on a 12-year-old girl
with severe DKA who developed anuric renal failure requiring
hemodialysis. These reports are particularly concerning in view
of the evolving body of literature indicating that AKI in chil-
dren is associated not only with increased morbidity and mor-
tality but also an increased risk of chronic kidney disease.11
The primary objective of this study was to determine the
proportion of children with type 1 diabetes, hospitalized for DKA
at BCCH over 5 years, who developed AKI. We hypothesized that,
because DKA is associated with both volume depletion and con-
servative fluid administration upon presentation, these chil-
dren are potentially at high risk for AKI, above the level of risk
expected by the rare reported cases in the literature. As a sec-
ondary objective, we sought to explore whether clinical signs
and laboratory parameters of volume depletion and acidosis are
associated with an increased risk for AKI in these patients.
Methods
Data Source
This study was conducted at BCCH, the only tertiary pediat-
ric hospital serving British Columbia, Canada. Cases of DKA
2/7 JAMA Pediatrics May 2017 Volume 171, Number 5 (Reprinted)
Copyright 2017 American Medical Association. All rights reserved.
Acute Kidney Injury in Children With Type 1 Diabetes
Key Points
Questions What proportion of pediatric patients with type 1
diabetes who present in diabetic ketoacidosis develop acute
kidney injury, and what are the associated risk factors?
Findings In this medical record review of 165 children with type 1
diabetes who were hospitalized for diabetic ketoacidosis, 106
(64.2%) met the criteria for acute kidney injury. Serum
bicarbonate level less than 10 mEq/L and an elevated heart rate
were found to be associated with an increased risk of severe acute
kidney injury.
Meaning Children in diabetic ketoacidosis are at high risk for
acute kidney injury, suggesting that clinicians should consider
acute kidney injury as a frequent complication in this population.
were identified using the Internal Classification of Diseases,
Tenth Revision (ICD-10) codes for diabetes (E10-14) for the pe-
riod September 1, 2008, through December 31, 2013. Patients
were eligible for inclusion in the study if they were aged 18 years
or younger and had confirmed DKA (blood glucose level ≥200
mg/dL, pH ≤7.3 or bicarbonate level ≤15 mEq/L, and elevation
of serum or urine ketones). (To convert glucose level to milli-
moles per liter, multiply by 0.0555; to convert serum bicar-
bonate level to millimoles per liter, multiply by 1.) Cases with
incomplete medical documentation were excluded. The Uni-
versity of British Columbia Clinical Research Ethics Board re-
viewed and approved the study protocol and waived the re-
quirement for patient consent. All data collection occurred
between September 8, 2014, and June 26, 2015. Data analysis
took place from August 25, 2015, to June 8, 2016.
Data Collection
Paper and electronic records were reviewed. Medical history,
current illness, and hospital admission were captured. Clinical
and biochemical assessments, including initial estimated level
of volume depletion and fluid resuscitation, were recorded. Se-
rum creatinine level was measured at BCCH using the enzy-
matic Ortho Diagnostics Vitros CREA method (Ortho-Clinical Di-
agnostics Inc). Initial physical examination data, including
height, weight, blood pressure, and heart rate, were recorded.
Case Definitions
The primary outcome variable, AKI, was defined by the Kid-
ney Disease/Improving Global Outcomes (KDIGO) serum cre-
atinine criteria.12 Because no study participants had avail-
able baseline serum creatinine values prior to admission, we
used an estimated glomerular filtration rate (GFR) of 120 mL/
min/1.73 m2 to calculate an expected baseline creatinine level
(EBC) using the Schwartz estimating equation.13 A GFR of 120
mL/min/1.73 m2 was selected on the basis of previously estab-
lished standards in pediatric AKI studies.14-16 However, with
normal GFR values13 ranging from 90 to 120 mL/min/1.73 m2,
a baseline GFR of 90 mL/min/1.73 m2 was also used in a sen-
sitivity analysis to calculate the most conservative estimates
of AKI. Stage 0 (no AKI) was defined as occurring if all creati-
nine values were less than 1.5 times the EBC. Stage 1 AKI oc-
curred if a creatinine value was 1.5 to less than 2 times the EBC.
jamapediatrics.com
Acute Kidney Injury in Children With Type 1 Diabetes
Stage 2 AKI occurred if a creatinine value was 2 to less than 3
times the EBC. Stage 3 AKI occurred if a creatinine value was
3 or more times the EBC. KDIGO AKI urine output criteria were
not used, because recording of hourly urine output rates was
inconsistent between cases. Corrected sodium (Na) was cal-
culated using this formula7:
Corrected Na = [(Glucose (mg/dL)/18) − 5.6] × 0.36
+ Serum Na.
A clinical estimation of volume depletion was documented as
mild, moderate, or severe by using the clinical categories on
BCCH’s DKA protocol for infants and children.
Statistical Analysis
Continuous variables were presented as median and inter-
quartile range (IQR), while categorical variables were pre-
sented as number and percentage. For the regression analy-
sis, AKI (the primary outcome variable) was classified as no AKI
(stage 0), mild AKI (stage 1), and severe AKI (stages 2 and 3).
Stages 2 and 3 AKI were combined into a severe AKI category
because these stages represent more substantial tubular in-
jury and were previously shown to be associated with poorer
outcomes, including increased mortality and hospital length
of stay, in other pediatric populations.15,17-19 Multinomial lo-
gistic regression (using no AKI as the reference category) was
used to identify potential factors associated with AKI. Vari-
ables were selected a priori on the basis of clinical impor-
tance and included age and sex as well as initial values for clini-
cally estimated volume depletion, initial heart rate, and serum
bicarbonate, corrected serum sodium, and hematocrit levels.
Note that bicarbonate level was categorized using the ac-
cepted cut point between mild and moderate to severe DKA
(10 mEq/L).20 Corrected sodium level was categorized as low
(≤134 mEq/L), normal (135-144 mEq/L), or elevated (≥145
mEq/L) because both hyponatremia and hypernatremia can
occur with kidney injury. (To convert sodium level to milli-
moles per liter, multiply by 1.) Hematocrit level was catego-
rized as either elevated or not elevated, with a cut point of 45%
chosen to reflect substantial hemoconcentration. (To convert
hematocrit level to a proportion of 1, multiply by 0.01.) Vari-
ables that were significant at P < .10 in the unadjusted analy-
sis were considered for the multivariable model. Age and sex
were added to the multivariable model irrespective of their sig-
nificance in the unadjusted analysis. The effect measures were
reported as odds ratio (OR) and corresponding 95% CI. All the
analyses were conducted in SAS/STAT software version 9.4
(SAS Institute Inc).21 All tests were 2-sided at a significance level
of P = .05.
Results
From September 1, 2008, to December 31, 2013, a total of 211
children were hospitalized for DKA at BCCH. Of these, 165 ad-
missions met the inclusion criteria for analysis. Reasons for ex-
clusion included the following: patient with type 1 diabetes was
admitted for a non-DKA reason (n = 2), DKA criteria were not
fully met (n = 8), medical record was not available (n = 3), medi-
jamapediatrics.com
Copyright 2017 American Medical Association. All rights reserved.
Original Investigation Research
cal documentation was incomplete (n = 31), and patient had
neonatal diabetes (n = 2).
Table 1 highlights the clinical characteristics for the en-
tire study population and for each AKI severity stage on ad-
mission. Overall, the admissions for DKA were characterized
by a slight preponderance of females (89 [53.9%]) with a me-
dian age of 10.6 years (interquartile range, 5.1-13.8 years). Over
half of the admissions (90 [54.5%]) were transfers from other
hospitals within British Columbia, and about one-quarter of
cases (40 [24.2%]) required intensive care unit (ICU) care.
Three-quarters of cases (125 [75.8%]) were newly diagnosed
with type 1 diabetes during the hospitalization.
One hundred six patients (64.2%) developed AKI during
the admission. Of those with AKI, 37 (34.9%), 48 (45.3%), and
21 (19.8%) reached a maximum AKI stage of 1, 2, and 3, respec-
tively. The proportion of AKI in children with DKA was higher
in those admitted to the pediatric ICU (34/40 [85%]) com-
pared with those who received care on the general pediatrics
ward (72/125 [57.6%]). Of the 106 patients, 105 (99.1%) devel-
oped AKI within 24 hours of hospitalization. Starting with their
initial AKI severity staging within the first 24 hours, 6 cases
subsequently increased in AKI severity from 24 to 48 hours of
hospitalization (cases increased in AKI severity from stage 0
to 1 [1 case], 1 to 2 [2 cases], and 2 to 3 [3 cases]), and 1 addi-
tional case increased in severity from stage 2 to 3 AKI at 48 to
72 hours of hospitalization. All cases had reached their maxi-
mum documented AKI stage by 72 hours. Finally, 2 patients
required hemodialysis for indications of fluid overload or oli-
guria during their hospitalization. The first was a 13-year-old
girl who underwent dialysis for 3 days but still had stage 3 AKI
at discharge. The next follow-up measurement of her creati-
nine level 9 months later had normalized with no evidence of
hypertension or albuminuria noted in the nephrology clinic.
The second patient was an 11-year-old girl who was treated with
hemodialysis for 2 days and then transferred to another hos-
pital with no follow-up records available. No cases of cerebral
edema or deaths were documented.
Fifty-four of 106 cases (50.9%) had documented resolution
of their AKI by 72 hours of hospitalization. Another 4 cases (3.8%)
had documented resolution by 96 hours. Two patients (1.9%)
were transferred to other centers with ongoing AKI; therefore,
we were unable to document AKI resolution; notably, 1 of these
2 patients underwent dialysis at BCCH. Furthermore, 2 cases
(1.9%), 1 of whom also had been receiving dialysis, still had AKI
at the time of discharge, but a follow-up visit to the nephrology
clinic was arranged as an outpatient. Finally, 44 cases (41.5%)
did not have documentation of AKI resolution prior to discharge,
and nephrology clinic follow-up was not arranged. Of these cases,
22 (50%) had severe AKI at their last measured creatinine level.
Of the 44 cases discharged without documented AKI resolution,
the median (IQR) peak and discharge serum creatinine levels
were 0.92 mg/dL (IQR, 0.79-1.02) at peak and 0.89 mg/dL (IQR,
0.79-0.95) at discharge for those with stage 1 AKI at discharge;
1.18 mg/dL (IQR, 1.10-1.36) at peak and 1.18 mg/dL (IQR, 1.1-1.3)
at discharge for those with stage 2 AKI at discharge; and 1.31 mg/
dL (IQR, 1.12-1.36) at peak and 1.31 mg/dL (IQR, 1.12-1.36) at dis-
charge for those with stage 3 AKI at discharge. (To convert cre-
atinine to micromoles per liter, multiply by 88.4.)
(Reprinted) JAMA Pediatrics May 2017 Volume 171, Number 5 3/7
 Research Original Investigation Acute Kidney Injury in Children With Type 1 Diabetes

Table 1. Characteristics of Children Aged 18 Years or Younger With Type 1 Diabetes, Grouped by Maximum Acute Kidney Injury Stage During Admission
for Diabetic Ketoacidosis
No AKI Stage 1 AKI Stage 2 AKI Stage 3 AKI Total
Characteristics (n = 59) (n = 37) (n = 48) (n = 21) (N = 165)
Patient Demographic Characteristics
Age, median (IQR), y 9.5 (4.8-13.4) 10.2 (5.6-13.3) 12.4 (7.9-14.2) 10.4 (4.5-12.8) 10.6 (5.1-13.8)
Males, No. (%) 21 (35.6) 23 (62.2) 25 (52.1) 7 (33.3) 76 (46.1)
Type of admissions, No. (%)
Direct to ED from home 44 (74.6) 19 (51.4) 10 (20.8) 2 (9.5) 75 (45.5)
Transfer 15 (25.4) 18 (48.6) 38 (79.2) 19 (90.5) 90 (54.5)
ICU admission, No. (%) 6 (10.2) 10 (27.0) 14 (29.2) 10 (47.6) 40 (24.2)
New diagnosis of type 1 diabetes, 50 (84.7) 27 (73.0) 30 (62.5) 18 (85.7) 125 (75.8)
No. (%)
Fluid Status
Initial estimated dehydration,
No. (%)
Mild 20 (33.8) 12 (32.4) 2 (4.2) 2 (9.5) 36 (21.8)
Moderate 22 (37.2) 11 (29.7) 20 (41.7) 5 (23.8) 58 (35.2)
Severe 12 (20.3) 12 (32.4) 19 (39.6) 11 (52.4) 54 (32.7)
Not recorded/other 5 (8.5) 2 (5.4) 7 (14.6) 3 (14.3) 17 (10.3)
Weight change, median (IQR), %a 6.4 (3.0-10.3) 5.7 (1.3-10.1) 6.6 (4.6-12.3) 10.9 (4.8-14.6) 6.7 (3.1-11.8)
Bolus received, No. (%) 17 (28.8) 20 (54.1) 30 (62.5) 18 (85.7) 85 (51.5)
Total bolus amount, No. (%)
No bolus 42 (71.2) 17 (45.9) 18 (37.5) 3 (14.3) 80 (48.3)
5 mL/kg 2 (3.4) 1 (2.7) 3 (6.3) 0 6 (3.6)
10 mL/kg 6 (10.2) 8 (21.6) 16 (33.3) 9 (42.9) 39 (23.6)
20 mL/kg 8 (13.6) 7 (18.9) 7 (14.6) 5 (23.8) 24 (14.5)
>20 mL/kg 2 (3.4) 3 (8.1) 3 (6.3) 3 (14.3) 11 (6.7)
Other 2 (3.4) 1 (2.7) 1 (2.1) 1 (4.8) 5 (3.0)
Initial Physical Examination
Heart rate, median (IQR), min 113 (98-128) 122 (106-138) 135 (122-146) 138 (130-146) 126 (110-140)
Initial Laboratory Values, Median (IQR)
pH 7.2 (7.1-7.3) 7.2 (7.0-7.2) 7.0 (7.0-7.1) 7.0 (7.0-7.1) 7.1 (7.0-7.2)
Serum bicarbonate level, mEq/L 9.0 (7.0-13.0) 8.0 (5.0-11.0) 5.0 (4.0-6.5) 6.0 (5.0-7.0) 7.0 (5.0-10.0)
Corrected serum Na level, mEq/Lb 143.0 (139.6-145.7) 145.6 (140.5-146.8) 145.1 (140.8-153.1) 148.2 (142.3-154.4) 144.6 (140.4-149.1)
Potassium level, mEq/L 4.5 (3.9-4.9) 4.6 (4.2-5.1) 4.8 (4.1-5.3) 5.1 (4.7-5.8) 4.7 (4-5.2)
Serum creatinine level, μmol/L 48.0 (35.0-57.0) 72.0 (60.0-82.0) 104.0 (87.0-118.5) 123.0 (109.0-173.0) 71.0 (51.0-103.0)
Serum creatinine level, mg/dL 0.5 (0.4-0.6) 0.8 (0.7-0.9) 1.2 (1.0-1.3) 1.4 (1.2-2.0) 0.8 (0.6-1.2)
SUN level, mg/dL 13.2 (11.2-17.6) 18.5 (15.4-20.7) 22.1 (18.2-27.2) 34.7 (23.8-44.8) 18.8 (14.0-25.2)
β-OHB level, mmol/L 8.7 (7.6-10.5) 9.7 (7.8-10.7) 11.4 (10.3-13.0) 11.8 (9.2-15.8) 10.1 (7.8-11.2)
Hematocrit level, % 42.0 (39.0-45.0) 44.0 (41.0-48.0) 46.0 (42.0-48.0) 48.0 (42.0-50.0) 44.0 (41.0-48.0)
Abbreviations: AKI, acute kidney injury; β-OHB, beta hydroxybutarate; per liter, multiply by 88.4; SUN to millimoles per liter, multiply by 0.357; and
ED, emergency department; ICU, intensive care unit; IQR, interquartile range; hematocrit to a proportion of 1, multiply by 0.01.
Na, sodium; SUN, serum urea nitrogen. a
Weight change from admission to discharge.
SI conversion factors: To convert serum bicarbonate, serum sodium, and b
Corrected Na = [(Glucose (mg/dL)/18) − 5.6] × 0.36 + Serum Na.
potassium to millimoles per liter, multiply by 1; serum creatinine to micromoles

Table 2 highlights the unadjusted and adjusted analysis
using a multinomial logistic regression model. All variables ex-
cept age and sex were statistically significant in the unad-
justed analysis, especially when comparing no AKI with se-
vere AKI. In the adjusted analysis, a lower serum bicarbonate
level of less than 10 mEq/L (compared with ≥10 mEq/L) was
associated with a 5-fold increase in the odds of severe AKI (ad-
justed odds ratio [aOR], 5.22; 95% CI, 1.35-20.22), whereas each
incremental increase of 5 beats/min in initial heart rate was as-
sociated with a 22% increase in the odds of severe AKI (aOR,
1.22; 95% CI, 1.07-1.39). Initial corrected sodium of 145 mEq/L
or greater (compared with 135-144 mEq/L) was associated with
a 3-fold increase in the odds of mild AKI (aOR, 3.29; 95% CI,
1.25-8.66).
The eTable in the Supplement contains a sensitivity analy-
sis using an estimated GFR of 90 mL/min/1.73 m2 for calculat-
ing the expected baseline creatinine. Based on this lower es-
timated GFR cutoff, 69 children (41.8%) met the criteria for AKI.
Of these children with AKI, 37 (53.6%) had mild and 32 (46.4%)
had severe AKI. In multinomial regression analysis based on

4/7 JAMA Pediatrics May 2017 Volume 171, Number 5 (Reprinted) jamapediatrics.com

Copyright 2017 American Medical Association. All rights reserved.

Acute Kidney Injury in Children With Type 1 Diabetes Original Investigation Research

Table 2. Multinomial Logistic Regression of Factors Associated With Acute Kidney Injury in Children
Aged 18 Years or Younger With Type 1 Diabetes Presenting With Diabetic Ketoacidosis

Estimate, Odds Ratio (95% CI)

Mild Acute Kidney Injurya Severe Acute Kidney Injurya
Factors Unadjusted Adjusted Unadjusted Adjusted
Patient Demographic Characteristics
Age, y
0-5 1 [Reference] 1 [Reference] 1 [Reference] 1 [Reference]
6-12 1.52 (0.54-4.27) 1.70 (0.48-6.07) 1.11 (0.45-2.71) 1.38 (0.39-4.88)
≥13 1.20 (0.41-3.51) 1.43 (0.36-5.68) 1.59 (0.66-3.80) 1.94 (0.52-7.22)
Males 2.97 (1.27-6.97) 3.92 (1.48-10.40) 1.57 (0.77-3.19) 1.24 (0.49-3.15)
Fluid Status
Initial estimated
dehydration
Mild 1 [Reference] 1 [Reference] 1 [Reference] 1 [Reference]
Moderate 0.83 (0.30-2.31) 0.49 (0.15-1.61) 5.68 (1.68-19.19) 1.67 (0.39-7.14)
Severe 1.67 (0.57-4.88) 0.54 (0.12-2.50) 12.50 (3.53-44.30) 1.09 (0.21-5.65)
Not recorded/other 0.67 (0.11-3.99) 0.34 (0.05-2.52) 10.00 (2.19-45.64) 3.14 (0.51-19.40)
Bolus received 2.91 (1.23-6.85) 2.86 (0.91-9.01) 5.65 (2.64-12.10) 2.48 (0.89-6.95)
Heart rate, minb 1.08 (0.98-1.20) 1.09 (0.96-1.24) 1.27 (1.15-1.40) 1.22 (1.07-1.39)
Initial Laboratory Values
Serum bicarbonate level,
mEq/L
<10 1.33 (0.58-3.04) 0.70 (0.23-2.17) 14.68 (4.73-45.51) 5.22 (1.35-20.22)
≥10 1 [Reference] 1 [Reference] 1 [Reference] 1 [Reference] Abbreviation: Na, sodium.

Corrected serum Na level, SI conversion factors: To convert

mEq/Lc serum bicarbonate and serum
≤134 5.66 (0.47-68.19) 7.87 (0.41-149.50) 10.19 (1.14-90.92) 10.72 (0.83-137.86) sodium to millimoles per liter,
multiply by 1; hematocrit to a
135-144 1 [Reference] 1 [Reference] 1 [Reference] 1 [Reference] proportion of 1, multiply by 0.01.
≥145 2.72 (1.14-6.49) 3.29 (1.25-8.66) 3.05 (1.45-6.41) 2.48 (0.99-6.24) a
Reference category: no AKI.
Hematocrit level, % b
The odds ratio shown is for every
<45 1 [Reference] 1 [Reference] 1 [Reference] 1 [Reference] 5–beats/min increase in heart rate.
c
≥45 1.53 (0.61-3.85) 0.82 (0.25-2.71) 4.45 (2.02-9.80) 1.83 (0.61-5.48) Corrected Na = [(Glucose
(mg/dL)/18) − 5.6] × 0.36 +
Unknown 0.89 (0.15-5.25) 1.02 (0.15-7.04) 2.46 (0.63-9.58) 2.35 (0.40-13.64)
Serum Na.

these estimates, a serum bicarbonate of less than 10 mEq/L was
associated with an increase in the odds of severe AKI, as in the
main analysis, but this time with more than 10-fold increase
in the odds of severe AKI (aOR, 10.95; 95% CI, 1.10-108.52). Each
incremental increase of 5 beats/min in initial heart rate was as-
sociated with an 18% increase in the odds of mild AKI (aOR,
1.18; 95% CI, 1.03-1.35) but not severe AKI (aOR, 1.16; 95% CI,
0.99-1.35), while initial corrected sodium did not reach statis-
tical significance.
Discussion
To our knowledge, this is the first study to report on the pro-
portion of children hospitalized with DKA who develop AKI.
Of note, we documented that 64% of patients met the criteria
for AKI during their hospitalization for DKA. Even with the use
of the most conservative estimate of baseline renal function,
the proportion of children with AKI was still high at 42% in the
sensitivity analysis. Of further concern was that 65% of pa-
tients with AKI met the criteria for severe AKI (stage 2 or 3),
suggesting that a large number of children with DKA may ex-
perience intrinsic tubular injury rather than a milder prerenal
or volume-responsive injury. Finally, our findings also sug-
gest an association between the severity of acidosis and vol-
ume depletion and the risk for severe AKI.
Two retrospective studies22,23 report AKI in adults with
DKA. Woodrow and colleagues22 reviewed 1661 cases of acute
renal failure seen over a 36-year period and identified 14 cases
directly associated with an episode of DKA in adults with type
1 diabetes. These patients had a 50% mortality rate, and all of
those identified as having AKI in the final 10 years of the study
required ICU management.22 Orban and colleagues23 subse-
quently reviewed 94 DKA admissions in a medical ICU and
found a 50% AKI incidence.
No epidemiologic studies on AKI in children with DKA ex-
ist for comparison, but 2 large studies of 3396 and 2106 pedi-
atric ICU admissions revealed AKI rates in pediatric ICU popu-
lations of 10% and 17.9%, respectively.24,25 In contrast, in our
study the proportion of AKI in children with DKA admitted to
the ICU was 85%. We postulate that the high AKI rate in ICU
hospitalizations for DKA compared with the broad ICU popu-
lation is associated with the severe intravascular depletion in-
herent in more severe cases of DKA. This theory is supported

jamapediatrics.com (Reprinted) JAMA Pediatrics May 2017 Volume 171, Number 5 5/7

Copyright 2017 American Medical Association. All rights reserved.

 Research Original Investigation Acute Kidney Injury in Children With Type 1 Diabetes

by our study findings that clinical markers of volume deple-
tion, specifically, elevated heart rate and corrected sodium level
at presentation to the hospital, were both associated with more
severe AKI. In comparison, Orban and colleagues23 found no
difference in serum sodium level among patients with and
without AKI; however, sodium values in this study were not
corrected for serum glucose level.
In addition to severity of volume depletion, more severe
acidosis was also associated with severe AKI in our study. A
serum bicarbonate level of less than 10 mEq/L on presenta-
tion was associated with a 5-fold increased odds for the de-
velopment of severe AKI compared with a serum bicarbonate
level of 10 mEq/L or higher. Whether severe acute acidosis has
direct physiological effects, including renal vasoconstriction
that causes more severe AKI in this population, is not known.
Orban and colleagues23 found no statistically significant dif-
ference in serum bicarbonate or serum pH in adults with DKA
with and without AKI; however, their selection criteria were
for patients admitted to the ICU for severe DKA, and the en-
tire group had a median bicarbonate level of 6.5 mEq/L, which
indicates that nearly all study participants had a bicarbonate
level more severe than the at-risk level identified in our study
(ie, bicarbonate <10 mEq/L).
The high rates of AKI in our study are concerning for both
short-term and long-term adverse health outcomes. Pediat-
ric AKI is associated with increased morbidity, including greater
need for and duration of ventilation, increased length of stay,
higher hospitalization costs, and increased mortality.16,24,26-32
In addition, for those who survive AKI, recent data suggest that
AKI likely results in permanent renal damage; these findings
have challenged the previous notion that AKI was a com-
pletely reversible event. In a recent systematic review that in-
cluded 13 cohort studies of adults with AKI, a single episode
of AKI was associated with an increased risk of developing
chronic kidney disease, with a pooled adjusted hazard ratio of
8.8 (95% CI, 2.1-25.5).33 Several observational studies of chil-
dren have also supported the link of AKI and long-term renal
dysfunction, with chronic kidney disease incidence ranging
from 10% to 69% following an episode of AKI.34-39
The patients with AKI in our study are of particular inter-
est given that children with type 1 diabetes are already at risk
for renal complications from diabetes.40 Although progres-
sion to macroalbuminuria and renal insufficiency in child-
hood is rare, diabetic nephropathy is a leading cause of end-
stage renal disease in adults.40,41 For this reason, it is especially
important to develop strategies to identify, monitor, and treat
additional renal insults, such as those that may occur with DKA.
Of concern was that 44 patients (42%) with AKI did not
have documented resolution of AKI prior to discharge or ar-
rangements for follow-up in the nephrology clinic. Of note, the
final AKI stage was severe for 50% of these children. These data
highlight that AKI is underrecognized both because of a lack
of awareness of AKI as a complication of DKA and because the
serum creatinine level in pediatric patients must be inter-
preted in the context of the child’s age and height. It is crucial
to develop or have in place systems that identify and monitor
abnormal markers of renal function in this population. Fur-
thermore, prospective longitudinal studies are needed to as-
sess the effect of these AKI episodes on the trajectory of renal
disease in children with diabetes.
Strengths and Limitations
This study should be interpreted within the context of its limi-
tations. The main limitation of this study is its retrospective
nature; therefore, the results rely on the accuracy and com-
pleteness of patient records. Furthermore, we did not have
complete urine output data with which to compare both the
creatinine and urine output criteria within the KDIGO AKI clas-
sification. In addition, as is common in pediatric popula-
tions, baseline serum creatinine values were not available, re-
sulting in the need to calculate an estimated baseline value.
Therefore, our results must be confirmed with prospective lon-
gitudinal studies. Nevertheless, this is the first large-scale study
to report AKI in pediatric patients with DKA. Furthermore, our
sample size is larger than those of the 2 existing studies22,23
assessing AKI in adults with DKA, and we were able to iden-
tify clinical factors that are associated with severe AKI in this
pediatric population.
Conclusions
To our knowledge, this is the first study to document a high
proportion of children with AKI among those hospitalized with
DKA. Severe AKI was associated with worsening markers of vol-
ume depletion and acidosis. Overall, these data suggest that
clinicians should consider AKI as a frequent complication that
accompanies pediatric DKA and should be especially alert to
its presence in severe presentations of DKA. Prospective lon-
gitudinal studies are urgently needed to better understand both
the risk factors for and long-term implications of AKI in this
population, especially because these children are already at risk
for chronic kidney disease secondary to diabetic nephropa-
thy over the long term.

ARTICLE INFORMATION
Accepted for Publication: January 4, 2017.
Published Online: March 13, 2017.
doi:10.1001/jamapediatrics.2017.0020
Author Contributions: Drs Hursh and Ronsley
share first authorship. Dr Panagiotopoulos had full
access to all the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Hursh, Mammen,
Panagiotopoulos.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Hursh, Ronsley, Islam,
Panagiotopoulos.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Hursh, Ronsley, Islam.
Study supervision: Mammen, Panagiotopoulos.
Conflict of Interest Disclosures: None reported.
Additional Contributions: Claire Ronsley, BSc,
Division of Endocrinology, British Columbia
Children’s Hospital, assisted with the data collection
for this study. Ms Ronsley did not receive
compensation for her contribution.
REFERENCES
1. Razavi Z. Frequency of ketoacidosis in newly
diagnosed type 1 diabetic children. Oman Med J.
2010;25(2):114-117.
2. Rewers A, Chase HP, Mackenzie T, et al.
Predictors of acute complications in children with
type 1 diabetes. JAMA. 2002;287(19):2511-2518.

6/7 JAMA Pediatrics May 2017 Volume 171, Number 5 (Reprinted) jamapediatrics.com

Copyright 2017 American Medical Association. All rights reserved.

Acute Kidney Injury in Children With Type 1 Diabetes
3. Dunger DB, Sperling MA, Acerini CL, et al; ESPE;
LWPES. ESPE/LWPES consensus statement on
diabetic ketoacidosis in children and adolescents.
Arch Dis Child. 2004;89(2):188-194.
4. Neu A, Willasch A, Ehehalt S, Hub R, Ranke MB;
DIARY Group Baden-Wuerttemberg. Ketoacidosis
at onset of type 1 diabetes mellitus in
children—frequency and clinical presentation.
Pediatr Diabetes. 2003;4(2):77-81.
5. Realsen J, Goettle H, Chase HP. Morbidity and
mortality of diabetic ketoacidosis with and without
insulin pump care. Diabetes Technol Ther. 2012;14
(12):1149-1154.
6. Lawrence SE, Cummings EA, Gaboury I,
Daneman D. Population-based study of incidence
and risk factors for cerebral edema in pediatric
diabetic ketoacidosis. J Pediatr. 2005;146(5):
688-692.
7. British Columbia Children’s Hospital. DKA
protocol. http://www.bcchildrens.ca/health
-professionals/clinical-resources/endocrinology
-diabetes/dka-protocol. Accessed November 11,
2016.
8. Skitch SA, Valani R. Treatment of pediatric
diabetic ketoacidosis in Canada: a review of
treatment protocols from Canadian pediatric
emergency departments. CJEM. 2015;17(6):656-661.
9. Murdoch IA, Pryor D, Haycock GB, Cameron SJ.
Acute renal failure complicating diabetic
ketoacidosis. Acta Paediatr. 1993;82(5):498-500.
10. Al-Matrafi J, Vethamuthu J, Feber J. Severe
acute renal failure in a patient with diabetic
ketoacidosis. Saudi J Kidney Dis Transpl. 2009;20
(5):831-834.
11. Greenberg JH, Coca S, Parikh CR. Long-term risk
of chronic kidney disease and mortality in children
after acute kidney injury: a systematic review. BMC
Nephrol. 2014;15:184.
12. KDIGO Acute Kidney Injury Working Group.
KDIGO clinical practice guideline for acute kidney
injury. Kidney Int Suppl. 2012;2:1-138.
13. Schwartz GJ, Work DF. Measurement and
estimation of GFR in children and adolescents. Clin J
Am Soc Nephrol. 2009;4(11):1832-1843.
14. Zappitelli M, Parikh CR, Akcan-Arikan A,
Washburn KK, Moffett BS, Goldstein SL.
Ascertainment and epidemiology of acute kidney
injury varies with definition interpretation. Clin J
Am Soc Nephrol. 2008;3(4):948-954.
15. Basu RK, Kaddourah A, Terrell T, et al;
Prospective Pediatric AKI Research Group (ppAKI).
Assessment of Worldwide Acute Kidney Injury,
Renal Angina and Epidemiology in critically ill
children (AWARE): study protocol for a prospective
observational study. BMC Nephrol. 2015;16:24.
16. Akcan-Arikan A, Zappitelli M, Loftis LL,
Washburn KK, Jefferson LS, Goldstein SL. Modified
jamapediatrics.com
Copyright 2017 American Medical Association. All rights reserved.
RIFLE criteria in critically ill children with acute
kidney injury. Kidney Int. 2007;71(10):1028-1035.
17. Fitzgerald JC, Basu RK, Akcan-Arikan A, et al;
Sepsis Prevalence, Outcomes, and Therapies Study
Investigators and Pediatric Acute Lung Injury and
Sepsis Investigators Network. Acute kidney injury in
pediatric severe sepsis: An independent risk factor
for death and new disability. Crit Care Med. 2016;44
(12):2241-2250.
18. Algaze CA, Koth AM, Faberowski LW, Hanley FL,
Krawczeski CD, Axelrod DM. Acute kidney injury in
patients undergoing the extracardiac fontan
operation with and without the use of
cardiopulmonary bypass. Pediatr Crit Care Med.
2017;18(1):34-43.
19. Zappitelli M, Krawczeski CD, Devarajan P, et al;
TRIBE-AKI consortium. Early postoperative serum
cystatin C predicts severe acute kidney injury
following pediatric cardiac surgery. Kidney Int. 2011;
80(6):655-662.
20. Wolfsdorf J, Glaser N, Sperling MA; American
Diabetes Association. Diabetic ketoacidosis in
infants, children, and adolescents: a consensus
statement from the American Diabetes Association.
Diabetes Care. 2006;29(5):1150-1159.
21. SAS Institute Inc. The SAS System for Windows.
Release 9.4. Cary, NC: SAS Institute Inc; 2002.
22. Woodrow G, Brownjohn AM, Turney JH. Acute
renal failure in patients with type 1 diabetes
mellitus. Postgrad Med J. 1994;70(821):192-194.
23. Orban JC, Maizière EM, Ghaddab A, Van
Obberghen E, Ichai C. Incidence and characteristics
of acute kidney injury in severe diabetic
ketoacidosis. PLoS One. 2014;9(10):e110925.
24. Alkandari O, Eddington KA, Hyder A, et al.
Acute kidney injury is an independent risk factor for
pediatric intensive care unit mortality, longer length
of stay and prolonged mechanical ventilation in
critically ill children: a two-center retrospective
cohort study. Crit Care. 2011;15(3):R146-R157.
25. Schneider J, Khemani R, Grushkin C, Bart R.
Serum creatinine as stratified in the RIFLE score for
acute kidney injury is associated with mortality and
length of stay for children in the pediatric intensive
care unit. Crit Care Med. 2010;38(3):933-939.
26. Duzova A, Bakkaloglu A, Kalyoncu M, et al;
Turkish Society for Pediatric Nephrology Acute
Kidney Injury Study Group. Etiology and outcome
of acute kidney injury in children. Pediatr Nephrol.
2010;25(8):1453-1461.
27. Alabbas A, Campbell A, Skippen P, Human D,
Matsell D, Mammen C. Epidemiology of cardiac
surgery–associated acute kidney injury in neonates:
a retrospective study. Pediatr Nephrol. 2013;28(7):
1127-1134.
28. Blinder JJ, Goldstein SL, Lee VV, et al.
Congenital heart surgery in infants: effects of acute
(Reprinted) JAMA Pediatrics May 2017 Volume 171, Number 5
Original Investigation Research
kidney injury on outcomes. J Thorac Cardiovasc Surg.
2012;143(2):368-374.
29. Morgan CJ, Zappitelli M, Robertson CM, et al;
Western Canadian Complex Pediatric Therapies
Follow-up Group. Risk factors for and outcomes of
acute kidney injury in neonates undergoing
complex cardiac surgery. J Pediatr. 2013;162(1):
120-127.e1.
30. Ozçakar ZB, Yalçinkaya F, Altas B, et al.
Application of the new classification criteria of the
Acute Kidney Injury Network: a pilot study in a
pediatric population. Pediatr Nephrol. 2009;24(7):
1379-1384.
31. Sutherland SM, Byrnes JJ, Kothari M, et al. AKI
in hospitalized children: comparing the pRIFLE,
AKIN, and KDIGO definitions. Clin J Am Soc Nephrol.
2015;10(4):554-561.
32. Fortenberry JD, Paden ML, Goldstein SL. Acute
kidney injury in children: an update on diagnosis
and treatment. Pediatr Clin North Am. 2013;60(3):
669-688.
33. Coca SG, Singanamala S, Parikh CR. Chronic
kidney disease after acute kidney injury:
a systematic review and meta-analysis. Kidney Int.
2012;81(5):442-448.
34. Mammen C, Al Abbas A, Skippen P, et al.
Long-term risk of CKD in children surviving
episodes of acute kidney injury in the intensive care
unit: a prospective cohort study. Am J Kidney Dis.
2012;59(4):523-530.
35. Georgaki-Angelaki HN, Steed DB, Chantler C,
Haycock GB. Renal function following acute renal
failure in childhood: a long term follow-up study.
Kidney Int. 1989;35(1):84-89.
36. Askenazi DJ, Feig DI, Graham NM, Hui-Stickle S,
Goldstein SL. 3-5 Year longitudinal follow-up of
pediatric patients after acute renal failure. Kidney Int.
2006;69(1):184-189.
37. Slack R, Hawkins KC, Gilhooley L, Addison GM,
Lewis MA, Webb NJ. Long-term outcome of
meningococcal sepsis-associated acute renal
failure. Pediatr Crit Care Med. 2005;6(4):477-479.
38. Viaud M, Llanas B, Harambat J. Renal outcome
in long-term survivors from severe acute kidney
injury in childhood. Pediatr Nephrol. 2012;27(1):
151-152.
39. Shaw NJ, Brocklebank JT, Dickinson DF, Wilson
N, Walker DR. Long-term outcome for children with
acute renal failure following cardiac surgery. Int J
Cardiol. 1991;31(2):161-165.
40. White NH. Long-term outcomes in youths with
diabetes mellitus. Pediatr Clin North Am. 2015;62(4):
889-909.
41. Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic
kidney disease: a report from an ADA Consensus
Conference. Diabetes Care. 2014;37(10):2864-2883.
7/7
Copyright of JAMA Pediatrics is the property of American Medical Association and its
content may not be copied or emailed to multiple sites or posted to a listserv without the
copyright holder's express written permission. However, users may print, download, or email
articles for individual use.