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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 Acute Kidney Injury in Children With Type 1 Diabetes

D
iabetic ketoacidosis (DKA) is a severe complication of
diabetes in children caused by a state of insulin defi- Key Points
ciency. It is defined by hyperglycemia, metabolic aci-
Questions What proportion of pediatric patients with type 1
dosis, and the production of ketoacids, and hyperglycemia diabetes who present in diabetic ketoacidosis develop acute
leads to an osmotic diuresis that causes volume depletion. It kidney injury, and what are the associated risk factors?
may occur at the initial presentation of newly diagnosed type
Findings In this medical record review of 165 children with type 1
1 diabetes, or in a child with preexisting type 1 diabetes in times
diabetes who were hospitalized for diabetic ketoacidosis, 106
of illness or insulin omission. Diabetic ketoacidosis is the lead- (64.2%) met the criteria for acute kidney injury. Serum
ing cause of hospitalization, morbidity, and mortality in chil- bicarbonate level less than 10 mEq/L and an elevated heart rate
dren with type 1 diabetes,1-5 and cerebral edema is the most were found to be associated with an increased risk of severe acute
serious complication that leads to morbidity and mortality.6 kidney injury.
To mitigate the risk of cerebral edema, pediatric-specific DKA Meaning Children in diabetic ketoacidosis are at high risk for
protocols have been developed and frequently recommend acute kidney injury, suggesting that clinicians should consider
conservative fluid administration at presentation. The DKA acute kidney injury as a frequent complication in this population.
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 were identified using the Internal Classification of Diseases,
regarding initial fluid management.8 Tenth Revision (ICD-10) codes for diabetes (E10-14) for the pe-
Acute kidney injury (AKI), previously referred to as acute re- riod September 1, 2008, through December 31, 2013. Patients
nal failure, is a common event in hospitalized children and im- were eligible for inclusion in the study if they were aged 18 years
plies a sudden worsening of the kidney’s ability to function. The or younger and had confirmed DKA (blood glucose level ≥200
clinical manifestations of pediatric AKI range from a mild increase mg/dL, pH ≤7.3 or bicarbonate level ≤15 mEq/L, and elevation
in serum creatinine to anuric renal failure that requires dialysis. of serum or urine ketones). (To convert glucose level to milli-
The most common risk factor for pediatric AKI is prerenal dis- moles per liter, multiply by 0.0555; to convert serum bicar-
ease or volume-responsive AKI, which is caused by hypovole- bonate level to millimoles per liter, multiply by 1.) Cases with
mia and reduced renal perfusion. If a prerenal insult is severe or incomplete medical documentation were excluded. The Uni-
prolonged, the injury can result in structural damage to the re- versity of British Columbia Clinical Research Ethics Board re-
nal parenchyma, a condition known as acute tubular necrosis. De- viewed and approved the study protocol and waived the re-
spite the marked intravascular volume depletion that occurs in quirement for patient consent. All data collection occurred
DKA and subsequent cautious fluid-rehydration strategies, AKI between September 8, 2014, and June 26, 2015. Data analysis
in children with DKA has not been systematically studied. Only took place from August 25, 2015, to June 8, 2016.
2 case reports9,10 have been published to date indicating that se-
vere kidney injury occurs in the pediatric DKA setting. Murdoch Data Collection
and colleagues9 reported on 2 girls, aged 13 and 14 years, with Paper and electronic records were reviewed. Medical history,
DKA complicated by anuric renal failure requiring dialysis. Both current illness, and hospital admission were captured. Clinical
girls had biopsy evidence of acute tubular necrosis. More re- and biochemical assessments, including initial estimated level
cently, Al-Matrafi and colleagues10 reported on a 12-year-old girl of volume depletion and fluid resuscitation, were recorded. Se-
with severe DKA who developed anuric renal failure requiring rum creatinine level was measured at BCCH using the enzy-
hemodialysis. These reports are particularly concerning in view matic Ortho Diagnostics Vitros CREA method (Ortho-Clinical Di-
of the evolving body of literature indicating that AKI in chil- agnostics Inc). Initial physical examination data, including
dren is associated not only with increased morbidity and mor- height, weight, blood pressure, and heart rate, were recorded.
tality but also an increased risk of chronic kidney disease.11
The primary objective of this study was to determine the Case Definitions
proportion of children with type 1 diabetes, hospitalized for DKA The primary outcome variable, AKI, was defined by the Kid-
at BCCH over 5 years, who developed AKI. We hypothesized that, ney Disease/Improving Global Outcomes (KDIGO) serum cre-
because DKA is associated with both volume depletion and con- atinine criteria.12 Because no study participants had avail-
servative fluid administration upon presentation, these chil- able baseline serum creatinine values prior to admission, we
dren are potentially at high risk for AKI, above the level of risk used an estimated glomerular filtration rate (GFR) of 120 mL/
expected by the rare reported cases in the literature. As a sec- min/1.73 m2 to calculate an expected baseline creatinine level
ondary objective, we sought to explore whether clinical signs (EBC) using the Schwartz estimating equation.13 A GFR of 120
and laboratory parameters of volume depletion and acidosis are mL/min/1.73 m2 was selected on the basis of previously estab-
associated with an increased risk for AKI in these patients. 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-
Methods sitivity analysis to calculate the most conservative estimates
Data Source of AKI. Stage 0 (no AKI) was defined as occurring if all creati-
This study was conducted at BCCH, the only tertiary pediat- nine values were less than 1.5 times the EBC. Stage 1 AKI oc-
ric hospital serving British Columbia, Canada. Cases of DKA curred if a creatinine value was 1.5 to less than 2 times the EBC.

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

Stage 2 AKI occurred if a creatinine value was 2 to less than 3 cal documentation was incomplete (n = 31), and patient had
times the EBC. Stage 3 AKI occurred if a creatinine value was neonatal diabetes (n = 2).
3 or more times the EBC. KDIGO AKI urine output criteria were Table 1 highlights the clinical characteristics for the en-
not used, because recording of hourly urine output rates was tire study population and for each AKI severity stage on ad-
inconsistent between cases. Corrected sodium (Na) was cal- mission. Overall, the admissions for DKA were characterized
culated using this formula7: 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
Corrected Na = [(Glucose (mg/dL)/18) − 5.6] × 0.36
half of the admissions (90 [54.5%]) were transfers from other
+ Serum Na.
hospitals within British Columbia, and about one-quarter of
A clinical estimation of volume depletion was documented as cases (40 [24.2%]) required intensive care unit (ICU) care.
mild, moderate, or severe by using the clinical categories on Three-quarters of cases (125 [75.8%]) were newly diagnosed
BCCH’s DKA protocol for infants and children. with type 1 diabetes during the hospitalization.
One hundred six patients (64.2%) developed AKI during
Statistical Analysis the admission. Of those with AKI, 37 (34.9%), 48 (45.3%), and
Continuous variables were presented as median and inter- 21 (19.8%) reached a maximum AKI stage of 1, 2, and 3, respec-
quartile range (IQR), while categorical variables were pre- tively. The proportion of AKI in children with DKA was higher
sented as number and percentage. For the regression analy- in those admitted to the pediatric ICU (34/40 [85%]) com-
sis, AKI (the primary outcome variable) was classified as no AKI pared with those who received care on the general pediatrics
(stage 0), mild AKI (stage 1), and severe AKI (stages 2 and 3). ward (72/125 [57.6%]). Of the 106 patients, 105 (99.1%) devel-
Stages 2 and 3 AKI were combined into a severe AKI category oped AKI within 24 hours of hospitalization. Starting with their
because these stages represent more substantial tubular in- initial AKI severity staging within the first 24 hours, 6 cases
jury and were previously shown to be associated with poorer subsequently increased in AKI severity from 24 to 48 hours of
outcomes, including increased mortality and hospital length hospitalization (cases increased in AKI severity from stage 0
of stay, in other pediatric populations.15,17-19 Multinomial lo- to 1 [1 case], 1 to 2 [2 cases], and 2 to 3 [3 cases]), and 1 addi-
gistic regression (using no AKI as the reference category) was tional case increased in severity from stage 2 to 3 AKI at 48 to
used to identify potential factors associated with AKI. Vari- 72 hours of hospitalization. All cases had reached their maxi-
ables were selected a priori on the basis of clinical impor- mum documented AKI stage by 72 hours. Finally, 2 patients
tance and included age and sex as well as initial values for clini- required hemodialysis for indications of fluid overload or oli-
cally estimated volume depletion, initial heart rate, and serum guria during their hospitalization. The first was a 13-year-old
bicarbonate, corrected serum sodium, and hematocrit levels. girl who underwent dialysis for 3 days but still had stage 3 AKI
Note that bicarbonate level was categorized using the ac- at discharge. The next follow-up measurement of her creati-
cepted cut point between mild and moderate to severe DKA nine level 9 months later had normalized with no evidence of
(10 mEq/L).20 Corrected sodium level was categorized as low hypertension or albuminuria noted in the nephrology clinic.
(≤134 mEq/L), normal (135-144 mEq/L), or elevated (≥145 The second patient was an 11-year-old girl who was treated with
mEq/L) because both hyponatremia and hypernatremia can hemodialysis for 2 days and then transferred to another hos-
occur with kidney injury. (To convert sodium level to milli- pital with no follow-up records available. No cases of cerebral
moles per liter, multiply by 1.) Hematocrit level was catego- edema or deaths were documented.
rized as either elevated or not elevated, with a cut point of 45% Fifty-four of 106 cases (50.9%) had documented resolution
chosen to reflect substantial hemoconcentration. (To convert of their AKI by 72 hours of hospitalization. Another 4 cases (3.8%)
hematocrit level to a proportion of 1, multiply by 0.01.) Vari- had documented resolution by 96 hours. Two patients (1.9%)
ables that were significant at P < .10 in the unadjusted analy- were transferred to other centers with ongoing AKI; therefore,
sis were considered for the multivariable model. Age and sex we were unable to document AKI resolution; notably, 1 of these
were added to the multivariable model irrespective of their sig- 2 patients underwent dialysis at BCCH. Furthermore, 2 cases
nificance in the unadjusted analysis. The effect measures were (1.9%), 1 of whom also had been receiving dialysis, still had AKI
reported as odds ratio (OR) and corresponding 95% CI. All the at the time of discharge, but a follow-up visit to the nephrology
analyses were conducted in SAS/STAT software version 9.4 clinic was arranged as an outpatient. Finally, 44 cases (41.5%)
(SAS Institute Inc).21 All tests were 2-sided at a significance level did not have documentation of AKI resolution prior to discharge,
of P = .05. 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
Results were 0.92 mg/dL (IQR, 0.79-1.02) at peak and 0.89 mg/dL (IQR,
From September 1, 2008, to December 31, 2013, a total of 211 0.79-0.95) at discharge for those with stage 1 AKI at discharge;
children were hospitalized for DKA at BCCH. Of these, 165 ad- 1.18 mg/dL (IQR, 1.10-1.36) at peak and 1.18 mg/dL (IQR, 1.1-1.3)
missions met the inclusion criteria for analysis. Reasons for ex- at discharge for those with stage 2 AKI at discharge; and 1.31 mg/
clusion included the following: patient with type 1 diabetes was dL (IQR, 1.12-1.36) at peak and 1.31 mg/dL (IQR, 1.12-1.36) at dis-
admitted for a non-DKA reason (n = 2), DKA criteria were not charge for those with stage 3 AKI at discharge. (To convert cre-
fully met (n = 8), medical record was not available (n = 3), medi- atinine to micromoles per liter, multiply by 88.4.)

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

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

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

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

ARTICLE INFORMATION Acquisition, analysis, or interpretation of data: All Children’s Hospital, assisted with the data collection
Accepted for Publication: January 4, 2017. authors. for this study. Ms Ronsley did not receive
Drafting of the manuscript: Hursh, Ronsley, Islam, compensation for her contribution.
Published Online: March 13, 2017. Panagiotopoulos.
doi:10.1001/jamapediatrics.2017.0020 Critical revision of the manuscript for important REFERENCES
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