The virus, severe acute respiratory syndrome coronavirus 2, that causes coronavirus disease 2019 (COVID-19) infected >12 million people around the world as of July 2020 (Johns Hopkins Coronavirus Tracker). Knowledge on pathophysiology, management, multiorgan effects, and postinfection complications is evolving. Several studies revealed variable AKI prevalence among hospitalized adults with COVID-19, as high as 76% in critically ill adults with higher risk of mortality (1). To our knowledge, no specific epidemiologic data on AKI in critically ill children with COVID-19 have been published, leading to gaps in our ability to plan for its implications in this ongoing pandemic.
We are conducting a multicenter, point-prevalence AKI study among critically ill children with COVID-19. We provide an epidemiologic snapshot of AKI among this cohort.
This cross-sectional analysis captured weekly data points. This interim analysis includes children (1 month to 18 years) from 41 centers (six countries; 32 in the United States) with confirmed severe acute respiratory syndrome coronavirus 2–positive diagnosis (on the basis of center testing protocols) admitted to intensive care units (ICUs) between April 15 and May 20, 2020.
The primary outcome was AKI defined by Kidney Disease Improving Global Outcomes creatinine criteria. Admission and peak creatinine on data capture days (or previous day if unavailable) were used. Baseline creatinine was the lowest within 3 months before admission or, if unknown, estimated using previously validated methods (2). Hospital outcomes censored at 14 days were (1) deceased, (2) hospitalized in ICU ≥14 days, or (3) presumed ICU hospitalization <14 days (when a patient is not included in two weekly date capture time points or not included in three date capture points and length of stay dates are <14 days). Final 28-day hospital mortality was determined.
Characteristics of participants with AKI versus participants without AKI were compared using distribution-appropriate univariable analyses. For characteristics with P value ≤0.10, univariable relative risks (RRs; 95% confidence intervals [95% CIs]) of AKI were calculated.
All centers’ ethical review boards approved the study and waived consent requirement. Deidentified data were electronically entered into REDCap, and analysis was conducted in SAS, version 9.4.
Only 26 of 41 (63%) centers (23 in the United States, three in Europe/Russia) had critically ill children who were COVID-19 positive during our catchment days. Of 106 included children, almost half (n=47; 44%; 95% CI, 35% to 54%) developed AKI: 47% (n=22) had stage 1, 23% (n=11) had stage 2, and 30% (n=14) had stage 3. No child received dialysis. Even though 71 children lacked baseline creatinine, AKI estimates were similar between those with and without a baseline creatinine (46%; 95% CI, 29% to 62% and 44%; 95% CI, 32% to 55%, respectively).
Table 1 displays demographic and clinical characteristics of children with and without AKI. Most children had at least one comorbidity (n=71; 67%), and almost 6% died (n=6). Vasopressor support and admission diagnosis of shock/hemodynamic instability were the only factors associated with higher risk for AKI (RR, 1.6; 95% CI, 1.1 to 2.5 and RR, 2.3; 95% CI, 1.5 to 3.5, respectively).
Table 1.
Epidemiology of AKI development among critically ill children who are coronavirus disease 2019 positive
| Characteristics | Total Coronavirus Disease 2019 Positive | AKI | No AKI |
|---|---|---|---|
| n (row %) | 106 | 47 (44) | 59 (56) |
| Date of enrollment | |||
| Week 1 | 25 (24) | 10 (21) | 15 (25) |
| Week 2 | 16 (15) | 9 (19) | 7 (12) |
| Week 3 | 9 (9) | 4 (9) | 5 (9) |
| Week 4 | 15 (14) | 6 (13) | 9 (15) |
| Week 5 | 21 (20) | 12 (26) | 9 (15) |
| Week 6 | 20 (19) | 6 (13) | 14 (24) |
| Age, yr, median (range) | 11.0 (0.1–17.8) | 10.5 (0.2–17.7) | 11.0 (0.1–17.8) |
| Age categories | |||
| Infants, 0–1 yr | 13 (12) | 4 (9) | 9 (15) |
| Toddlers, 1–5 yr | 17 (16) | 9 (19) | 8 (14) |
| Children, 5–13 yr | 30 (28) | 15 (32) | 15 (25) |
| Adolescents, ≥13 yr | 46 (43) | 19 (40) | 27 (46) |
| Sex | |||
| Females | 52 (49) | 26 (55) | 26 (44) |
| Males | 54 (51) | 21 (45) | 33 (56) |
| Race | |||
| White | 37 (35) | 17 (36) | 20 (34) |
| Black | 34 (32) | 17 (36) | 17 (29) |
| Asian | 2 (2) | 2 (4) | 0 (0) |
| Unknown | 33 (31) | 11 (23) | 22 (37) |
| Ethnicity | |||
| Non-Hispanic, non-Latino, non-Spanish | 62 (59) | 31 (66) | 31 (53) |
| Hispanic, Latino, Spanish | 26 (25) | 10 (21) | 16 (27) |
| Unknown | 18 (17) | 6 (13) | 12 (20) |
| Locationa | |||
| United States | 100 (94) | 43 (92) | 57 (97) |
| Western Europe | 1 (0.9) | 0 (0) | 1 (2) |
| Eastern Europe/Russia | 5 (5) | 4 (9) | 1 (2) |
| Baseline eGFR, ml/min per 1.73 m2, median (range)b | 112 (24–458) | 128 (24–458) | 105 (71–203) |
| Baseline serum creatinine, mg/dl, median (range)b | 0.5 (0.1–1.7) | 0.4 (0.1–1.7) | 0.5 (0.1–1.1) |
| Admission serum creatinine, mg/dL, median (range)c | 0.6 (0.1–5.6) | 0.8 (0.1–5.6) | 0.4 (0.1–1.1) |
| Peak serum creatinine, mg/dL, median (range)d | 0.6 (0.1–5.6) | 0.8 (0.3–5.6) | 0.4 (0.1–1.1) |
| Any chronic condition | 71 (67) | 28 (60) | 43 (73) |
| No chronic condition | 35 (33) | 19 (40) | 16 (27) |
| Common chronic conditions | |||
| Seizures/epilepsy | 16 (15) | 8 (17) | 8 (14) |
| Congenital heart disease (corrected and uncorrected) | 11 (10) | 6 (13) | 5 (8) |
| Asthma | 11 (10) | 5 (11) | 6 (10) |
| Admission reasons, multiple allowed | |||
| Shock/hemodynamic instability | 39 (37) | 27 (58) | 12 (20) |
| Sepsis/infection | 30 (28) | 14 (30) | 16 (27) |
| Respiratory distress | 52 (49) | 22 (47) | 30 (51) |
| CNS symptoms | 10 (9) | 3 (6) | 7 (12) |
| Other | 26 (25) | 7 (15) | 19 (32) |
| Nephrotoxin medication exposuree | 43 (41) | 20 (43) | 23 (39) |
| Maximum percent fluid overload, median (range)f | 3 (−10, 110) | 2 (−10, 110) | 5 (−5, 100) |
| Respiratory support | |||
| None | 48 (45) | 19 (40) | 29 (49) |
| Noninvasive | 28 (26) | 13 (28) | 15 (25) |
| Invasive | 30 (28) | 15 (32) | 15 (25) |
| Vasopressor support | 31 (29) | 19 (40) | 12 (20) |
| ECMO | 2 (2) | 2 (4) | 0 (0) |
| Mortalityg | 6 (6) | 3 (6) | 3 (5) |
| Length of hospitalization <14 d | 84 (79) | 36 (77) | 48 (81) |
| Length of hospitalization ≥14 d | 12 (11) | 8 (17) | 4 (7) |
Data are presented as N (column percentages) except where indicated. CNS, central nervous system; ECMO, extracorporeal membrane oxygenation.
Only regional location provided to maintain anonymity of centers/patients.
Baseline creatinine was missing for 71 patients, and height was missing for four; so, accurate baseline eGFR is only available for 31 (29.2%) patients. The remainder of baseline creatinine values were estimated by standard estimating equations (Materials and Methods).
Missing n=1.
Peak serum creatinine on the basis of weekly ascertainment. Therefore, true maximum peak creatinine may have been missed, and this may underestimate the true peak creatinine during the child’s hospitalization.
Nephrotoxic medications are defined on the basis of the large pediatric quality improvement initiative, Nephrotoxic Injury Negated by Just in time Action (5).
Fluid overload = (net fluid in − net fluid out)/intensive care unit admit weight.
The 28-d hospital mortality (missing n=1).
We found a high prevalence of AKI among critically ill children with COVID-19 (44%). This matches what has been seen in adult ICU AKI studies on COVID-19 (1). Compared with previous pediatric ICU-associated AKI research, the AKI prevalence with COVID-19 was much higher (44% versus 26%), although differences exist in inclusion criteria and centers (3).
We did not see the degree of AKI severity as seen in adult COVID-19 studies as no child in this analysis received dialysis. It should be noted that our cohort comes primarily from the United States during the earlier part of the COVID-19 pandemic, when testing was limited and children were more isolated. Subsequent waves of the pandemic may appear differently. Despite general findings of less severe disease in children compared with adults, 6% of our study population died. This raises concerns given the rising cases of COVID-19 globally and in the United States specifically, and a recent prediction model suggests that if COVID-19 remains unabated, pediatric ICUs could be overwhelmed (4). Our findings should be confirmed with additional in-depth pediatric studies.
Only half of participating centers had patients with COVID-19 to include during the analysis period. It could be argued that children are less likely to contract COVID-19, but newer reports suggest otherwise, with rising pediatric cases. Our 6% mortality rate suggests that pediatric severe disease is certainly possible. Thus, we feel low inclusion rates at some centers may primarily be driven by minimized transmission to children as a downstream effect of good population-level control.
It is important to note that our AKI estimate is likely an underestimation as we only used creatinine change to define AKI and not urine output.
We observed a high prevalence of AKI in critically ill children with COVID-19. With the rising cases worldwide, particularly in the United States, it is likely that AKI rates in critically ill children will also rise. With the complexity that AKI adds to the medical care of children, clinicians need to be even more diligent with early AKI identification, careful attention to fluid balance, and minimization of nephrotoxic medications, so that these patients do not suffer potentially avoidable consequences.
Disclosures
D. Askenazi reports consultancy agreements with AKI Foundation, Baxter, Bioporto, Inc., CHF Solutions, and Medtronic and receiving research funding from Baxter Renal Products and CHF Solutions. R.K. Basu reports consultancy agreements with Baxter Healthcare Solutions, BD, Biomerieux, BioPorto Diagnostics, and Potrero and speakers bureau for Baxter and BioPorto Diagnostics. E.C. Bjornstad reports that Bioporto, Inc. provided free supplies for a past research project in Malawi (using their NGALds dipstick). S.L. Goldstein reports consultancy agreements with Baxter Healthcare, Bioporto, Inc., CHF Solutions, Fresenius, Kaneka, Inc., La Jolla Pharmaceuticals, MediBeacon, Medtronic, Otsuka, Reata, and Renibus; ownership interest in MediBeacon; receiving research funding from Baxter Healthcare, Bioporto, Inc., and CHF Solutions; receiving honoraria from Baxter Healthcare and Fresenius; patents and inventions with Vigilanz; serving as a scientific advisor or member of MediBeacon; and speakers bureau for Baxter Healthcare and Fresenius. M. Zappitelli reports consultancy agreements with Bioporto, Inc., CytoPheryx Inc., and Eloxx Pharmaceuticals; receiving honoraria from Bioporto, Inc. and Eloxx Pharmaceuticals; and other interests/relationships with the Canadian Pediatric Nephrologists Association, the Canadian Society of Nephrology, and the Kidney Foundation of Canada. The remaining author has nothing to disclose.
Funding
Grant support was provided by National Institutes of Health grant 2UL1TR001425-05A1.
Acknowledgments
Our centralized data collection is housed at Cincinnati Children’s Hospital Medical Center via grant support from the Center for Clinical and Translational Science and Training (2UL1TR001425-05A1).
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
Contributor Information
Collaborators: SPARC Investigators, Katherine Irby, Paras Khandhar, Catherine Morgan, Erica Blender Brown, Sarah Velazquez de Leon, Ronke Awojoodu, Barsha Chakraborty, Mark Peters, Vamsi Yarlagadda, Cody Tigges, Rukshana Shroff, Allie Michelle DaCar, Felice Su, Ayse Arikan, Joana Tala, David Kwiatkowski, Emily Duffey, Rosario Ocampo, Rebecca Hammack, Utpal Bhalala, Werther Brunow de Carvalho, Glenda Hefley, Cathy Sheppard, Ronish Gupta, Vimal Chadha, Diane Liu, Beatrice Goilav, Minh Dien Duong, Alexandra Mazo, Nayan Shetty, Laura O’Malley, Dawn Jones, Christine Batchelder, Matthew Barhight, Elizabeth Kring, Amanda Hassinger, Catherine Ross, Nadine Straka, Pooja Nawathe, Gary Goulin, Stephen Gorga, Chaandini Jayachandran, Itay Ayalon, Sameer Kamath, Melissa Harward, Susan Martin, Natasa Stajic, Katja Gist, Jennifer Jetton, Brynna Van Wyk, Dwight Bailey, Jennifer Lamothe, Lee Polikoff, Navya Kirla, Rahul Chanchlani, David Selewski, Dana Fuhrman, Cassandra Formeck, Noureddin Nourbakhsh, Michelle Starr, Shina Menon, Hirotsugu Kitayama, Chris Parshuram, Jasmine Lee, Scott Sutherland, Felice Su, Robert Woroniecki, Rachel Sirignano, Leanna Huard, Brankica Spasojevic, Snezana Rsovac, Joshua Frazier, William Bortcosh, Duane Williams, E. Vincent S. Faustino, Casey Stulce, Aveneh Ghanam, Grace Chong, Vikas Dharnidharka, Tara Neumayr, Daniel Garros, Lydia Fong, Gonzalo Guerra, Akash Deep, Richard Hackbarth, Sapna Kudchadkar, Julie Fitzgerald, Rosario O’Campo, Anuj Khatri, Leslie Walther, Irene Pacheco, Pranali Awadhare, Ivana Cerovic, Bijana Medjo, Zaccaria Ricci, Rashid Alobaidi, Sean Bagshaw, Brendan Crawford, Richard Blaszak, Juan Francisco Collado Caparros, Yael Feinstein, and Michelle Moss
References
- 1.Hirsch JS, Ng JH, Ross DW, Sharma P, Shah HH, Barnett RL, Hazzan AD, Fishbane S, Jhaveri KD; Northwell COVID-19 Research Consortium and the Nephrology COVID-19 Research Consortium : Acute kidney injury in patients hospitalized with COVID-19. Kidney Int 98: 209–218, 2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Hessey E, Ali R, Dorais M, Morissette G, Pizzi M, Rink N, Jouvet P, Lacroix J, Phan V, Zappitelli M: Evaluation of height-dependent and height-independent methods of estimating baseline serum creatinine in critically ill children. Pediatr Nephrol 32: 1953–1962, 2017. [DOI] [PubMed] [Google Scholar]
- 3.Kaddourah A, Basu RK, Bagshaw SM, Goldstein SL; AWARE Investigators: Epidemiology of acute kidney injury in critically ill children and young adults. N Engl J Med 376: 11–20, 2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Pathak EB, Salemi JL, Sobers N, Menard J, Hambleton IR: COVID-19 in children in the United States: Intensive care admissions, estimated total infected, and projected numbers of severe pediatric cases in 2020. J Public Health Manag Pract 26: 325–333, 2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Goldstein SL, Dahale D, Kirkendall ES, Mottes T, Kaplan H, Muething S, Askenazi DJ, Henderson T, Dill L, Somers MJG, Kerr J, Gilarde J, Zaritsky J, Bica V, Brophy PD, Misurac J, Hackbarth R, Steinke J, Mooney J, Ogrin S, Chadha V, Warady B, Ogden R, Hoebing W, Symons J, Yonekawa K, Menon S, Abrams L, Sutherland S, Weng P, Zhang F, Walsh K: A prospective multi-center quality improvement initiative (NINJA) indicates a reduction in nephrotoxic acute kidney injury in hospitalized children. Kidney Int 97: 580–588, 2020. [DOI] [PubMed] [Google Scholar]