Clinical Research Article | Published:

Late onset neonatal acute kidney injury: results from the AWAKEN Study



Most studies of neonatal acute kidney injury (AKI) have focused on the first week following birth. Here, we determined the outcomes and risk factors for late AKI (>7d).


The international AWAKEN study examined AKI in neonates admitted to an intensive care unit. Late AKI was defined as occurring >7 days after birth according to the KDIGO criteria. Models were constructed to assess the association between late AKI and death or length of stay. Unadjusted and adjusted odds for late AKI were calculated for each perinatal factor.


Late AKI occurred in 202/2152 (9%) of enrolled neonates. After adjustment, infants with late AKI had higher odds of death (aOR:2.1, p = 0.02) and longer length of stay (parameter estimate: 21.9, p < 0.001). Risk factors included intubation, oligo- and polyhydramnios, mild-moderate renal anomalies, admission diagnoses of congenital heart disease, necrotizing enterocolitis, surgical need, exposure to diuretics, vasopressors, and NSAIDs, discharge diagnoses of patent ductus arteriosus, necrotizing enterocolitis, sepsis, and urinary tract infection.


Late AKI is common, independently associated with poor short-term outcomes and associated with unique risk factors. These should guide the development of protocols to screen for AKI and research to improve prevention strategies to mitigate the consequences of late AKI.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Clinical Trial registry name and registration number: Assessment of Worldwide Acute Kidney injury Epidemiology in Neonates (AWAKEN), NCT02443389


  1. 1.

    Jetton, J. G. et al. Assessment of worldwide acute kidney injury epidemiology in neonates: design of a retrospective cohort study. Front. Pediatr. 4, 68 (2016).

  2. 2.

    Jetton, J. et al. Incidence and outcomes of neonatal acute kidney injury (AWAKEN): a multicentre, multinational, observational cohort study. Lancet Child Adolesc. Health 1, 184–194 (2017).

  3. 3.

    Charlton, J. R. et al. on behalf of the Neonatal Kidney Collaborative. Incidence and Risk Factors of Early Onset Neonatal Acute Kidney Injury. CJASN. (2018).

  4. 4.

    Carmody, J. B., Swanson, J. R., Rhone, E. T., Charlton, J. R. Recognition and Reporting of Acute Kidney Injury in Very Low Birth Weight Infants. Clin. J. Am. Soc. Nephrol. 9, 2036–2043 (2014). PMID: 25280497. PMCID: 4255405.

  5. 5.

    Askenazi, D. J. et al. Fluid overload and mortality are associated with acute kidney injury in sick near-term/term neonate. Pediatr. Nephrol. 28, 661–666 (2013).

  6. 6.

    Jetton, J. G. & Askenazi, D. J. Acute kidney injury in the neonate. Clin. Perinatol. 41, 487–502 (2014).

  7. 7.

    Jacobs, S. E., et al Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst. Rev.:CD003311 (2013).

  8. 8.

    Kellum, J. A., Lameire, N. & KDIGO AKI Guideline Work Group. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit. Care 17, 204 (2013).

  9. 9.

    Hsu, C. W., Yamamoto, K. T., Henry, R. K., De Roos, A. J. & Flynn, J. T. Prenatal risk factors for childhood CKD. J. Am. Soc. Nephrol. 25, 2105–11 (2014).

  10. 10.

    White, S. L. et al. Is low birth weight an antecedent of CKD in later life? A systematic review of observational studies. Am. J. Kidney Dis. 54, 248–261 (2009).

  11. 11.

    Rodriguez, E. et al. Impact of recurrent acute kidney injury on patient outcomes. Kidney Blood. Press. Res. 43, 34–44 (2018).

  12. 12.

    Thakar, C. V., Christianson, A., Himmelfarb, J. & Leonard, A. C. Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus. Clin. J. Am. Soc. Nephrol. 6, 2567–2572 (2011).

  13. 13.

    Sutherland, M. R. et al. Accelerated maturation and abnormal morphology in the preterm neonatal kidney. J. Am. Soc. Nephrol. 22, 1365–1374 (2011).

  14. 14.

    Rodriguez, M. M. et al. Comparative renal histomorphometry: a case study of oligonephropathy of prematurity. Pediatr. Nephrol. 20, 945–949 (2005).

  15. 15.

    Pfister, R. H. & Soll, R. F. Initial respiratory support of preterm infants: the role of CPAP, the INSURE method, and noninvasive ventilation. Clin. Perinatol. 39, 459–481 (2012).

  16. 16.

    Tapia, J. L. et al. Randomized trial of early bubble continuous positive airway pressure for very low birth weight infants. J. Pediatr. 161, 75–80.e1 (2012).

  17. 17.

    Morley, C. J. et al. Nasal CPAP or intubation at birth for very preterm infants. N. Engl. J. Med. 358, 700–708 (2008).

  18. 18.

    SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Finer, N. N. et al. Early CPAP versus surfactant in extremely preterm infants. N. Engl. J. Med. 362, 1970–1979 (2010).

  19. 19.

    Criss, C. N., et al. Acute kidney injury in necrotizing enterocolitis predicts mortality. Pediatr. Nephrol. 33, 503–510 (2017). Epub 2017 Oct 5.

  20. 20.

    Garg, P. M., Tatum, R., Ravisankar, S., Shekhawat, P. S. & Chen, Y. H. Necrotizing enterocolitis in a mouse model leads to widespread renal inflammation, acute kidney injury, and disruption of renal tight junction proteins. Pediatr. Res. 78, 527–532 (2015).

  21. 21.

    Morgan, C. J. et al. Risk factors for and outcomes of acute kidney injury in neonates undergoing complex cardiac surgery. J. Pediatr. 162, 120–127.e1 (2013).

  22. 22.

    Blinder, J. J. et al. Congenital heart surgery in infants: effects of acute kidney injury on outcomes. J. Thorac. Cardiovasc. Surg. 143, 368–374 (2012).

  23. 23.

    Goldstein, S. L. et al. A sustained quality improvement program reduces nephrotoxic medication-associated acute kidney injury. Kidney Int. 90, 212–221 (2016).

  24. 24.

    Kent, A. L. et al. Indomethacin administered early in the postnatal period results in reduced glomerular number in the adult rat. Am. J. Physiol. Ren. Physiol. 307, F1105–F1110 (2014).

  25. 25.

    Kent, A. L., Brown, L., Broom, M., Broomfield, A. & Dahlstrom, J. E. Increased urinary podocytes following indomethacin suggests drug-induced glomerular injury. Pediatr. Nephrol. 27, 1111–1117 (2012).

  26. 26.

    Kume, T., Saglam, B., Ergon, C. & Sisman, A. R. Evaluation and comparison of Abbott Jaffe and enzymatic creatinine methods: could the old method meet the new requirements? J. Clin. Lab. Anal. 32 (2018)

  27. 27.

    Hermida, F. J. et al. Comparison between ADVIA Chemistry systems Enzymatic Creatinine_2 method and ADVIA chemistry systems creatinine method (kinetic Jaffe method) for determining creatinine. Scand. J. Clin. Lab. Invest. 74, 629–636 (2014).

  28. 28.

    Stausberg, J., Koch, D., Ingenerf, J. & Betzler, M. Comparing paper-based with electronic patient records: lessons learned during a study on diagnosis and procedure codes. J. Am. Med. Inform. Assoc. 10, 470–477 (2003).

Download references


Cincinnati Children’s Hospital Center for Acute Care Nephrology provided funding to create and maintain the AWAKEN Medidata Rave electronic database. The Pediatric and Infant Center for Acute Nephrology (PICAN) provided support for web meetings, for the NKC steering committee annual meeting at the University of Alabama at Birmingham (UAB), as well as support for some of the AWAKEN investigators at UAB (DA, LBJ, RJG). PICAN is part of the Department of Pediatrics at the University of Alabama at Birmingham (UAB), and is funded by Children’s of Alabama Hospital, the Department of Pediatrics, UAB School of Medicine, and UAB’s Center for Clinical and Translational Sciences (CCTS, NIH grant UL1TR001417). Finally, the AWAKEN study was supported at the University of New Mexico by the Clinical and Translational Science Center (CTSC, NIH grant UL1TR001449). The authors would also like to thank the outstanding work of the following clinical research personnel and colleagues for their involvement in AWAKEN: Ariana Aimani, Samantha Kronish, Ana Palijan, MD, Michael Pizzi—Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada; Laila Ajour, BS, Julia Wrona, BS—University of Colorado, Children's Hospital Colorado, Aurora, Colorado, USA; Melissa Bowman, RN—University of Rochester, Rochester, New York, USA; Teresa Cano, RN, Marta G. Galarza, MD, Wendy Glaberson, MD, Aura Arenas Morales, MD, Denisse Cristina Pareja Valarezo, MD—Holtz Children’s Hospital, University of Miami, Miami, Florida, USA; Sarah Cashman, BS, Madeleine Stead, BS—University of Iowa Children’s Hospital, Iowa City, Iowa, USA; Jonathan Davis, MD, Julie Nicoletta, MD—Floating Hospital for Children at Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA; Alanna DeMello—British Columbia Children’s Hospital, Vancouver, British Columbia, Canada; Lynn Dill, RN—University of Alabama at Birmingham, Birmingham, Alabama, USA; Ellen Guthrie, RN—MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, USA, Nicholas L. Harris, BS, Susan M. Hieber, MSQM—C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan, USA; Katherine Huang, Rosa Waters—University of Virginia Children’s Hospital, Charlottesville, Virginia, USA; Judd Jacobs, Ryan Knox, BS, Hilary Pitner, MS, Tara Terrell—Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA; Nilima Jawale, MD—Maimonides Medical Center, Brooklyn, New York, USA; Emily Kane—Australian National University, Canberra, Australia; Vijay Kher, DM, Puneet Sodhi, MBBS—Medanta Kidney Institute, The Medicity Hospital, Gurgaon, Haryana, India; Grace Mele—New York College of Osteopathic Medicine, Westbury, New York, USA; Patricia Mele, DNP—Stony Brook Children’s Hospital, Stony Brook, New York, USA; Charity Njoku, Tennille Paulsen, Sadia Zubair—Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas, USA; Emily Pao—University of Washington, Seattle Children's Hospital, Seattle, Washington, USA; Becky Selman RN, Michele Spear, CCRC—University of New Mexico Health Sciences Center Albuquerque, New Mexico, USA; Melissa Vega, PA-C—The Children’s Hospital at Montefiore, Bronx, New York, USA; Leslie Walther RN—Washington University, St. Louis, Missouri, USA.

The Neonatal Kidney Collaborative (NKC) members listed in Appendix are non-author contributors and served as collaborators and site investigators for the AWAKEN study. They collaborated in protocol development and review, local IRB submission, data collection and participated in drafting or review of the manuscript. The Neonatal Kidney Collaborative (NKC) members listed below are non-author contributors and served as collaborators and site investigators for the AWAKEN study and deserve a PUBMED citation. They collaborated in protocol development and review, local IRB submission, data collection and participated in drafting or review of the manuscript.

Neonatal Kidney Collaborative (NKC)

Namasivayam Ambalavanan, MD13, David T. Selewski, MD12, Jeffery Fletcher, PhD14, Carolyn L Abitbol, MD15, Marissa DeFreitas, MD15, Shahnaz Duara, MD15, Ronnie Guillet, MD, PhD16, Erin Rademacher, MD16, Carl D’Angio, MD16, Maroun J. Mhanna, MD17, Rupesh Raina, MD17, Deepak Kumar, MD17, Ayse Akcan Arikan, MD10, Stuart L. Goldstein, MD18, Amy T. Nathan, MD18, Juan C. Kupferman, MD19, Alok Bhutada, MD19, Elizabeth Bonachea, MD20, John Mahan, MD20, Arwa Nada, MBBCH21, Jennifer Jetton, MD22, Tarah T. Colaizy, MD22, Jonathan M. Klein, MD22, F. Sessions Cole, MD23, T. Keefe Davis, MD23, Lawrence Milner, MD24, Alexandra Smith, MD24, Kimberly Reidy, MD25, Frederick J. Kaskel, MD25, Katja M. Gist, DO5, Mina H. Hanna, MD26, Craig S. Wong, MD27, Catherine Joseph, MD27, Tara DuPont, MD27, Amy Staples, MD27, Surender Khokhar, MD28, Sofia Perazzo, MD11, Patricio E. Ray, MD11, Cherry Mammen, MD29, Anne Synnes, MDCM29, Pia Wintermark, MD30, Sidharth K. Sethi, MD31, Sanjay Wazir, MD32, Smriti Rohatgi, MD33, Danielle E. Soranno, MD5, Katja M. Gist, DO5, Aftab S. Chishti, MD26, Mina H. Hanna, MD26, Robert Woroniecki, MD34, Shanty Sridhar, MD34, Jonathan R. Swanson MD35, Michael Zappitelli, MD36

Author contributions

J.R.C. and A.L.K. contributed to the conceptualization and design of the study, collected data, aided the data analysis, and drafted the initial manuscript. L.B. and R.G. completed the data analysis and interpretation, contributed to the drafting and revising the manuscript. D.A. contributed to the conceptualization and design of the study, aided in data analysis, and contributed to the revising of the manuscript for critically important intellectual content. P.D.B., M.F., J.G., S.H., S.I., A.M., R.K.O., S.R., C.J.R., M.R., S.S., and M.S. contributed to the study design, collecting or supervising the collection of data, and revising the manuscript for critically important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Author information

Competing interests

J.R.C. is a co-owner of Sindri Technologies, LLC. She receives funding from the National Institutes of Health-National Institutes of Diabetes and Digestive and Kidney Diseases (R01DK110622, R01DK111861). D.J.A. serves on the speaker board for Baxter (Baxter, USA), and the Acute Kidney Injury (AKI) Foundation (Cincinnati, OH, USA); he also receives grant funding for studies not related to this manuscript from Octapharma AG (Switzerland), and the National Institutes of Health—National Institutes of Diabetes and Digestive and Kidney Diseases (NIH-NIDDK, R01 DK103608). S.H. is also funded through NIH-NIDDK, R01 DK103608. All the remaining authors declare no competing interests.

Clinical Trial registry name and registration number

Assessment of Worldwide Acute Kidney injury Epidemiology in Neonates (AWAKEN), NCT02443389.

Correspondence to Jennifer R. Charlton.


    Supplementary information

    1. Supplementary information

    Rights and permissions

    Reprints and Permissions

    About this article

    Verify currency and authenticity via CrossMark
    Fig. 1
    Fig. 2
    Fig. 3
    Fig. 4