Advertisement

Pediatric Drugs

, Volume 19, Issue 1, pp 59–67 | Cite as

Identifying High-Risk Medications Associated with Acute Kidney Injury in Critically Ill Patients: A Pharmacoepidemiologic Evaluation

  • Morgan B. Slater
  • Andrea Gruneir
  • Paula A. Rochon
  • Andrew W. Howard
  • Gideon Koren
  • Christopher S. ParshuramEmail author
Original Research Article

Abstract

Background

Nephrotoxic medications are a common cause of acute kidney injury (AKI). Critically ill children receive more medication than other inpatients; however, the risk of nephrotoxic medication-induced AKI in these children is not well understood.

Objective

The aim of this study was to determine the association between exposure to nephrotoxic medications in the intensive care unit (ICU) and the development of AKI amongst critically ill children, adjusting for differences in underlying risk.

Methods

We conducted a nested case–control study among a cohort of patients admitted to a paediatric intensive care unit between January 2006 and June 2009. Cases were identified according to the RIFLE criteria. Using incidence density sampling, controls were matched 1:1 according to pre-ICU nephrotoxic drug exposure. Administration of nephrotoxic medications and other known risk factors of AKI were evaluated during the ICU stay prior to the diagnosis of AKI.

Results

A total of 914 patients in the cohort developed AKI and had an identifiable matched control. Eighty-seven percent of cases and 74% of controls were exposed to one or more nephrotoxic medications in the ICU during the study period. Furosemide (administered to 67.8% of patients), vancomycin (28.7%), and gentamicin (21.4%) were the most frequently administered nephrotoxic drugs. Patients who developed AKI were more likely to be exposed to at least one nephrotoxic medication and risk increased with increasing number of nephrotoxic medications. Ganciclovir (adjusted odds ratio [AOR] 4.7; 95% CI 1.7–13.0), furosemide (AOR 1.9; 95% CI 1.4–2.4), and gentamicin (AOR 1.8; 95% CI 1.4–2.4) significantly increased the odds of developing AKI after adjusting for underlying differences in risk factors of AKI.

Conclusion

This is the first study to assess the association between risk-adjusted nephrotoxic medication exposure and the development of AKI in critically ill children. Nephrotoxic medication exposure was common amongst children in the ICU and we found AKI was associated with the administration of specific drugs after adjustment for important risk factors.

Keywords

Intensive Care Unit Furosemide Acute Kidney Injury Intensive Care Unit Admission Ganciclovir 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The authors would like to thank Dr. Valeria Rac, Dr. Joseph Amuah, Helena Frndova, Winnie Seto, Tony Pyle, Traci Peggie, Sarah Ashley, and Christina Stevancec for their advice and assistance. Morgan Slater was supported through a Canadian Institutes of Health Research Frederick Banting and Charles Best Canada Graduate Scholarship, the Ontario Student Opportunity Trust Fund—Hospital for Sick Children Foundation Student Scholarship Program, and an Ontario Graduate Scholarship.

Compliance with Ethical Standards

Disclosure of potential conflicts of interest

All authors (M. Slater, A. Gruneir, P. Rochon, A. Howard, G. Koren, C. Parshuram) declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required.

Funding sources

This work was supported by the following scholarships awarded to Morgan Slater: a Canadian Institutes of Health Research Frederick Banting and Charles Best Canada Graduate Scholarship, the Ontario Student Opportunity Trust Fund—The Hospital for Sick Children Foundation Student Scholarship Program, and an Ontario Graduate Scholarship. Dr. C Parshuram received operational funding from the Canadian Institutes of Health Research that supported completion of the study and was administered by the SickKids Research Institute.

References

  1. 1.
    Akcan-Arikan A, Zappitelli M, Loftis LL, Washburn KK, Jefferson LS, Goldstein SL. Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int. 2007;71(10):1028–35.CrossRefPubMedGoogle Scholar
  2. 2.
    Plotz FB, Bouma AB, van Wijk JA, Kneyber MC, Bokenkamp A. Pediatric acute kidney injury in the ICU: an independent evaluation of pRIFLE criteria. Intensive Care Med. 2008;34(9):1713–7.CrossRefPubMedGoogle Scholar
  3. 3.
    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):933–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Washburn KK, Zappitelli M, Arikan AA, Loftis L, Yalavarthy R, Parikh CR, et al. Urinary interleukin-18 is an acute kidney injury biomarker in critically ill children. Nephrol Dial Transpl. 2008;23(2):566–72.CrossRefGoogle Scholar
  5. 5.
    Zappitelli M, Washburn KK, Arikan AA, Loftis L, Ma Q, Devarajan P, et al. Urine neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in critically ill children: a prospective cohort study. Crit Care. 2007;11(4):R84.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bresolin N, Bianchini AP, Haas CA. Pediatric acute kidney injury assessed by pRIFLE as a prognostic factor in the intensive care unit. Pediatr Nephrol. 2013;28(3):485–92.CrossRefPubMedGoogle Scholar
  7. 7.
    Alkandari O, Eddington KA, Hyder A, Gauvin F, Ducruet T, Gottesman R, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Zwiers AJ, de Wildt SN, Hop WC, Dorresteijn EM, Gischler SJ, Tibboel D, et al. Acute kidney injury is a frequent complication in critically ill neonates receiving extracorporeal membrane oxygenation: a 14-year cohort study. Crit Care. 2013;17(4):R151.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Hui-Stickle S, Brewer ED, Goldstein SL. Pediatric ARF epidemiology at a tertiary care center from 1999 to 2001. Am J Kidney Dis. 2005;45(1):96–101.CrossRefPubMedGoogle Scholar
  10. 10.
    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):184–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Askenazi DJ, Griffin R, McGwin G, Carlo W, Ambalavanan N. Acute kidney injury is independently associated with mortality in very low birthweight infants: a matched case–control analysis. Pediatric Nephrol. 2009;24(5):991–7.CrossRefGoogle Scholar
  12. 12.
    Sanchez-Pinto LN, Goldstein SL, Schneider JB, Khemani RG. Association between progression and improvement of acute kidney injury and mortality in critically ill children. Pediatr Crit Care Med. 2015;16(8):703–10.CrossRefPubMedGoogle Scholar
  13. 13.
    Selewski DT, Cornell TT, Heung M, Troost JP, Ehrmann BJ, Lombel RM, et al. Validation of the KDIGO acute kidney injury criteria in a pediatric critical care population. Intensive Care Med. 2014;40(10):1481–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Working Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int. 2012;Supplement 2:1–138.Google Scholar
  15. 15.
    Slater MB, Gruneir A, Rochon PA, Howard AW, Koren G, Parshuram CS. Risk factors of acute kidney injury in critically ill children. Pediatr Crit Care Med. 2016;17(9):e391–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Moffett BS, Goldstein SL. Acute kidney injury and increasing nephrotoxic-medication exposure in noncritically-ill children. Clin J Am Soc Nephrol. 2011;6(4):856–63.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Cullen DJ, Sweitzer BJ, Bates DW, Burdick E, Edmondson A, Leape LL. Preventable adverse drug events in hospitalized patients: a comparative study of intensive care and general care units. Crit Care Med. 1997;25(8):1289–97.CrossRefPubMedGoogle Scholar
  18. 18.
    Rhone ET, Carmody JB, Swanson JR, Charlton JR. Nephrotoxic medication exposure in very low birth weight infants. J Matern Fetal Neonatal Med. 2014;27(14):1485–90.CrossRefPubMedGoogle Scholar
  19. 19.
    Sinclair EA, Yenokyan G, McMunn A, Fadrowski JJ, Milstone AM, Lee CK. Factors associated with acute kidney injury in children receiving vancomycin. Ann Pharmacother. 2014;48(12):1555–62.CrossRefPubMedGoogle Scholar
  20. 20.
    Totapally BR, Machado J, Lee H, Paredes A, Raszynski A. Acute kidney injury during vancomycin therapy in critically ill children. Pharmacotherapy. 2013;33(6):598–602.CrossRefPubMedGoogle Scholar
  21. 21.
    Moffett BS, Hilvers PS, Dinh K, Arikan AA, Checchia P, Bronicki R. Vancomycin-associated acute kidney injury in pediatric cardiac intensive care patients. Congenit Heart Dis. 2015;10(1):E6–10.CrossRefPubMedGoogle Scholar
  22. 22.
    Rao S, Abzug MJ, Carosone-Link P, Peterson T, Child J, Siparksy G, et al. Intravenous acyclovir and renal dysfunction in children: a matched case control study. J Pediatr. 2015;166(6):1462–8e1–4.Google Scholar
  23. 23.
    Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8(4):R204–12.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Schwartz GJ, Haycock GB, Spitzer A. Plasma creatinine and urea concentration in children: normal values for age and sex. J Pediatr. 1976;88(5):828–30.CrossRefPubMedGoogle Scholar
  25. 25.
    Szklo M, Nieto J. Epidemiology: beyond the basics, 2nd ed. Burlington: Jones and Bartlett Learning; 2006.Google Scholar
  26. 26.
    World Health Organization. International statistical classification of diseases and related health problems 10th revision. 2010 [cited 2013 February 12, 2013]; Available from: http://apps.who.int/classifications/icd10/browse/2010/en.
  27. 27.
    Pollack MM, Ruttimann UE, Getson PR. Pediatric risk of mortality (PRISM) score. Crit Care Med. 1988;16(11):1110–6.CrossRefPubMedGoogle Scholar
  28. 28.
    Leteurtre S, Martinot A, Duhamel A, Gauvin F, Grandbastien B, Nam TV, et al. Development of a pediatric multiple organ dysfunction score: use of two strategies. Med Decis Making. 1999;19(4):399–410.CrossRefPubMedGoogle Scholar
  29. 29.
    Knoderer CA, Gritzman AL, Nichols KR, Wilson AC. Late-occurring vancomycin-associated acute kidney injury in children receiving prolonged therapy. Ann Pharmacother. 2015;49(10):1113–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Aydin SI, Seiden HS, Blaufox AD, Parnell VA, Choudhury T, Punnoose A, et al. Acute kidney injury after surgery for congenital heart disease. Ann Thorac Surg. 2012;94(5):1589–95.CrossRefPubMedGoogle Scholar
  31. 31.
    Morgan CJ, Zappitelli M, Robertson CM, Alton GY, Sauve RS, Joffe AR, et al. Risk factors for and outcomes of acute kidney injury in neonates undergoing complex cardiac surgery. J Pediatr. 2013;162(1):120–7e1.Google Scholar
  32. 32.
    Viswanathan S, Manyam B, Azhibekov T, Mhanna MJ. Risk factors associated with acute kidney injury in extremely low birth weight (ELBW) infants. Pediatric Nephrol. 2012;27(2):303–11.CrossRefGoogle Scholar
  33. 33.
    Bailey D, Phan V, Litalien C, Ducruet T, Merouani A, Lacroix J, et al. Risk factors of acute renal failure in critically ill children: a prospective descriptive epidemiological study. Pediatr Crit Care Med. 2007;8(1):29–35.CrossRefPubMedGoogle Scholar
  34. 34.
    Roy AK, Mc Gorrian C, Treacy C, Kavanaugh E, Brennan A, Mahon NG, et al. A comparison of traditional and novel definitions (RIFLE, AKIN, and KDIGO) of acute kidney injury for the prediction of outcomes in acute decompensated heart failure. Cardiorenal Med. 2013;3(1):26–37.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Rodrigues FB, Bruetto RG, Torres US, Otaviano AP, Zanetta DM, Burdmann EA. Incidence and mortality of acute kidney injury after myocardial infarction: a comparison between KDIGO and RIFLE criteria. PLoS One. 2013;8(7):e69998.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Bastin AJ, Ostermann M, Slack AJ, Diller GP, Finney SJ, Evans TW. Acute kidney injury after cardiac surgery according to risk/injury/failure/loss/end-stage, acute kidney injury network, and kidney disease: improving global outcomes classifications. J Crit Care. 2013;28(4):389–96.CrossRefPubMedGoogle Scholar
  37. 37.
    Sutherland SM, Byrnes JJ, Kothari M, Longhurst CA, Dutta S, Garcia P, et al. AKI in hospitalized children: comparing the pRIFLE, AKIN, and KDIGO definitions. Clin J Am Soc Nephrol. 2015;10(4):554–61.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Siew ED, Matheny ME, Ikizler TA, Lewis JB, Miller RA, Waitman LR, et al. Commonly used surrogates for baseline renal function affect the classification and prognosis of acute kidney injury. Kidney Int. 2010;77(6):536–42.CrossRefPubMedGoogle Scholar
  39. 39.
    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):948–54.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Zavada J, Hoste E, Cartin-Ceba R, Calzavacca P, Gajic O, Clermont G, et al. A comparison of three methods to estimate baseline creatinine for RIFLE classification. Nephrol Dial Transpl. 2010;25(12):3911–8.CrossRefGoogle Scholar
  41. 41.
    Thongprayoon C, Cheungpasitporn W, Harrison AM, Kittanamongkolchai W, Ungprasert P, Srivali N, et al. The comparison of the commonly used surrogates for baseline renal function in acute kidney injury diagnosis and staging. BMC Nephrol. 2016;17:6.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Girardeau Y, Trivin C, Durieux P, Le Beller C, Louet Agnes LL, Neuraz A, et al. Detection of drug–drug interactions inducing acute kidney injury by electronic health records mining. Drug Saf. 2015;38(9):799–809.CrossRefPubMedGoogle Scholar
  43. 43.
    Menon S, Kirkendall ES, Nguyen H, Goldstein SL. Acute kidney injury associated with high nephrotoxic medication exposure leads to chronic kidney disease after 6 months. J Pediatr. 2014;165(3):522–7e2.Google Scholar
  44. 44.
    Ali T, Khan I, Simpson W, Prescott G, Townend J, Smith W, et al. Incidence and outcomes in acute kidney injury: a comprehensive population-based study. J Am Soc Nephrol. 2007;18(4):1292–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Hsu RK, McCulloch CE, Dudley RA, Lo LJ, Hsu CY. Temporal changes in incidence of dialysis-requiring AKI. J Am Soc Nephrol. 2013;24(1):37–42.CrossRefPubMedGoogle Scholar
  46. 46.
    Yamout H, Levin ML, Rosa RM, Myrie K, Westergaard S. Physician prevention of acute kidney injury. Am J Med. 2015;128(9):1001–6.CrossRefPubMedGoogle Scholar
  47. 47.
    Goldstein SL, Kirkendall E, Nguyen H, Schaffzin JK, Bucuvalas J, Bracke T, et al. Electronic health record identification of nephrotoxin exposure and associated acute kidney injury. Pediatrics. 2013;132(3):e756–67.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Morgan B. Slater
    • 1
    • 2
  • Andrea Gruneir
    • 3
    • 4
    • 5
    • 6
  • Paula A. Rochon
    • 4
    • 5
    • 6
    • 7
  • Andrew W. Howard
    • 2
    • 5
    • 8
    • 9
  • Gideon Koren
    • 10
  • Christopher S. Parshuram
    • 1
    • 2
    • 5
    • 11
    • 12
    Email author
  1. 1.Department of Critical Care MedicineThe Hospital for Sick ChildrenTorontoCanada
  2. 2.Child Health Evaluative SciencesThe Hospital for Sick ChildrenTorontoCanada
  3. 3.Department of Family MedicineUniversity of AlbertaEdmontonCanada
  4. 4.Women’s College Research InstituteWomen’s College HospitalTorontoCanada
  5. 5.Institute of Health Policy, Management and EvaluationUniversity of TorontoTorontoCanada
  6. 6.Institute for Clinical Evaluative SciencesTorontoCanada
  7. 7.Department of MedicineUniversity of TorontoTorontoCanada
  8. 8.Division of Orthopaedic SurgeryThe Hospital for Sick ChildrenTorontoCanada
  9. 9.Department of SurgeryUniversity of TorontoTorontoCanada
  10. 10.Department of PaediatricsUniversity of TorontoTorontoCanada
  11. 11.Division of Clinical Pharmacology and ToxicologyThe Hospital for Sick ChildrenTorontoCanada
  12. 12.Interdepartmental Division of Critical Care MedicineUniversity of TorontoTorontoCanada

Personalised recommendations