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Drug-associated kidney injury in children: a disproportionality analysis of the FDA Adverse Event Reporting System

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Abstract

Drug-associated kidney injury is related to longer hospitalization and increased risk of chronic kidney disease and mortality. However, there is currently a lack of large population studies on drug-associated kidney injury in children. This study aimed to study perform data mining to generate hypotheses on drugs, which may deserve to be assessed as per their potential risk of increasing kidney injury in children. We extracted and analyzed reports on drugs associated with kidney injury in children in the FDA Adverse Event Reporting System (FAERS). We conducted a disproportionality analysis using proportional reporting ratio (PRR) to evaluate the association between drugs and kidney injury in children. Meanwhile, comparisons were performed with drug labels to identify drugs that, despite not having kidney injury currently mentioned in their labels, may potentially be associated with risks of kidney injury in children. A total of 6347 children had drug-associated kidney injury in the FAERS database. The top five drugs with the highest PRR were gentamicin (PRR = 12.28, N = 157 cases, Chi-Squared = 1602.77), piperacillin-tazobactam (PRR = 9.77, N = 129 cases, Chi-Squared = 1003.24), amlodipine (PRR = 8.98, N = 271 cases, Chi-Squared = 1861.46), vancomycin (PRR = 8.91, N = 295 cases, Chi-Squared = 1998.64), and ceftriaxone (PRR = 8.00, N = 251 cases, Chi-Squared = 1494.02). According to drug labels, 9 drugs (9/30) were classified as potential nephrotoxins.

Conclusions: Approximately one-third of drugs associated with kidney injury in children do not list kidney injury as a side effect in their drug labels. Future studies are therefore warranted to evaluate whether these drugs are associated with such a risk.

What is Known:

• Nephrotoxic drugs are an increasingly common cause of acute kidney injury in hospitalized children.

• Currently, no study has systematically combed drugs associated with kidney injury in children.

What is New:

• Approximately a third of drugs showing signals for potential kidney injury in children in data mining do not mention this side effect in their drug labels.

• This study provides data on drugs needing further study to determine whether they might increase the risk of kidney injury in children.

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Data availability

The datasets used and analyzed during this study are available from the corresponding authors on reasonable request.

Abbreviations

AKI:

Acute kidney injury

FAERS:

FDA Adverse Event Reporting System

PRR:

Proportional reporting ratio

ATC:

Anatomical Therapeutic Chemical

MedDRA:

Medical Dictionary for Regulatory Activities

SMQ:

Standardized MedDRA query

References

  1. Ronco C, Bellomo R, Kellum JA (2019) Acute kidney injury. Lancet 394(10212):1949–1964. https://doi.org/10.1016/S0140-6736(19)32563-2

    Article  CAS  PubMed  Google Scholar 

  2. Bellomo R, Kellum JA, Ronco C (2012) Acute kidney injury. Lancet 380(9843):756–766. https://doi.org/10.1016/S0140-6736(11)61454-2

    Article  PubMed  Google Scholar 

  3. Naughton CA (2008) Drug-induced nephrotoxicity. Am Fam Physician 78(6):743–750

    PubMed  Google Scholar 

  4. Uchino S, Kellum JA, Bellomo R et al (2005) Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 294(7):813–818. https://doi.org/10.1001/jama.294.7.813

    Article  CAS  PubMed  Google Scholar 

  5. Faught LN, Greff MJ, Rieder MJ, Koren G (2015) Drug-induced acute kidney injury in children. Br J Clin Pharmacol 80(4):901–909. https://doi.org/10.1016/j.jpeds.2012.11.069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chen N, Aleksa K, Woodland C, Rieder M, Koren G (2006) Ontogeny of drug elimination by the human kidney. Pediatr Nephrol 21(2):160–168. https://doi.org/10.1007/s00467-005-2105-4

    Article  PubMed  Google Scholar 

  7. Bentley ML, Corwin HL, Dasta J (2010) Drug-induced acute kidney injury in the critically ill adult: recognition and prevention strategies. Crit Care Med 38(6 Suppl):S169–S174. https://doi.org/10.1097/CCM.0b013e3181de0c60

    Article  CAS  PubMed  Google Scholar 

  8. Patzer L (2008) Nephrotoxicity as a cause of acute kidney injury in children. Pediatr Nephrol 23(12):2159–2173. https://doi.org/10.1007/s00467-007-0721-x

    Article  PubMed  PubMed Central  Google Scholar 

  9. Chan JC, Williams DM, Roth KS (2002) Kidney failure in infants and children. Pediatr Rev 23(2):47–60. https://doi.org/10.1542/pir.23-2-47

    Article  PubMed  Google Scholar 

  10. Askenazi DJ, Griffin R, McGwin G, Carlo W, Ambalavanan N (2009) Acute kidney injury is independently associated with mortality in very low birthweight infants: a matched case-control analysis. Pediatr Nephrol 24(5):991–997. https://doi.org/10.1007/s00467-009-1133-x

    Article  PubMed  Google Scholar 

  11. Andreoli SP (2009) Acute kidney injury in children. Pediatr Nephrol 24(2):253–263. https://doi.org/10.1007/s00467-008-1074-9

    Article  PubMed  PubMed Central  Google Scholar 

  12. Hui-Stickle S, Brewer ED, Goldstein SL (2005) Pediatric ARF epidemiology at a tertiary care center from 1999 to 2001. Am J Kidney Dis 45(1):96–101. https://doi.org/10.1053/j.ajkd.2004.09.028

    Article  PubMed  Google Scholar 

  13. Harambat J, van Stralen KJ, Kim JJ, Tizard EJ (2012) Epidemiology of chronic kidney disease in children. Pediatr Nephrol 27(3):363–373. https://doi.org/10.1007/s00467-011-1939-1

    Article  PubMed  Google Scholar 

  14. Warady BA, Chadha V (2007) Chronic kidney disease in children: the global perspective. Pediatr Nephrol 22(12):1999–2009. https://doi.org/10.1007/s00467-006-0410-1

    Article  PubMed  PubMed Central  Google Scholar 

  15. Mehta RL, Awdishu L, Davenport A et al (2015) Phenotype standardization for drug-induced kidney disease. Kidney Int 88(2):226–234. https://doi.org/10.1038/ki.2015.115

    Article  PubMed  PubMed Central  Google Scholar 

  16. Tiong HY, Huang P, Xiong S, Li Y, Vathsala A, Zink D (2014) Drug-induced nephrotoxicity: clinical impact and preclinical in vitro models. Mol Pharm 11(7):1933–1948. https://doi.org/10.1021/mp400720w

    Article  CAS  PubMed  Google Scholar 

  17. Misurac JM, Knoderer CA, Leiser JD, Nailescu C, Wilson AC, Andreoli SP (2013) Nonsteroidal anti-inflammatory drugs are an important cause of acute kidney injury in children. J Pediatr. 162(6):1153–9, 1159.e1. https://doi.org/10.1016/j.jpeds.2012.11.069

  18. Nolin TD, Himmelfarb J (2010) Mechanisms of drug-induced nephrotoxicity. Handb Exp Pharmacol 196:111–130. https://doi.org/10.1007/978-3-642-00663-0_5

    Article  CAS  Google Scholar 

  19. Singh NP, Ganguli A, Prakash A (2003) Drug-induced kidney diseases. J Assoc Physicians India 51:970–979

    CAS  PubMed  Google Scholar 

  20. Subeesh V, Maheswari E, Singh H, Beulah TE, Swaroop AM (2019) Novel Adverse Events of Iloperidone: A Disproportionality Analysis in US Food and Drug Administration Adverse Event Reporting System (FAERS) Database. Curr Drug Saf 14(1):21–26. https://doi.org/10.2174/1574886313666181026100000

    Article  CAS  PubMed  Google Scholar 

  21. U.S. Food and Drug Administration (2018) FDA Adverse Event Reporting System (FAERS) Quarterly Data Extract Files. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-adverse-event-reporting-system-faers. Accessed 20 Sept 2022

  22. Shen J, Yang J, Zhao B (2019) A Survey of the FDA’s Adverse Event Reporting System Database Concerning Urogenital Tract Infections and Sodium Glucose Cotransporter-2 Inhibitor Use. Diabetes Ther 10(3):1043–1050. https://doi.org/10.1007/s13300-019-0611-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. U.S. Food and Drug Administration (2018) Data Mining at FDA: White Paper. https://www.fda.gov/science-research/data-mining/data-mining-FDA-white-paper. Accessed 18 Oct 2022

  24. Duggirala HJ, Tonning JM, Smith E et al (2016) Use of data mining at the Food and Drug Administration. J Am Med Inform Assoc 23(2):428–434. https://doi.org/10.1093/jamia/ocv063

    Article  PubMed  Google Scholar 

  25. Böhm R, Bulin C, Waetzig V, Cascorbi I, Klein HJ, Herdegen T (2021) Pharmacovigilance-based drug repurposing: The search for inverse signals via OpenVigil identifies putative drugs against viral respiratory infections. Br J Clin Pharmacol 87(11):4421–4431. https://doi.org/10.1111/bcp.14868

    Article  CAS  PubMed  Google Scholar 

  26. Böhm R, Höcker J, Cascorbi I, Herdegen T (2012) OpenVigil–free eyeballs on AERS pharmacovigilance data. Nat Biotechnol 30(2):137–138. https://doi.org/10.1038/nbt.2113

    Article  CAS  PubMed  Google Scholar 

  27. Medical Dictionary for Regulatory Activities (2022) Introductory Guide MedDRA Version 25.1. https://admin.meddra.org/sites/default/files/guidance/file/intguide_25_1_English.pdf. Accessed 12 Oct 2022

  28. Lopez MJ, Tadi P (2022) Drug Labeling. In: StatPearls. StatPearls Publishing, Treasure Island (FL). https://www.ncbi.nlm.nih.gov/books/NBK557743/

  29. Khadem TM, van Manen RP, Brown J (2014) How safe are recently FDA-approved antimicrobials? A review of the FDA adverse event reporting system database. Pharmacotherapy 34(12):1324–1329. https://doi.org/10.1002/phar.1519

    Article  PubMed  Google Scholar 

  30. Khouri C, Hlavaty A, Roustit M et al (2021) Investigating the association between ALK receptor tyrosine kinase inhibitors and pulmonary arterial hypertension: a disproportionality analysis from the WHO pharmacovigilance database. Eur Respir J. 58(6)2101576. https://doi.org/10.1183/13993003.01576-2021

  31. Duron D, Blaise S, Cracowski JL, Roustit M, Khouri C (2021) Drug-induced skin ulcers: A disproportionality analysis from the WHO pharmacovigilance database. J Am Acad Dermatol 85(1):229–232. https://doi.org/10.1016/j.jaad.2020.08.013

    Article  PubMed  Google Scholar 

  32. Caster O, Aoki Y, Gattepaille LM, Grundmark B (2020) Disproportionality Analysis for Pharmacovigilance Signal Detection in Small Databases or Subsets: Recommendations for Limiting False-Positive Associations. Drug Saf 43(5):479–487. https://doi.org/10.1007/s40264-020-00911-w

    Article  PubMed  PubMed Central  Google Scholar 

  33. Evans SJ, Waller PC, Davis S (2001) Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf 10(6):483–486. https://doi.org/10.1002/pds.677

    Article  CAS  PubMed  Google Scholar 

  34. Hoste EA, Bagshaw SM, Bellomo R et al (2015) Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med 41(8):1411–1423. https://doi.org/10.1007/s00134-015-3934-7

    Article  PubMed  Google Scholar 

  35. Mehta RL, Pascual MT, Soroko S et al (2004) Spectrum of acute renal failure in the intensive care unit: the PICARD experience. Kidney Int 66(4):1613–1621. https://doi.org/10.1111/j.1523-1755.2004.00927.x

    Article  PubMed  Google Scholar 

  36. Perazella MA (2012) Drug use and nephrotoxicity in the intensive care unit. Kidney Int 81(12):1172–1178. https://doi.org/10.1038/ki.2010.475

    Article  CAS  PubMed  Google Scholar 

  37. Hosohata K, Inada A, Oyama S, Furushima D, Yamada H, Iwanaga K (2019) Surveillance of drugs that most frequently induce acute kidney injury: A pharmacovigilance approach. J Clin Pharm Ther 44(1):49–53. https://doi.org/10.1111/jcpt.12748

    Article  CAS  PubMed  Google Scholar 

  38. Zappitelli M, Moffett BS, Hyder A, Goldstein SL (2011) Acute kidney injury in non-critically ill children treated with aminoglycoside antibiotics in a tertiary healthcare centre: a retrospective cohort study. Nephrol Dial Transplant 26(1):144–150. https://doi.org/10.1093/ndt/gfq375

    Article  PubMed  Google Scholar 

  39. Morales AI, Detaille D, Prieto M et al (2010) Metformin prevents experimental gentamicin-induced nephropathy by a mitochondria-dependent pathway. Kidney Int 77(10):861–869. https://doi.org/10.1038/ki.2010.11

    Article  CAS  PubMed  Google Scholar 

  40. Perazella MA (2009) Renal vulnerability to drug toxicity. Clin J Am Soc Nephrol 4(7):1275–1283. https://doi.org/10.2215/CJN.02050309

    Article  CAS  PubMed  Google Scholar 

  41. Douglass EC, Reynolds M, Finegold M, Cantor AB, Glicksman A (1993) Cisplatin, vincristine, and fluorouracil therapy for hepatoblastoma: a Pediatric Oncology Group study. J Clin Oncol 11(1):96–99. https://doi.org/10.1200/JCO.1993.11.1.96

    Article  CAS  PubMed  Google Scholar 

  42. Pritchard J, Brown J, Shafford E et al (2000) Cisplatin, doxorubicin, and delayed surgery for childhood hepatoblastoma: a successful approach-results of the first prospective study of the International Society of Pediatric Oncology. J Clin Oncol 18(22):3819–3828. https://doi.org/10.1200/JCO.2000.18.22.3819

    Article  CAS  PubMed  Google Scholar 

  43. Pabla N, Dong Z (2008) Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int 73(9):994–1007. https://doi.org/10.1038/sj.ki.5002786

    Article  CAS  PubMed  Google Scholar 

  44. Arany I, Safirstein RL (2003) Cisplatin nephrotoxicity. Semin Nephrol 23(5):460–464. https://doi.org/10.1016/s0270-9295(03)00089-5

    Article  CAS  PubMed  Google Scholar 

  45. Li J, Khot A, Burbury K (2012) Acute kidney injury requiring dialysis following carmustine and etoposide during autologous stem cell transplantation. Chemotherapy 58(5):349–351. https://doi.org/10.1159/000343661

    Article  CAS  PubMed  Google Scholar 

  46. Cordero C, Loboda C, Clerc-Urmès I, Clément L, Pochon C, Chastagner P (2017) Unexpected acute renal injury after high-dose etoposide phosphate and total body irradiation in children undergoing hematopoietic stem cell transplantation. Pediatr Blood Cancer 64(12). https://doi.org/10.1002/pbc.26669

  47. Bell S, Farran B, McGurnaghan S et al (2017) Risk of acute kidney injury and survival in patients treated with Metformin: an observational cohort study. BMC Nephrol 18(1):163. https://doi.org/10.1186/s12882-017-0579-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Naha K, Suryanarayana J, Aziz RA, Shastry BA (2014) Amlodipine poisoning revisited: Acidosis, acute kidney injury and acute respiratory distress syndrome. Indian J Crit Care Med 18(7):467–469. https://doi.org/10.4103/0972-5229.136078

    Article  PubMed  PubMed Central  Google Scholar 

  49. Sakaeda T, Tamon A, Kadoyama K, Okuno Y (2013) Data mining of the public version of the FDA Adverse Event Reporting System. Int J Med Sci 10(7):796–803. https://doi.org/10.7150/ijms.6048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation for Young Scholars of China (72004151).

Author information

Authors and Affiliations

  1. Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, China

    Miao Zhang, Hailong Li, Liang Huang, Yan Liu, Xue-Feng Jiao, Linan Zeng, Zhi-Jun Jia & Wei Zhang

  2. Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, China

    Miao Zhang, Hailong Li, Liang Huang, Yan Liu, Xue-Feng Jiao, Linan Zeng, Zhi-Jun Jia & Wei Zhang

  3. NMPA Key Laboratory for Technical Research On Drug Products In Vitro and In Vivo Correlation, Chengdu, China

    Miao Zhang, Hailong Li, Liang Huang, Yan Liu, Xue-Feng Jiao, Linan Zeng, Zhi-Jun Jia & Wei Zhang

  4. Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, China

    Miao Zhang, Hailong Li, Liang Huang, Yan Liu, Xue-Feng Jiao, Linan Zeng, Zhi-Jun Jia, Guo Cheng & Wei Zhang

  5. West China School of Pharmacy, Sichuan University, Chengdu, China

    Miao Zhang, Yan Liu & Zhi-Jun Jia

  6. Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China

    Guo Cheng

  7. Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Sichuan University, Chengdu, China

    Guo Cheng

  8. West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China

    Lingli Zhang

  9. Medical Big Data Center, Sichuan University, Chengdu, China

    Lingli Zhang

  10. Chinese Evidence-Based Medicine Center, West China Hospital, Sichuan University, Chengdu, China

    Wei Zhang

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  1. Miao Zhang
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  2. Hailong Li
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  9. Lingli Zhang
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  10. Wei Zhang
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Contributions

HL, WZ, and LL Z designed the study; MZ and LH performed the data analysis; MZ, HL, WZ, and LL Z managed and checked all the data. All authors contributed equally to the results interpretation and manuscript writing. All authors read, checked, and approved the final manuscript.

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Correspondence to Lingli Zhang or Wei Zhang.

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Zhang, M., Li, H., Huang, L. et al. Drug-associated kidney injury in children: a disproportionality analysis of the FDA Adverse Event Reporting System. Eur J Pediatr 182, 4655–4661 (2023). https://doi.org/10.1007/s00431-023-05146-2

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