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Acute kidney injury during cisplatin therapy and associations with kidney outcomes 2 to 6 months post-cisplatin in children: a multi-centre, prospective observational study

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Abstract

Background

Few studies describe acute kidney injury (AKI) burden during paediatric cisplatin therapy and post-cisplatin kidney outcomes. We determined risk factors for and rate of (1) AKI during cisplatin therapy, (2) chronic kidney disease (CKD) and hypertension 2–6 months post-cisplatin, and (3) whether AKI is associated with 2–6-month outcomes.

Methods

This prospective cohort study enrolled children (aged < 18 years at cancer diagnosis) treated with cisplatin from twelve Canadian hospitals. AKI during cisplatin therapy (primary exposure) was defined based on Kidney Disease: Improving Global Outcomes (KDIGO) serum creatinine criteria (≥ stage one). Severe electrolyte abnormalities (secondary exposure) included ≥ grade three hypophosphatemia, hypokalemia, or hypomagnesemia (National Cancer Institute Common Terminology Criteria for Adverse Events v4.0). CKD was albuminuria or decreased kidney function for age (KDIGO guidelines). Hypertension was defined based on the 2017 American Academy of Pediatrics guidelines.

Results

Of 159 children (median [interquartile range [IQR]] age: 6 [2–12] years), 73/159 (46%) participants developed AKI and 55/159 (35%) experienced severe electrolyte abnormalities during cisplatin therapy. At median [IQR] 90 [76–110] days post-cisplatin, 53/119 (45%) had CKD and 18/128 (14%) developed hypertension. In multivariable analyses, AKI was not associated with 2–6-month CKD or hypertension. Severe electrolyte abnormalities during cisplatin were associated with having 2–6-month CKD or hypertension (adjusted odds ratio (AdjOR) [95% CI]: 2.65 [1.04–6.74]). Having both AKI and severe electrolyte abnormalities was associated with 2–6-month hypertension (AdjOR [95% CI]: 3.64 [1.05–12.62]).

Conclusions

Severe electrolyte abnormalities were associated with kidney outcomes. Cisplatin dose optimization to reduce toxicity and clear post-cisplatin kidney follow-up guidelines are needed.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We sincerely thank all the study participants and their families. We acknowledge the work of the following clinical research personnel for their involvement in the study: Pina Giuliano, Karen Mazil, Jessica Scheidl, Susan Talmey and Tao Wang (Alberta Children's Hospital, Calgary, Alberta, Canada); Octavia Choi, Cecilia Crosby, Jessica Davis, Fatima Dharsee, Mateo Farfan, Rohan Kakkar, Nicole Kelly, Alecia Lim, Alicia Oger, Ritu Ratan, Jennifer Sergeant and Grace Tam (British Columbia Children’s Hospital, Vancouver, British Columbia, Canada); Nancy Coreas, Megan Friesen, Rebekah Hiebert, Jodi Karwacki, Krista Mueller, Ashley Ouelette and Kiera Unger (CancerCare Manitoba, Winnipeg, Manitoba, Canada); Barbara Desbiens, Melanie Ernst, Marie-Christine Gagnon and Nadine Roy (Centre Hospitalier Universitaire de Québec—Université Laval, Quebec, Quebec, Canada); Ernestine Chablis, Bianka Courcelle, Angélique Courtade, Catherine Desjean, Marc-Antoine Nadeau, Marie Saint-Jacques, Martine Therrien and Caroline Tra (Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada); Sandra Blamires, Tianna Deluzio, Becky Malkin, Mariam Mikhail and Leslie Paddock (Children’s Hospital: London Health Sciences Centre, London, Ontario, Canada); Nathan Adolphe, Brooke Bowerman, Isabelle Laforest, Oluwatoni Adeniyi, Kelly-Ann Ramakko and Jenna-Lee Tremblay (Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada); Mandy Bouchard (IWK Health Centre, Halifax, Nova Scotia, Canada); Shawde Harris and Rachel Simpson (McMaster Children’s Hospital, Hamilton, Ontario, Canada); Anelise Espirito Santo, Jackie Girgis, Dominique Lafrenière, Martine Nagy and Sandra Pepin (Montreal Children’s Hospital, MUHC, Montreal, Quebec, Canada); Linda Churcher, Dianne Cortez, Kevin Dietrich, Brenda Ennis, Nicholas Howe, Crystal Lefebvre, Nicole Orrell and Holly Sykora (Stollery Children's Hospital, Edmonton, Alberta, Canada); Abongnwen Abianui, Rachel Alix, Beren Avci, Aparna Bhan, Eric Lee, Darshika Mistry, Niwethaa Nadesan, Nicholas Pasquale, Subitha Rajakumaran, Grace Tran, Megan Wood and Elyze Yamasaki (The Hospital for Sick Children, Toronto, Ontario, Canada). Thank you to the Epidemiology Coordinating and Research Centre team (Departments of Pharmacology and Medicine, University of Alberta, Edmonton, Canada) for data support, entry, queries and management. We would like to thank Anat Halevy, MSc (University of British Columbia, Vancouver, Canada) for the ABLE Study support. Thank you to Michael Pizzi and Olivier Pouliot (Research Institute of the MUHC team members) for their contributions. We also thank Vedran Cockovski (Hospital for Sick Children, Toronto, Canada) for his contributions. They were compensated for their time. Members of the ABLE Study Group include Sylvain Baruchel, MD (Hospital for Sick Children, Toronto, Canada), Eric Bouffet, MD (Hospital for Sick Children, Toronto, Canada), Tom Blydt-Hansen MD (British Columbia Children’s Hospital, Vancouver, Canada), Bruce C. Carleton, PharmD (BC Children’s Hospital Research Institute, Vancouver, Canada), Geoff D. E. Cuvelier, MD (CancerCare Manitoba, Winnipeg, Canada), Sunil Desai, MBChB (University of Alberta, Edmonton, Canada), Prasad Devarajan, MD (Cincinnati Children’s Hospital Medical Center, Cincinnati, USA), Conrad Fernandez, MD (IWK Health Centre, Halifax, Canada), Adam Fleming, MD (McMaster Children’s Hospital at Hamilton Health Sciences, Hamilton, Canada), Paul Gibson, MD (Children’s Hospital: London Health Sciences Centre, London, Canada), Caroline Laverdière, MD (Centre Hospitalier Universitaire Sainte-Justine, Montreal, Canada), Victor Lewis, MD (Alberta Children’s Hospital, Calgary, Canada), Cherry Mammen, MD, MHSc (British Columbia Children’s Hospital, Vancouver, Canada), Mary L. McBride, MSc (University of British Columbia, Vancouver, Canada), Bruno Michon, MD (Centre Hospitalier Universitaire de Québec—Université Laval, Quebec Canada), Lesley G. Mitchell, MSc (University of Alberta, Alberta, Canada), Maury Pinsk, MD (University of Manitoba, Winnipeg, Canada), Raveena Ramphal, MBChB (Children’s Hospital of Eastern Ontario, Ottawa, Canada), Shahrad Rod Rassekh MD, MHSc (British Columbia Children’s Hospital, Vancouver, Canada), Colin J. D. Ross, PhD (BC Children’s Hospital Research Institute, Vancouver, Canada), Christine Sabapathy, MD (MUHC, Montreal, Canada), Kirk R. Schultz, MD (British Columbia Children’s Hospital, Vancouver, Canada), Ross T. Tsuyuki PharmD MSc (University of Alberta, Edmonton, Canada), Michael Zappitelli, MD, MSc (Toronto Hospital for Sick Children, Toronto, Canada) and Alexandra Zorzi, MD (Children’s Hospital: London Health Sciences Centre, London, Canada)

Funding

This work was supported by a Team Grant from the Canadian Institutes of Health Research (CIHR) and its partners, the Canadian Cancer Society, the C17 Research Network, the Garron Family Cancer Center at the Hospital for Sick Children, and the Pediatric Oncology Group of Ontario, which was awarded to Kirk R. Schultz, Sylvain Baruchel, Mary L. McBride, Lesley G. Mitchell, S. Rod Rassekh, Ross T. Tsuyuki, and Michael Zappitelli. This work was also supported by Start-up funds from the SickKids Research Institute. A Fonds de recherche du Québec—Santé (FRQS) Doctoral Training Bursary awarded to Kelly R. McMahon also helped support this work. Colin J. Ross was supported by a Michael Smith Foundation for Health Research Scholar Award.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Division of Nephrology, Research Institute of the McGill University Health Centre, Montreal, QC, Canada

    Kelly R. McMahon, Frédérik Crépeau-Hubert & Ana Palijan

  2. Faculty of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC, Canada

    Kelly R. McMahon

  3. Department of Pediatrics, Division of Nephrology, The Hospital for Sick Children, Toronto, ON, Canada

    Asaf Lebel

  4. Pediatric Nephrology Unit, Ha’Emek Medical Center, Afula, Israel

    Asaf Lebel

  5. Department of Pediatrics, Division of Hematology/Oncology/Bone Marrow Transplantation, University of British Columbia, British Columbia Children’s Hospital, Vancouver, BC, Canada

    Shahrad Rod Rassekh & Kirk R. Schultz

  6. Department of Pediatrics, Division of Pediatric Nephrology, University of British Columbia, British Columbia Children’s Hospital, Vancouver, BC, Canada

    Tom D. Blydt-Hansen & Cherry Mammen

  7. Research Institute in Oncology and Hematology, CancerCare Manitoba, Department of Pediatrics and Child Health, Division of Pediatric Oncology-Hematology-BMT, University of Manitoba, Winnipeg, MB, Canada

    Geoffrey D. E. Cuvelier

  8. Department of Pediatrics and Child Health, Section of Pediatric Nephrology, University of Manitoba, Winnipeg, MB, Canada

    Maury Pinsk

  9. Department of Pediatrics, Division of Translational Therapeutics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada

    Bruce C. Carleton

  10. Epidemiology Coordinating and Research Centre, Departments of Pharmacology and Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada

    Ross T. Tsuyuki & Debbie Boyko

  11. Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada

    Colin J. D. Ross

  12. Faculty of Health Sciences, Queen’s University, Kingston, ON, Canada

    Louis Huynh

  13. Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada

    Mariya Yordanova

  14. Child Health Evaluative Sciences, Peter Gilgan Centre For Research and Learning, Room 11th floor, 11.9722, 686 Bay Street, Toronto, ON, M5G 0A4, Canada

    Stella Wang, Jasmine Lee & Michael Zappitelli

  15. Department of Pediatrics, Division of Nephrology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

    Michael Zappitelli

  16. Department of Pediatrics, Division of Pediatric Nephrology, Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada

    Michael Zappitelli

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  1. Kelly R. McMahon
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  2. Asaf Lebel
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  3. Shahrad Rod Rassekh
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  4. Kirk R. Schultz
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  5. Tom D. Blydt-Hansen
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  6. Geoffrey D. E. Cuvelier
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  7. Cherry Mammen
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  8. Maury Pinsk
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  9. Bruce C. Carleton
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  10. Ross T. Tsuyuki
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  11. Colin J. D. Ross
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  12. Louis Huynh
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  13. Mariya Yordanova
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  14. Frédérik Crépeau-Hubert
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  15. Stella Wang
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  16. Ana Palijan
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  17. Jasmine Lee
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  18. Debbie Boyko
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  19. Michael Zappitelli
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Consortia

for the Applying Biomarkers to Minimize Long-Term Effects of Childhood/Adolescent Cancer Treatment (ABLE) Research Study Group

Contributions

Conceptualization: McMahon, Lebel, Rassekh, Schultz, Blydt-Hansen, Cuvelier, Mammen, Pinsk, Tsuyuki, Ross, Palijan, Zappitelli; Data curation: McMahon, Lebel, Rassekh, Blydt-Hansen, Cuvelier, Mammen, Pinsk, Carleton, Tsuyuki, Huynh, Yordanova, Crépeau-Hubert, Wang, Boyko Zappitelli; Formal analysis: McMahon, Wang, Zappitelli; Funding acquisition: McMahon, Rassekh, Schultz, Blydt-Hansen, Cuvelier, Tsuyuki, Ross, Zappitelli; Investigation: McMahon, Rassekh, Schultz, Blydt-Hansen, Cuvelier, Mammen, Pinsk, Zappitelli; Methodology: McMahon, Lebel, Rassekh, Blydt-Hansen, Mammen, Pinsk, Carleton, Tsuyuki, Huynh, Yordanova, Crépeau-Hubert, Palijan, Boyko, Zappitelli; Project administration: McMahon, Rassekh, Schultz, Cuvelier, Tsuyuki, Ross, Huynh, Yordanova, Crépeau-Hubert, Palijan, Lee, Boyko, Zappitelli; Resources: McMahon, Rassekh, Schultz, Tsuyuki, Palijan, Boyko, Zappitelli; Software: Tsuyuki, Boyko, Zappitelli; Supervision: McMahon, Lebel, Rassekh, Schultz, Cuvelier, Tsuyuki, Palijan, Zappitelli; Writing-original draft: McMahon, Zappitelli; Writing-review and editing: All authors.

Corresponding author

Correspondence to Michael Zappitelli.

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The authors declare no competing interests.

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Supplementary Information

Below is the link to the electronic supplementary material.

Graphical Abstract (PPTX 74 KB)

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Supplementary file2 Study Procedure Detailing Sample and Data Collection and Study Measurements.Legend: A: Description of cancer treatment flow and study time points from Baseline (pre-cisplatin) to the 2–6-Month Study Visit. B: Description of data collection and study procedures at the various study time points (Baseline; Early Cisplatin Visit; Late Cisplatin Visit; During cisplatin treatment; Between cisplatin end and the 2–6-Month Study Visit; at the 2–6-Month Study Visit). The figure is not shown to scale time-wise horizontally. Abbreviations: GFR: Glomerular Filtration Rate; BP: Blood pressure; PICU: Pediatric Intensive Care Unit. (PDF 118 KB)

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Supplementary file3 Definition of eAKI and Electrolyte Abnormalities and Need for Supplementation at 2–6 Months Adapted from the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 [26]. (PDF 104 KB)

Supplementary file4 Cancer Treatment Protocols by Cancer Type. (PDF 118 KB)

Supplementary file5 Details on Drugs and Treatments Included in Cancer Treatment Protocols.a. (PDF 106 KB)

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Supplementary file6 Blood and Urine Collection Success and Analyte and Clinical Measurements Obtained at the 2–6-Month Study Visit.a (PDF 99 KB)

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Supplementary file7 Data Collection Success Rate and Missing Data Rate from Baseline to 2–6-Month Study Visit. (PDF 166 KB)

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Supplementary file8 Characteristics at Baseline, During Cisplatin Treatment and Between Cisplatin End and the 2–6-Month Post-Cisplatin Visit in Study Participants with versus without 2–6-Month Kidney Outcome Data. (PDF 124 KB)

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Supplementary file9 Change in Estimated GFR From Baseline to End of Cisplatin Therapy to 2–6 Months Post-Cisplatin Therapy End. (PDF 120 KB)

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Supplementary file10 Details on Drugs and Treatments Stratified by CKD and HTN Status at the 2–6-Month Study Visit. (PDF 129 KB)

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Supplementary file11 Characteristics of Study Participants by CKD or HTN Status at the 2–6-Month Study Visit. (PDF 128 KB)

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Supplementary file12 Baseline Measured or Estimated GFR of Study Participants by SCr-AKI During Cisplatin Therapy Status (Excluding 24 Hour Creatinine Clearance). (PDF 89 KB)

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Supplementary file13 AKI Rates and Types During Cisplatin Therapy and Univariable Associations with 3-Month Outcomes Using the Stricter Time Window (56–112 Days Post-Cisplatin). (PDF 129 KB)

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Supplementary file14 AKI Rates and Types During Cisplatin Therapy and Univariable Associations with 2–6-Month Outcomes With Participants With an Indeterminable Outcome Status Considered As Not Having the Outcome. (PDF 125 KB)

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Supplementary file15 AKI Rates and Types During Cisplatin Therapy and Univariable Associations with Low Estimated GFR for Age at 2–6 Months. (PDF 114 KB)

Supplementary file16 AKI Rate in Patients who were Cisplatin Naïve Versus Not Upon Enrollment. (PDF 102 KB)

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McMahon, K.R., Lebel, A., Rassekh, S.R. et al. Acute kidney injury during cisplatin therapy and associations with kidney outcomes 2 to 6 months post-cisplatin in children: a multi-centre, prospective observational study. Pediatr Nephrol 38, 1667–1685 (2023). https://doi.org/10.1007/s00467-022-05745-5

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