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other·nephrology, oncology, pediatrics, preclinical research, animal science·PMC10542898

Early clinical indicators of acute kidney injury caused by administering high-dose methotrexate therapy to juvenile pigs

Frontiers in Nephrology · 6 authors, 6 centres

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TL;DR

During the first 28 hours, 81% of pigs had at least one serum creatinine increase greater than 0.3 g/dL indicative of AKI.

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During the first 28 hours, 81% of pigs had at least one serum creatinine increase greater than 0.3 g/dL indicative of AKI. A plasma MTX clearance rate of less than 90% during the initial 4 hours after infusion and serum creatinine increases greater than 0.3 g/dL at 6 and 8 hours predicted AKI at 28 hours (p < 0.05 and p < 0.001, respectively). At infusion conclusion, a creatinine rise above 0.3 g/dL or serum MTX greater than 5,000 μmol/L identified increased risk of severe AKI. The high incidence of AKI in this model exceeds the 2%–12% reported in patients.

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other

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nephrology

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AI pipeline

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ORIGINAL PAPER

PMC10542898

Early clinical indicators of acute kidney injury caused by administering high-dose methotrexate therapy to juvenile pigs

Frontiers in Nephrology

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ABSTRACT

Abstract Introduction Early identification of compromised renal clearance caused by high-dose methotrexate (HDMTX) is essential for initiating timely interventions that can reduce acute kidney injury and MTX-induced systemic toxicity. Methods We induced acute kidney injury (AKI) by infusing 42 juvenile pigs with 4 g/kg (80 g/m2) of MTX over 4 hours without high-volume alkalinizing hydration therapy. Concentrations of serum creatinine and MTX were measured at 15 time points up to 148 hours, with 10 samples collected during the first 24 hours after the start of the HDMTX infusion. Results During the first 28 hours, 81% of the pigs had increases in the concentrations of serum creatinine in one or more samples indicative of AKI (i.e., > 0.3g/dL increase). A rate of plasma MTX clearance of less than 90% during the initial 4 hours after the HDMTX infusion and a total serum creatinine increase at 6 and 8 hours after starting the infusion greater than 0.3 g/dL were predictive of AKI at 28 hours ( p < 0.05 and p < 0.001, respectively). At conclusion of the infusion, pigs with a creatinine concentration more than 0.3 g/dL higher than baseline or serum MTX greater than 5,000 μmol/L had an increased risk of severe AKI. Conclusions Our findings suggest that serum samples collected at conclusion and shortly after HDMTX infusion can be used to predict impending AKI. The pig model can be used to identify biological, environmental, and iatrogenic risk factors for HDMTX-induced AKI and to evaluate interventions to preserve renal functions, minimize acute kidney injury, and reduce systemic toxicity. Keywords: methotrexate, creatinine, acute kidney injury, chemotherapy, pig, animal model, clearance

CITATION EXPORT

Randal K Buddington, Thomas Wong, Karyl K Buddington et al.. Early clinical indicators of acute kidney injury caused by administering high-dose methotrexate therapy to juvenile pigs. Frontiers in Nephrology. (2023). https://doi.org/10.3389/fneph.2023.1193494

AUTHORS

6 · 6 CENTRES

Randal K Buddington, Thomas Wong, Karyl K Buddington, Torben S Mikkelsen, Xueyuan Cao, Scott C Howard

1 College of Health Sciences, University of Memphis, Memphis, TN, United States
2 Division of Endocrinology, University of Tennessee Health Sciences Center (UTHSC), Memphis, TN, United States
3 Department of Biological Sciences, University of Memphis, Memphis, TN, United States
4 Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
5 College of Nursing, Resonance, Memphis, TN, United States
6 Department of Health Promotion and Disease Prevention, University of Tennessee Health Science Center, Memphis, TN, United States