Buddington Randal K, Wong Thomas, Buddington Karyl K, Mikkelsen Torben S, Cao Xueyuan, Howard Scott C
College of Health Sciences, University of Memphis, Memphis, TN, United States.
Division of Endocrinology, University of Tennessee Health Sciences Center (UTHSC), Memphis, TN, United States.
Front Nephrol. 2023 Sep 12;3:1193494. doi: 10.3389/fneph.2023.1193494. eCollection 2023.
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.
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.
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 ( < 0.05 and < 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.
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.
早期识别由大剂量甲氨蝶呤（HDMTX）引起的肾脏清除功能受损，对于及时采取干预措施以减少急性肾损伤和MTX诱导的全身毒性至关重要。
我们在4小时内给42只幼年猪输注4 g/kg（80 g/m²）的MTX以诱导急性肾损伤（AKI），且未进行大量碱化水化治疗。在长达148小时的15个时间点测量血清肌酐和MTX浓度，在HDMTX输注开始后的前24小时内采集10份样本。
在最初的28小时内，81%的猪在一个或多个样本中血清肌酐浓度升高，表明存在AKI（即升高>0.3g/dL）。HDMTX输注后最初4小时内血浆MTX清除率低于90%，以及输注开始后6小时和8小时血清肌酐总升高大于0.3 g/dL，可预测28小时时的AKI（分别为<0.05和<0.001）。输注结束时，肌酐浓度比基线高0.3 g/dL以上或血清MTX大于5000 μmol/L的猪发生严重AKI的风险增加。
我们的研究结果表明，在HDMTX输注结束时和结束后不久采集的血清样本可用于预测即将发生的AKI。猪模型可用于识别HDMTX诱导的AKI的生物学、环境和医源性危险因素，并评估保护肾功能、尽量减少急性肾损伤和降低全身毒性的干预措施。
