Shiau Justin, Engel Patti, Olsen Mark, Pais Gwendolyn, Chang Jack, Scheetz Marc H
Department of Pharmacy Practice, College of Pharmacy, Midwestern University, Downers Grove, Illinois, USA.
Department of Pharmacy, Northwestern Memorial Hospital, Chicago, Illinois, USA.
Antimicrob Agents Chemother. 2025 Feb 13;69(2):e0123624. doi: 10.1128/aac.01236-24. Epub 2025 Jan 17.
Vancomycin causes kidney injury by accumulating in the proximal tubule, likely mediated by megalin uptake. Protamine is a putative megalin inhibitor that shares binding sites with heparin and is approved for the treatment of heparin overdose. We employed a well-characterized Sprague-Dawley rat model to assess kidney injury and function in animals that received vancomycin, protamine alone, or vancomycin plus protamine over 5 days. Urinary KIM-1 was used as the primary measure for kidney injury, while plasma iohexol clearance was calculated to assess kidney function. Animals had samples drawn pre-treatment in order to serve as their own controls. Additionally, since protamine is not a known nephrotoxin, the protamine group also served as a control. Cellular inhibition studies were performed to assess the ability of protamine to inhibit organic anion transporter (OAT1 and OAT3) and organic cation transporter-2 (OCT2). Rats that received vancomycin alone had significantly increased urinary KIM-1 on day 2 (24.9 ng/24 h, 95% CI 1.87-48.0) compared to the protamine alone group. By day 4, animals that received protamine with their vancomycin had KIM-1 amounts that were elevated compared to protamine alone as a base comparison (KIM-1 29.0 ng/24 h, 95% CI 5.0-53.0). No statistically observed differences were identified for iohexol clearance changes between drug groups or when comparing clearance change from baseline ( > 0.05). No substantial inhibition of OAT1, OAT3, or OCT2 was observed with protamine. IC values for protamine were 0.1 mM for OAT1 and OAT3 and 0.043 mM for OCT2. Protamine, when added to vancomycin therapy, delays vancomycin-induced kidney injury as defined by urinary KIM-1 in the rat model by 1-3 days. Protamine putatively acts through the blockade of megalin and does not appear to have significant inhibition on OAT1, OAT3, or OCT2. Since protamine is an approved FDA medication, it has clinical potential as a therapeutic to reduce vancomycin-related kidney injury; however, greater utility may be found by pursuing compounds with fewer adverse event liabilities.
万古霉素通过在近端小管中蓄积导致肾损伤，这可能是由巨膜蛋白摄取介导的。鱼精蛋白是一种公认的巨膜蛋白抑制剂，它与肝素共享结合位点，已被批准用于治疗肝素过量。我们采用了一种特征明确的Sprague-Dawley大鼠模型，以评估在5天内接受万古霉素、单独使用鱼精蛋白或万古霉素加鱼精蛋白的动物的肾损伤和功能。尿KIM-1用作肾损伤的主要测量指标，同时计算血浆碘海醇清除率以评估肾功能。动物在治疗前采集样本以作为自身对照。此外，由于鱼精蛋白不是已知的肾毒素，鱼精蛋白组也用作对照。进行细胞抑制研究以评估鱼精蛋白抑制有机阴离子转运体（OAT1和OAT3）和有机阳离子转运体-2（OCT2）的能力。与单独使用鱼精蛋白组相比，单独接受万古霉素的大鼠在第2天尿KIM-1显著增加（24.9 ng/24 h，95% CI 1.87-48.0）。到第4天，与单独使用鱼精蛋白作为基础对照相比，接受万古霉素加鱼精蛋白的动物的KIM-1量有所升高（KIM-1 29.0 ng/24 h，95% CI 5.0-53.0）。在药物组之间或比较与基线的清除率变化时，未观察到碘海醇清除率变化有统计学差异（>0.05）。未观察到鱼精蛋白对OAT1、OAT3或OCT2有实质性抑制作用。鱼精蛋白对OAT1和OAT3的IC值为0.1 mM，对OCT2的IC值为0.043 mM。在大鼠模型中，当鱼精蛋白添加到万古霉素治疗中时，由尿KIM-1定义的万古霉素诱导的肾损伤延迟1至3天。鱼精蛋白可能通过阻断巨膜蛋白起作用，并且似乎对OAT1、OAT3或OCT2没有显著抑制作用。由于鱼精蛋白是一种已获美国食品药品监督管理局批准的药物，它具有作为减少万古霉素相关肾损伤的治疗药物的临床潜力；然而，通过研究具有较少不良事件风险的化合物可能会发现更大的效用。
