Mohamed Fahim, Endre Zoltan H, Pickering John W, Jayamanne Shaluka, Palangasinghe Chathura, Shahmy Seyed, Chathuranga Umesh, Wijerathna Thilini, Shihana Fathima, Gawarammana Indika, Buckley Nicholas A
South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka; Department of Pharmacy, Faculty of Allied Health Sciences, University of Peradeniya, Sri Lanka; Department of Nephrology, Prince Of Wales Hospital and Clinical School, University of New South Wales, Sydney, Australia; TACT Research Group, Department of Pharmacology, SOMS, Sydney Medical School, University of Sydney, NSW, Australia.
Department of Nephrology, Prince Of Wales Hospital and Clinical School, University of New South Wales, Sydney, Australia; Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand.
Toxicol Lett. 2016 Sep 6;258:1-10. doi: 10.1016/j.toxlet.2016.06.001. Epub 2016 Jun 7.
Acute kidney injury (AKI) is common following glyphosate surfactant herbicide (GPSH) self-poisoning. Serum creatinine (sCr) is the most widely used renal biomarker for diagnosis of AKI although a recent study in rats suggested that urinary kidney injury molecule-1 predicted AKI earlier and better after GPSH-induced nephrotoxicity. We explored the utility of a panel of biomarkers to diagnose GPSH-induced nephrotoxicity in humans. In a prospective multi-centre observational study, serial urine and blood samples were collected until discharge and at follow-up. The diagnostic performance of each biomarker at various time points was assessed. AKI was diagnosed using the Acute Kidney Injury Network (AKIN) definitions. The added value of each biomarker to sCr to diagnose AKI was assessed by the integrated discrimination improvement (IDI) metric. Of 90 symptomatic patients, 51% developed AKI and 5 patients who developed AKIN≥2 died. Increased sCr at 8 and 16h predicted moderate to severe AKI and death. None of the 10 urinary biomarkers tested increased above normal range in patients who did not develop AKI or had mild AKI (AKIN1); most of these patients also had only minor clinical toxicity. Absolute concentrations of serum and urinary cystatin C, urinary interleukin-18 (IL-18), Cytochrome C (CytoC) and NGAL increased many fold within 8h in patients who developed AKIN≥2. Maximum 8 and 16h concentrations of these biomarkers showed an excellent diagnostic performance (AUC-ROC ≥0.8) to diagnose AKIN≥2. However, of these biomarkers only uCytoC added value to sCr to diagnose AKI when assessed by IDI metrics. GPSH-induced nephrotoxicity can be diagnosed within 24h by sCr. Increases in uCytoC and uIL-18 confirm GPSH-induces apoptosis and causes mitochondrial toxicity. Use of these biomarkers may help to identify mechanism specific targeted therapies for GPSH nephrotoxicity in clinical trials.
急性肾损伤（AKI）在草甘膦表面活性剂除草剂（GPSH）自服中毒后很常见。血清肌酐（sCr）是诊断AKI最广泛使用的肾脏生物标志物，尽管最近一项在大鼠中的研究表明，尿肾损伤分子-1在GPSH诱导的肾毒性后能更早且更好地预测AKI。我们探讨了一组生物标志物在诊断人类GPSH诱导的肾毒性中的效用。在一项前瞻性多中心观察性研究中，连续收集尿液和血液样本直至出院及随访。评估了每个生物标志物在不同时间点的诊断性能。使用急性肾损伤网络（AKIN）定义诊断AKI。通过综合判别改善（IDI）指标评估每个生物标志物对sCr诊断AKI的附加值。在90例有症状的患者中，51%发生了AKI，5例发生AKIN≥2的患者死亡。8小时和16小时时sCr升高预测了中度至重度AKI和死亡。在未发生AKI或仅有轻度AKI（AKIN1）的患者中，所检测的10种尿生物标志物均未升高至正常范围以上；这些患者大多数也仅有轻微的临床毒性。发生AKIN≥2的患者血清和尿胱抑素C、尿白细胞介素-18（IL - 18）、细胞色素C（CytoC）和中性粒细胞明胶酶相关脂质运载蛋白（NGAL）的绝对浓度在8小时内增加了许多倍。这些生物标志物的最大8小时和16小时浓度在诊断AKIN≥2时显示出优异的诊断性能（AUC-ROC≥0.8）。然而，在这些生物标志物中，当通过IDI指标评估时，只有尿细胞色素C对sCr诊断AKI有附加值。GPSH诱导的肾毒性可在24小时内通过sCr诊断。尿细胞色素C和尿IL - 18的升高证实了GPSH诱导细胞凋亡并导致线粒体毒性。在临床试验中使用这些生物标志物可能有助于识别针对GPSH肾毒性的机制特异性靶向治疗方法。
