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IntroductionCisplatin is a widely used chemotherapeutic agent prescribed to treat solid tumors. However, its clinical application is limited because of cisplatin- induced nephrotoxicity. A known complication of cisplatin is acute kidney injury (AKI). Deletion polymorphisms of GSTM1 and GSTT1, members of the glutathione S-transferase family, are common in humans and are presumed to be associated with various kidney diseases. However, the specific roles and mechanisms of GSTM1 and GSTT1 in cisplatin induced AKI remain unclear.MethodsTo investigate the roles of GSTM1 and GSTT1 in cisplatin-induced AKI, we generated GSTM1 and GSTT1 knockout mice using CRISPR-Cas9 technology and assessed their kidney function under normal physiological conditions and cisplatin treatment. Using ELISA kits, we measured the levels of oxidative DNA and protein damage, along with MDA, SOD, GSH, and the GSH/GSSG ratio in wild-type and GSTM1/GSTT1 knockout mice following cisplatin treatment. Additionally, oxidative stress levels and the expression of ferroptosis-related proteins in kidney tissues were examined through Western blotting, qPCR, immunohistochemistry, and immunofluorescence techniques.ResultsHere, we found that GSTT1 and GSTM1 were downregulated in the renal tubular cells of AKI patients and cisplatin-treated mice. Compared with WT mice, Gstm1/Gstt1-DKO mice were phenotypically normal but developed more severe kidney dysfunction and exhibited increased ROS levels and severe ferroptosis after injecting cisplatin.DiscussionOur study revealed that GSTM1 and GSTT1 can protect renal tubular cells against cisplatin-induced nephrotoxicity and ferroptosis, and genetic screening for GSTM1 and GSTT1 polymorphisms can help determine a standard cisplatin dose for cancer patients undergoing chemotherapy.

BackgroundPeritonitis is considered as one of the most serious complications that cause hospitalization in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). There is limited evidence on the impact of the parathyroid hormone (PTH) on the first peritoneal dialysis (PD)-associated peritonitis episode. We aimed to investigate the influence of serum intact parathyroid hormone (iPTH) on peritonitis in patients undergoing PD.MethodsThis was a retrospective cohort study. Patients undergoing initial CAPD from a single center in China were enrolled. The baseline characteristics and clinical information were recorded. The primary outcome of interest was the occurrence of the first PD-associated peritonitis episode. Five Cox proportional hazard models were constructed in each group set. In group set 1, all participants were divided into three subgroups by tertiles of the serum concentration of iPTH; in group set 2, all participants were divided into three subgroups based on the serum concentration of iPTH with 150 pg/ml interval (300 pg/ml). Hazard ratios and 95% confidence intervals (CIs) were calculated for each model. The multivariate linear regression analysis elimination procedure assessed the association between the clinical characteristics at baseline and the iPTH levels. Restricted cubic spline models were constructed, and stratified analyses were also conducted.ResultsA total of 582 patients undergoing initial PD (40% women; mean age, 45.1 ± 11.5 years) from a single center in China were recruited. The median follow-up duration was 25.3 months. Multivariate Cox regression analysis showed that, in the fully adjusted model, a higher serum iPTH level (tertile 3, iPTH >300 pg/ml) was significantly associated with a higher risk of PD-associated peritonitis at 3 years [tertile 3: hazard ratio (HR) = 1.53, 95%CI = 1.03–2.55, p = 0.03; iPTH > 300 pg/ml: HR = 1.57, 95%CI = 1.08–2.27, p = 0.02]. The hazard ratio for every 100 pg/ml increase in serum iPTH level was 1.12 (95%CI = 1.05–1.20, p

Introduction: Cisplatin is a widely used chemotherapeutic agent prescribed to treat solid tumors. However, its clinical application is limited because of cisplatininduced nephrotoxicity. A known complication of cisplatin is acute kidney injury (AKI). Deletion polymorphisms of GSTM1 and GSTT1, members of the glutathione S-transferase family, are common in humans and are presumed to be associated with various kidney diseases. However, the specific roles and mechanisms of GSTM1 and GSTT1 in cisplatin induced AKI remain unclear. Methods: To investigate the roles of GSTM1 and GSTT1 in cisplatin-induced AKI, we generated GSTM1 and GSTT1 knockout mice using CRISPR-Cas9 technology and assessed their kidney function under normal physiological conditions and cisplatin treatment. Using ELISA kits, we measured the levels of oxidative DNA and protein damage, along with MDA, SOD, GSH, and the GSH/GSSG ratio in wild-type and GSTM1/GSTT1 knockout mice following cisplatin treatment. Additionally, oxidative stress levels and the expression of ferroptosis-related proteins in kidney tissues were examined through Western blotting, qPCR, immunohistochemistry, and immunofluorescence techniques. Results: Here, we found that GSTT1 and GSTM1 were downregulated in the renal tubular cells of AKI patients and cisplatin-treated mice. Compared with WT mice, Gstm1/Gstt1-DKO mice were phenotypically normal but developed more severe kidney dysfunction and exhibited increased ROS levels and severe ferroptosis after injecting cisplatin. Discussion: Our study revealed that GSTM1 and GSTT1 can protect renal tubular cells against cisplatin-induced nephrotoxicity and ferroptosis, and genetic screening for GSTM1 and GSTT1 polymorphisms can help determine a standard cisplatin dose for cancer patients undergoing chemotherapy. [ABSTRACT FROM AUTHOR]