The role of phospholipid transfer protein in sepsis-associated acute kidney injury.

backgroundPhospholipid transfer protein (PLTP), a glycoprotein widely expressed in the body, is primarily involved in plasma lipoprotein metabolism. Previous research has demonstrated that PLTP can exert anti-inflammatory effects and improve individual survival in patients with sepsis and endotoxemia by neutralizing LPS and facilitating LPS clearance. However, the role of PLTP in sepsis-associated acute kidney injury (SA-AKI) and the specific mechanism of its protective effects are unclear. This study aimed to assess the potential role of PLTP in SA-AKI.

methodsThis is a population-based prospective observational study of patients with sepsis admitted to the intensive care unit. Blood samples were collected on days 1, 3, 5, and 7 after admission to the ICU. Plasma PLTP lipotransfer activity was measured to assess outcomes, including the incidence of SA-AKI and 30-day major adverse kidney events (MAKE 30). The correlation between PLTP lipotransfer activity and SA-AKI and MAKE 30 was evaluated through logistic regression modeling. Receiver operating characteristic curves were used to assess the diagnostic value of PLTP lipotransfer activity for SA-AKI and MAKE 30. The PLTP lipotransfer activity was categorized into high and low groups based on the optimal cut-off values. The differences between the high and low PLTP lipotransfer activity groups in terms of MAKE 30 were evaluated using Kaplan-Meier analysis. The SA-AKI mouse model was established via cecum ligation and puncture (CLP) in the animal experimental phase. The impact of PLTP on renal function was then investigated in wild-type and PLTP ± mice. The wild-type mice were given recombinant human PLTP (25 μg, 200 μL each/dose) via the tail vein at 1-, 7-, and 23-h intervals on the day preceding CLP. The control group received an equal volume of solvent. The 10-day survival and kidney function among the treatment groups were then evaluated.

resultsA total of 93 patients were enrolled in this clinical trial, of which 52 developed acute kidney injury (AKI). A total of 32 patients died over the course of the 30-day follow-up period, 34 underwent kidney replacement therapy, 37 developed persistent acute kidney injury, and 55 patients met the composite endpoint. The plasma PLTP lipotransfer activity was identified as an independent predictor of SA-AKI (crude OR = 0.96, 95% CI 0.95-0.98, p < 0.001; adjusted OR = 0.92, 95% CI 0.86-0.96, p = 0.001) and MAKE 30 (crude OR = 0.97, 95% CI 0.96-0.98, p < 0.001; adjusted OR = 0.96, 95% CI 0.93-0.98, p = 0.001). The area under the curve (AUC) of plasma PLTP lipotransfer activity within 24 h of ICU admission could predict the occurrence of SA-AKI and MAKE 30 in septic patients (AUC values; 0.87 (95% CI 0.79-0.94) and 0.87 (95% CI 0.80-0.94), respectively). The cumulative incidence of main kidney adverse events was significantly lower in the high group than in the low group (p < 0.001). Compared with the controls, creatinine levels were significantly elevated in the CLP mice, while PLTP lipotransfer activity was significantly decreased at 24 h postoperatively. Moreover, the PTLP ± mice exhibited significantly impaired renal function and markedly elevated plasma levels of inflammatory mediators compared with the wild-type CLP mice. Notably, human recombinant PTLP significantly prolonged 10-day survival, improved renal function, and attenuated mitochondrial structural damage in wild-type CLP mice.

conclusionsThese findings indicate that PLTP is a potential therapeutic target in sepsis-associated acute kidney injury.