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

Background

Phospholipid 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.

Methods

This 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.

Results

A 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.

Conclusions

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

Key Points

1. PLTP and Inflammation Regulation: PLTP plays a role in neutralizing lipopolysaccharide (LPS) and modulating inflammatory responses, suggesting its potential protective effects in sepsis and SA-AKI.
2. Association Between PLTP and SA-AKI: A prospective study of 93 septic patients found that lower PLTP lipotransfer activity was significantly associated with increased risk of SA-AKI and major adverse kidney events within 30 days (MAKE 30).
3. Predictive Value of PLTP: Plasma PLTP levels were independent predictors of SA-AKI and MAKE 30, with an area under the curve (AUC) of 0.87 for both outcomes, demonstrating strong diagnostic potential.
4. PLTP and Kidney Function: Patients with lower PLTP activity had significantly higher creatinine levels and worse renal function outcomes, indicating its potential as a biomarker for AKI severity.
5. Animal Model Findings: A mouse model of SA-AKI using cecal ligation and puncture (CLP) showed that PLTP-deficient mice had worsened renal function, higher inflammation, and increased mortality compared to wild-type mice.
6. Therapeutic Effects of Recombinant PLTP: Administration of recombinant human PLTP in septic mice improved 10-day survival, reduced renal injury, and decreased inflammatory cytokine levels, highlighting its therapeutic potential.
7. PLTP and Kidney Microcirculation: PLTP deficiency was associated with impaired renal microcirculation, suggesting a role in maintaining endothelial function and reducing hypoxia-induced kidney injury.
8. Mitochondrial Protection: Electron microscopy of renal tissues showed that recombinant PLTP helped preserve mitochondrial structure, reducing oxidative stress and apoptosis in tubular epithelial cells.
9. PLTP as a Therapeutic Target: The study suggests that increasing PLTP activity could be a novel strategy for preventing SA-AKI and mitigating kidney damage in sepsis.
10. Future Research Directions: Further studies are needed to validate PLTP’s clinical applications, explore its molecular mechanisms in SA-AKI, and develop targeted therapies for septic kidney injury.

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