The Role of Alpha-1-Acid Glycoprotein in the Diagnosis and Treatment of Crush Syndrome-Induced Acute Kidney Injury

Abstract

Background: Crush syndrome (CS) is the most common cause of deaths following earthquakes and other disasters. The pathogenesis of CS has yet to be fully elucidated. Thus, clinical choice of ideal drug treatments for CS remains deficient. Methods and Results: In this study, we first evaluated the relation between extrusion force and the severities of CS. Rats were exposed to different extrusion forces: 1 kg, 3 kg, 5 kg, and 8 kg, respectively. Survival rates, crushed muscle tissue edema, serum biochemical parameters, and histopathological staining were used to assess severity. Our results showed that there were no statistical differences in survival rate or changes in thigh circumference among the different extrusion forces groups. However, serum levels of potassium, creatine kinase, blood urea nitrogen, creatinine, and myoglobin were elevated at 12-and 24-h post-decompression in 5 kg and 8 kg groups, compared with 1 kg and 3 kg groups. Histopathological staining demonstrated that the degree of organ damage to kidney, muscle, and lung tissues correlated with increasing extrusion force. We next analyzed changes in serum protein profiles in 3 kg or 5 kg extrusion pressure groups. A total of 76 proteins (20 upregulated, 56 downregulated) were found to be altered at all three time points (0, 12, and 72 h) post-decompression, compared with the control group. Three common upregulated proteins alpha-1-acid glycoprotein (a1-AGP), neutrophil gelatinase-associated lipocalin (NGAL), and Haptoglobin were selected for validation of increased expression. a1-AGP was explored as a treatment for CS-induced acute kidney injury (AKI). Intraperitoneal injection of a1-AGP protected kidneys from CS-induced AKI by regulating TNF-a and IL-6 production, attenuating neutrophil recruitment, and reducing renal cell apoptosis. Conclusion: Our findings demonstrated that the severity of crush injury is causally related to extrusion pressure and increase in blood serum markers. Our identification of the biomarker and treatment candidate, a1-AGP, suggests its implication in predicting the severity of CS and its use as a mediator of CSinduced AKI, respectively.

Breaking New Ground: Standardizing Rat Models for Crush Syndrome Investigations

“…There is a significant weight difference between male and female rats of the same age; for example, an 8-week-old male rat typically weighs 280 to 330 g, while a female rat usually weighs 195 to 235 g. Through preliminary experiments, we determined that the ideal experimental animal is an 8-week-old male rat weighing 280 to 300 g. This ensures that there is sufficient muscle mass to induce AKI. Compared with our research, previous studies have indicated that a male rat weighing 220 to 240 g, when compressed on both lower limbs with a force of 5 kg for 16 h, has a 24 h survival rate of 80% (9). We believe that weight (muscle content) and age are the primary factors causing this significant discrepancy in survival rates.…”

“…These discrepancies lead to variability in research outcomes, hindering the reproducibility of the model. To address these challenges, our team enhanced and iterated upon the foundation of the initial digital platform, independently developing a new generation multichannel intelligent small animal crush injury platform (9,10). We equipped it with an actuator specifically designed for small animals, a fixed position limiter, and a high-precision pressure sensor.…”

“…To understand the multifaceted nature of CS, the adoption and refinement of an appropriate animal model are crucial. Our team, entrenched in the study of CS, innovatively developed a multichannel intelligent small-animal crush injury platform, evolving from the foundational machine (9,10). The primary objective of this study is to use this platform for extensive preliminary experiments to establish a stable rat CS model and to validate the reliability of the equipment and the reproducibility of the model.…”

Anti-high-mobility group box-1 (HMGB1) mediates the apoptosis of alveolar epithelial cells (AEC) by receptor of advanced glycation end-products (RAGE)/c-Jun N-terminal kinase (JNK) pathway in the rats of crush injuries

“…Prolonged compression of limb muscles and subsequent decompression is essential in the development of crush syndrome (CS) [ 1 ], including hyperkalemia, metabolic acidosis, hypovolemic shock, acute kidney injury, and disseminated intravascular coagulation [ 2 ]. The sequential damage in the kidney after crush injury is not the unique dysfunctional organ [ 3 ]. It has been proved that the secondary damage in the lung [ 4 – 6 ], heart [ 7 ], and liver [ 8 ] contributes to multiple organs failure [ 9 ].…”

What's New in Shock, December 2021?

“…Another study of renal protection utilizes a rodent model of crush injury. With this model, investigators from the Institute of Disaster Medicine in China identified proportional increase in serum potassium, creatine kinase, blood urea nitrogen, creatinine and myoglobin at 12 to 24 h after crush trauma (19). From this reproducible injury model, the authors evaluated protein profiles in study animals.…”