Key findings
In this study, we found a significant association between the nadir platelet count in the first 48 hours after ICU admission and AKI after hemorrhagic shock. The nadir platelet count in the first 48 hours after ICU admission could predict the development of AKI in hemorrhagic shock patients. Moreover, we found that the nadir platelet count added significant accuracy to this prediction when combined with sCysC.
Relationship to previous studies
AKI is commonly encountered in cases of hemorrhagic shock. Previous studies have mainly recruited traumatic hemorrhagic shock patients as the study subjects, and it had been carried out that the incidence of AKI is as high as 50% after trauma9. However, in this study, 71 of the 124 hemorrhagic shock patients (57.3%) had shock caused by gastrointestinal hemorrhage, and the study results showed that the prevalence of AKI among hemorrhagic shock patients was approximately 58%, which roughly corresponds with the results of previous studies. Although most trauma patients have no medical history and are younger than the usual ICU population, previous studies have proposed that age and comorbidities remain risk factors for AKI in trauma patients19,20. In this study, hemorrhagic shock patients with sepsis, COPD or acute hepatic insufficiency had a higher probability of developing AKI. It has been reported that the development of AKI is associated with poorer clinical outcomes21. In this study, hemorrhagic shock patients with AKI had a longer length of ICU stay and an increased risk of mortality. Therefore, early recognition of AKI is important and may help improve the clinical course of AKI.
Platelets and AKI
Platelets play important roles in thrombosis, hemostasis, inflammation and infection22. It has been shown that thrombocytopenia is associated with longer ICU stays, a higher incidence of bleeding events, greater transfusion requirements, and higher mortality23. In general, the pathophysiology of hemorrhagic shock leading to thrombocytopenia can be defined by five mechanisms: hemodilution24, elevated levels of platelet consumption25, compromise of platelet production26, increased platelet sequestration27, and increased platelet destruction. Platelets play an important role not only in hemostasis after hemorrhagic shock but also in the pathology of ischemia/reperfusion (I/R) injury, which is one of the main causes of AKI28. The pathophysiology of I/R injury is a complex cascade of events, including the release of oxygen free radicals, followed by damage to proteins, lipids, mitochondria, and deranged tissue oxygenation29. Previous studies have demonstrated that inflammatory molecules are expressed within a few minutes of I/R injury, including platelet-activating factor30; hence, it is reasonable to believe that platelet activation caused by hemorrhagic shock is associated with I/R injury. The mechanism between thrombocytopenia after hemorrhagic shock and AKI is not currently fully understood currently. We speculate that this may be related to thrombocytopenia exacerbating hemorrhagic shock, leading to prerenal hypoperfusion, as well as the involvement of platelet activation in I/R injury, which requires further investigation.
In other clinical studies of the thrombocytopenia and AKI, the degree of thrombocytopenia was used as a marker of the severity during sepsis, which may show different levels of severity depending on the lowest level of platelets reached31. Miklos D et al.32 found a significant association between postoperative nadir platelet count, defined as the lowest in-hospital value after coronary artery bypass graft surgery, and AKI as well as short-term mortality. Heng F et al.33 found that the nadir platelet count during hospitalization was an independent predictor of AKI in heat stroke patients, in which the ROC curve of the nadir platelet count in AKI detection was 0.73, and the cutoff value of the nadir platelet count was 30×109/L, with a sensitivity and specificity of 90% and 81% respectively. In a study by Ming W13, the ROC curve demonstrated that the nadir platelet count in the first 48 hours after ICU admission remained a significant predictor of AKI after hemorrhagic shock, with a sensitivity and specificity of 82% and 77%, respectively, and the cutoff value for the nadir platelet count was 75×109/L. In this study, AKI in patients with hemorrhagic shock could be identified with a sensitivity of 83% at a specificity of 79% (AUC =0.862) by the nadir platelet count (cutoff value =97.5×109/L).
sCysC and AKI
CysC, a 13-kDa endogenous cysteine proteinase inhibitor, is produced by all nucleated cells in the human body and released into plasma34-36, From there, more than 99% is filtered by the glomeruli without significant protein binding and then reabsorbed by proximal renal tubular epithelial cells, so the level of sCysC can be used to measure the functional damage of the kidney37,38. In addition, some clinical studies have shown that sCysC is not affected by age or sex39, thyroid function40, glycemic status41 or the use of glucocorticoids42. Thus, an increasing number of studies consider that sCysC has value for the early detection and diagnosis of AKI43. Shu C et al.44 found that sCysC collected within the first 8 hours after trauma could be used as a marker to predict AKI in 57 patients with traumatic hemorrhagic shock with an ROC plots of 0.728. Farid Zand et al.45 found that a high sCysC level within 24 hours after ICU admission may have prognostic value in predicting early AKI and mortality due to multiple trauma. In this study, the ROC curve of sCysC to predict AKI in hemorrhagic shock patients was 0.772 with a sensitivity of 64% and specificity of 79%, which was similar to the results of the previous study.
To data, there is no single marker that can reflect the complexity of the pathogenesis of AKI46. Hence, using two or more indicators to jointly predict AKI has become a popular topic. In a study assessing of 17 clinical renal biomarkers to predict AKI in ICU patients47, the ROC curve of sCysC for predicting AKI was 0.785, but sCysC plus the N-acetyl-β-d-glucosaminidase-to-creatinine ratio (NAG/Cr) (AUC = 0.856) and sCysC plus the APACHE II score (AUC = 0.868) showed better performance for predicting AKI. In another study evaluating clinical renal biomarkers in ICU adults48, the panel of sCysC plus urinary NAG showed superior discriminative performance in AKI detection when compared with the individual panel. Jianchao M et al.49 found that sCysC plus a clinical model that included the APACHE II score, serum creatinine, and vasopressors used at ICU admission performed better on sepsis-induced AKI prediction than the original model. Yujun D et al.50 found that for predicting AKI after resection of intracranial space-occupying lesions, the composite of sCysC and urinary NAG outperformed either individual biomarker. However, the performance of the nadir platelet count, sCysC and their combination for AKI prediction in hemorrhagic shock patients has not been previously studied. In this study, sCysC at ICU admission could predict the occurrence of AKI in hemorrhagic shock patients. Although there was no significant difference between the nadir platelet count and sCysC in AKI detection, sCysC combined with the nadir platelet count was more accurate in predicting the occurrence of AKI in hemorrhagic shock patients, which adds further prospects regarding the use of sCysC in clinical studies predicting the occurrence of AKI.
Limitations
This study had some limitations. First, it was a retrospective study, and there were a limited number of patients eligible for inclusion in the study. Moreover, many different risk factors are involved in the pathogenesis of AKI occurring, so it was difficult to control for bias and confounders. Finally, this study only revealed the predictive capability of the nadir platelet count for AKI and did not expose the mechanisms between platelets and the occurrence of AKI. As a result, further prospective, large-scale studies examining biomarkers at different time points are necessary to validate and explain the findings.