Renal failure is associated with high mortality in septic shock patients. To clarify the mechanism of septic kidney injury is the cornerstone of early prediction and treatment. Sepsis is characterized by excessive and persistently dysregulated systemic inflammatory response, which eventually cause end organ damage(22–24). During the progression of sepsis, AKI is one the common complications in clinical settings(7, 8). The pathophysiology of AKI development is not well understood. It is widely accepted that microcirculatory dysfunction(6, 25, 26) and excessive inflammation both contributed to epithelial and tubular cell damage(27–29). AKI is defined by abnormalities of series of biomarkers of kidney function, such as creatinine, urea nitrogen, urine volume, and even some clinical biomarkers, such as cystine, neutrophils gelatinase-associated lipid delivery protein (NGAL), kidney injury molecule–1(KIM–1), etc. However, as for creatinine, urea nitrogen, urine, they are often influenced by other known and unknown factors. Moreover, such biomarkers of kidney function are not being tested routinely in developing countries. therefore, there is an urgent need for early detection biomarkers of renal function simply and routinely.
Inflammatory response dysfunction is the key pathophysiological mechanism of septic-AKI. There are some inflammatory markers (IL1, IL16, TNF-a, PCT, CRP, WBC, PLT, lymphocytes, platelets, platelets/lymphocytes, etc.) that have been used to monitor the inflammatory response in clinical practices. In our study, those clinical parameters were used to detect the relationships of AKI with univariant and multivariant regression analysis. Particularly, considering the very limited approaches to monitor the systemic inflammation in septic shock patients, serum PCT level outweighs other inflammatory biomarkers (e.g. IL6, TNF alpha) due to its convenient accessibility in developing country. Our data showed that only PCT and APACHE-II score were identified as risk factors for AKI development, especially PCT which adds up to the clinical significance of our findings.
PCT is a precursor of calcitonin which is undetectable in physiological state and could be significantly induced by bacteria infection(30). Thus, PCT has been widely used as a biomarker for infection and sepsis(12, 13). Higher PCT level has also been shown to be associated with increased AKI development in patients with suspected infection(31) and reduced recovery from AKI in critically ill patients(32). However, the mechanism of how PCT contributed to AKI development was not fully understood. More aspects of PCT in AKI development have been revealed. Indeed, in the setting of sepsis, previous study has shown that PCT could be induced by bacterial toxins and can mediate direct cytotoxicity on mesangial cells by increasing synthesis of proinflammatory cytokines(33). Moreover, PCT has also been shown act as a chemoattractant for monocytes at inflammation site and higher PCT level would recruit more monocytes and contribute to the inflammation-mediated cell injury(34). Apart from cytotoxicity and inflammation, increased PCT level has also been reported to be associated with increased creatinine and decreased glomerular filtration rate(35–37). And higher level of PCT was observed in AKI patients compared to non-AKI patients (38, 39). Based on those findings, PCT level is expected to exhibit an approximately linear relationship with AKI development and increased PCT level in blood is expected to be associated with higher risk of AKI in patients.
However, our data demonstrated a nonlinear relationship between PCT level within 48 hours admission to ICU and AKI development in septic shock patients, which suggested that increased PCT may not always indicate higher risk of AKI in septic shock patients. Specifically, within a certain range, increased PCT level is associated with decreased AKI development in septic shock patients. The mechanism behind this non-linear association is largely unknown. It is reasonable to speculate that at the early time of infection, the PCT level was associated with extent of host inflammatory response and the AKI was possibly caused by toxins from invaded pathogens. Therefore, more invaded pathogens lead to severer inflammatory response and higher PCT level. Afterwards, appropriate inflammatory response was necessary to combat invaded pathogens, which could explain why increased PCT level was associated with decreased AKI development. Eventually, excessive inflammatory response with extremely high PCT level would inevitably add up risk to AKI development. On the side, the discrepancies may be attributed to the usage of different timepoint PCT values. In previous studies, the authors used the PCT values on admission to ICU while we used the highest value of PCT level within 48 hours admission. The former is a static value that does not reflect the effect of treatment on PCT and organ function. The latter is a dynamic value that reflects the effect of treatment on PCT and organ function.
Previous studies on PCT and AKI have not considered the influence of confounding factors. As a biomarker of inflammation, PCT is also influenced by age and gender. We notice that age and gender might be a confounder factor in our study. So, we did subgroup analysis based the age and gender, which have been shown to be associated with AKI development. Actually, young age and female gender has been reported to be two protective factors in AKI(40–43). Older patients (≥75 years) have significantly higher in-hospital ICU mortality than younger patients in sepsis(21). In this study, we used this cutoff point of age and further divided our patients into four group based on age and gender. We found that serum AKI exhibited significantly higher level in AKI group based on the data from the entire cohort. However, after we did stratification analysis based on age and gender, we found serum AKI level was actually significantly higher in AKI group only for female septic shock patients who were less than 75 years old (<75 female).. Moreover, we did observe a trend of higher of serum PCT level in AKI patients of other three groups (< = 75 male, ≥75 male, ≥75 female),, though not statistically significant.
Our study has following limitations. Firstly, this is a retrospective study of relatively small sample size in a single center. And the study may be confounded and biased by other unknown factors. Thus, the evidence grade of this study is compromised to some extent. Secondly, we identified PCT as an early predictive biomarker of AKI development in septic shock patients in ICU. However, our AOC curve analysis did not show a robust sensitivity (63%) or specificity (67%) probably due to small sample size. Thirdly, though we looked age and gender, other unknown confounding factors may bias our results. More large- scale randomized clinical trials are needed to validate our results.
In conclusion, we found a nonlinear relationship between PCT level within 48 hours admission to ICU and AKI with septic shock patients and PCT could be used as a biomarker of AKI in female patients under 75 years with septic shock. Based on our study, elevated PCT within 48 hours admission to ICU may suggest a better prognostic factor of AKI with septic shock.