Decreased serum magnesium (Mg²⁺) is commonly seen in critically ill patients. Hypomagnesemia is significantly more frequent in patients with severe acute pancreatitis. Acute kidney injury (AKI) in patients with acute pancreatitis (AP) is associated with an extremely high mortality. The association underlying serum Mg²⁺ and AKI in AP has not been elucidated.

To explore the association between serum Mg²⁺ on admission and AKI in patients with AP.

A retrospective observational study was conducted in a cohort of patients (n = 233) with AP without any renal injury before admission to our center from August 2015 to February 2019. Demographic characteristics on admission, severity score, laboratory values and in-hospital mortality were compared between patients with and without AKI.

A total of 233 patients were included for analysis, including 85 with AKI. Compared to patients without AKI, serum Mg²⁺ level was significantly lower in patients with AKI at admission [OR = 6.070, 95%CI: 3.374-10.921, P < 0.001]. Multivariate logistic analysis showed that lower serum Mg²⁺ was an independent risk factor for AKI [OR = 8.47, 95%CI: 3.02-23.72, P < 0.001].

Our analysis indicates that serum Mg²⁺ level at admission is independently associated with the development of AKI in patients with AP and may be a potential prognostic factor.

Acute pancreatitis (AP) is an autodigestive disease triggered by acinar cells, and about 20% of the patients progress to fatal severe acute pancreatitis (SAP)[1-4]. Acinar cell injury accompanied by intracellular electrolyte imbalance, further aggravating cell damage and even death is the recognized pathogenesis of AP[5,6]. In particular, organelle damage caused by intracellular calcium (Ca²⁺) influx into mitochondria is the main risk factor for AP[7]. An in vitro AP model showed that Ca²⁺ channel antagonists could effectively reduce Ca²⁺ influx and increase mitochondrial membrane potential, thereby protecting acinar cells[8,9]. As an important cation in cells, magnesium (Mg²⁺) is a coenzyme involved in a variety of enzymatic reactions and plays a role in maintaining membrane potential and physiological function[10-12]. In addition, Mg²⁺ plays a protective role in AP acinar cells by antagonizing Ca²⁺ signals[13]. On the contrary, abnormal regulation of Mg²⁺ acts as a pivotal trigger in the pathogenesis of AP[14].

Acute kidney injury (AKI) is a common complication of SAP with poor prognosis, especially when patients require renal replacement therapy, the mortality rate is > 75%[15,16]. SAP-associated AKI is related to systemic inflammatory response syndrome (SIRS), hypoxemia, renal microcirculation injury after trypsin release, renal perfusion pressure reduction caused by intraperitoneal high pressure or low blood volume, endotoxins and reactive oxides[17]. Therefore, early prediction of AKI in AP is very important to improve the course and prognosis of the disease.

AKI is often accompanied by complex electrolyte disturbances[18]. However, the relationship between Mg²⁺ and the occurrence of AP-associated AKI in AP pathophysiology has not been fully elucidated. Based on the beneficial role of Mg²⁺ in acinar cells of AP, we therefore sought to assess the value of serum Mg²⁺ on admission in correlation with the incidence of AKI in AP.

In this research, we examined the involvement of serum Mg²⁺ and AKI in AP patients. Our results suggest that serum Mg²⁺ levels detected at admission were significantly lower in AP patients with AKI than in non-AKI patients. Moreover, the low serum Mg²⁺ group had a longer ICU and hospital stay than the non-low serum Mg²⁺ group. Furthermore, serum Mg²⁺ was revealed as an independent risk factor for the development of AKI. Therefore, serum Mg²⁺ is an effective predictor of AKI after AP.

Mg²⁺ is a well-known divalent cation abundant in human cells and is concentrated in mitochondria. It mainly plays the role of a cofactor in enzyme reactions and a second messenger in cellular signaling pathways[19-21]. In the physiological state of acinar cells, Mg²⁺ plays an antagonistic role in the influx of Ca²⁺ channel ions and inhibits the secretion of intracellular enzymes[9,22]. In the acinar cell model of AP, the addition of Mg²⁺ mitigates the effects of AP by inhibiting Ca²⁺ influx into the mitochondria, thereby reducing the secretion of digestive enzymes and promoting ATP generation[14]. In conclusion, Mg²⁺ plays an important regulatory role in the pathophysiological state of acinar cells. Mitochondria are the key organelles for the energy supply in acinar cells. It is obvious that Mg²⁺ plays an important role in maintaining mitochondrial homeostasis and ATP generation from this perspective.

The persistent influx of Ca²⁺ into the mitochondria of acinar cells in AP leads to increased oxygen radicals further triggering cell necrosis, which in turn induces SIRS[23-25]. This imbalance leads to further inflammatory response and oxygen radical production, resulting in multiple organ dysfunction including AKI[26]. Therefore, it is important to prevent the continuous influx of Ca²⁺ into mitochondria to reduce acinar cell necrosis and inhibit trypsin activation in AP. This is consistent with research in animal experiments[8,9]. In a murine model, the risk of triggering AP was decreased by inhibiting Ca²⁺ release-activated Ca²⁺ channels[27]. To the best of our knowledge, hypomagnesemia is commonly seen in severely ill patients including those with SAP[28]. In our SAP patients, there was a significant negative correlation between the incidence of AKI and adjusted serum Mg²⁺ on admission.

AKI as a complication, which is associated with increased mortality, occurs in approximately 15%-70% of SAP patients[18,29]. Therefore, early prediction of AKI in hospitalized patients with AP is imperative, especially for screening graded treatment strategies[30]. Currently, there are various clinical methods to predict the occurrence of AKI in patients with AP. On the whole, current studies on biomarkers for AP-associated AKI are insufficient, and the number of patients included in the analysis was limited. In addition, from the latest clinical evidence on the markers of AKI in AP, PCT showed relatively better clinical predictive value than neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C[31-33]. At present, serum or urine NGAL and serum cystatin C are recognized as the best laboratory indicators for predicting AKI in AP with good diagnostic accuracy. However, these single-center clinical data are not convincing enough. Large multicenter clinical studies on biomarkers are of great clinical value in identifying AKI in AP.

However, the relationship between admission serum Mg²⁺ level and AKI incidence in patients with AP has not been fully elucidated. Our results are the first to show that reduced serum Mg²⁺ levels are significantly associated with an increased risk of AKI in patients with AP. We found that Mg²⁺ level of 0.755 mg/dL was an effective cut-off point for in-hospital AKI occurrence, with a sensitivity of 77.7%, and specificity of 63.5%.

However, there are some limitations to our analysis. Firstly, our study did not consider the value of peripheral blood Mg²⁺; thus, the reliability of the actual level of free Mg²⁺ in peripheral blood may be significantly reduced from this perspective. Secondly, the causal relationship between Mg²⁺ and AP-associated AKI still needs to be verified by a large number of prospective studies. Thirdly, our analysis included only one checkup at admission, and as serum Mg²⁺ is a dynamic state, it may not fully reflect the true status of Mg²⁺ in these patients. From this perspective, dynamic serum Mg²⁺ measurement after admission is more objective in predicting AP-associated AKI. Finally, there may be methodological bias in our analysis, it is necessary to explore new machine models (such as train-validation models) to verify the current analysis results.

Our analysis indicates that serum Mg²⁺ level at admission is independently associated the development of AKI in patients with AP and may be a potential prognostic factor.