The calcium-sensing receptor in sepsis and septic shock, mechanistic pathways and translational perspectives: a systematic review

BACKGROUND: Sepsis and septic shock are major causes of mortality in critically ill patients. They are linked to widespread metabolic and immune dysregulation, including alterations in calcium and phosphate homeostasis. The calcium-sensing receptor (CaSR) not only plays a role in mineral balance, but also modulates key immune pathways and may contribute to the pathogenesis of sepsis. METHODS: A systematic literature review was conducted according to PRISMA 2020 guidelines. Four databases (PubMed, EMBASE, Cochrane Library, and Google Scholar) were searched for studies published since 1990. To be eligible for inclusion, articles had to be original research, reviews, or clinical trials involving adult models (mammalian or human). Full-text availability was required. Risk of bias was assessed for all studies included. RESULTS: Sixty-six articles met the inclusion criteria: 49 original studies and 17 reviews. No randomized controlled trials or meta-analyses were identified. Most studies relied on in vitro or in vivo models. CaSR was consistently reported to be upregulated or activated following exposure to bacterial and inflammatory stimuli in immune cells, including monocytes and lymphocytes. CaSR activation promotes proinflammatory cytokine release, notably IL-1β via the NOD like receptor family 3 (NLRP3) inflammasome although results in intestinal epithelial models remain inconsistent. In non-septic models, CaSR activation was associated with tissue and organ injury, including renal and cardiac damage, as well as vasoplegia related to endothelial dysfunction. Preclinical models of pneumonia and endotoxemia suggest that CaSR antagonists may effectively mitigate inflammation and organ injury. CONCLUSION: This systematic review identifies the CaSR as an amplifier of the host inflammatory response across both septic and non-septic preclinical models The lack of robust clinical data underscores the need for translational studies assessing CaSR expression or activity in patients with sepsis or septic shock, alongside in vivo validation of CaSR inhibition as a therapeutic strategy.