Proton Pump Inhibitor and Tacrolimus Uses are Associated With Hypomagnesemia in Connective Tissue Disease: a Potential Link With Renal Dysfunction and Recurrent Infection.

Hironari Hanaoka,Hideto Tsujimoto,Noriyasu Seki,Jun Kikuchi,Tsutomu Takeuchi,Yuko Kaneko,Kenji Chiba

doi:10.3389/fphar.2021.616719

Hironari Hanaoka, Hideto Tsujimoto + Show 5 more

Open Access

https://doi.org/10.3389/fphar.2021.616719

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Abstract

Background: Low levels of serum magnesium perturb renal tubular cell function and lymphocytes, resulting in renal deterioration and an imbalance in mononuclear cells. This study investigated the mechanism and influence of hypomagnesemia in patients with connective tissue disease. Methods: We retrospectively evaluated patients with connective tissue disease and available serum magnesium data who visited Keio University Hospital in 2019. Patients were divided into two groups: those with (serum magnesium < 1.8 mg/dl) and those without hypomagnesemia; their rates of hospitalization for severe infection and cumulative renal deterioration were compared. Patients’ fractions of lymphocytes and natural killer and dendritic cell subsets, as measured by fluorescence-activated cell sorting (FACS) analysis, were also compared. Results: Among 284 patients, hypomagnesemia was detected in 63 (22.2%). Multivariate analysis revealed that the use of proton pump inhibitors [odds ratio (OR), 1.48; p = 0.01] and tacrolimus (OR, 6.14; p < 0.01) was independently associated with hypomagnesemia. In addition, the renal deterioration rate was significantly higher in tacrolimus and/or proton pump inhibitor users with hypomagnesemia (p = 0.01). The hospitalization rate for severe infection was also higher in patients with hypomagnesemia (p = 0.04). FACS analysis showed lower CD8+ T cell, CD19+ B cell, natural killer cell, and dendritic cell counts in patients with hypomagnesemia (p = 0.03, p = 0.02, p = 0.02, and p = 0.03, respectively). Conclusion: The use of tacrolimus and proton pump inhibitors may be associated with hypomagnesemia and lead to poor renal outcomes and severe infection in patients with connective tissue disease.

Highlights

Magnesium (Mg) is an abundant intracellular cation that acts as a co-factor for more than 300 enzymes involved in a number of fundamental functions
Calcineurin inhibitors (CNIs) are associated with low serum Mg concentrations (Barton et al, 1987; Navaneethan et al, 2006), both pump inhibitors (PPIs) and CNIs, including tacrolimus (TAC), are frequently used in patients with connective tissue disease (CTD) (Takahashi et al, 2011; Takeuchi et al, 2014; Mok, 2016; Mok et al, 2016; Ueno et al, 2016; Hanaoka et al, 2019; Kaneko et al, 2020; Takada et al, 2020), little is known about their influence on serum Mg levels in the management of CTD
We reviewed the data of consecutive patients who visited Keio University Hospital from January 2019–December 2019, and were diagnosed with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), polymyositis/dermatomyositis (PM/DM), Sjögren syndrome (SS), systemic sclerosis (SSc), mixed connective tissue disease (MCTD), anti-neutrophil cytoplasmic antibody-related vasculitis, or other rheumatic diseases according to their respective classification criteria (Bohan and Peter, 1975; Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee, 1980; Benhamou et al, 1988; Yamaguchi et al, 1992; Hochberg, 1997; Vitali et al, 2002; Taylor et al, 2006; Watts et al, 2007; Aletaha et al, 2010; Dasgupta et al, 2012; Tani et al, 2014; Bashardoust, 2015; Jinnin et al, 2018; Wallace et al, 2020; Heinle and Chang, 2014; Behcet’s Disease Research Committee of Japan.1974)

Summary

Introduction

Magnesium (Mg) is an abundant intracellular cation that acts as a co-factor for more than 300 enzymes involved in a number of fundamental functions. Several medications are known to influence serum Mg levels through these mechanisms. Calcineurin inhibitors (CNIs) are associated with low serum Mg concentrations (Barton et al, 1987; Navaneethan et al, 2006), both PPIs and CNIs, including tacrolimus (TAC), are frequently used in patients with connective tissue disease (CTD) (Takahashi et al, 2011; Takeuchi et al, 2014; Mok, 2016; Mok et al, 2016; Ueno et al, 2016; Hanaoka et al, 2019; Kaneko et al, 2020; Takada et al, 2020), little is known about their influence on serum Mg levels in the management of CTD. This study investigated the mechanism and influence of hypomagnesemia in patients with connective tissue disease

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