Ceftriaxone Calcium Crystals Induce Acute Kidney Injury by NLRP3-Mediated Inflammation and Oxidative Stress Injury.

Zhang Yifan,Jia Ruipeng,Ge Yuzheng,Ning Benxiang,Xu Luwei,Zhou Liuhua,Xu Zheng

doi:10.1155/2020/6428498

Abstract

Objective To investigate the role of inflammatory reactions and oxidative stress injury in the mechanisms of ceftriaxone calcium crystal-induced acute kidney injury (AKI) both in vivo and in vitro. Methods Male Sprague Dawley rats were randomly divided into five groups of ten each according to different concentrations of ceftriaxone and calcium. Based on the levels of serum creatinine (Scr) and blood urea nitrogen (BUN), the AKI group was chosen for the subsequent experiments. Kidney histological examination and immunohistochemistry were performed. The expression of NLRP3 and IL-1β protein and the concentrations of oxidative stress markers such as ROS, MDA, and H2O2 in kidney tissues were estimated. In parallel, HK-2 human renal proximal tubule cells were exposed to ceftriaxone calcium crystals. The mRNA expression levels of NLRP3 and IL-1β and the concentrations of oxidative stress markers were evaluated. Finally, cell viability and rat survival were also assessed. Results The results showed that significantly increased Scr and BUN levels, consistent with morphological changes and kidney stones, were found in the rats that received the highest concentration of ceftriaxone (1000 mg/kg) combined with calcium (800 mg/kg). The activation of the NLRP3 inflammasome axis and the marked elevation of MDA, H2O2, and ROS levels were observed both in vivo and in vitro. High expression of Nrf2, HO-1, and NQO1 was also documented. In addition, cell apoptosis and rat mortality were promoted by ceftriaxone calcium crystals. Conclusions Notably, we found that ceftriaxone-induced urolithiasis was associated with a high risk of AKI and NLRP3-mediated inflammasome and oxidative stress injury were of major importance in the pathogenesis.

Highlights

Ceftriaxone, a potent, semisynthetic, third-generation cephalosporin has a wide spectrum of powerful antimicrobial activities
The results showed that the H2O2 and MDA concentrations in the kidney tissues were significantly increased in the acute kidney injury (AKI) group compared with those in the control group
Our findings suggested that the inflammasome and oxidative stress injury were of major importance in the loss of kidney function that occurred in ceftriaxone calcium crystal-induced kidney disease, an important example of crystal nephropathy

Summary

Introduction

Ceftriaxone, a potent, semisynthetic, third-generation cephalosporin has a wide spectrum of powerful antimicrobial activities. Ceftriaxone is highly soluble as a sodium salt. It can bind with calcium ions, producing a poorly soluble ceftriaxone–calcium salt that forms precipitates in the urinary tract, known as urolithiasis [2]. Its incidence is relatively rare, ceftriaxone-induced urolithiasis could lead to severe complications, such as acute kidney injury (AKI) [3]. The traditional concept of crystal-induced kidney injury focuses on urinary tract obstruction. Bilateral obstructive urolithiasis can cause acute kidney injury, but tubular crystal plugs and casts rarely obstructed enough nephrons at the same time to explain AKI [5]. Our previous study found that in addition to urinary obstruction, which is well-known, crystalline nephropathy could contribute to ceftriaxone calculiinduced AKI [4]

Methods

Results

Conclusion