Altered CD73-Adenosine Signaling Linked to Infection in Patients undergoing hemodialysis

Abstract

Fangfang Xiang,1– 4,* Zhen Zhang,1,* Yuxin Nie,1 Xuesen Cao,1 Yang Li,1 Xiaohong Chen,1 Shaomin Gong,1 Jianzhou Zou,1 Jie Teng,1 Xiaoqiang Ding,1– 4 Bo Shen1– 4 1Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Renal Disease and Blood Purification, Shanghai, People’s Republic of China; 3Shanghai Medical Center of Kidney, Shanghai, People’s Republic of China; 4Shanghai Institute of Kidney and Dialysis, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bo Shen, Department of Nephrology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, People’s Republic of China, Email [email protected]: Infection is the most common cause of hospitalization and the second most common cause of mortality among patients undergoing hemodialysis (HD). The enzyme CD73, a cell surface 5′-nucleotidase, regulates the balance between pro-inflammatory nucleotides and anti-inflammatory adenosine. Diminished CD73-adenosine signaling contributes to severe infections.Methods: In this prospective cohort study, 393 patients who underwent HD for over six months were evaluated for CD73+Tcell ratios and were followed up for three years to track infection events. Kaplan–Meier curves and Cox regression analyses were used to evaluate the relationship between CD73+T cells and infections; meanwhile, multiple logistic regression analysis was used to analyze differences among infection groups. In addition, a 5/6 nephrectomy (5/6 Nx) rat model and cecal ligation and puncture (CLP) were used to verify the effect of chronic kidney disease (CKD) and sepsis on CD73-adenosine signaling.Results: Decreased CD73+ T cells were independently associated with increased infection risk over one and three years. The hazard ratios for one- and three-year infection incidences were 3.173 (95% CI 1.782– 5.650, p < 0.001) and 1.429 (95% CI 1.052– 1.992, p = 0.035), respectively. Furthermore, they were associated with recurrent and fatal severe infections. Animal models demonstrated reduced CD73 mRNA transcript and adenosine receptor levels, along with decreased serum adenosine levels in CKD. Impairment of CD73-adenosine signaling was more pronounced after CLP in CKD rats.Conclusion: Lower CD73+T cell levels are strongly associated with infection complications in patients undergoing HD. Altered CD73-adenosine signaling likely plays a substantial role in immune dysfunction in CKD. Keywords: adenosine, CD73, hemodialysis, infection, T cell dysfunction

Keywords

• adenosine
• cd73
• hemodialysis
• infection
• t cell dysfunction