Group IIA Secretory Phospholipase A2 Predicts Graft Failure and Mortality in Renal Transplant Recipients by Mediating Decreased Kidney Function

Abstract

The acute phase protein group IIA secretory phospholipase A2 (sPLA2-IIA) has intrinsic proatherosclerotic properties. The present prospective cohort study investigated whether plasma sPLA2-IIA associates with graft failure, cardiovascular, and all-cause mortality in renal transplant recipients (RTRs), patients with accelerated atherosclerosis formation both systemically and within the graft. In 511 RTRs from a single academic center with stable graft function >1 year, baseline plasma sPLA2-IIA was determined by ELISA. Primary end points were death-censored graft failure and mortality (median follow-up, 7.0 years). Baseline sPLA2-IIA was higher in RTRs than in healthy controls (median 384 ng/dL (range 86–6951) vs. 185 ng/dL (range 104–271), p < 0.001). Kaplan–Meier analysis demonstrated increased risk for graft failure (p = 0.002), as well as cardiovascular (p < 0.001) and all-cause mortality (p < 0.001), with increasing sPLA2-IIA quartiles. Cox regression showed strong associations of sPLA2-IIA with increased risks of graft failure (hazard ratio (HR) = 1.42 (1.11–1.83), p = 0.006), as well as cardiovascular (HR = 1.48 (1.18−1.85), p = 0.001) and all-cause mortality (HR = 1.39 (1.17−1.64), p < 0.001), dependent on parameters of kidney function. Renal function during follow-up declined faster in RTRs with higher baseline sPLA2-IIA levels. In RTRs, sPLA2-IIA is a significant predictive biomarker for chronic graft failure, as well as overall and cardiovascular disease mortality dependent on kidney function. This dependency is conceivably explained by sPLA2-IIA impacting negatively on kidney function.

Recent progress of nanomedicine in secreted phospholipase A2 as a potential therapeutic target

“…59 The sPLA2-IIA can also increase the expression of COX-2 and ROS and exert pro-inflammatory signals through M-type receptors to promote the formation of atherosclerotic lesions. 60 So far, many sPLA2 inhibitors have been developed to reduce the risk of myocardial injury caused by atherosclerosis. For example, A-001 is a kind of inhibitor of the sPLA2 enzyme, and varespladib (A-002) is an orally bioavailable prodrug of A-001.…”

“…59 The sPLA2-IIA can also increase the expression of COX-2 and ROS and exert pro-inflammatory signals through M-type receptors to promote the formation of atherosclerotic lesions. 60…”

Group IIA secreted phospholipase A2 inhibition by elemolic acid as a function of anti-inflammatory activity

“…Supporting that, the raised GIIA concentration is evident in most of the inflammatory exudates and plasma of arthritis patients 5 , inflammatory bowel diseases, acute coronary syndrome 6 , asthma 7 , atherosclerosis 8 , acute respiratory distress syndrome (ARDS) 6 and recently, elevated levels of GIIA was found in samples of COVID-19 patients and it is parallel to disease severity 9 . GIIA is also a biomarker for cardiovascular diseases 10 , 11 , sepsis 12 and chronic graft failure 13 .…”

Sinapicacid Inhibits Group IIA Secretory Phospholipase A2 and Its Inflammatory Response in Mice

“…In healthy people, the concentration of sPLA 2 -IIA is minimal (3 ng/mL) but increases significantly (250–500 ng/mL) during infection and injuries [ 5 ]. The sPLA 2 -IIA concentration has been elevated in most inflammatory fluids of patients with rheumatoid arthritis [ 6 ], asthma [ 7 ], atherosclerosis [ 8 ], and acute respiratory distress syndrome [ 9 ], as well as a biomarker for cardiovascular complications [ 10 , 11 ], sepsis [ 12 ] and transplant rejection [ 13 ].…”