Impact of transplantation on neutrophil extracellular trap formation in patients with end-stage renal disease

Abstract

Increased neutrophil extracellular trap (NET) formation associates with high cardiovascular risk and mortality in patients with end-stage renal disease (ESRD). However, the effect of transplantation on NETs and its associated markers remains unclear. This study aimed to characterize circulating citrullinated Histone H3 (H3cit) and Peptidyl Arginase Deiminase 4 (PAD4) in ESRD patients undergoing transplantation and evaluate the ability of their neutrophils to release NETs. This prospective cohort study included 80 healthy donors and 105 ESRD patients, out of which 95 received a transplant. H3cit and PAD4 circulating concentration was determined by enzyme-linked immunosorbent assay in healthy donors and ESRD patients at the time of enrollment. An additional measurement was carried out within the first 6 months after transplant surgery. In vitro NET formation assays were performed in neutrophils isolated from healthy donors, ESRD patients, and transplant recipients. H3cit and PAD4 levels were significantly higher in ESRD patients (H3cit, 14.38 ng/mL [5.78–27.13]; PAD4, 3.22 ng/mL [1.21–6.82]) than healthy donors (H3cit, 6.45 ng/mL [3.30–11.65], P < .0001; PAD4, 2.0 ng/mL [0.90–3.18], P = .0076). H3cit, but not PAD4, increased after transplantation, with 44.2% of post-transplant patients exhibiting high levels (≥ 27.1 ng/mL). In contrast, NET release triggered by phorbol 12-myristate 13-acetate was higher in neutrophils from ESRD patients (70.0% [52.7–94.6]) than healthy donors (32.2% [24.9–54.9], P < .001) and transplant recipients (19.5% [3.5–65.7], P < .05). The restoration of renal function due to transplantation could not reduce circulating levels of H3cit and PAD4 in ESRD patients. Furthermore, circulating H3cit levels were significantly increased after transplantation. Neutrophils from transplant recipients exhibit a reduced ability to form NETs.

Tacrolimus maintains the balance of NETs by inducing DNA methylation of neutrophils to reduce immune rejection

“…However, the release of NETs can also cause tissue damage, and excessive or inappropriate NETs formation has been implicated in the development of autoimmune and in ammatory diseases. It is possible that NETs could be formed in response to the stress of surgery or because of in ammation or infection during the transplantation process [38][39][40][41][42][43][44]. More research is needed to understand the role of NETs in organ transplantation and the potential consequences of NET formation.…”

Tacrolimus Maintains the Balance of Neutrophil Extracellular Traps by Inducing DNA Methylation of Neutrophils to Reduce Immune Rejection

“…However, the release of NETs can also cause tissue damage, and excessive or inappropriate NET formation has been implicated in the development of autoimmune and inflammatory diseases. It is possible that NETs could be formed in response to the stress of surgery or because of inflammation or infection during the transplantation process [40][41][42][43][44][45][46]. More research is needed to understand the role of NETs in organ transplantation and the potential consequences of NET formation.…”

NETs-Induced Thrombosis Impacts on Cardiovascular and Chronic Kidney Disease

“…There are contrasting findings on the stimuli-induced NETs formation capacity of neutrophils in CKD stage 5 (Table 2). Some authors observed increased NETs production by neutrophils isolated from dialysis patients upon phorbol-12-myristate-13-acetate (PMA) stimulation, 148,149 along with increased PAD4 levels in serum 149 or increased NE activity in both resting and PMA-stimulated neutrophils. 148 In contrast, others reported a decreased NETs formation capacity of isolated neutrophils from dialysis patients upon stimulation with PMA, lipopolysaccharide, or the Ca 2+ ionophore A23187 compared with healthy controls 15 (Table 2).…”

“…differences between predialysis patients or patients on hemodialysis or peritoneal dialysis. 149 Also, increased levels of histone-DNA complexes 147,148,150 as well as myeloperoxidase-DNA complexes 150 have been detected in hemodialysis patients, with even higher levels in those reaching a composite endpoint of all-cause mortality or loss of vascular access, compared to those who did not 150 (Table 1).…”

“…When focusing on H3cit (citrullinated histone H3) and PAD4 as markers of NETs formation, patients in CKD stage 5 revealed increased levels of H3cit and PAD4 in blood compared to healthy controls, without significant differences between predialysis patients or patients on hemodialysis or peritoneal dialysis. 149 Also, increased levels of histone-DNA complexes 147,148,150 as well as myeloperoxidase-DNA complexes 150 have been detected in hemodialysis patients, with even higher levels in those reaching a composite endpoint of all-cause mortality or loss of vascular access, compared to those who did not 150 (Table 1).…”