Neutrophil Function in Patients With Chronic Kidney Disease: A Systematic Review and Meta-Analysis

Abstract

Background: Patients with chronic kidney disease (CKD) are at increased cardiovascular risk. Since neutrophils play a central role in atherosclerosis and cardiovascular disease, this study analyzed neutrophil function in CKD patients.

Methods: A systematic review of neutrophil function in CKD patients compared to controls was performed according to PRISMA guidelines by searching PubMed and the Web of Science. A meta-analysis summarized the production of reactive oxygen species (ROS) in CKD patients on dialysis in Forest plots. Influencer outlier analyses evaluated risk of bias.

Results: Overall, 92 studies were included, of which 18 in the meta-analysis. Although study heterogeneity was high, the systematic review identified primarily reduced phagocytosis capacity but increased neutrophil degranulation and basal ROS production in neutrophils from CKD patients on hemodialysis compared to controls. Phagocytosis and basal ROS production were mainly unaltered in non-dialysis dependent CKD patients and CKD patients on peritoneal dialysis. The meta-analysis confirmed increased ROS generation in basal conditions predominantly in CKD patients on hemodialysis (Hedges g = 1.20, 95% CI: [0.32; 2.09]), with an insufficient study number for a clear comparison to CKD patients on peritoneal dialysis. However, upon neutrophil stimulation with sterile inflammatory triggers, ROS production was also increased in neutrophils from patients on peritoneal dialysis (Hedges g = 0.89, 95% CI: [0.34; 1.43]).

Conclusion: Increased degranulation and basal ROS formation were observed in neutrophils of CKD patients on hemodialysis, which could contribute to their increased cardiovascular risk. Future studies should compare neutrophil activity in patients of different CKD stages and comorbidities also in relation to cardiovascular outcomes.

Keywords: chronic kidney disease; neutrophils; reactive oxygen species.

FIGURE 1

Flow chart of study selection for systematic review and meta‐analysis of neutrophil function in CKD. CKD, chronic kidney disease; NET, neutrophil extracellular traps; ROS, reactive oxygen species.

FIGURE 2

Summary of studies reporting on neutrophil parameters in specific CKD patient cohorts (compared to healthy controls). Graphical summary of Table 2. “Inconclusive” indicates no overall conclusion due to insufficient study number. CKD, chronic kidney disease; HD, hemodialysis; NET, neutrophil extracellular traps; n.s., not specified; PD, peritoneal dialysis; ROS, reactive oxygen species.

FIGURE 3

Meta‐analysis shows no overall significant difference in neutrophil ROS production between CKD patients on either hemodialysis or peritoneal dialysis versus controls. Forest plot of neutrophil ROS production in dialysis patients compared to healthy controls, with subgroup analysis of the effect of dialysis type. CI, confidence interval; CKD, chronic kidney disease; E. coli , Escherichia coli ; HD, hemodialysis; fMLP, N‐formyl‐methionyl‐leucyl‐phenylalanine; PD, peritoneal dialysis; PMA, Phorbol 12‐myristate 13‐acetate; S. aureus , Staphylococcus aureus ; SD, standard deviation; S. epidermidis , Streptococcus epidermidis; TNFα, tumor necrosis factor α.

FIGURE 4

Meta‐analysis of ROS production by resting or stimulated neutrophils from CKD patients on dialysis. (A) Meta‐analysis shows increased ROS production by resting neutrophils from predominantly hemodialysis‐patients versus controls. Forest plot of neutrophil ROS production in dialysis patients compared to healthy controls, with analysis of the subgroup “resting neutrophils”. Provided is a zoomed extract from the full meta‐analysis of the effect of stimulus presence and type on ROS generation in neutrophils, as displayed in Figure S4. (B) Meta‐analysis shows increased ROS generation in neutrophils of PD patients, when stimulated with stimuli reflecting sterile inflammatory conditions. Forest plot of neutrophil ROS production in dialysis patients compared to healthy controls upon neutrophil stimulation with fMLP, fMLP and TNFα or PMA. CI, confidence interval; CKD, chronic kidney disease; fMLP, N‐formyl‐methionyl‐leucyl‐phenylalanine; HD, hemodialysis; PD, peritoneal dialysis; PMA, Phorbol 12‐myristate 13‐acetate; SD, standard deviation, TNFα, tumor necrosis factor α.