Complement Activation in Peritoneal Dialysis–Induced Arteriolopathy

Abstract

Cardiovascular disease (CVD) is the leading cause of increased mortality in patients with CKD and is further aggravated by peritoneal dialysis (PD). Children are devoid of preexisting CVD and provide unique insight into specific uremia- and PD-induced pathomechanisms of CVD. We obtained peritoneal specimens from children with stage 5 CKD at time of PD catheter insertion (CKD5 group), children with established PD (PD group), and age-matched nonuremic controls (=6/group). We microdissected omental arterioles from tissue layers not directly exposed to PD fluid and used adjacent sections of four arterioles per patient for transcriptomic and proteomic analyses. Findings were validated in omental and parietal arterioles from independent pediatric control (=5), CKD5 (=15), and PD (=15) cohorts. Transcriptomic analysis revealed differential gene expression in control versus CKD5 arterioles and in CKD5 versus PD arterioles. Gene ontology analyses revealed activation of metabolic processes in CKD5 arterioles and of inflammatory, immunologic, and stress-response cascades in PD arterioles. PD arterioles exhibited particular upregulation of the complement system and respective regulatory pathways, with concordant findings at the proteomic level. In the validation cohorts, PD specimens had the highest abundance of omental and parietal arteriolar C1q, C3d, terminal complement complex, and phosphorylated SMAD2/3, a downstream effector of TGF- Furthermore, in the PD parietal arterioles, C1q and terminal complement complex abundance correlated with the level of dialytic glucose exposure, abundance of phosphorylated SMAD2/3, and degree of vasculopathy. We conclude that PD fluids activate arteriolar complement and TGF- signaling, which quantitatively correlate with the severity of arteriolar vasculopathy.

The Complement System in Dialysis: A Forgotten Story?

“…However, while systemic complement activation (the fluid phase) is similar between PD patients and patients with ESKD, higher intravascular complement depositions (solid phase) have been shown in children with PD compared to non-PD children with ESKD. Omental and parietal arterioles from PD patients demonstrated a higher presence of C1q, C3d, and C5b-9 ( 88 ).…”

“…Likewise, complement regulators were also shown to be downregulated in arterioles of PD patients. Furthermore, the C5b-9 deposition seen in the arterioles of PD patients correlated with the level of dialytic glucose exposure ( 88 ). However, this is probably not the only mechanism responsible for complement activation in PD patients.…”

“…The effects of complement activation during PD include the induction of tissue injury, inflammation, coagulation, and fibrosis. However, complement activation in PD patients has also been linked to long-term effects such as cardiovascular risk ( 88 ). In different experimental models, complement activation during PD leads to direct damage of the peritoneum.…”

The role of the complement factor B‒arginase‒polyamine molecular axis in uremia‐induced cardiac remodeling in mice

“…(F) CFB increased the ARG1 activity in BMDMs, resulting in the overproduction of polyamine. (6) and production of collagen (7), leading to progressive cardiac fibrosis (8). (9) nor-NOHA effectively inhibited the ARG1 activity in macrophages.…”

“…Cardiovascular complications are most common in patients with chronic kidney diseases [7], and heart failure is the leading cause of mortality in patients with end-stage renal disease (ESRD) [8,9]; therefore, the role of complement system in the development of heart failure during ESRD is paid more and more attention by nephrologists. Aukrust et al reported that complement is related to heart failure for the first time, putting forward that complement components have potential as biomarkers of incident heart failure [10].…”