Acute effects of hemodialysis on cytokine transcription profiles: Evidence for C-reactive protein-dependency of mediator induction

Oxidative stress and inflammation predict cardiovascular events in chronic hemodialysis patients. Hemodialysis activates the kallikrein-kinin system, increasing bradykinin. Bradykinin promotes inflammation but also stimulates endothelial release of tissue-plasminogen activator and inhibits platelet aggregation. Understanding the detrimental and beneficial effects of endogenous bradykinin during hemodialysis has implications for the treatment of cardiovascular disease in the hemodialysis population. To test the hypothesis that bradykinin contributes to the inflammatory and fibrinolytic responses to dialysis, we conducted a double-blind, randomized, placebo-controlled crossover study comparing the effect of the bradykinin B 2 receptor blocker HOE-140 with vehicle on markers of oxidative stress, inflammation, fibrinolysis, and coagulation in nine hemodialysis patients without coronary artery disease. Bradykinin receptor antagonism did not affect the mean arterial pressure or heart rate response to dialysis. Monocyte chemoattractant protein 1 (MCP-1) peaked postdialysis; HOE-140 blunted the increase in MCP-1 (5.9 Ϯ 5.9 versus 25.6 Ϯ 20.1 pg/ml, P ϭ 0.01). HOE-140 also abolished the increase in plasminogen activator inhibitor 1 (PAI-1) antigen observed at the end of dialysis. In contrast, HOE-140 significantly accentuated the effect of dialysis on F 2 -isoprostanes and P-selectin. Taken together, these results suggest that endogenous bradykinin contributes to increases in MCP-1 and PAI-1 antigen after hemodialysis via its B 2 receptor. Factors that increase the production of bradykinin or decrease its degradation may enhance the inflammatory response to hemodialysis.

Section: Discussionsupporting

confidence: 66%

mentioning

confidence: 99%

Endogenous Bradykinin Contributes to Increased Plasminogen Activator Inhibitor 1 Antigen following Hemodialysis

Marney¹,

Ma²,

Luther

et al. 2009

“…However, in one study, it has been observed that acute transcription of anti-inflammatory cytokines following HD was significantly lower in patients with high serum CRP levels. 36 In contrast, transcription of proinflammatory cytokines (including IL-1␤ and TNF-␣) was induced in equal concentrations, regardless of baseline CRP levels. IL-1␤ and TNF-␣ are known to induce expression of the CCR5 ligands CCL4 and CCL5 in renal disease.…”

Section: Discussionmentioning

confidence: 96%

CCR5 Deletion Protects Against Inflammation-Associated Mortality in Dialysis Patients

Muntinghe¹,

Verduijn²,

Zuurman³

et al. 2009

The CC-chemokine receptor 5 (CCR5) is a receptor for various proinflammatory chemokines, and a deletion variant of the CCR5 gene (CCR5⌬32) leads to deficiency of the receptor. We hypothesized that CCR5⌬32 modulates inflammation-driven mortality in patients with ESRD. We studied the interaction between CCR5 genotype and levels of high-sensitivity C-reactive protein (hsCRP) in 603 incident dialysis patients from the multicenter, prospective NEtherlands COoperative Study on the Adequacy of Dialysis (NECOSAD) cohort. CCR5 genotype and hsCRP levels were both available for 413 patients. During 5 yr of follow-up, 170 patients died; 87 from cardiovascular causes. Compared with the reference group of patients who had the wild-type CCR5 genotype and hsCRP Յ 10 mg/L (n ϭ 225), those carrying the deletion allele with hsCRP Յ 10 mg/L (n ϭ 55) had similar mortality, and those carrying the wild-type genotype with hsCRP Ͼ 10 mg/L (n ϭ 108) had an increased risk for mortality (HR: 1.82; 95% CI: 1.29 to 2.58). However, those carrying the deletion allele with hsCRP Ͼ 10 mg/L (n ϭ 25) had a mortality rate similar to the reference group; this seemingly protective effect of the CCR5 deletion was even more pronounced for cardiovascular mortality. We replicated these findings in an independent Swedish cohort of 302 ESRD patients. In conclusion, the CCR5⌬32 polymorphism attenuates the adverse effects of inflammation on overall and cardiovascular mortality in ESRD.

“…The etiology of inflammation is complex and includes underlying uremia and the continuous contact between blood and dialyzer/dialysate. Indeed, the hemodialysis procedure results in increased leukocyte transcript levels of many proinflammatory cytokines 13 and circulating cytokines increase and remain high at least 2 hours after the end of dialysis. 12 In our study, valsartan and ramipril reduced the levels of IL-6 and IL-8 during hemodialysis.…”

Section: Discussionmentioning

confidence: 99%

“…10,11 Hemodialysis induces an acute increase in white blood cellular transcription and circulating concentrations of inflammatory markers. 12,13 Inflammatory cytokines, in turn, increase the expression of prothrombotic factors, such as plasminogen activator inhibitor-1 (PAI-1), 14 the major inhibitor of fibrinolysis by inactivating the tissue plasminogen activator (tPA). Increased PAI-1 antigen levels and activity in MHD patients correlate with increased risk of coronary artery disease.…”

mentioning

confidence: 99%

Comparative Effects of Angiotensin-Converting Enzyme Inhibition and Angiotensin-Receptor Blockade on Inflammation during Hemodialysis

Gamboa¹,

Pretorius²,

Todd-Tzanetos³

et al. 2012

Biomarkers of oxidative stress and inflammation predict cardiovascular events in maintenance hemodialysis patients. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) reduce cardiovascular mortality in the general population, but their benefit in maintenance hemodialysis patients is not fully explored. To test whether ACE inhibitors and ARBs differentially affect markers of oxidative stress, inflammation, and fibrinolysis during hemodialysis, we conducted a randomized, doubleblind, placebo-controlled 333 crossover study. We randomly assigned 15 participants undergoing hemodialysis to placebo, ramipril (5 mg/d), and valsartan (160 mg/d) for 7 days, with a washout period of 3 weeks in between the treatments. On the morning of the seventh day of drug treatment, participants underwent serial blood sampling during hemodialysis. Neither ramipril nor valsartan affected BP during hemodialysis. Ramipril increased IL-1b concentrations (P=0.02) and decreased IL-10 concentrations (P=0.04) compared with placebo. Valsartan and ramipril both lowered IL-6 levels during dialysis (P,0.01 for each compared with placebo). Valsartan increased F 2 -isoprostane levels, and ramipril suggested a similar trend (P=0.09). Valsartan and ramipril both lowered D-dimer levels (P,0.01 for both), whereas only ramipril seemed to prevent a rise in vWf levels (P=0.04). In summary, during hemodialysis, valsartan induces a greater anti-inflammatory effect compared with ramipril, although ramipril seems to prevent dialysis-induced endothelial dysfunction as measured by levels of vWf. A prospective clinical trial is necessary to determine whether ACE inhibitors and ARBs also differ with respect to their effects on cardiovascular mortality in this population. 23: 334-342, 201223: 334-342, . doi: 10.1681 In ESRD patients, cardiovascular death accounts for .50% of overall mortality and the risk of cardiovascular death is 30 times higher than in the general population. 1,2 Moreover, patients undergoing maintenance hemodialysis (MHD) have a 5-year survival rate of 10% after acute myocardial infarction. 3 Traditional risk factors, as used in Framingham risk scoring, only explain half of the excessive cardiovascular mortality observed in ESRD patients, 4 and it is thought that other factors contribute to the high cardiovascular mortality among ESRD patients. J Am Soc NephrolIncreased oxidative stress and inflammation may contribute to accelerated atherosclerosis and cardiovascular events in patients with MHD. 5,6 Markers of oxidative stress, such as F 2 -isoprostanes, are increased in MHD patients. 7,8 Inflammatory markers, particularly IL-1, IL 6, and TNFa, are also elevated in MHD patients and are associated with