Atorvastatin Increases Erythropoietin-Stimulating Agent Hyporesponsiveness in Maintenance Hemodialysis Patients: Role of Anti-Inflammation Effects

Abstract

Erythropoietin-stimulating agent (ESA) hyporesponsiveness is aggravated by chronic inflammation in maintenance hemodialysis (MHD) patients. Dyslipidemia is prevalent in MHD patients. Statin therapy has been demonstrated to not only be effective in lowering lipid levels, but also numerous pleiotropic effects including anti-inflammatory, anti-fibrotic and endothelial function improvement. Recently, a retrospective study has shown that statin therapy decreases ESA requirements in MHD patients. We conducted a prospective study to analyze the effect of statin therapy on ESA hyporesponsiveness, and especially emphasized its anti-inflammatory benefits in MHD patients. This prospective study enrolled 30 patients with baseline cholesterol >220 mg/dl. Low-dose atorvastatin (10 mg/day) was prescribed for 12 weeks. We prospectively recorded patients’ biochemistry and hematological profiles, ESA prescription and some inflammatory markers at baseline, 4 weeks and 12 weeks. Statistically significant changes were noted after 4 and 12 weeks of statin therapy for cholesterol (272.5 ± 41.1 to 184.4 ± 37.6 and 196.4 ± 40.2 mg/dl, p < 0.05) and ESA hyporesponsiveness, which demonstrated as erythropoietin to hematocrit ratio (EHR) (129.3 ± 58.2 to 122.3 ± 53.5 and 121.0 ± 53.3 EPO U/Hct/week, p < 0.05). Mean values for proinflammatory cytokines included interleukin-6 and tumor necrotic factor-α levels decreased by 30.8 and 10.6%, respectively. Thus, these data suggest that statin therapy may improve ESA hyporesponsiveness in dialysis patients. This improvement in ESA hyporesponsiveness is associated with the effects of statins on inflammation.

Endogenous Erythropoietin and the Association with Inflammation and Mortality in Diabetic Chronic Kidney Disease

“…Our results that elevated EPO levels were in large part related to the level of inflammation are in line with the described mechanisms. Interestingly, recent reports demonstrated diminished EPO resistance after statin treatment potentially through pleiotropic "inflammation-lowering" effects (27,28). However, in our study we could not detect any effect of statin treatment on the described associations.…”

Individual Response Variations to Erythropoietin Stimulating Agents in Patients on Maintenance Hemodialysis.

“…This study showed a positive significant association between statins use and ERI. This comes in agreement with several studies because of statins' pleiotropic properties that reduce inflammation [59][60][61]. By contrast, others [62] failed to show a statistical significant decrease in the CRP levels, suggesting a mechanism other than decrease in inflammation for the reduction of ERI.…”

ESAs in Dialysis Patients

“…29 Optimizing adequacy of dialysis or switching patients to alternative modalities, such as peritoneal dialysis 30 or nocturnal 31 hemodialysis, may also result in lower ESA dosage. Treating inflammation either with drugs, such as pentoxyfilline 32 or a statin, 33 or treating an underlying infection or treating hyperparathyroidism also seem effective in reducing ESA dosage without causing the Hb to fall. For some patients who are waiting for a kidney allograft, long-term ESA therapy will be necessary because blood transfusion must be avoided to minimize the risk for sensitization.…”