Asymmetric Dimethylarginine Contributes to the Impaired Response to Erythropoietin in CKD-Anemia

Abstract

Erythropoietin-resistant anemia is associated with adverse cardiovascular events in patients with ESRD, but the underlying mechanism remains unclear. Here, we evaluated the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). In 54 patients with advanced CKD, erythrocyte but not plasma ADMA levels independently associated with low hemoglobin values, although levels of both types of ADMA were elevated compared with those in healthy volunteers. Furthermore, erythrocyte ADMA level associated with the erythropoietin resistance index in patients receiving a weekly injected dose of erythropoiesis-stimulating agents standardized for hemoglobin levels and body weight, whereas it correlated with the erythropoietin demand index (plasma erythropoietin units divided by the hemoglobin value) in patients not receiving erythropoiesis-stimulating agents. Compared with sham-operated controls, wild-type mice with 5/6 subtotal nephrectomy (Nx), a remnant kidney model with advanced CKD, had decreased hemoglobin, hematocrit, and mean corpuscular volume values but increased erythrocyte and plasma ADMA and plasma erythropoietin levels. In comparison, dimethylarginine dimethlaminohydrolase-1 transgenic (DDAH-1 Tg) mice, which efficiently metabolized ADMA, had significant improvements in all of the values except those for erythropoietin after 5/6 Nx. Additionally, wild-type Nx mice, but not DDAH-1 Tg Nx mice, had reduced splenic gene expression of erythropoietin receptor and erythroferrone, which regulates iron metabolism in response to erythropoietin. This study suggests that erythrocyte ADMA accumulation contributes to impaired response to erythropoietin in predialysis patients and advanced CKD mice suppression of erythropoietin receptor expression.

The Many Facets of Erythropoietin Physiologic and Metabolic Response

“…In the elderly, elevated EPO levels were associated with increased risk of death, and in renal transplant recipients higher endogenous plasma EPO was associated with cardiovascular mortality and all-cause mortality (den Elzen et al, 2010;Sinkeler et al, 2012). Elevated EPO levels may be indicative of EPO resistance resulting from underlying co-morbidities including inflammation, iron status, malnutrition and disrupted NO metabolism (Ganz and Nemeth, 2016;Yokoro et al, 2017). The increase risk of adverse effects with high exogenous EPO administration is exemplified in extreme athletes who use EPO as a performanceenhancing drug.…”

Baseline Soluble Anti-erythropoietin Antibody Level Is an Independent Associated Factor for Follow-Up Erythropoietin Demand in Maintenance Dialysis Patients With End-Stage Renal Disease: A Prospective Cohort Study

“…Anemia is considered the most frequent complication in patients with end-stage renal disease (ESRD), especially in the subpopulation on maintenance dialysis (1). It has also been identified as an independent risk factor/predictor for major cardiovascular events, including heart failure and atherosclerosis (2).…”

“…It has been demonstrated that up to 10% of patients in the erythropoietin-stimulating agent (ESA)-treated population have a lower erythropoietin response (1,4,5). Furthermore, an imbalance between the production of EPO and the demand for EPO is another pivotal reason for anemia in patients treated with ESA.…”

“…Erythropoietin demand reflects the need for erythropoietin (including endogenous and exogenous EPO) in ESRD patients in order to produce sufficient Hb to eliminate anemia (6,7). Previous studies have shown that maintenance of dialysis patients with ESRD may be characterized by a greater erythropoietin demand or require a larger amount of ESA (1,6). The erythropoietin demand index (EDI) is an indicator of the requirement for EPO, which is calculated as plasma erythropoietin units divided by the hemoglobin value (1).…”

“…Previous studies have shown that maintenance of dialysis patients with ESRD may be characterized by a greater erythropoietin demand or require a larger amount of ESA (1,6). The erythropoietin demand index (EDI) is an indicator of the requirement for EPO, which is calculated as plasma erythropoietin units divided by the hemoglobin value (1).…”