Asymmetric dimethylarginine contributes to the impaired response to erythropoietin in CKD-anemia

Erythropoietin-resistant anemia is associated with adverse cardiovascular events in patients with ESRD, but the underlyingmechanismremains 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 associatedwithlowhemoglobin values, althoughlevelsofboth typesofADMAwereelevatedcompared 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 levelsandbodyweight,whereasit correlatedwith theerythropoietindemandindex (plasmaerythropoietinunits 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 efficientlymetabolized ADMA, had significant improvements in all of the values except those for erythropoietin after 5/6Nx. Additionally,wild-typeNxmice,butnotDDAH-1TgNxmice, hadreducedsplenicgene expression of erythropoietin receptor anderythroferrone,which regulates ironmetabolism inresponsetoerythropoietin.This study suggests that erythrocyteADMAaccumulationcontributes toimpaired responsetoerythropoietin inpredialysispatients and advancedCKDmice via suppression of erythropoietin receptor expression.