L-carnitine for anemia in hemodialysis patients: a last resort.

In this issue of the Clinical Journal of the American Society of Nephrology, Mercadal and colleagues address whether the biologically active form of carnitine, L-carnitine (LC), offers an adjuvant erythropoietic effect to patients with newly diagnosedESRDundergoingmaintenance hemodialysis (1). Their hypothesis, addressed in the CARNIDIAL trial (NCT 00322322) stems fromabundant clinical and bioscientific data that have suggested a multiplicity of salutary effects of LC in the anemia of CKD. LC is adialyzable, 162-Dquaternaryamine that is not bound to albumin in plasma and is stored primarily in muscle. It is also knownas vitaminBT (T for theTenebrio species) after its discovery as a mealworm growth factor in 1952 (2). It is the product of the multistep metabolism of 6-N-trimethyllysine. Carnitine production may also be driven by the ingestion of certain foodstuffs after its methylated precursor is liberated from proteins during normal digestion, in particular, milk and red meat (hence its name). Nutritional supplements of carnitine abound. The biosynthesis of LC in humans takes place principally in the kidney and liver, a vitamin C–dependent process. After cellular entry, LC transports cytosolic fatty acids into the mitochondrion for b oxidation to acetyl coenzyme (CoA) and is thus a regulator of ketogenesis. The parent molecule is first acylated to acylcarnitine with acyl CoA by carnitine acyltransferase I, which is localized to the outer mitochondrial membrane. Subsequently, the acylated moiety is translocated into the mitochondrialmatrix by a specific translocase, resident on the outer mitochondrial membrane. Finally, acylcarnitine, via the inner mitochondrial membrane carnitine acyltransferase II, returns as carnitine to the cytosol as acyl CoA becomes engaged in b oxidation to acetyl CoA and, from there, to liberation of energy through the tricarboxylic acid cycle. Aside from its energy-productive role, especially in kidney, liver, brain, and skeletal muscle, LC has potentially beneficial roles in the maintenance of bone mass and mitigation of oxidant stress. Acting as an antioxidant, LCmay reduce lipid peroxidation, thereby reducing potential cellular membrane damage during oxidant stress (3,4). Plasma levelsofLCare less thanone tenth tissue levels, and active transport of LC into tissues takes place. The turnover time in kidney is approximately 24 minutes. Plasma LC levels—both free and total—among patients who have not yet reached ESRD may be elevated (4–6). However, there is a depression of the free-to-total LC level in patients undergoing hemodialysis, and levels may decrease 75% during a hemodialysis session because both moieties are dialyzable (7). With time, free and total plasma levels decline in patients receiving maintenance hemodialysis, thereby reducing plasma free-to-total carnitine (free and acylated forms) and free carnitine-to-acylcarnitine ratios (8). Correspondingly, skeletal muscle–free LC in hemodialysis patients may decrease (9,10). Because gut absorption of carnitine is unimpaired (11), reversal of this deficiency by oral supplementation is biologically plausible and reasonable. Manymechanisms have been attributed as causative with regard to the beneficial effects of LC in the anemia of CKD. In CKD, erythrocyte, cellular free levels are elevated, and the total carnitine level is normal, increasing the free-to-total carnitine ratio (12). However, were LC deficiency to occur, several mechanisms might contribute to the anemia of CKD.Reducedmembrane stability and enhanced osmotic fragility, with a consequent reduction of red cell half-life and suboptimal reticulocytosis, could conspire to reduce hematocrit even beyond the reduction due to erythropoietin deficiency (13). Before the erythropoietin-stimulating agent (ESA) era, Albertazzi (14) and Trovato (15) and their colleagues observed that LC supplementation (1 g/d) increased hematocrit and reticulocyte counts in their respective studies of 12 hemodialysis patients observed for 6 months and a separate, small, 12-month, double-blind, placebo-controlled trial. In Trovato and colleagues’ study (15), all 46 participants were adequately treated with folic acid, vitamin B12, and ferric gluconate at the terminus of each hemodialysis session. LC supplementation was administered per protocol, and the 24% mean hematocrit at baseline decreased 2%; in the treatment group, hematocrit increased 12% without the benefit of ESA treatment. Later, inESA-treatedpatients,Kooistraandcolleagues observed that the total LC and free levels demonstrated an inverse relationship with hematocrit in maintenance hemodialysis patients (16). In their study, LC demonstrated a beneficial effect in patients with hematocrit ,30%. However, contradictory studies challenging the utility of LC in treating anemia in hemodialysis patients emerged (17,18). Caruso and colleagues established no overall effect of LC on hemoglobin levels after 6 months of treatment in their trial (18). LC-treated Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit, Michigan