NDT Advance Access originally published online on November 28, 2006
Nephrology Dialysis Transplantation 2007 22(3):955-956; doi:10.1093/ndt/gfl741
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Reply: potential Mode of Action of L-carnitine on uraemic anaemia
Email: a.arduini{at}iperboreal-pharma.comSir,
We thank Di Iorio et al. [1] for their interest in our paper. The findings of their study provide another piece of evidence to support the notion that L-carnitine (LC) treatment may improve the anaemic status of haemodialysis patients irrespective of EPO sensitivity. A more in-depth discussion of the potential mode of action of LC on uraemic anaemia may thus be worthwhile.
Uraemic red blood cells (RBCs) must survive a variety of chemical and physical insults (i.e. oxidative stress, haemodialysis (HD) sessions), which severely affect the biophysical properties of RBC membrane and, hence, contribute to a significant reduction of RBC life span [2]. LC has been shown to favourably affect key biophysical properties of normal erythrocytes [3]. In keeping with these actions, LC might improve renal anaemia by alleviating the deteriorated rheological properties of uraemic RBCs [4]. In addition to the biophysical intervention, LC is able to exert a favourable metabolic action in a cellular environment deprived of any sub-cellular organelle. LC is known for its role in facilitating the transport of long-chain fatty acids across the mitochondrial membrane. However, LC also plays a pivotal role in the membrane phospholipid fatty acid turnover [3], a metabolic pathway involved in the repair process of oxidatively injured membrane phospholipids. A large body of evidence indicates that uraemic RBCs are continuously exposed to oxidative stress, which may oxidatively damage their lipid and protein components [2]. Since oxidized phospholipids may severely impair membrane properties, repairing them could improve membrane integrity and potentially reduce haemolysis. Thus, despite the lack of mitochondria, evidence for a role of LC in red cell metabolism is suggested by the presence of LC and carnitine palmitoyl-transferase (CPT) in the RBC, and their involvement in membrane phospholipid fatty acid turnover. That this may be occurring in RBCs of HD patients is suggested by the observation that LC treatment of these patients partially restored the alteration of the long-chain acyl-CoA/free CoA ratio associated with significant reduction of key enzymes involved in membrane phospholipid fatty acid turnover [5].
If the above discussion argues that an important LC target is the mature, circulating RBC (peripheral action), one may not exclude the fact that the ameliorative action of LC on uraemic anaemia may be present at the level of erythropoiesis (central action). Recent evidence seem to support the latter hypothesis. Matsumura et al. [6] demonstrated that the addition of high amounts of LC (>200 µM) to erythroid colonies in cell cultures from fetal mouse liver, a major location of erythropoiesis during the embryonic period, resulted in a significant increase of such erythroid colonies. Some reports have also indicated that the elevation in inflammatory cytokines and oxidative parameters correlated with rhEPO resistance, and that LC treatment improved these impairments [7].
In an attempt to gain more definitive information on the potential action of LC on erythropoiesis, Kitamura et al. [8] investigated the erythropoietic effect of LC using cells from mouse bone marrow, where erythropoiesis takes place only after birth. The authors have clearly shown that in the presence of 0.5 or 1.0 IU/ml of rhEPO, LC at concentrations >200 µM significantly enhanced CFU-E colony formation in mouse bone marrow cell cultures.
Although these observations are still preliminary, some conjecture may be offered regarding the potential effect of LC on differentiation during RBC maturation. Programmed cell death is known to occur during the differentiation of progenitor cells. Erythropoietin contributes to RBC maturation by retarding apoptosis, thus allowing erythroid progenitors to complete their differentiation programmes. Indeed, a major negative regulation of erythropoiesis is the caspase-mediated cleavage of GATA-1 or other erythropoietic factors [9]. Mutomba et al. [10] reported that LC at millimolar levels inhibits the activation of caspases at various point in the Fas ligation pathway in Jurkat cells. Collectively, these reports suggest that LC influences erythropoiesis, possibly by inhibiting the apoptosis of progenitor cells.
A better understanding of the mechanisms involved in LC-mediated effect on uraemic anaemia, peripheral and/or central action, will help to clarify the role of LC in the treatment of renal anaemia.
Conflict of interest statement: A.A. is currently the Director of the Research and Development Department of Iperboreal Pharma Srl.
1Department of Research
and Development
Iperboreal Pharma Srl, Pescara
2Department of Medicine
Institute of Nephrology
University G. d’Annunzio, Chieti, Italy
References
- Arduini A, Bonomini M, Clutterbuck EJ, et al. (2006) Effect of L-carnitine administration on erythrocyte survival in haemodialysis patients. Nephrol Dial Transplant 21:2671–2672.
[Free Full Text] - Locatelli F, Canard B, Eckardt KU, et al. (2006) Oxidative stress in end-stage renal disease: an emerging threat to patient outcome. Nephrol Dial Transplant 18:1272–1280.
- Arduini A, Holme S, Sweeney JD, et al. (1997) Addition of L-carnitine to additive solution-suspended red cells stored at 4 degrees C reduces in vitro hemolysis and improves in vivo viability. Transfusion 37:166–174.[CrossRef][ISI][Medline]
- Matsumura M, Hatakeyama S, Koni I, et al. (1996) Correlation between serum carnitine levels and erythrocyte osmotic fragility in hemodialysis patients. Nephron 72:574–578.[ISI][Medline]
- de los Reyes B, Navarro JA, Perez-Garcia R, et al. (1998) Effects of L-carnitine on erythrocyte acyl-CoA, free CoA, and glycerophospholipid acyltransferase in uremia. Am J Clin Nutr 67:386–390.[Abstract]
- Matsumura M, Hatakeyama S, Koni I, et al. (1998) Effect of L-carnitine and palmitoyl-L-carnitine on erythroid colony formation in fetal mouse liver cell culture. Am J Nephrol 18:355–358.[CrossRef][ISI][Medline]
- Golper TA, Goral S, Becker BN, et al. (2003) L-Carnitine treatment of anemia. Am J Kidney Dis 41:S27–S34.[CrossRef][ISI][Medline]
- Kitamura Y, Satoh K, Satoh K, et al. (2005) Effect of L-carnitine on erythroid colony formation in mouse bone marrow cells. Nephrol Dial Transplant 20:981–984.
[Abstract/Free Full Text] - De Maria R, Zeuner A, Domenichelli C, et al. (1999) Negative regulation of erythropoiesis by caspase-mediated cleavage of GATA-1. Nature 401:489–493.[CrossRef][Medline]
- Mutomba MC, Yuan H, Konyavko M, et al. (2000) Regulation of the activity of caspases by L-carnitine and palmitoylcarnitine. FEBS Lett 478:19–25.[CrossRef][ISI][Medline]
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