NDT Advance Access originally published online on April 12, 2006
Nephrology Dialysis Transplantation 2006 21(9):2671-2672; doi:10.1093/ndt/gfl155
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Effect of L-carnitine administration on erythrocyte survival in haemodialysis patients
Email: a.arduini{at}iperboreal-pharma.comSir,
Anaemia is a common finding in patients requiring maintenance haemodialysis (HD), and represents one of the leading causes of increased cardiovascular morbidity and mortality in these patients. While the main defect responsible for anaemia in chronic renal failure patients is inadequate production of erythropoietin, there is evidence that other factors may also be involved. Several studies have shown that L-carnitine (LC) supplementation may have a beneficial effect on renal anaemia [1], but the underlying mechanisms responsible for such an effect have not yet been elucidated.
In an attempt to obtain more conclusive evidence on the effect of LC on uraemic anaemia, a double-blind, placebo-controlled study was carried out in 29 stable HD patients with secondary LC deficiency. Patients received 20 mg/kg dry body weight of either LC or placebo (saline) i.v. after each dialysis, for 24 weeks. The primary endpoint of the study was improvement in red blood cell (RBC) survival in patients treated with LC. Exclusion criteria included: Hb <8 g/dl in past 2 months, change in rHuEPO dose in previous 4 weeks, serum ferritin <200 µg/l, urea reduction ratio <65%, PTH >60 pmol/l, blood pressure >160/105 mmHg, body weight >100 kg, or the presence of an infection, malignancy, or extrarenal cause of anaemia. Intravenous iron saccharate was used to maintain serum ferritin >200 µg/l and rHuEPO dose was adjusted in order to maintain a target pre-dialysis haematocrit between 30 and 35% throughout the entire study.
RBC survival was evaluated by the 51Cr labelling procedure, a gold standard methodology in RBC survival studies [2]. Autologous 51Cr-labelled RBCs were infused at week 0. Blood samples were taken three times a week pre-dialysis and the 51Cr activity corrected for elution and haematocrit. The T1/2 of the labelled cells was calculated using linear regression. The study was repeated at week 24.
Two placebo patients withdrew (one underwent transplantation, one due to abdominal pain), and one LC patient receiving a blood transfusion was excluded from the analysis. There was no difference in RBC survival between placebo (mean T1/2 40.2 days, SD ± 8.9, median 41.0) and LC group (mean T1/2 39.1, SD ± 7.5, median 39) at baseline. As shown in Figure 1, RBC survival increased in the LC group from baseline to week 24 by a mean of 3.6 days (SD ± 10.6, median 1.0), compared with a decrease of 4.8 days (SD ± 11.1, median –8.0 days) in the placebo group. Estimate of the treatment difference was 8.5 days (95% CI 0.3, 17.2). The median erythropoietin dose (adjusted for body weight) decreased from baseline in the LC group, compared with an increase in the placebo group, although there were no statistically significant differences between the treatment groups. In the LC group, the haemoglobin concentration increased by 0.16 g/dl (11.1 ± 1.4 vs 11.3 ± 0.8 g/dl) compared with a decrease of 0.65 g/dl (11.1 ± 1 vs 10.4 ± 1.2 g/dl) in the placebo group, and the haematocrit increased by 0.48 (33.8 ± 4 vs 34.3 ± 3.6) compared with a decrease of 1.35 (33.6 + 3.1 vs 32.3 + 3.4) in the placebo group. There were fewer intradialytic hypotensive episodes in the LC group (1.3 vs 4.5), and no difference between the two groups in adverse event rate, C-reactive protein levels and serum ferritin.
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The biophysical properties of the erythrocyte membrane and its cytoskeletal network are fundamental for RBC survival in the blood stream [3]. Indeed, RBCs must survive a variety of chemical and physical insults during their lifespan, and the loss of their elastic properties may severely compromise tissue oxygenation. Erythrocyte deformability has been found to be impaired in uraemia [4] and to correlate with shortened RBC survival time [5]. LC treatment of HD patients seems to alleviate their anaemic condition. A recent meta-analysis of the randomized LC trials performed before and after the advent of erythropoietin therapy shows a beneficial effect of LC supplements on anaemia control in maintenance HD patients [1]. This conclusion is consistent with the concept that LC may favourably affect the impaired rheological and metabolic properties of erythrocytes in HD patients [6]. Furthermore, LC has been shown to improve the visco-elastic properties of non-uraemic human RBCs [7].
Our present data show a clear tendency of LC, compared with placebo, to improve RBC survival. The statistical analysis performed on T1/2 did not reach a P-value <0.05, reaching a borderline value of 0.058. However, due to the higher variability detected in the study than that assumed on sample size calculation, the study was under powered. Furthermore, relevant haematological values increased from baseline to week 24 in the LC group, compared with a small decline in the placebo group. This was despite a lower dose of erythropoietin in the LC group, as previously reported [8]. More direct experimental evidence for the beneficial effect of LC on RBC survival comes from an RBC conservation study [9]. In a paired cross-over study, the addition of LC to the preservation solution of packed RBCs reduced haemolysis during storage and increased subsequent in vivo recovery and survival of 51Cr-labelled RBCs. In this study, it was also shown that the membrane phospholipid fatty acid turnover, a key process in the repair of oxidatively damaged phospholipids, was favourably affected by the expansion of the intra-RBC LC pool. Additional evidence that this may occur in RBCs of HD patients was provided by de los Reyes et al. [10].
We report the first randomized controlled trial of the effects of LC on erythrocyte survival in HD patients. There was a strong trend towards improved RBC survival in the treated group (P = 0.058), and this mechanism might explain in part the reported benefit of LC supplements on anaemia control in HD patients.
Conflict of interest statement. A. Arduini is currently the Director of the Research and Development Department of Iperboreal Pharma Srl.
1 Department of Research & Development Iperboreal Pharma Srl Pescara Italy2 Department of Medicine Institute of Nephrology University G. d’Annunzio Chieti Italy3 Department of Haematology and4 Division of Medicine Imperial College London Hammersmith Hospital London UK
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