Servicio de Nefrología, Hospital General Universitario, Gregorio Marañón, Madrid, Spain
Sir,
We have read with interest the Editorial Comment by Bommer entitled Saving erythropoietin by administering L-carnitine? [1]. We would like to submit two comments regarding that paper concerning L-carnitine and its metabolism.
L-Carnitine deficiency in patients on maintenance haemodialysis.
Total carnitine balance depends on the carnitine content and its precursors in the diet, the endogenous synthesis of carnitine, its transport to the tissues and its excretion. In the human body, 100200 µmol carnitine is synthesized per day and a normal diet contains between 300 and 400 µmol/day. Its elimination is mainly via the urinary route, with a small proportion being biliar. Renal synthesis of carnitine in terminal renal failure is, significantly diminished for obvious reasons, as is urinary excretion. Renal clearance of acylcarnitine is 48 times greater than free carnitine clearance, because of preferential free carnitine reabsorption in the tubules. The ingestion of carnitine and its precursors, L-lysine, L-methionine and its co-factors, may be very low due to diets with low protein content. In patients with advanced renal failure who do not yet require haemodialysis (HD), serum carnitine levels are usually normal, but a high acylcarnitine/free carnitine ratio is found. This is due to the fact that, although synthesis is diminished, renal elimination is reduced as well.
Patients with terminal renal failure on chronic dialysis lose considerable amounts of carnitine through HD [2]. Carnitine has a molecular weight of 162 Da, is water soluble and only a small proportion is bound to plasma proteins. This favours elimination by HD, which explains our results in terms of clearance and relationship to urea (0.74 µmol) and creatinine (0.91 µmol) clearances [2]. Mean carnitine loss per HD has been calculated to be 685 µmol [2]. In spite of the relatively higher elimination of acylcarnitines with high permeability membranes, we found no significant difference in total carnitine levels between patients who habitually used these membranes and those who used the low permeability cuprophan membrane. This means that the other components of carnitine balance are at least as important as the more or less marked loss during HD.
Therefore, a carnitine deficiency is likely in patients with low protein intake and high HD dose. The percentage of patients with low plasma free carnitine in our study [2] was high with respect to the general population on dialysis. This is probably due to several factors: a high number of malnourished patients, a large proportion of whom are on high efficiency dialysis with highly permeable membranes and because most of the patients had been dialysed for many years.
It has been observed that tissue carnitine deficiency is directly correlated to low levels of free serum carnitine and high levels of acylcarnitines. We have looked for clinical and biochemical parameters related to a low free carnitine plasma level. The latter is directly related to plasma albumin and PCR, and inversely to Kt/V. Plasma albumin depends mainly on hepatic protein synthesis and may be diminished because of liver malfunction, inflammation and lack of amino acid precursors in the diet, among other causes. PCR depends on protein ingestion. In case it is low, PCR is diminished. Endogenous carnitine synthesis may also be low due to the lack of its precursors in low protein diets. Therefore serum carnitine is related to albumin as an indicator of protein synthesis, to PCR as an indicator of protein ingestion and to Kt/V as a measurement of its perdialytic loss [2]. HD patients with a serum albumin lower than 4 g/dl, a PCR lower than 1 and a Kt/V greater than 1 (Sargent, Gohst) have carnitine deficiency. Thus, severe malnourished patients on HD exhibited low levels of serum carnitine [2]. Malnourished HD patients ingesting a low protein diet and receiving a high dialysis dose, especially in case of the use of highly permeable membranes, develop carnitine deficiency. The administration of carnitine supplements may be indicated in these patients.
Possible mechanisms through which L-carnitine may improve anaemia in HD patients.
We have measured carnitine palmitoyl transferase activity (CPT) [3], glycerophospholipid acyltransferase (LAT), free carnitine (FC) and long chain acyl carnitine (LCAC) levels in erythrocytes of HD patients and controls [4]. Patients had reduced CPT and LAT activities and increased ratios of LCAC to FC in the erythrocytes. After treatment with L-carnitine we observed a significant increase in CPT and LAT activities as well as in the long-chain acyl-CoA/free CoA ratio. This erythrocyte CPT is different from mitochondrial CPT. As suggested previously by Arduini et al. [5], L-carnitine and its acyl esters should be considered as part of the defensive biochemical network devoted to protection against free radical toxicity. This network consists of a primary defence barrier that prevents oxidative injury by scavenging the initiating species and terminating the radical propagation reactions, and a secondary defence system that eventually repairs the damage that occurs after the oxidative attack. Several reports show that carnitine protects the heart against ischaemia-reperfusion injury. More importantly, our data reveal that L-carnitine belongs to the secondary antioxidant repair system. In fact, L-carnitine induces the activity of both CPT and LAT in erythrocytes, which modulate the acyl flux in erythrocyte membranes, restoring a favourable acyl-CoA/FCoA ratio. This mechanism would favour the removal and replacement of oxidatively modified molecules, such as lysophospholipid, thereby allowing the recovery of cellular integrity. These data may help to explain the longer life span of erythrocytes observed in some uraemic patients treated with L-carnitine [6].
References
Sektion Nephrologie, Medizinische, Universitatsklinik, Heidelberg, Germany
We thank Dr Rodriguez-Benitez et al. for their letter to the editor concerning our editorial titled Saving erythropoietin by administering L-carnitine?. We agree with the authors that carnitine is removed from the serum by haemodialysis (HD). However, this does not result in a documented deficiency of carnitine. We also agree that it is likely that the quality of diet is more important than HD treatment with respect to carnitine levels in dialysis patients.
The clinical role of L-carnitine in renal anaemia and the potential mechanisms by which it may influence it are not yet proven but remain speculative. In experimental studies the mechanical stability of erythrocytes was improved by L-carnitine and in this context it is interesting to note that lipid components of the erythrocyte membrane were influenced by acetyl-carnitine [1,2]. In good agreement with these findings, a decrease in osmotic fragility of erythrocytes has been reported after carnitine therapy in non-Epo treated patients [3]. In Epo-treated patients however, a beneficial effect of carnitine on osmotic fragility has not been found and the persistent increase of absolute reticulocyte count under carnitine therapy suggests that other mechanisms than the improved stability of erythrocyte membranes must be considered to explain the Epo-saving effect of carnitine therapy in some, but not all, dialysis patients [46]. For that reason we cannot agree with the postulate of Rodriguez-Benitez et al. that carnitine therapy prolongs the life-span of erythrocytes and is followed by an improvement of anaemia in all dialysis patients. Carnitine therapy may improve anaemia in some, but clearly not all dialysis patients, and this effect is unpredictable [4].
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