|Year : 2010 | Volume
| Issue : 3 | Page : 454-459
|The role of oral L-Carnitine therapy in chronic hemodialysis patients
Alaa A Sabry
Nephrology Department, Urology and Nephrology Center, Mansoura University, Egypt
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|Date of Web Publication||26-Apr-2010|
| Abstract|| |
To evaluate the effects of L-carnitine oral supplementation on anemia and cardiac function in patients on maintenance hemodialysis (HD), we studied 55 adult chronic HD patients at our center during the period from January 2006 to June 2006 and divided them into two groups; a group of 20 patients who received 1,500 mg/day oral L-carnitine and a control group of 35 patients. Both groups were on erythropoietin therapy. Echogardiographic studies were performed before and at the end of the study. The mean hemoglobin levels were comparable in the L-carnitine group and the control group at the start and after 6 months of therapy (8.63 ± 1.77 and 9.39 ± 2.02 gm/dL, P= 0.18; 10.49 ± 1.65 and 10.92 ± 2.48 gm/dL, P= 0.76, respectively). The mean weekly maintenance dose of erythropoietin was not statistically significantly different in Lcarnitine group (80.16 ± 35.61 units/kg) and the control group (91.9 ± 38.21 units/kg, P= 0.20). In addition no significant improvement could be observed in the echogardiographic findings in the L-carnitine group after therapy. We conclude that our study revealed no significant improvement in hemoglobin, erythropoietin dose and echocardiographic findings after six months of therapy. Long-term studies including larger number of patients are required to clarify the questionable role of L-carnitine in the HD patients.
|How to cite this article:|
Sabry AA. The role of oral L-Carnitine therapy in chronic hemodialysis patients. Saudi J Kidney Dis Transpl 2010;21:454-9
| Introduction|| |
Carnitine (3-hydroxi-4-N-trimethylammoniobutanoate) is a short organic hydrosoluble molecule and is present in biological materials like free carnitine and acylcarnitines, which constitute the carnitine system. In humans, carnitine plays a pivotal role in energy metabolism through the transportation of long-chain fatty acids across the inner mitochondrial membrane and in controlling the rates of beta oxidations of long-chain fatty acids with subsequent energy production.  Plasma carnitine accounts only for approximately 1% of the total body carnitine pool, with over 98% of carnitines present in the skeletal and cardiac muscles. A small amount is also present in the kidney, liver and brain. ,
Hemodialysis (HD) may promote excessive carnitine losses through dialysis filters. Dialysis therapy can cause a decrease in both free carnitine and plasma acylcarnitines after only six months of dialysis treatment.  In addition; palmitoil transferase carnitine activity is reduced in the skeletal muscle and red cells of the dialysis patients. 
Anemia is an independent risk factor for the development of heart failure and a predictor of mortality in dialysis patients.  Furthermore, recombinant Human Erythropoietin (rHuEPO) resistance has been associated with congestive heart failure and dialysis-related hypotension L-carnitine therapy was reported to be an effective treatment for these problems associated with anemia,  and supplemental carnitine may protect cardiac muscles against oxidative stress, hypoxia, and ischemia. 
A number of studies have shown improvements in cardiac function in patients with kidney failure associated with carnitine therapy. , However, many of these studies were small or not well controlled.
We investigate in this study the role of oral L-carnitine supplementation on anemia and cardiac dysfunction management in chronic hemodialysis patients.
| Patients and Methods|| |
We recruited patients from the maintenance HD populations at the Mansoura urology and nephrology center units during the period from January 2006 to June 2006. This study was approved by our local institutional research and ethics board. We studied 55 adult chronic HD patients who were on treatment 3 times weekly for a period of at least six months. We excluded patients with erythropoietin resistance, malignancy, infection, inflammation, thyroid disorders, and claudication. During the screening period, it was also confirmed that patients were effectively dialyzed and unlikely to require changes in dialysis prescription. This assessment was based on stability of urea clearance, assessed by Kt/V at a value greater than 1.2 with less than 20% variation during the previous 3 months, during which time postdialysis weight had to be stable within 3 kg.
Pre-dialysis blood samples were obtained to determine the baseline levels of blood urea nitrogen, creatinine, calcium, phosphorus, sodium, potassium, complete blood count, serum iron, ferritin, transferrin saturation, and liver function tests.
Transthoracic Echocardiographs were performed by the same operator for patients on L-carnitine therapy before starting therapy and after 6 months later.
After baseline evaluations, the patients were randomized to carnitine therapy or placebo. We administered 1500 mg L-carnitine orally at the termination of each dialysis session in the therapy group.
All treatment-emergent adverse events occurring during the course of the study were recorded.
Patients received erythropoietin therapy subcutaneously targeting hemoglobin levels between 11-12 gm/dL with supplemental iron sac-charate therapy whenever indicated.
The study ended after 6 months, and all the patients were reassessed clinically and their same baseline laboratory investigations were repeated.
| Statistical Analysis|| |
Analysis was performed using the statistical package for social studies (SPSS) for windows software package release 11. Results were presented as the mean ±SD for normally distributed data or the median and confidence intervals for skewed data. Student t-test and Chi-squared test were applied as appropriate. A P value of < 0. 05 was considered significant.
| Results|| |
[Table 1] shows that the gender distribution and the HD durations were comparable in the Lcarnitine and control groups (male/female 12/8 and 24/11 respectively, P= 0.36) (51.36 ± 18.14 and 53.83 ± 15.17 months, respectively, P= 0.86). The patients in the L-carnitine group were older (47.66 ± 17.73 years) compared to the control group patients (37.9 ± 14.7 years), however, the difference was not statistically significant. No statistical difference was observed regarding either the cause of kidney disease or the dose of dialysis between both groups.
[Table 2] shows that at the start and 6 months after therapy, serum hemoglobin levels were comparable in the L-carnitine group and control group (8.63 ± 1.77 and 9.39 ± 2.02 gm/dL, P= 0.18, 10.5 ± 1.65 and 10.9 ± 2.48 gm/dL P= 0.76 respectively). The weekly maintenance dose of erythropoietin, the number of patients who received IV iron, the monthly dose of IV iron, or serum ferritin levels were not statistically significantly different between both groups.
[Table 3] shows no significant improvement could be observed in echogardiographic findings in the L-Carnitine group after 6 months of therapy.
| Discussion|| |
Our study showed that six months oral Lcarnitine supplementation did not decrease in erythropoietin requirement to maintain the hemoglobin levels and no improvement in the echocardiographic findings.
In healthy individuals, plasma and tissue levels of L-carnitine remain relatively constant because of homeostatic control mechanisms. The healthy human kidney plays a vital role in this control, primarily through extensive and saturable tubular reabsorption, synthesis of Lcarnitine, and selective excretion of short chain carnitine esters. HD lacks the homeostatic control mechanisms involved in the conservation of L-carnitine.
The principal biological role of L-carnitine is to facilitate the transport of fatty acids across the inner mitochondrial membrane. 
Studies evaluating L-carnitine levels in HD patients reveal that before starting maintenance hemodialysis, the mean pre-dialysis plasma levels were slightly greater than the normal range (> 50 mmol/L) indicating L-carnitine accumulation in uremia caused by impaired renal excretion of the molecule. However, during the first month of hemodialysis therapy, plasma Lcarnitine concentrations declined by approximately 30%, and after 12 months they decreased by approximately 40%, with a pattern suggesting an ongoing decline. 
L-Carnitine is not bound to plasma proteins and therefore is freely filtered at the glomerulus.  However, at plasma concentrations greater than approximately 60 mmol/L the fractional reabsorption begins to decrease because of partial saturation of the tubular transporter. 
L-Carnitine is efficiently removed from blood during HD. Within a single HD session, plasma L-carnitine levels decrease by approximately 70% to 75%. Plasma clearance of L-carnitine during HD is approximately 7.8 L/h, or 130 mL/min. This is at least 30 times greater than the expected renal clearance of L-carnitine in a healthy individual (1 to 3 mL/min).  accordingly, patients on chronic HD therapy are likely to have a dialysis-associated carnitine disorder (DCD) in which a secondary carnitine deficiency arises because of a combination of factors; inadequate intake, impaired renal synthesis of carnitine and its efficient removal by HD. In addition to the absolute deficiency of Lcarnitine encountered with a DCD, there is disruption of the normal ratio of free to acylcarnitines. 
A large number of studies have been conducted over the past 20 years to assess the efficacy of supplemental L-carnitine in treating certain dialysis-related clinical disorders. However, many of these studies have been small, retrospective trials, and few blinded, placebo-controlled large-scale trials have been conducted. In addition, the prescription of L-carnitine (e.g. dose, route, duration of treatment) and patient population (e.g. dialysis age) differ greatly from one study to the next hindering study comparisons.
There is a convincing evidence from studies conducted before the availability of rHuEPO on the efficacy of L-carnitine in correcting anemia in HD patients. ,, However, the results of the studies investigating the role of L-carnitine as adjuvant for the treatment of rHuEPO hyporesponsivness in HD patients show inconsistencies, several studies have reported effectiveness of L-carnitine in hemodialysis patients, ,, while others failed to confirm this. ,,,
Despite our use of a high oral dose of Lcarnitine we did not observe an rHuEPO saving effect, similar to Kletzmayr J et al  who did not find a clear advantage of low or highdose L-carnitine supplementation (25 mg/kg).
We did not measure L-carnitine serum level because in 1994 the American Association of Kidney disease Consensus Group noted that plasma carnitine levels have not been shown to be good predictors of the clinically effective carnitine dose. 
In our study we used L-carnitine without discrimination between those responsive and hyporesponsive patients aiming for EPO dose reduction even in responsive patients. A number of studies have shown that the patient population appears to be separated into 'responders' and 'non-responders', but could not reach a conclusion about this classification similar to our findings. ,
The salutary effects of L-carnitine on anemia center on improvement of erythrocyte survival, specifically through enhanced erythrocyte membrane stability. ,, Conversely, Kletzmayr et al  were unable to confirm an increase in erythrocyte survival time in L-carnitine-treated patients.
There are several additional cellular-based mechanisms that might explain the effect of Lcarnitine on the erythropoietic process; rHuEPO resistance has been correlated with elevation of levels of inflammatory mediators, interleukin-6, tumor necrosis factor-α, and interferon. ,
Cardiac disease is the leading cause of death among patients with ESRD accounting for almost half of all deaths in patients with and without diabetes. 
Results of studies done to investigate the role of L-carnitine therapy in improvement of myocardial function in HD patients also are not consistent. In our study no significant improvement was observed regarding myocardial function assessed by echocardiographic studies. Other studies have been performed with also negative results. ,,,
A number of studies have shown improvements in cardiac function in patients with kidney failure associated with carnitine therapy. However, many of these studies were small or not well controlled. ,,,,
We conclude that the role of L-carnitine in HD patients is still questionable. Our study revealed no observable significant improvement in requirements of erythropoietin or echocardiographic findings after 6 months of therapy. Additional randomized controlled trials of sufficient power to clarify the mechanism of action and correlation of carnitine level with clinical efficacy may lead to a better understanding of the beneficial effect of L-carnitine on HD patients.
| Acknowledgement|| |
We are very grateful to Michelle Chambers, Psychological Assistant, HMP Littlehey, Huntingdon, UK, for the linguistic revision of the manuscript.
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Alaa A Sabry
Lecturer of Nephrology and Internal Medicine, Urology and Nephrology Center, Mansoura University
[Table 1], [Table 2], [Table 3]
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