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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2010  |  Volume : 21  |  Issue : 3  |  Page : 454-459
The role of oral L-Carnitine therapy in chronic hemodialysis patients


Nephrology Department, Urology and Nephrology Center, Mansoura University, Egypt

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Date of Web Publication26-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

How to cite this URL:
Sabry AA. The role of oral L-Carnitine therapy in chronic hemodialysis patients. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2019 Oct 14];21:454-9. Available from: http://www.sjkdt.org/text.asp?2010/21/3/454/62725

   Introduction Top


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. [1] 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. [2],[3]

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. [4] In addition; palmitoil transferase carnitine activity is redu­ced in the skeletal muscle and red cells of the dialysis patients. [5]

Anemia is an independent risk factor for the development of heart failure and a predictor of mortality in dialysis patients. [6] 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, [7] and supplemental carnitine may protect cardiac muscles against oxidative stress, hypoxia, and ischemia. [8]

A number of studies have shown improve­ments in cardiac function in patients with kid­ney failure associated with carnitine thera­py. [9],[10] 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 Top


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 Top


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 Top


[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 Top


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. [11]

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. [12]

L-Carnitine is not bound to plasma proteins and therefore is freely filtered at the glomeru­lus. [13] However, at plasma concentrations greater than approximately 60 mmol/L the fractional reabsorption begins to decrease because of partial saturation of the tubular transporter. [14]

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). [3] 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. [15]

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. [10],[16],[17] 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, [18],[19],[20] while others failed to confirm this. [21],[22],[23],[24]

Despite our use of a high oral dose of L­carnitine we did not observe an rHuEPO sa­ving effect, similar to Kletzmayr J et al [21] 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. [25]

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. [21],[22]

The salutary effects of L-carnitine on anemia center on improvement of erythrocyte survival, specifically through enhanced erythrocyte mem­brane stability. [19],[26],[27] Conversely, Kletzmayr et al [21] 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. [28],[29]

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. [30]

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. [31],[32],[33],[34]

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. [7],[18],[35],[3],[37]

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 Top


We are very grateful to Michelle Chambers, Psychological Assistant, HMP Littlehey, Hun­tingdon, UK, for the linguistic revision of the manuscript.

 
   References Top

1.Zammit VA. Carnitine acyltransferase: Func­tional significance of subcellular distribution and membrane topology. Progr Lipid Res 1999; 38:199-224.  Back to cited text no. 1      
2.Evans AM. Dialysis-related carnitine disorder and levocarnitine pharmacology. Am J Kidney Dis 2003;41(Suppl 4):S13-26.  Back to cited text no. 2      
3.Evans AM, Fornasini G. Pharmacokinetics of L-carnitine. Clin Pharmacokinet 2003;42:941­-67.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]  
4.De los Reyes B, Navarro JA, Perez-Garcia R, et al. Effects of L-carnitine on erythrocyte acylCoA, free CoA, and glycerophospholipid acyltrans­ferase in uremia. Am J Clin Nutr 1998;67:386­-90.  Back to cited text no. 4      
5.Spagnoli LG, Palmieri G, Mauriello A, et al. Morphometric evidence of the trophic effect of L-carnitine on human skeletal muscle. Nephron 1990;55:16-23.  Back to cited text no. 5  [PUBMED]    
6.Ahmad S, Robertson HT, Golper TA, et al. Multicenter trial of L-carnitine in maintenance hemodialysis patients. II. Clinical and bio­chemical effects. Kidney Int 1990;38:912-8.  Back to cited text no. 6      
7.Romagnoli GF, Naso A, Carraro G, Lidestri V. Beneficial effects of L-carnitine in dialysis patients with impaired left ventricular function: An observational study. Curr Med Res Opin 2002;18:172-5.  Back to cited text no. 7  [PUBMED]    
8.Fritz IB, Arrigoni-Martelli E. Sites of action of carnitine and its derivatives on the cardiovas­cular system: Interactions with membranes. Trends Pharmacol Sci 1993;14:355-60.  Back to cited text no. 8      
9.Van Es A, Henny FC, Kooistra MP, Lobatto S, Scholte HR. Amelioration of cardiac function by L-carnitine administration in patients on haemodialysis. Contrib Nephrol 1992;98:28-35.  Back to cited text no. 9  [PUBMED]    
10.Trovato GM, Ginardi V, Di Marco V, Dell' Aira A, Corsi M. Long term L-carnitine treat­ment of chronic anemia of patients with end­stage renal failure. Curr Ther Res 1982;31: 1042-9.  Back to cited text no. 10      
11.Rebouche CJ, Seim H. Carnitine metabolism and its regulation in microorganisms and mammals. Annu Rev Nutr 1998;18:39-61.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]  
12.Wanner C, Horl WH. Carnitine abnormalities in patients with renal insufficiency: Pathophy­siological and therapeutical aspects. Nephron 1988;50:89-102.  Back to cited text no. 12      
13.Pace S, Longo A, Toon S, Rolan P, Evans AM. Pharmacokinetics of propionyl-L-carnitine in humans: Evidence for saturable tubular reab­sorption. Br J Clin Pharmacol 2000;50:441-8.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]  
14.Engel AG, Rebouche CJ, Wilson DM, Glasgow AM, Romshe CA, Cruse RP. Primary systemic carnitine deficiency. II. Renal handling of carnitine. Neurology 1981;31:819-25.  Back to cited text no. 14      
15.Golper TA, Wolfson M, Ahmad S, et al: Multi­center trial of L-carnitine in maintenance hemodialysis patients. I. Carnitine concentra­tions and lipid effects. Kidney Int 1990;38: 904-11.  Back to cited text no. 15      
16.Centers for Medicare and Medicaid Services: 2001 Annual Report: End-stage renal disease clinical performance measures project. Am J Kidney Dis 2002;39(suppl 2):S1-98.  Back to cited text no. 16      
17.Bellinghieri G, Savica V, Mallamace A, et al. Correlation between increased serum and tissue L-carnitine levels and improved muscle symptoms in hemodialyzed patients. Am J Clin Nutr 1983;38:523-31.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]  
18.Matsumoto Y, Sato M, Ohashi H, et al. Effects of L-carnitine supplementation on cardiac mor­bidity in hemodialyzed patients. Am J Nephrol 2000;20:201-7.  Back to cited text no. 18  [PUBMED]  [FULLTEXT]  
19.Nikolaos S, George A, Telemachos T, Maria S, Yannis M, Konstantinos M. Effect of L­carnitine supplementation on red blood cell deformability in hemodialysis patients. Ren Fail 2000;22:73-80.  Back to cited text no. 19  [PUBMED]    
20.Labonia WD. L-Carnitine effects on anemia in hemodialyzed patients treated with erythro­poietin. Am J Kidney Dis 1995;26:757-64.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]  
21.Kletzmayr J, Mayer G, Legenstein E, et al. Anemia and carnitine supplementation in hemo­dialyzed patients. Kidney Int Suppl 1999;69: S93-106.  Back to cited text no. 21  [PUBMED]    
22.Caruso U, Leone L, Cravotto E, Nava D. Effects of L-carnitine on anemia in aged hemodialysis patients treated with recombinant human erythropoietin: A pilot study. Dial Transplant 1998;27:498-506.  Back to cited text no. 22      
23.Nilsson-Ehle P, Cederblad G, Fagher B, Monti M, Thysell H. Plasma lipoproteins, liver func­tion and glucose metabolism in haemodialysis patients: Lack of effect of L-carnitine supple­mentation. Scand J Clin Lab Invest 1985;45: 179-84.  Back to cited text no. 23  [PUBMED]    
24.Lilien MR, Duran M, Quak JM, Frankhuisen JJ, Schroder CH. Oral L-carnitine does not decrease erythropoietin requirement in pedia­tric dialysis. Pediatr Nephrol 2000;15:17-20.  Back to cited text no. 24      
25.Consensus Group Statement. Role of L­carmitine in treating renal dialysis patients. Dial Transplant 1994;23:177-81.  Back to cited text no. 25      
26.Arduini A, Gorbunov N, Arrigoni-Martelli E, et al. Effects of L-carnitine and its acetate and propionate esters on the molecular dynamics of human erythrocyte membrane. Biochim Biophys Acta 1993;1146:229-35.  Back to cited text no. 26  [PUBMED]    
27.Matsumura M, Hatakeyama S, Koni I, Mabuchi H, Muramoto H. Correlation between serum carnitine levels and erythrocyte osmotic fra­gility in hemodialysis patients. Nephron 1996; 72:574-8.  Back to cited text no. 27  [PUBMED]    
28.Berard E, Barrillon D, Iordache A, Bayle J, Cassuto-Viguier E. Low dose of L-carnitine improves membrane fragility of erythrocytes in hemodialysis patients. Nephron 1994;68:145.  Back to cited text no. 28      
29.Goicoechea M, Martin J, de Sequera P, et al. Role of cytokines in the response to erythro­poietin in hemodialysis patients. Kidney Int 1998;54:1337-43.  Back to cited text no. 29  [PUBMED]  [FULLTEXT]  
30.Vesela E, Racek J, Trefil L, Jankovy'ch V, Pojer M: Effect of L-carnitine supplementation in hemodialysis patients. Nephron 2001;88: 218-23.  Back to cited text no. 30      
31.US Renal Data System: Excerpts from the USRDS 2001 Annual Data Report: Atlas of End-Stage Renal Disease in the United Sates. Am J Kidney Dis 2001;38(suppl 3):S135-S146.  Back to cited text no. 31      
32.Fagher B, Cederblad G, Monti M, et al. Car­nitine and left ventricular function in haemo­dialysis patients. Scand J Clin Lab Invest 1985;45:193-8.  Back to cited text no. 32  [PUBMED]    
33.Sakurabayashi T, Takaesu Y, Haginoshita S, et al. Improvement of myocardial fatty acid meta­bolism through L-carnitine administration to chronic hemodialysis patients. Am J Nephrol 1999;19:480-4.  Back to cited text no. 33  [PUBMED]  [FULLTEXT]  
34.Trovato GM, Iannetti E, Murgo AM, Car­pinteri G, Catalano D. Body composition and longterm levo-carnitine supplementation. Clin Ther 1998;149:209-14.  Back to cited text no. 34      
35.Wanic-Kossowska M, Piszczek I, Rogacka D, Czarnecki R, Koziol L, Czekalki S. The effi­cacy of the substitution of carnivit in patients with chronic failure treated with hemodialysis. Pol Arch Med Wewn 1999;102:885-91 .  Back to cited text no. 35      
36.Sakurabayashi T, Takaesu Y, Haginoshita S, et al. Improvement of myocardial fatty acid metabolism through L-carnitine administration to chronic hemodialysis patients. Am J Nephrol 1999;19:480-4.  Back to cited text no. 36  [PUBMED]  [FULLTEXT]  
37.Pauly DF, Pepine CJ. The role of carnitine in myocardial dysfunction. Am J Kidney Dis 2003;41(4 Suppl 4):S35-43.  Back to cited text no. 37      

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Correspondence Address:
Alaa A Sabry
Lecturer of Nephrology and Internal Medicine, Urology and Nephrology Center, Mansoura University
Egypt
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    Tables

  [Table 1], [Table 2], [Table 3]

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    Abstract
    Introduction
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    Statistical Analysis
    Results
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    Acknowledgement
    References
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