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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2017  |  Volume : 28  |  Issue : 3  |  Page : 477-482
Carnitine reduced erythropoietin dose required and improved cardiac function of patients on maintenance hemodialysis


1 Department of Biochemistry, Institute of Medullasin, Kamakura; Fureai Clinic Izumi, Yokahama, Kanagawa, Japan
2 Department of Biochemistry, Institute of Medullasin, Kamakura, Japan

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Date of Web Publication18-May-2017
 

   Abstract 

Intravenous administration of 2 g carnitine in every hemodialysis (3 times/week), for 8–10 months, reduced doses of darbepoetin alfa required to maintain adequate hemoglobin levels (10–11 g/dL) into 10% of the initial doses. There was also a significant increase in plasma transferrin saturation, increase in left ventricular ejection fraction, and decrease in plasma brain natriuretic peptides.

How to cite this article:
Aoki Y, Yamamoto T. Carnitine reduced erythropoietin dose required and improved cardiac function of patients on maintenance hemodialysis. Saudi J Kidney Dis Transpl 2017;28:477-82

How to cite this URL:
Aoki Y, Yamamoto T. Carnitine reduced erythropoietin dose required and improved cardiac function of patients on maintenance hemodialysis. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2017 Jul 22];28:477-82. Available from: http://www.sjkdt.org/text.asp?2017/28/3/477/206445

   Introduction Top


Patients on maintenance hemodialysis (HD) often develop anemia, cardiac dysfunction, muscle weakness, and muscle cramp. In almost all HD patients, carnitine is deficient because it is removed from the body by HD, atrophied kidneys of patients in renal failure cannot create sufficient amount of carnitine, and HD patients usually refrain from taking enough meat or fishes which contain a large amount of carnitine.

A quarter of carnitine, a quaternary ammonium with one carboxyl group, is produced in the body. The rest is taken from food. It plays an important role in lipid metabolism because it binds to acyl-coenzyme A (CoA) to produce acylcarnitine by carnitine palmitoyltransferase in the intermembrane space of mitochondria. Acylcarnitine is transported into matrix by carnitine-acylcarnitine translocalase in the internal membrane, where it is converted to acyl-CoA. Acyl-CoA is metabolized by β oxidation to produce adenosine triphosphate (ATP). Therefore, carnitine is considered to play an essential role in the metabolism of fatty acids (particularly long chain fatty acids) in the mitochondria producing ATP by transporting acyl-CoA to mitochondrial matrix.

In patients on maintenance HD, carnitine is removed through hemodiafilter causing carni- tine deficiency.

Functions of carnitine have been reported to suppress thyroid function,[1] improve of cardiac function,[2],[3] and male sterility.[4],[5]

In this report, we investigate the role of carnitine in the improvement of renal anemia and cardiac function.


   Materials and Methods Top


Determination of plasma carnitine concentration

Plasma carnitine concentration was determined as follows: the incubation mixture contained 0.1M Tris-HCL (pH 8.0) 0.5 mL, acetyl-CoA (3 mg/mL) 0.04 mL, 5,5’-dithiobis (2-nitro- benzoic acid, 1 mg/mL) 0.04 mL, carnitine acetyltransferase (Sigma, 4 mg/mL) 0.02 mL, and 0.05 mL of plasma in a final volume of 0.65 mL. Tubes were incubated at 37°C for 15 min, and the absorbance at 412 nm of the supernatant was determined to calculate carni- tine concentration in plasma.

[Table 1] shows characteristics of 98 patients enrolled in this study. Ages of patients ranged from 40 to 92 years old (36 males and 18 females). Duration of HD ranged from nine months to 39 years. The cause of chronic kidney disease was diabetes mellitus in 46 patients, chronic glomerulonephritis in 24 patients, and renal arteriosclerosis in 28 patients. Patients with severe comorbidities such as active chronic hepatitis, serious heart failure, severe gastrointestinal hemorrhage, and those with antibodies against darbepoetin alfa were excluded from this study. Darbepoetin alfa was employed as erythropoietin in this study.
Table 1: Patients' characteristics.

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Twenty-three patients were injected with 2 g carnitine at the end of every HD for 8–10 months and thereafter 1 g carnitine was injected on every HD for 10 months. HD was performed on every patient for 3.5–4 h/day, three times a week with Kt/V between 1.2 and 1.6.

Brain natriuretic peptides (BNP), serum iron, and plasma transferrin levels were determined by Hokenkagaku Institute in Yokohama. Left ventricular ejection fraction (LVEF) was determined by echocardiogram. Cardiothoracic ratio (CTR) was calculated from breast X-ray films.

Data were expressed as the mean ±SD. Student’s t-test for paired samples was applied for analysis of results.


   Results Top


As shown in [Figure 1], the plasma carnitine level of patients on maintenance HD before carnitine therapy was extremely low when compared with that of normal participants (P <0.01). After carnitine treatment for two to three months, it increased significantly to normal or above the normal levels (P <0001).
Figure 1: Plasma carnitine levels in patients on maintenance hemodialysis.
Left, normal participants: middle, patients on maintenance hemodialysis before carnitine treatment: right, patients on maintenance hemodialysis after carnitine administration for 2–3 months.


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The dose of darbepoetin alfa required to maintain hemoglobin levels at the 10–11 g/dL range in patients receiving 2 g carnitine in every HD decreased markedly as compared with those required by patients without carni- tine therapy [Figur 2]. [Figure 3] shows changes of the amount of darbepoetin alfa required between that before carnitine therapy and that after 8–10 months of carnitine administration. It can be seen carnitine therapy for 8–10 months resulted in a 90% reduction amount in the dose of darbepoetin alfa. On the other hand, patients without carnitine therapy required essentially the same dose of darbepoetin alfa.
Figure 2: Changes of amounts of darbepoetin alfa required to maintain subnormal hemoglobin levels (10–11 g/dL) in the peripheral blood during carnitine therapy. Amounts of darbepoetin alfa required were monitored for 11 months.

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Figure 3: Amounts of erythropoietin (darbepoetin alfa) required to maintain hemoglobin levels in the peripheral blood between 10 and 11 g/dL.
Left, amounts of darbepoetin alfa required before carnitine therapy, and right, those after 8–10 months of carnitine therapy.


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Effect of different doses of carnitine on the dose of darbepoetin alfa required to maintain adequate hemoglobin levels is shown in [Figure 4]. A dose of 2 g carnitine at the end of every HD session was significantly more effective in reducing the dose of darbepoetin alfa than that of 1 g carnitine as shown in [Figure 4].
Figure 4: Comparison of doses of carnitine on the amount of darbepoetin alfa required to maintain subnormal (10–11 g/dL) hemoglobin levels in the peripheral blood.
Left, 2 g carnitine. Right, 1 g carnitine.


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Although plasma ferritin levels remained essentially unchanged after carnitine therapy for 8–10 months, the level of transferrin saturation significantly increased after carnitine therapy [Figure 5].
Figure 5: Effect of carnitine administration on TSAT.
Left, TSAT of patients before canitine therapy, and that after 8–10 months of carnitine administration.
TSAT: Ttransferrin saturation.


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LVEF which shows systolic capacity of left ventricle increased significantly (P <0.001) after carnitine therapy for 8–10 months as shown in [Figure 6] also. The level of plasma BNP, on the other hand, decreased significantly (P <0.002) [Figure 7]. CTR which indicates relative volume of heart decreased slightly but not significantly [Figure 8].
Figure 6: Changes of LVEF by the treatment with carnitine for 8–10 months.
NBP: Brain natriuretic peptides


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Figure 7: Changes of BNP by carnitine administration for 8–10 months.
LVEF: Left ventricular ejection fraction.


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Figure 8: Effect of carnitine on CTR. Changes of CTR by carnitine therapy were monitored before and after carnitine therapy for 8–10 months.
CTR: Cardiothoracic ratio.


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   Discussion Top


Carnitine deficiency causes dysfunction of heart and muscle.[2],[3] Administration of carni- tine improved renal anemia.[6],[7] Carnitine also reduced the amount of erythropoietin required to treat anemia in patients on maintenance HD.[8],[9],[10],[11] Carnitine deficiency of patients on maintenance HD may result from its loss during HD. decrease synthesis by failing kidneys and poor intake of foods rich in carnitine.

The mechanism of improvement of renal anemia by carnitine treatment is not so clear until now. Although carnitine is said to reduce apoptosis of erythrocytes, because it alters lipid components in plasma membrane of erythrocytes,[6] erythrocyte survival of uremic patients is not so short as to explain every reason of renal anemia.[12] Long-chain acyl- carnitine is speculated to enhance erythro- poiesis based on the finding that palmitoyl- carnitine enhanced erythroid colony formation in the fetal mouse liver cell culture.[13] However, the effect of carnitine on the development of erythroblasts from precursor cells in the bone marrow remains to be clarified.

Carnitine plays an essential role in acyl-CoA metabolism by transporting it into the mitochondrial matrix from the cytosol, where it is oxidized by β oxidation to produce ATP and acetyl-CoA which is metabolized in TCA cycle to succinyl-CoA. Succinyl-CoA is the substrate of delta-aminolevulinic acid (ALA) synthetase, the rate-limiting enzyme in heme synthesis pathway.[14],[15] ALA formed in the mitochondrial matrix is transported into the cytosol and metabolized to protoporphyrin IX.

Administration of carnitine to patients on maintenance HD was reported to reduce the dose of the requited erythropoietin by 20- 65%.[8],[9],[10],[11] In contrast to previous reports[8],[9],[10],[11] which saved 20%-65% of erythropoietin by carnitine treatment, the present study saved 90% of that as shown in results. The reason is speculated that the amount of carnitine administered intravenously (2 g/HD, 6 g/week) is larger than that of other studies reported until now.[8],[9],[10],[11] Larger amounts of carnitine are considered to be more effective in improving renal anemia than small amounts. In fact, administration of 2 g carnitine in every HD was more effective than that of 1 g carnitine as shown in our study. Furthermore, longer duration of carnitine treatment in the present study may be another reason for the excellent effect of carnitine.[8],[9],[10],[11]

The improvement of cardiac functions such as the decrease of BNP in the plasma and the increase of LVEF are considered to be caused by enhanced metabolism of fatty acids in the mitochondria of heart muscles producing ATP.

From carnitine, trimethylamine is produced in the intestine by intestinal bacteria.[16] Tri- methylamine is metabolized to trimethylamine N-oxide by flavin-containing oxidase in the liver. Trimethylamine N-oxide is known to worsen arteriosclerosis.[16] However, trimethyl- amine cannot be produced from carnitine in other organs, other than the intestine because intestinal bacteria are not present in them. Because carnitine injected intravenously cannot be converted to trimethylamine in the body, even a large amount of carnitine injection is not expected to worsen arteriosclerosis.

In conclusion, this report showed that intravenous administration of a large amount of carnitine to patients on maintenance HD for long periods improves renal anemia markedly and also cardiac function.


   Acknowledgments Top


Technical assistance of Miss Yuko Ishimori and Miss Yu Okubo is greatly appreciated.

Conflict of interest: None declared.

 
   References Top

1.
Benvenga S, Amato A, Calvani M, Trimarchi F. Effects of carnitine on thyroid hormone action. Ann N Y Acad Sci 2004;1033:158-67.  Back to cited text no. 1
[PUBMED]    
2.
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. 2
[PUBMED]    
3.
Sakurabayashi T, Miyazaki S, Yuasa Y, et al. L-carnitine supplementation decreases the left ventricular mass in patients undergoing hemodialysis. Circ J 2008;72:926-31.  Back to cited text no. 3
[PUBMED]    
4.
Menchini-Fabris GF, Canale D, Izzo PL, Olivieri L, Bartelloni M. Free L-carnitine in human semen: Its variability in different andrologic pathologies. Fertil Steril 1984;42: 263-7.  Back to cited text no. 4
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5.
Ng CM, Blackman MR, Wang C, Swerdloff RS. The role of carnitine in the male reproductive system. Ann N Y Acad Sci 2004; 1033:177-88.  Back to cited text no. 5
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6.
Trovato GM, Ginvardi V, Marco VD, Dell’Aira AE, Corsi M. Long-term L-canitine treatment of chronic anemia of patients with endo-stage renal failure. Curr Ther Res 1982;31:1042-9.  Back to cited text no. 6
    
7.
Albertazzi A, Capelli P, Di Paolo B, Pola P, Tondi P, Vaccario O. Endocrine-metabolic effects of L-carnitine in patients on regular dialysis treatment. Proc Eur Dial Transplant Assoc 1983;19:302-7.  Back to cited text no. 7
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8.
Kadiroglu AK, Yilmaz ME, Sit D, Kara IH, Isikoglu B. The evaluation of postdialysis L- carnitine administration and its effect on weekly requiring doses of rHuEPO in hemodialysis patients. Ren Fail 2005;27:367- 72.  Back to cited text no. 8
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9.
Labonia WD. L-carnitine effects on anemia in hemodialyzed patients treated with erythro- poietin. Am J Kidney Dis 1995;26:757-64.  Back to cited text no. 9
[PUBMED]    
10.
Kudoh Y, Aoyama S, Torii T, et al. Long-term effects of oral L-carnitine supplementation on anemia in chronic hemodialysis. Cardiorenal Med 2014;4:53-9.  Back to cited text no. 10
[PUBMED]    
11.
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. 11
[PUBMED]    
12.
Arduini A, Bonomini M, Clutterbuck EJ, Laffan MA, Pusey CD. Effect of L-carnitine administration on erythrocyte survival in haemodialysis patients. Nephrol Dial Transplant 2006;21:2671-2.  Back to cited text no. 12
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13.
Matsumura M, Hatakeyama S, Koni I, Mabuchi H. Effect of L-carnitine and palmitoyl-L-carnitine on erythroid colony formation in fetal mouse liver cell culture. Am J Nephrol 1998;18:355-8.  Back to cited text no. 13
[PUBMED]    
14.
Aoki Y, Urata G, Wada O, Takaku F. Measurement of delta-aminolevulinic acid synthetase activity in human erythroblasts. J Clin Invest 1974;53:1326-34.  Back to cited text no. 14
[PUBMED]    
15.
Aoki Y, Muranaka S, Nakabayashi K, Ueda Y. delta-Aminolevulinic acid synthetase in erythroblasts of patients with pyridoxine- responsive anemia. Hypercatabolism caused by the increased susceptibility to the controlling protease. J Clin Invest 1979;64:1196-203.  Back to cited text no. 15
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16.
Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of L- carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013;19:576-85.  Back to cited text no. 16
    

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Correspondence Address:
Yosuke Aoki
Department of Biochemistry, Institute of Medullasin, Kamakura, Kanagawa
Japan
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DOI: 10.4103/1319-2442.206445

PMID: 28540882

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