| Abstract|| |
L-Carnitine supplementation has shown beneficial effects in patients on hemodialysis. We studied 36 ESRD adult patients with a mean age of 47.5 ± 15 years to evaluate the effect of LCarnitine supplementation on hemoglobin, lipid levels and physical performance in patients on hemodialysis. The study group consisted of 18 randomly selected patients who received L-Carnitine 15 mg/kg and the control group consisted of 18 randomly selected patients who received equal volume of normal saline as a placebo three times a week for six months. Laboratory tests were performed at baseline, then monthly until the end of the study. A significant increase in the hemoglobin (Hb) and hematocrit (HCT) in the presence of unchanged doses of erythropoietin hormonal supplementation was observed (pre 79 ± 7.5 gm/l, post 103 ± 10.6 gm/l) P<0.001 (pre 24± 2 %, post 33 ± 4%) P<0.001 respectively) in the L-Carnitine treated group. Similarly total serum cholesterol (TCL) and serum triglyceride (TG) levels showed a statistically significant decrease in the study group, TCL (pre 4.6 ± 1.2, post 3.7 ± 1.1 mmol/L), P <0.03 and TG (pre 3.1 ± 1.7, post 1.8 ± 0.6 mmol/L) P < 0.004. The physical performance as assessed by mild and moderate exercise showed a trend towards improvement. There was a significant increase in free carnitine and total carnitine levels in the LCarnitine treated group. In conclusion, these results demostrate positive effect of L-Carnitine supplementation in the hemodialysis patients marked by an increase in Hb, HCT, a decrease in TCL and TG and improved physical performance in comparison to the control group.
Keywords: ESRD, Dialysis, Anemia, L-Carnitine.
|How to cite this article:|
Mitwalli AH, Al-Wakeel JS, Alam A, Tarif N, Abu-Aisha H, Rashed M, Al Nahed N. L-Carnitine Supplementation in Hemodialysis Patients. Saudi J Kidney Dis Transpl 2005;16:17-22
|How to cite this URL:|
Mitwalli AH, Al-Wakeel JS, Alam A, Tarif N, Abu-Aisha H, Rashed M, Al Nahed N. L-Carnitine Supplementation in Hemodialysis Patients. Saudi J Kidney Dis Transpl [serial online] 2005 [cited 2020 Jan 23];16:17-22. Available from: http://www.sjkdt.org/text.asp?2005/16/1/17/32946
| Introduction|| |
L-Carnitine is a quaternary amine known to transfer long chain fatty acids from cytoplasm into the mitochondrial matrix to be oxidized.  Skeletal muscles and myocardium utilize fatty acid oxidation as the main source of energy, which makes them carnitine dependent. Carnitine is synthesized in the liver and kidneys from lysine and methionine. There is marked reduction in the production of carnitine in end-stage renal disease (ESRD) patients. , Furthermore, a considerable loss of carnitine in the dialysate decreases the levels of free and total carnitine in the plasma. ,,,
L-Carnitine supplementation in ESRD patients has recently been shown to improve hemoglobin (Hb) and hematocrit (HCT) values and reduce the need for erythropoietin. , Furthermore, there is improvement of the physical performance and the histological morphology of the type I and IIa fibers of the skeletal muscles in the supplemented patients. ,,,,, Various studies have also reported the effects on cholesterol and triglycerides; one study showed transient effects on lowering triglycerides and high density lipoprotein (HDL) cholesterol levels, whereas other studies reported significant increase in the HDL cholesterol levels. ,,
The aim of this study is to assess the effect of L-Carnitine supplementation on Hb, HCT, and lipid levels (particularly total cholesterol (TCL) and triglycerides (TG), and physical performance in adult patients on maintenance hemodialysis.
| Patients and Methods|| |
We studied 36 chronic hemodialysis patients who consented to be part of the study and were randomized in a single blind manner to receive L-Carnitine or placebo at King Khalid University Hospital, Riyadh, Saudi Arabia, for a period of six months between July 2002 -December 2002.
Five patients dropped from the placebo group after two months due to traveling to another city and their data is not included in the analysis. There were 18 patients supplemented with L-carnitine (study group) and 13 patients who had the placebo (control group). The mean age of patients in both groups was 54 ± 15 years and 42 ± 14 years, respectively. There were seven (39%) males in L-Carnitine group and four (31%) males in the control group.
All ESRD patients in the study were on hemodialysis 4-5 hours, three times a week with an average KT/V of 1.2 for more than a year. The mean blood flow rate of 350 ml/min and bicarbonate dialysate flow rate of 500 ml/min were maintained during dialysis.
The selection criteria included ambulatory patients with no evidence of secondary hyperparathyroidism, severe arthritis, congestive heart failure or respiratory disease, limiting their physical ability. The patients were on the same dose of subcutaneous erythropoietin during the preceding 12 weeks and had not received blood transfusion during that period. Iron stores were adequate during the study (serum ferritin levels > 100 µg/L) and the patients were on oral iron supplement. The patients were not on any anti-lipidemic agents and there was no modification of diet during the study period.
Other parameters included baseline urea, serum creatinine, HCT, Hb, TCL, TG, calcium (Ca), phosphorus (P) and liver function tests that include serum albumin, bilirubin and liver enzymes, besides intact parathyroid hormone (I-PTH), plasma free carnitine (FC), total carnitine (TC) and acyl carnitine (AC). All investigations were performed as baseline and were repeated monthly until the end of the study. Carnitine levels (FC, TC, AC) measurements were done in a specialized lab using the following method.  A 3.16-inch circle blood spot (7µL) was punched out by standard hole punch and kept in a well of a microplate. Blood was extracted with 100 ml of methanolic solution containing 0.125 mmol carnitine and then subjected to mass spectrometry with HPLC pump and autosampler (JASCO International Company Limited, Tokyo, Japan). For free carnitine and acyl carnitine determination precursor ions scan of the peak at m/z 85 were monitored in the range of m/z 215-500. Sequence for free carnitine and acyl carnitine was precursor ion of mass 85 from 215 to 500 Da scan time = 3 seconds, cone voltage = 28 V, and collision calculated energy 25 ev. Free carnitine was calculated from the ration of FC m/z 218 to that of its internal standard D 3 C m/z 221 relative to internal standard added during sample preparation. Acyl carnitine, propionyl carnitine and palmitoyl carnitine together gave total carnitine.
The physical performance was tested on two occasions, at the beginning of the study (zero time) and at the end of the sixth month of LCarnitine supplementation (end of the study). The patients were asked to walk for a distance of 90-feet in a straight hallway and then climb up one flight of stairs with record of the time the patient took to perform each exercise. , Furthermore, any symptom that might occur such as dyspnea, muscle pain or cramps, chest pain was recorded. These two exercises were done on separate days to avoid the effect of one exercise on the other and it was also made sure that the exercises were not done on dialysis days. Patients in the L-Carnitine group received 15 mg/kg L-Carnitine (Sigma Tau Pharmaceuticals, Incorporated) intravenously after each hemodialysis session and the control group received equal amount of normal saline in the same manner.
| Statistical Analysis|| |
All the data are presented as the mean ± standard deviation. Student t-test was used to evaluate the statistical significance of various parameters and a p-value of < 0.05 was considered significant. Chi-square test was used to measure the significance of the physical performance between the two groups.
| Results|| |
In the control group, the FC and TC did not reach a statistically significant difference at the end of the study and in spite of the observed decrement of the AC levels; such reduction did not reach a statistically significant value. On the other hand, the study group reached a statistically significant increase in both FC and TC levels. Furthermore, the AC levels were related at the end of the study resulting in a more significant decrease in the AC: FC ratio as compared with the control group, [Table - 1].
The Hb and Hct in both groups were not significantly different at baseline. However, a significant increase in Hb and Hct was observed in the L-Carnitine group in the post study values in comparison to the control group, [Table - 1].
Similarly, a significant decrease in TCL and TG was noted in the L-Carnitine group in comparison to the control group, [Table - 1].
The physical performance showed improvement, since more patients in the L-Carnitine Groups were able to cover the 90-feet walk distance in < 30 seconds and climb stairs in < 60 seconds, [Table - 2]. However, the improvement in the physical performance did not reach statistically significant difference.
The decrements observed in the levels of 1-PTH were statistically significant in both groups, [Table - 1].
| Discussion|| |
ESRD patients suffer from various problems either related to renal failure or secondary to the hemodialysis procedure. Anemia is a common finding in ESRD patients resulting from decreased production of erythropoietin, iron deficiency, hyperparathyroidism, and aluminum toxicity and decreased erythrocytes survival due to osmotic fragility. Moreover there is some loss of blood during the hemodialysis procedure. ,,, In our study, iron deficiency was excluded and there was only mild hyperparathyroidism noted in the study group. Furthermore, serum aluminum levels were < 50 μg/L in both groups.
In patients undergoing hemodialysis, carnitine deficiency was reported either as a result of enhanced clearance in the dialysate, decreased biosynthesis, or reduced dietary protein intake. ,,, The TC and FC levels were low in patients undergoing chronic hemodialysis compared with the normal controls and the AC to FC ratio was higher suggesting abnormal mitochondrial oxidation. 
L-Carnitine supplementation in patients who required higher dosages of erythropoietin and had increased osmotic fragility of erythrocytes showed improvement in HCT. ,,,,,
Lipids in the erythrocyte membranes and Na-K pumps are the major factors keeping the biconcave shape of erythrocytes.  In carnitine deficiency, the osmotic fragility of erythrocytes probably results from altered lipid metabolism with increased free fatty acids that act as a natural inhibitor of the Na-K pump. , this was shown by Labonia as an improvement in the Na-K pump activity of erythrocytes after carnitine supplementation.  In another recent study, Labonia noted a 38% decrease in the requirement of erythropoietin dose after L-Carnitine supplementation.  lately Boran et al also noted a 50% reduction in erythropoietin dose after L-Carnitine supplementation.  Labonia, however, did not notice any change in the osmotic fragility of the erythrocytes and erythropoietin levels suggesting a possibility of enhancing the effect of erythropoietin on stem cells in bone marrow (erythroid precursors). In our study, there was no decrease in the dose of erythropoietin in the L-Carnitine group but we observed a significant improvement in the HCT and Hb level.
L-Carnitine therapy has shown variable effects on serum lipids. Analysis of the different Lcarnitine studies by Golper et al showed improvement in lipid levels in the majority of their patients.  Bohles et al showed a significant increase in HDL cholesterol levels with a Decrease in the AC/FC ratio.  However, Krol et al showed transient lowering effects on both TG and HDL in 14 patients.  In our study, there was a statistically significant decline in the TCL and TG levels, while there was no comparable improvement in the control group.
ESRD patients usually complain of fatigue and weakness, however, modest improvement in exercise performance occurs after erythropoietin replacement therapy.  The skeletal muscle biopsies in the hemodialysis patients compared to normal controls revealed low levels of the total and free carnitine content. ,, Studies have shown that patients on hemodialysis have 50-70% less oxygen consumption with peak exercise and this showed improvement with carnitine therapy. ,,, there is an increase in the lactate accumulation in the muscles of the hemodialysis patients who have lower exercise threshold than the normal controls.  This was associated with higher levels of AC in the muscle biopsies of the ESRD patients. Improved exercise performance and increased carnitine content (both free and total) were reported after carnitine supplementation. , Ahmad et al also showed that maximal oxygen consumption improved with progressive work exercise test after carnitine supplementation suggesting improvement in the mitochondrial oxidation with increasing exercise.  These patients were also noted to have less cramps and hypotension during hemodialysis. Type I and Type II muscle fibers use carnitine for oxidative metabolism. Giovani et al found an increase of 7% in the diameter of Type I and Type II skeletal muscle fibers and a significant decrease in atrophic fibers after L-Carnitine supplementation.  In our study, the physical performance was described by walking 90 feet distance and by going up one flight of stairs and comparing the average consumed time. Physical performance has been evaluated by different methods in hemodialysis patients. This method was utilized for convenience and was able to provide a rough estimate of the patients' physical performance. There was a trend towards improvement in physical performance though it did not reach a statistically significant level. This was probably due to the fact that changes in muscle histology and performance takes longer time to show a positive effect and/or there may be two subsets of patients, responders and non-responders to carnitine therapy as was shown by others. ,
In summary, the results of this study support the earlier positive effects of L-Carnitine supplementation in hemodialysis patients. The improvement of the hemoglobin and hematocrit values and the decline of the total cholesterol and triglyceride levels were significant. Trends in improvement of physical performance were also noted.
| Acknowledgement|| |
We would like to thank Ms Miriam G C Tampos and Ms Leonida. D. Campos for providing excellent secretarial assistance in preparing this manuscript.
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Ahmed Hassan Mitwalli
Division of Nephrology, Department of Medicine (38), King Khalid University Hospital, P O Box 2925, Riyadh 11461
[Table - 1], [Table - 2]