Re-evaluation
of l-carnitine in Chronic Hemodialysis
Yasuo Kudoh
Yasuo Kudoh, Kidney Center, Sapporo South One
Hospital, S1W13, Chuou-ku, Sapporo, 060-0061, Japan
Correspondence to:
Yasuo Kudoh M.D, Kidney Center, Sapporo South One Hospital, S1W13, Chuou-ku, Sapporo,
060-0061, Japan.
Email:
yasuo0302@view.ocn.ne.jp
Telephone: +81-11-271-3711
Fax: + 81-11-281-0275
Received: August 5, 2015
Revised: September 1, 2015
Accepted: September 5, 2015
Published online: October 26, 2015
ABSTRACT
L-carnitine has been administered in chronic hemodialysis
patients worldwide for the past decade. Although it has been shown that
L-carnitine deficiency can be improved by supplementation, evidence of the
beneficial effects has not been fully confirmed clinically. The reason why
there are so many controversies among the clinical trials is likely to be due
to the heterogeneity of the study protocols, such as the difference of dosage,
administration route, duration, sample size, characteristics of subjects,
reliable methods, qualified outcomes, but mainly confidence in the study itself
whether it is an RCT or not. Even meta-analysis has been influenced strongly by
these biases. In order to overcome these uncertainties, a highly sophisticated,
large scale RCT has been suggested. However, it might be quite difficult to
achieve such a trial at the moment, as Wasserstein pointed out. In this review
article, we attempt to reconcile the complicated strands concerning the
efficacy of l-carnitine in chronic hemodialysis patients one at a time.
© 2015 ACT. All rights reserved.
Key words: L-carnitine;
Hemodialysis; Anemia; Hypotension; Physical capacity
Kudoh Y. Re-evaluation of l-carnitine in
Chronic Hemodialysis. Journal of Nephrology Research 2015; 1(2):
49-60 Available from: URL:
http://www.ghrnet.org/index.php/jnr/article/view/1339
Carnitine kinetics
In order to investigate the pharmacokinetics of l-carnitine, one
compartment open model[1] for oral intake, two[2] and
three[3,4] compartment models for intravenous administration have
been utilized respectively. These analyses are quite useful not only to
understand the physiological and pathological dynamics of l-carnitine but also
to clarify an optimal carnitine supplementation method in terms of tissue
carnitine concentration.
1.
Absorption
Carnitine intake is reported to be 23-135 mg/day in adults[5] or
1-15μmol/kg/day in human[6]. Red meat contains rich carnitine such
as mutton (209mg/100g), pork loin (70mg/100g) and beef fillet (60mg/100g). On
the other hand, vegetables contains little carnitine such as broccoli
(0.3mg/100g) and wheat (0.4mg/100g). Therefore. vegans take less than 1μmol/kg/day
from food[6]. Plasma l-carnitine levels in strict vegetarians are
approximately 10-20 % lower than in adults on a mixed diet[7].
Carnitine in an omnivorous diet is absorbed from the intestinal mucosa by
passive diffusion and active transport (OCTN2: carnitine organic cation
transporter) mechanisms[5]. However, the absorption speed is
relatively slow (absorption time constant 0.025 /hr) comparing to the excretion
(excretion time constant 0.3 /hr in normal subject)[1]. Absorption
is characterized by slow mucosal uptake, prolonged mucosal retention, and a
very slow mucosal exit process[8]. After oral l-carnitine, maximum
increase in plasma carnitine was observed after several hours[1,9,10].
In addition,
it has been suggested that bioavailability is quite small, such as 16% after 2g[11],
5% after 6g[11], 5-18% after 1-6g[5] and 5-25% after
600mg-7g[6] administration, respectively. Because there is a
threshold of intestinal absorption, a large amount of oral administration is
not necessarily effective. It is suggested that the mucosal absorption of
carnitine is already saturated at the 2g dose[11]. Unabsorbed
carnitine is excreted in feces and a part of it is converted into butyrobetaine[6],
trimethylamine[12] and acyl-carnitine[13] by microbiota
in the large intestine.
2. Distribution
and tissue uptake
Absorbed carnitine is diffused to extracellular fluid space[2,14]
and taken into tissues by means of active transport[6] (Figure. 1).
The half-life of the distribution phase is about half-hour, while that of the
terminal beta phase is 2-6.5 hours after intravenous administration showing
dose-related elimination[2,11]. Because the main energy source is
supposed to be lipid in muscle[15], it is not surprising that the
Michaelis Menten (Km) constant (concentration at which membrane transport is
half maximally saturated) in muscle is thousand times lower than those in
kidney, liver and brain[16]. Total content of l-carnitine is
estimated to be 120 mmol in healthy adult[17,18], and 98% of body
carnitine is found in skeletal and cardiac muscle[4].
Cultured
muscle cells demonstrated that a high affinity component with a Km of 2-5 μM,
as well as a low affinity component with a Km of 80 μM which was changed during
maturation[19,20]. Carnitine transport in muscle strips was with a
Km of 60 μM[19]. Rebouche summarized[21] that skeletal
muscle carnitine content was only dependent on plasma carnitine concentration
at low concentrations (<70μM). In our recent study, it is demonstrated that
the active transport might be mainly depend on high affinity component (5-20μM)
in chronic hemodialysis patients[22]. Therefore, the normal plasma
carnitine concentration of 40 μM/L is sufficient to yield near maximal rates of
muscle carnitine uptake[18].
Although
passive diffusion is suggested in the human culture muscle under extremely high
concentrations[20], it is not proved in vivo[18]
and the effect of passive diffusion could be too small to be considered in
clinical condition.
3. Synthesis
and metabolism
L-carnitine is a low molecular amine (molecular weight 162) which is
produced in liver, kidney and epididymis[23] (Figure 2). Carnitine
is synthesized from only synthetic substrate, trimethyl-lysine, which is made
by the degradation of nuclear proteins such as histone and myosin. Because
there is no methylase in mammalians, lysine, monomethyl-lysine and dimethyl-lysine
are not counted as synthetic substrates of carnitine. Trimethyl-lysine is
changed to butyrobetaine in each tissue. Because the urinary excretion of
trimethyl-lysine is quite large[24], it is speculated that there is
an enough supply of synthetic substrate[25].
It has been
reported[26] that the limiting factors of carnitine synthesis are
(1) amount of trimethyl-lysine as synthetic substrate; (2) transport of
butyrobetaine to liver and kidney; (3) γ-butyrobetaine hydroxylase activity. It
is reported[27] that the transport constant of butyrobetaine to
liver is extremely large. It is speculated that the γ-butyrobetaine hydroxylase
activity is enough high by means of the studies of human liver and kidney
biopsy[28], and postmortem tissue[29].
The rate of
carnitine biosynthesis in humans has been estimated to be about 1 to 2 μmol/kg
body wt/day[6]. In our previous study[1], the carnitine
synthesis in hemodialysis patients was reduced to less than one tenth of normal
subjects. Although a minor degree of decarboxylation to β-methylcholine has
been reported[30], the metabolic clearance of l-carnitine is thought
to be negligible[5].
4. Excretion
and tissue turnover
Renal carnitine clearance is reported[14] to be 1 to 3
ml/min/kg, which is similar to that of creatinine (molecular weight 113). The
extent of reabsorption of urinary tubules is about 98-99% under baseline
conditions[23]. On the other hand, the threshold of tubular
reabsorption in healthy adults is similar in magnitude to the plasma
l-carnitine concentrations[5]. Therefore, this (threshold
homeostatic mechanism) serves to maintain circulating carnitine concentration
in a narrow normal range[6]. Actually, it is reported that urinary
recoveries during first 24 hours is 70% after 2g, and 82% after 6g intravenous
administration, respectively[11].
It is well
known that some drugs, such as valproic acid[5], zidovudine[31],
ibuprofen[32] and so on[5], interfere with the tubular
transport of l-carnitine via OCTN2. In Fanconi’s syndrome, the fractional
excretion is markedly increased to 20-30%[19].
Because
carnitine is not combined with protein in blood, the extraction rate of
dialyzer during single pass is reported to be 74%[3]. It is
estimated that weekly loss (3 session 4hr per week) is about 1000μmol in
hemodialysis patients[13,33]. The daily excretion of carnitine is
100-300 μmol in humans[16]. Thus, weekly total carnitine losses are
similar in normal subjects and hemodialysis patients[33,34], although
the dialysis loss is irreversible.
Renal
clearance of acetyl-l-carnitine was approximately fourfold greater than that of
l-carnitine in healthy adult men under baseline condition[13]. The
extraction ratios of l-carnitine and acetyl-l-carnitine during hemodialysis
were reported to be about 0.74 and 0.7, respectively[35]. Therefore,
the hemodialysis device lacks selectivity of carnitine derivatives.
The whole body turnover time is reported to be about 66 days[4].
The rate constant for the exit of l-carnitine from muscle into the central
compartment is estimated to be about 0.005 /hr, meaning that the half-life of
this process is about 5-6 days[5]. Because skeletal muscle contains
3,000-5,000 nmol total carnitine/g, it has a turnover of several days[4,18].
The slow turnover of muscle carnitine and the effectiveness of renal
reabsorption result in a slow whole body turnover[19].
Plasma and tissue
carnitine concentrations in chronic hemodialysis patients
1. Plasma
carnitine level
Plasma carnitine concentration is maintained within
narrow range, 40-50 μmol/L in normal subjects. Plasma and serum l-carnitine
levels tend to be approximately 10-20% lower in women[7,36,37]. The
extremely high concentration of carnitine in the epididymis by the action of
androgen hormones is observed[16]. Because of the regulation of
steroid hormones[38], plasma carnitine levels in normal male may be
higher than in females. On the other hand, we reported[37] that
chronic hemodialysis results in a significant reduction of plasma carnitine
levels and no significant difference is observed in plasma carnitine levels
between male and female. (Figure 3 left) It is also demonstrated[39]
recently that the histogram of plasma l-carnitine concentration in hemodialysis
patients shifted to left side (lower concentration area), comparing to that in
normal subjects. (Figure 3 right).
However, there
is still disagreement about pre-dialysis plasma level of carnitine. Our result
is consistent with those in previous reports[17,40-42], but not with
those from others[43-46], in which plasma carnitine levels recovered
to almost equal or surpass normal levels until next dialysis. Firstly,
considering the fact that meat or protein contains rich l-carnitine, the
difference in eating habits may be related in part to the discrepancy in
pre-dialysis plasma carnitine levels among countries. Secondly, it is
interesting to say that there is a negative correlation between plasma
carnitine concentration and dialysis duration[47] (Figure 4 left).
Recently, we re-confirmed an exponential correlation between plasma carnitine
level and dialysis duration, using larger sample size (more than 100 patients)
by means of enzyme cycling method[39] (Figure 4 right).
Therefore, the
reason of discrepancy about plasma carnitine concentration in chronic
hemodialysis patients is suggested to be mainly due to the difference of
dialysis duration in subjects. Talking about carnitine deficiency in
hemodialysis patients, dialysis duration has to be considered, because the
dialysis duration is thought to be relatively short in Europe and USA.
The
measurement of plasma l-carnitine has been achieved by means of DTNB method or
tandem mass spectrometer. However, it becomes easier recently to measure plasma
l-carnitine concentration by enzyme cycling method[39], which
enables automation and Kit for the l-carnitine measurement. The studies
concerning plasma carnitine level could be done more easily in near future.
2. Muscle
carnitine concentration
It is well known that the transport of carnitine from muscle to plasma
is quite slow phase[3,4]. Therefore, muscle carnitine concentration
is thought to decrease with apparent time span after the cessation of carnitine
supply. Actually, it is reported[48] that the plasma and muscle
carnitine concentration gradually decreased until it reached stable around
14-16 weeks after the end of carnitine treatment.
Therefore, it
is reasonable to think that both plasma and muscle carnitine contents might be
depleted in chronic hemodialysis patients, if the dialysis duration is enough
long[17,49,50]. In fact, it has been reported that the muscle
carnitine content in hemodialysis patients decreased to 50-70% normal[17,48,51,52]
(Figure 5), although a few suggested normal muscle carnitine concentration in
hemodialysis patients[45,46].
Pathophysiological role
of l-carnitine in chronic hemodialysis patients
1.
Physiological role of l-carnitine
Firstly, l-carnitine is an essential factor for the membrane transport
of acyl-CoA compounds, especially across the mitochondrial membrane and β-oxidation
of lipid (Figure 6). Therefore, carnitine is a key regulator of mitochondrial
energy metabolism. Secondly, l-carnitine also regulates the acetyl-CoA/CoA
ratio, thereby affecting the pyruvate dehydrogenase activity and the oxidation
metabolism of glucose. Thirdly, carnitine plays an additional role in the cell
by removing potentially toxic organic acids by esterification forming acyl
carnitine. Fourthly, several actions of l-carnitine on circulating red blood
cell were reported[53]. L-carnitine and carnitine palmitoyl
transferase in red blood cell play a role in terms of membrane phospholipid
fatty acid turnover. L-carnitine may improve the viscoelastic properties of red
blood cell by intervening on both the outer and inner side of the erythrocyte
membrane. Fifthly, the anti-inflammatory activity of l-carnitine[54]
and the prevention of apoptosis[55] were also suggested.
2.
Pathophysiological role of carnitine deficiency (animal model)
In 1988, Koizumi et al reported[56] a strain of CH3.OH mouse
with visceral fatty infiltration inherited in an autosomal recessive manner.
This mouse was later named the juvenile visceral steatosis (JVS) mouse. They
subsequently found a marked decrease of the serum, liver, and muscle carnitine
levels in JVS mice and established that this mouse was a model of systemic
carnitine deficiency.
JVS mice show
cardiac hypertrophy which is caused by enlargement of the cardiac muscle cell
associated with increases of non-collagen protein and DNA content[57]
(Figure 7). Cardiac and skeletal muscle cells of these mice exhibited a
ragged-red appearance after trichrome staining, which is observed in the
patients with mitochondrial myopathy[58]. Electron microscopy demonstrated
compression or distortion of the myofibril bundles, the increased number of
mitochondria and lipid droplets in the cells.
In the cardiac
muscle cells, the bundles of myofibrils were buried under numerous
mitochondria, suggesting the existence of disturbed contractile function in the
heart of JVS mice. In fact, most of JVS mice die of a cardiac insufficiency by
3-4 weeks after the birth. It is reported that the content of skeletal muscle
carnitine in these mice decreased to 20% normal[59] and the
mechanism of systemic carnitine deficiency might be due to the carnitine
transport defect[60,61].
3.
Pathophysiological role of carnitine deficiency (human finding)
It has been reported that inherited systemic carnitine deficiency might
be one of the causes of familial cardiomyopathy in human[62,63].
Therefore, it is reasonable to suppose that acquired carnitine deficiency may
be one of the causes of dialysis resistant cardiomegaly in patients with
chronic hemodialysis. In our previous study[37], the CTR (cardio
thoracic ratio) was inversely correlated with plasma carnitine levels. This
result strongly suggests the above–mentioned hypothesis.
Bertoli et
al reported[17] the presence of numerous lipid droplets within
muscle fiber in hemodialysis patients by histological examination. It is also
reported[64] that hemodialysis patients with muscle symptoms exhibit
a significantly lower level of free carnitine and higher acyl/free carnitine
ratio than those without symptoms. Taking account of a positive correlation
between endogenous muscle carnitine content and maximal exercise capacity in
hemodialysis patients[49], systemic carnitine deficiency may
influence the morphological and functional damage of muscle in hemodialysis
patients.
Despite the absence
of mitochondria in mammalian red blood cell (RBC), evidence for a role of
carnitine in RBC metabolism is suggested by the presence of carnitine in RBC[53].
There are some studies that found a significant negative correlation of plasma
total carnitine levels and rHuEPO (recombinant human erythropoietin)
requirement in hemodialysis patients[65,66]. Carnitine deficiency
might contribute to renal anemia in hemodialysis patients.
Optimal supplementation
method in chronic hemodialysis patients
1. Oral and
intravenous administration
L-carnitine has been supplied for the secondary deficiency in chronic
hemodialysis patients worldwide as an oral or intravenous use[22].
However, the direct comparison of oral to intravenous administration has not
been reported in these patients[67].
It has been
thought that it might be difficult to maintain high plasma carnitine level and
increase the muscle content in healthy control after oral administration[18,68],
because of the low bioavailability and kidney adjustment. However, oral
l-carnitine supplementation might be effective in hemodialysis patients,
because renal excretion is completely diminished in these patients. Accelerated
recovery of post-dialysis plasma carnitine fall by oral carnitine is reported[10].
It is also reported[69] that muscle levels of carnitine increased to
normal levels after 60 days of oral l-carnitine (2g/day) treatment. Considering
about lower bioavailability after larger dose of oral intake, it might be
useful that small oral dosage of carnitine is administered frequently.
It is known
that there are no serious side effects after oral administration, although
minor gastrointestinal symptoms such as transient nausea, vomiting and diarrhea
have been reported.
On the other
hand, there is no doubt that the intravenous administration of l-carnitine just
after hemodialysis procedure is effective. It has not been reported that the
supra-physiological level of plasma carnitine observed after intravenous
administration induced any adverse effects.
Fagher et
al reported[70] that the muscle carnitine level increased about
60% after 6 weeks of 2g intravenous carnitine administration. It is also
reported[71] that the muscle carnitine level increased 200% after 6
months of 20mg/kg intravenous administration.
If the
bioavailability is supposed to be 20%, total amount of l-carnitine absorbed
into body is 1,400 mg/week (1,000mg¡Á0.2¡Á7) after oral 1,000mg daily
supplementation. This amount might be equal to 1,500mg/week (500mg¡Á3times) after 500mg intravenous administration (after each dialysis
session). Therefore, it is suggested that oral and intravenous supplementation
might have equal efficacy from the view point of total carnitine supply,
although the plasma carnitine concentration curves after administration were
quite different[22] (Figure 8).
2. Dosage and
duration
The dosage of l-carnitine has not been established. L-carnitine
treatment regimens used up to now in hemodialysis derive from the empirical
evidence of efficacy inferred from previous studies[48,72]. Weekly
necessary dose of l-carnitine in hemodialysis patients would be calculated like
below. 1. ordinary oral intake 160mg/w; 2. synthesis 160mg/w; 3. excretion to
dialysate 160mg/w (please refer each chapter). Almost 500mg l-carnitine supply
weekly (1+2+3) might be enough dosage. Although 20mg/kg of l-carnitine after
each dialysis procedure has become the most widely used intravenous dosage in
clinical studies[53], smaller dosage might be sufficient.
The dosages of
carnitine supplemented in children on chronic dialysis have been reported to be
oral 20mg/kg/day[73,74] or intravenous 20-40mg/kg three times weekly
at the end of each dialysis session[75], which is almost same as
those in adult patients.
Early recovery of
muscle carnitine content has been reported 6 weeks after the supplementation[70].
In our recent studies, improvement of clinical outcomes such as anemia[76],
physical capacity[77], cardiac function[78],
intradialytic hypotension[78], has been observed almost 3 months
after the administration. Therefore, it is suggested that the duration of
administration should be more than 3months and l-carnitine therapy should be
discontinued if no clinical improvement has occurred within 9-12 months[79].
In summary, oral administration of
l-carnitine has been recommended to be 1-2 g after hemodialysis session or
divided dosage in UK and Germany, and 1.8-3.6 g/day (three times a day) in
Japan. However, much smaller dosage such as 500mg/day (three times a day) might
be sufficient. Intravenous dosage has been recommended to be 10-20 mg/kg after
each hemodialysis session, since 1990th. However, much smaller dosage such as
3-5 mg/kg after each hemodialysis session might be possible. Further
examination concerning the dosage of l-carnitine should be necessary.
3. Peritoneal
dialysis
Studies concerning the use of l-carnitine for peritoneal dialysis
patients are far less than those of hemodialysis patients. Because the plasma
free carnitine levels in the peritoneal dialysis patients have been reported to
be lower[80,81], oral supplementation has to be useful. Actually,
the beneficial effects of carnitine supplementation on renal anemia[82]
and lipid profile[83] have been reported in these patients. Oral
dosages in those studies were 2g/day[82] and 50mg/kg[83]
respectively, although the peritoneal administration (2g/bag) has been
highlighted recently[84].
Clinical trial of
carnitine supplementation in chronic hemodialysis patients
Carnitine has been given to hemodialysis patients for the first time in
1978 by Bizzi et al[10] in Italy, because of the clinical
benefit, as suggested by a report in a patient with systemic carnitine
deficiency[85]. Since that time, many clinical trials using
exogenous carnitine administration have been done in hemodialysis patients.
In 1994, AAKP
(American Association of Kidney Patients) carnitine renal dialysis consensus
group recommended[72] carnitine treatment for certain conditions in
dialysis patients who do not adequately respond to standard therapy, by means
of analyzing the results of 42 published studies in approximately 600
hemodialysis patients on the effects of l-carnitine supplementation. Those
conditions are 1. muscle cramps and hypotension, 2. lack of energy, 3. skeletal
muscle weakness and/or myopathy, 4. cardiomyopathy, 5. anemia of uremia
unresponsive to or requiring large doses of EPO. In 1999, the U.S. Food and
Drug Administration (FDA) granted approval for the use of the injectable
levocarnitine for the prevention and treatment of carnitine deficiency in
patients with end-stage renal disease who are undergoing dialysis.
In 2002,
Centers for Medicare & Medicaid Services (CMS) referred the matter
concerning about a national coverage decision on the use of levocarnitine for
end-stage renal disease patients to the Medicare Coverage Advisory Committee
(MCAC).
According to
the decision memo, a literature search was conducted using the following terms:
carnitine, kidney failure, chronic or renal dialysis, or dialysis. Multiple
searches resulted in 186 articles. 44 were initially excluded for the following
reasons: non-English, non-human subjects, acute renal failure. The following
inclusion criteria were applied to these 142 articles: clinical trials, human
ESRD subjects, minimum of 10 subjects, published after 1980, clinically
relevant outcome measures.
After applying
these inclusion criteria, there were 36 articles, including the 16 RCTs, 19
non-randomized clinical trials (primarily crossover design), and one case
series. The overall subject population from the 36 studies was approximately
1,100 subjects. Twenty-four studies investigated intravenous administration of
carnitine, 12 studies investigated oral administration, and 4 examined
carnitine in the dialysate solution. In general, the number of subjects in each
study was small. Only 9 of the 36 studies enrolled more than 30 subjects. The
study duration varied from as little as four weeks to greater than one year,
with a mean follow-up of 23.3 weeks. A majority of these studies utilized
double blinded methodology with a placebo control group.
Outcome
measures were grouped into following five general categories based on specific
outcome measures that are similar to categories used in the National Kidney
Foundation’s Kidney Disease Outcomes Quality Initiative (K/DOQI): 1. anemia, 2.
intra and interdialytic complications or symptoms, 3. cardiac function, 4.
exercise capacity and muscle strength, 5. lipid metabolism.
As a result,
intravenous levocarnitine was only covered in ESRD patients who have been on
dialysis for a minimum of three months for one of the following indications.
Patients must have documented carnitine deficiency, as noted by a pre-dialysis
plasma free carnitine level <40 micromol/L, along with signs and symptoms of
erythropoietin-resistant anemia or hypotension on hemodialysis.
Soon after
this decision, critical comment was published and it was suggested that new
randomized prospective controlled trial should be conducted to determine the
utility of iv l-carnitine supplementation for anemia management and refractory
dialysis associated hypotension[86].
In 2003,
National Kidney Foundation Carnitine Consensus Conference recommended[79]
the administration of l-carnitine for selected dialysis patients with clinical
manifestations of dialysis –related carnitine disorder such as anemia that is
hyporesponsive to erythropoietin therapy, intradialytic hypotension,
cardiomyopathy, and skeletal muscle dysfunction manifested as generalized
fatigability.
Although it
has been shown that L-carnitine deficiency can be improved by supplementation,
evidence of the beneficial effects has not been fully confirmed clinically. The
reason why there are so many controversies among the clinical trials is likely
to be due to the heterogeneity of the study protocols, such as the difference
of dosage, administration route, duration, sample size, characteristics of
subjects, reliable methods, qualified outcomes, but mainly confidence in the
study itself whether it is an RCT or not. Even meta-analysis has been
influenced strongly by these biases. In order to overcome these uncertainties,
a highly sophisticated, large scale RCT has been suggested. However, it might
be quite difficult to achieve such a trial at the moment, as Wasserstein
pointed out[87]. In this review article, we attempt to reconcile the
complicated strands concerning the efficacy of l-carnitine in chronic
hemodialysis patients one at a time.
1. Renal anemia
In 2002, the Medicare Coverage Advisory Committee (MCAC) reported that
the use of levocarnitine to treat ESRD patients with erythropoietin-resistant
anemia is clinically effective, and therefore, reasonable and necessary. A
total of eleven studies were reviewed[69,88-97], eight of which were
randomized controlled trials (RCTs)[88-91,93-96], concerning the
effect of carnitine on anemia parameters. All but two studies included less
than 30 patients. Eight studies involved IV carnitine, two involved oral
carnitine, and one delivered carnitine via dialysate.
Of the eleven
studies reviewed, 5 studies reported that carnitine caused an increase or
prevented a decrease in hemoglobin or hematocrit compared to placebo[69,89,91,96,97].
Of the 5 studies that examined erythropoietin requirement, 4 studies showed a
decrease in erythropoietin use after treatment with carnitine or an increase in
erythropoietin requirements in the control group[89-92].
However, the
therapeutic role of l-carnitine in the anemia of ESRD has been debated,
especially in 2005[98,99], and 2006[100,101].
In KDOQI
clinical practice guideline and clinical practice recommendations for anemia in
chronic kidney disease 2006, the Work Group reported that there is insufficient
evidence of efficacy to recommend use of l-carnitine in the management of
anemia in patients with CKD[67]. The statement is supported by
results from 6 available RCTs of IV l-carnitine administration to ESR-treated
HD patients[89-91,94,102,103].
Five of the 6
RCTs were judged to be of low quality. The RCTs were characterized by small
numbers of enrolled patients, short duration of observation, concomitant use of
IV and oral iron, adjustments in ESA dosage, high dropout rates, and
uncertainty about specific ESA and/or iron dosing during the study. A
probability of bias rendered the overall quality of evidence very low[67].
In KDIGO
clinical practice guideline for anemia in chronic kidney disease 2012, adjuvant
therapy including l-carnitine is not suggested, because there is no convincing
evidence for recommendation[104]. However, the quality of the
supporting evidence is shown as very low (2D), which means that the estimate of
effect is very uncertain, and often will be far from the truth.
In 2011,
Bonomini et al reviewed[53], concerning pharmacological use of
l-carnitine in uremic anemia. They suggested that in two studies[93,103],
l-carnitine administration did not show any favorable action on anemia, whereas
in two other studies[89,90] l-carnitine administration seemed to be
efficacious in improving the anemic condition only in a sub-group of HD
patients.
Labonia WD
reported[91] that l-carnitine treatment promoted a 38.1% reduction
in rHuEPO requirement in the active group (1g intravenously after every
dialysis session for 6months, p<0.02). This active group (responder)
was 7 out of 13 patients. Kletzmayr et al revealed[90] that
after four months of coadministration of intravenous iron and l-carnitine, the
rHuEPO requirement decreased in 8 of 19 evaluable HD patients. In these
responders, the weekly rHuEPO dose was decreased significantly by 36.9±23.3% (p<0.001).
However, the rHuEPO requirement was unchanged when all carnitine-treated
patients were compared between at study entry and after four months treatment.
This result
was consistent with those of Labonia WD[91] and the recent our study[76].
Although the beneficial effect of l-carnitine supplementation on renal anemia
was not observed in all patients, at least 40% patients (responder) showed
significant improvement of ERI (almost 40% reduction of rHuEPO dose) in our
study[76] (Figure 9). Reuter et al suggested[66] that the
apparent dichotomy of patients between responder and non-responder may depend
on the proportion of non-acetyl acylcarnitines within the total carnitine pool.
This might be coincident with recent our study[76], because
acyl/free carnitine ratio is a strong predicting factor distinguishing
responder from non-responder.
Although it
might be speculated that a low acyl/free carnitine ratio indicates a better
tendency to erythropoietin responsiveness after carnitine supplementation,
further examination must be waited to answer the question of which patients
would benefit from and should receive l-carnitine.
2.
Intradialytic hypotension and other complications
(1) Intradialytic hypotension
According to the comment of the Medicare Coverage Advisory Committee
(MCAC) in 2002, the three studies reviewed, Ahmad[105], Casciani[106]
and Fujita[107], all showed reduction in hypotensive episodes with
carnitine. Although the studies were relatively small and contained
methodological flaws, there was consistency and reproducibility of results, the
flaws were not fatal, and the magnitude of the benefit was of the moderate
size. As a result, the evidence is adequate to conclude that the use of
levocarnitine to treat hypotension on hemodialysis that is unresponsive to
usual management and interfere with dialysis is clinically effective, and,
therefore, reasonable and necessary. The use of l-carnitine for intradialytic
hypotension has been described in European Best Practice Guidelines on
Haemodialysis (EBPG) 2007[108] and K/DOQI clinical practice guidelines
for cardiovascular disease in dialysis patients 2005[109].
In 2008, Lynch
et al reported a meta-analysis concerning the effects of l-carnitine on
dialysis-related hypotension[110]. All published English-language
reports of randomized placebo controlled trial of l-carnitine supplementation
in adult long-term hemodialysis patients were assessed. Analysis of the 5
studies[94,103,105,106,111] examining the response of intradialytic
hypotension to l-carnitine supplementation yielded a pooled odds ratio of 0.28
(95% confidence interval 0.04-2.23, p=0.2). They concluded that the
available evidence does not confirm a beneficial effect of l-carnitine
supplementation on intradialytic hypotension.
However, the
small number of available studies yielded limited statistical power. In
addition, there was considerable inter-study heterogeneity. For example,
treatment length was short such as 8 weeks in two studies[106,111].
Mean age of the subjects in two studies was relatively young, 47.8 and 43.8
years old, respectively[105,111]. Outcome considered in two studies
was all or nothing assessment, carnitine 1/10 vs placebo 1/10[111]
and carnitine 0/13 vs placebo 0/13[103], respectively.
Therefore, more quantitative analysis should be required.
Recently we
reported[78] that hypotensive episodes significantly decreased from
4 to 1.3 times per month (p<0.05) 3months after the l-carnitine
supplementation comparing to placebo, although patient’s body weight did not
change significantly (Figure 10). The findings might indicate that l-carnitine
has great potential for use in the treatment of dialysis-related
hypotension.
(2) intradialytic other complications
In 2002, MCAC reported that the evidence is not
adequate to conclude that the use of levocarnitine to treat other intra and
inter dialytic complications or symptoms, such as muscle cramp, fatigue,
asthenia, and quality of the measurements is clinically effective. The studies
reported conflicting results, the outcomes were heterogeneous and non-specific,
and some studies had important methodological flaws, although 6 out of 9
studies reviewed had positive results[64,69,70,88,94,95,105,106,112].
In 2008, a
meta-analysis revealed[110] that the available evidence does not
confirm a beneficial effect of l-carnitine supplementation on dialysis-related
muscle cramping, although suggestive [a pooled odds ratio of 0.30 (95%
confidence interval 0.09-1.00, p=0.05)].
3. Cardiac
function
Although several studies[113-115] did show significant
improvement in ejection fraction ((EF) with the use of levocarnitine, these
studies were not adequately controlled. Therefore, it is not possible to
determine if the purported increase of EF were caused by levocarnitine or other
factors. The patient populations were not the same in the various studies and
therefore, conclusion about the clinical effectiveness of levocarnitine cannot
be drawn across these studies. Only two randomized double blind control study
about the relationship of l-carnitine and cardiac function have been reported
so far[45,78]. Fagher et al reported in 1985[45]
that carnitine depletion is not responsible for cardiac dysfunction in patients
on hemodialysis and there was no improvement in EF after carnitine
supplementation. However, their patients had normal levels of skeletal and
blood carnitine. Hemodialysis durations in their patients were not described.
Echocardiographic measurements were performed 16-18 h prior to dialysis. The
duration of l-carnitine administration in their study was relatively short (6
weeks).
In our current
study[78], it is not emphasized that l-carnitine has a positive
inotropic effect, because the increase of ejection fraction in treated group is
only 3% and statistical significance is marginal. However, taking account of
the significant reduction of hypotensive episodes during hemodialysis
procedure, l-carnitine treatment might positively affect cardiac function even
for the patients with normal cardiac function.
4. Physical
capacity
The benefit of l-carnitine treatment on muscle function and weakness is
not established[116-121]. Although clinical assessment of
symptomatology always presents serious problems of interpretation and reliability,
studies that used more objective measures to evaluate exercise capacity also
revealed conflicting results[70,88,103,105,122-125]. Most of these
trials used heterogeneous design or assessment methods that have been poorly
validated in dialysis patients.
Ahmad et al
reported[105] that VO2max (maximal oxygen consumption) measured
during a progressive work exercise test improved significantly and calculated mid-arm
muscle area increased in the carnitine treated group (20mg/kg intravenously,
6month) (Figure 11 left). On the other hand, Brass et al reported[88]
that l-carnitine supplementation (20mg/kg intravenously, 6month) increased
plasma carnitine concentrations, but did not affect VO2max (Figure 11 right).
After
carnitine administration, an increase of total electromyography power was
noted, suggesting that carnitine has a prevalent myotrophic effect[125].
Increased amplitude of the motor action potential, and improved motor unit
characteristics were reported[122]. Conflicting results were
reported in another study, in which no significant changes in sensory and motor
nerve conduction velocities or in vibration threshold were noted after
carnitine treatment[70].
Carnitine
supplementation lowered serum myoglobin[123] and increased about 7%
in the diameter of type I and type IIa fibers, which can utilize carnitine for
fatty acid oxidation to produce energy[124]. However, Vaux et al
reported that muscle bioenergetics failed to improve after carnitine
administration (20mg/kg intravenously, 16week) by the use of magnetic resonance
spectroscopy and near-infrared spectroscopy[103].
In order to
clarify the effects of l-carnitine on physical capacity and lipid metabolism,
CPX (cardio-pulmonary exercise test using bicycle ergometer) was performed
before and after 3 month oral l-carnitine supplementation under double blind
conditions, recently[77]. The exercise time decreased and HR (AT)
(heart rate at anaerobic threshold) increased in control group 3 months after
study period, but there was no such change observed in treated group. It was
indicated that the shift of energy source from carbohydrate to lipid makes
oxygen demand increase.
It is reported[126]
that l-carnitine supplementation resulted in RER (respiratory exchange rate)
reduction, suggesting an increase in lipid oxidation and possible glycogen
sparing. The l-carnitine supplementation might have some beneficial effects on
physical capacity in chronic hemodialysis patients due to the improvement of
lipid metabolism in muscle.
5. Lipid
profile
There is little data to support the use of levocarnitine for the
treatment of any type of dyslipidemia[118,127]. The majority of
studies showed no significant changes in lipid parameters, although a few
recent meta-analyses suggest a promising effect of l-carnitine on
LDL-cholesterol[128,129]. Moreover, there are well-established
effective lipid lowering therapies that already exist. There were no studies that
directly compared carnitine therapy to conventional lipid lowering therapy.
Trimethylamine-N-oxide
(TMO) formation after oral l-carnitine administration
Recently it is highlighted that TMO from intestinal microbial
metabolism of l-carnitine may enhance cardiovascular risk via promoting
atherosclerosis lesion development[130]. However, it is still
premature to conclude whether oral l-carnitine supplementation is really
harmful at the moment[131].
Tang et al
reported[132] that participants who had major adverse cardiovascular
events had higher baseline TMO levels (3.0-8.8 μM) compared with those who did
not have cardiovascular events (2.4-5.9μM). On the other hand, Bain et al
demonstrated[12] that plasma concentrations of TMO were continually
rising and approximately doubled from 289±236.1 to 529±237.9 μM in a two-week
period after oral administration of l-carnitine at a dose of 1g daily. It is
interesting to say that the plasma levels of TMO in hemodialysis patients
already increased more than 40 times higher than that in risky group reported
by Tang et al.
Recently, it
has been reported that there was no correlation between TMO and atherosclerosis
in hemodialysis patients[133,134]. Fukami et al reported[133]
that although oral l-carnitine supplementation was associated with increased
TMO levels, it might be beneficial on vascular injury in patients on
hemodialysis because of decreasing markers of vascular injury and oxidative
stress such as soluble forms of intracellular adhesion molecule-1 (sICAM-1),
vascular cell adhesion molecule-1 (sVCAM-1), and malondialdehyde (MDA) levels.
It is also
reported[134] that serum TMO concentrations were markedly elevated
and correlated directly with biochemical markers of nutritional status and
inversely with markers of inflammation in patients receiving hemodialysis.
There was no significant association between serum TMO concentrations and
all-cause mortality, cardiovascular death, or hospitalizations. For now, there
is no specific rationale to restrict from oral l-carnitine supplementation in
hemodialysis patients.
CONFLICT OF INTERESTS
There is no conflict of interest.
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Peer reviewer: Riham Eid El-Sayed Abo-Sayed Ahmed,
Pediatric Nephrology and Dialysis Unit, Mansoura University Children’s
Hospital, Mansoura University, Mansoura, Egypt.
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