Carnitine and Hemodialysis
Guido Bellinghieri, MD, Domenico Santoro, MD, Menotti Calvani, MD, Agostino Mallamace, MD,
and Vincenzo Savica, MD
● Carnitine, gamma-trimethyl-beta-hydroxybutyrobetaine, is a small molecule widely present in all cells from
prokaryotic to eukaryotic. It is an important element in the beta-oxidation of fatty acids. A lack of carnitine in
hemodialysis patients is caused by insufficient carnitine synthesis and particularly by the loss through dialytic
membranes, leading in some patients to carnitine depletion with a relative increase of esterified forms. The authors
found a decrease in plasma-triglyceride and increase of high-density lipoprotein cholesterol (HDL-Chol) in dialysis
patients during carnitine treatment. Many studies have shown that L-carnitine supplementation leads to improvements in several complications seen in uremic patients, including cardiac complications, impaired exercise and
functional capacities, muscle symptoms, increased symptomatic intradialytic hypotension, and erythropoietinresistant anemia, normalizing the reduced carnitine palmitoyl transferase activity in red cells. In addition, carnitine
supplementation may improve protein metabolism and insulin resistance. Recently, carnitine supplementation has
been approved by the US Food and Drug Administration not only for the treatment, but also for the prevention of
carnitine depletion in dialysis patients. Regular carnitine supplementation in hemodialysis patients can improve
their lipid metabolism, protein nutrition, antioxidant status, and anemia requiring large doses of erythropoietin, It
also may reduce the incidence of intradialytic muscle cramps, hypotension, asthenia, muscle weakness, and
cardiomyopathy. Am J Kidney Dis 41(S1):S116-S122.
© 2003 by the National Kidney Foundation, Inc.
INDEX WORDS: Carnitine; dialysis; metabolism; anemia; acyl to free carnitine ratio.
C
ARNITINE (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 together
with the cellular proteins required for their metabolism and transport.
The history of carnitine dates from 1905, when
Gulewitsch and Krimberg1 discovered this molecule in Liebig’s meat extract. From this time,
many studies have been carried out on the role of
carnitine and acylcarnitine in metabolism. The
main studies were addressed to (1) ␤-oxidation
of long-chain (and middle-chain) fatty acids in
mitochondria; (2) acetyl storage and transfer in
mitochondria, cells, and between organs; (3)
From the Division of Nephrology, University of Messina;
the Papardo Hospital, Messina; and Sigma-Tau, Messina,
Italy.
We acknowledge the Commemorative Association for the
Japan World Exposition (1970), Japanese Association of
Dialysis Physicians, Osaka Pharmaceutical Manufacturers
Association, and the Pharmaceutical Manufacturers Association of Tokyo for financial support to publish this supplement.
Address reprint requests to Domenico Santoro, MD, Division of Nephrology, University of Messina, C.da Conte
Coop. Sperone, Is.3 pal. E, 98168 Messina, Italy. E-Mail:
[email protected]
© 2003 by the National Kidney Foundation, Inc.
0272-6386/03/4101-0126$30.00/0
doi:10.1053/ajkd.2003.50099
S116
shuttle of activated middle-and short-chain acids
from peroxisomes to mitochondria; (4) Transport
of potentially toxic, activated acids out of mitochondria ensuring the availability of free CoA.2
The role of carnitine in long-chain fatty acids
mitochondria metabolism has been known for
more than 50 years, and just 25 years ago, the
first case of primary carnitine deficiency and its
life incompatibility was described. A chronic
carnitine deficiency induced an accumulation of
fatty acids in tissues and changes in energy
metabolism characterized by hypoglycemia, hyperammoniemia, cardiomyopathy, and severe
muscle weakness.3
In humans, carnitine plays a pivotal role in
energy metabolism through the transportation of
long-chain fatty acids across the inner mitochondrial membrane and controlling the rates of betaoxidations of long-chain fatty acids with subsequent energy production (ATP).4 The shuttle of
long-chain fatty acids into the mitochondria is
controlled by at least 3 different proteins: carnitine palmitoyltransferase I (CPT-I), acylcarnitine
translocase (CT), and carnitine palmitoyltransferase II(CPT-II); Fig 1. 5Moreover, carnitine
also is involved in glucose mitochondria metabolism.6 This action is caused by pyruvate dehydrogenase together with carnitine-acyltransferase
(CAT), which shuttle acetyl groups of acetylCoA from the mitochondria to carnitine thus
inducing acylcarnitine. The result of this action
American Journal of Kidney Diseases, Vol 41, No 1, Suppl 1 (March), 2003: pp S116-S122
CARNITINE AND UREMIA
Fig 1. The whole transport system of carnitine and
its esters from blood as far as the mitochondrial matrix.
S117
is a decrease in mitochondria levels of acyl-CoA
that would otherwise inhibit pyruvate dehydrogenase activity.
It has been shown that carnitine has other roles
in the cell correlated to the distribution of the
same enzymes (CPT-I, CPT-II, CT, CAT) not
only in mitochondria but also in other parts of the
cell.7
Under normal conditions, carnitine distribution in skeletal muscle accounts for more
than 90% of total body carnitine, whereas
only 1.6% of total body carnitine is contained
in the liver and the kidney and 0.6% in extracellular fluids.8 Brain concentration is relatively low, although it represents one of
the few organs with endogen biosynthesis capability. In body fluids, carnitine is present in
free and esterified forms (acylcarnitines). Remarkably, the proportion of esterified carnitine
may vary considerably with nutritional status,
exercise level, and disease state. In humans
under normal conditions, acylcarnitines account for about 20% of total carnitine in serum, 10% to 15% in muscle and liver and 50%
to 60% in the urine. More than 90% of filtered
carnitine (at normal plasma concentrations) is
reabsorbed by the proximal renal tubule.9 Carnitine plasma concentrations result from the
combination of intestinal rearbsorbtion, mild
endogenous synthesis, and high renal rearbsorbtion. Hemodialysis may promote excessive
losses because filters do not allow carnitine
Fig 2. Mechanisms of
transport of free carnitine
and acyl-carnitine through
the kidneys and evidence of
free carnitine losses during
hemodialysis session, because filters do not allow carnitine reabsorption.
S118
reabsorption (Fig 2). Serum carnitine is considered a problem when it is lower than 20 ␮mol/L.
Plasma concentration of free carnitine is in
dynamic balance with that of acylcarnitines, and
the acyl to free carnitine ratio is considered
normal when it is ⱕ0.4.
Acyl and free carnitine serum concentrations
are, respectively, 12.8 ⫾ 7.4 and 67 ⫾ 21.8
␮mol/L (acyl to free carnitine ratio ⱕ0,4) and in
cerebrospinal fluid, respectively, 3.5 ⫾ 1.2 e
5.4 ⫾ 2.1 ␮mol/L.10 In urine, the acyl/free carnitine ratio is modified for almost the total presence of the esterified form.
CARNITINE METABOLISM IN THE UREMIC
PATIENT
The disturbance and progressive metabolic
dysfunction of the carnitine system owing to the
uremic state is not likely to get worse during
dialysis treatment. Hemodialysis involves carnitine as one of the solutes capable of crossing the
dialyzer membrane through osmosis, which, because of the increase in the age of the patients on
dialysis, impairs the metabolic system. Older
patients on dialysis present with changes in the
serum concentration of carnitine during dialysis
treatment that are correlated to a decrease in
carnitine contents, thus, leading to a dysfunction
of carnitine metabolism and a decreased tolerance of tissues to osmotic stress.
In the absence of dialysis therapy, the uremic patient presents greater serum concentrations of free and total carnitine, reaching values between 84 and 117 ␮mol/L. Long-and
short-chain acylcarnitines show an increase
that is directly correlated to serum creatinine
and therefore to the progression of the uremic
state. Carnitine muscular concentrations greater
than those observed in the healthy subject and
alterations in the lipidic metabolism are included in these situations.11
Dialysis therapy in uremic patients determines a decrease in both free carnitine and
plasmatic acylcarnitines after only 6 months of
dialysis treatment. Such concentrations are
lower after only one single dialysis treatment.
After 6 months of treatment with carnitine
given through intravenous injection at the end
of the dialysis session, plasma concentrations
of free carnitine and acylcarnitines undoubtly
are greater than the concentrations observed in
BELLINGHIERI ET AL
healthy subjects. Concentrations above normal
can be observed immediately after the dialysis
session.12
Therefore, during dialysis treatment, there is a
loss of carnitine, but we can observe that although in the normal subject the acyl to free
carnitine ratio is 1:5, in the dialysis patient it is
1:3, both before and after dialysis treatment. In
addition to such values, we can observe in the
normal subject a loss of carnitine of about 500
mg with an acyl to free carnitine ratio of 1:1 and,
in the dialytic patient, a lower loss of carnitine of
about 180 mg with an acyl to free carnitine ratio
of 1:2 on a weekly basis.12 The special contribution of the kidney to the carnitine systemic balance is more evident when we observe subjects
on a vegeterian diet characterized by very low
carnitine content, which is present, on the contrary, in a great number in an omnivorous diet
(ie, diet includes meat). It is worth noting that
almost the same loss of carnitine can be observed
in both vegeterians and uremic patients, compared with carnitine dietary contents, which undoubtely are greater in the dialysis patient. Vegeterians show a normal acyl to free carnitine ratio
against low carnitine contents. Quantitative and
qualitative alterations in the carnitine present in
urine also are noteworthy: lacto-ovovegeterians
eliminate about 180 mg of carnitine with an acyl
to free carnitine ratio of 5:1, whereas vegeterians
eliminate about 100 mg of carnitine with an acyl
to free carnitine ratio of 34:1.13
It is evident that the exclusion of the kidney
leads to an alteration in the acyl to free carnitine
ratio, but the exclusion of the kidney does not
explain the loss of carnitine including problems
concerning its synthesis, transport, and enzymes.14 As far as the synthesis is concerned, the
absence of the kidney makes the liver the main
source of endogenous carnitine. The hypothesis
that the liver synthesis may be inhibited or reduced has not been investigated yet. It is well
known that the plasmatic concentration of ␧-Ntrimetyl-lisyne, as a former in the carnitine synthesis, is considerably greater than that in the
normal subject, who does not show noteworthy
levels.14
The transportation of carnitine leads to different impairments. The increase in ␧-N-trimetyllisyne inhibits in a competitive way the highaffinity carnitine carrier, Na⫹-dependent, organic
CARNITINE AND UREMIA
cation/carnitine transporter (OCTN2), which is
itself transported. In addition, even worsening its
function, the same carrier is inhibited by some
drugs, ie, cefsoludine, emetin, and cortisone,
which are used in the therapy of the dialytic
patient.15 The metabolic effects of decreased
transportation of carnitine are exemplified by a
gene deletion animal models codifying for
OCTN2 in which hypertriglyceride levels can be
observed.16
As far as the carnitine-dependent enzymes are
concerned, it has been observed that the palmitoiltransferase carnitine activity is reduced in the
skeletal muscle and in the red cells of the dialysis
patient.17,18
It is well known that patients on hemodialysis have low plasmatic carnitine concentrations, although they have a diet with a normal
carnitine intake and a loss during dialysis
lower than the loss of normal subjects through
urinary excretion. Patients on hemodialysis
treated for more than 12 months with Lcarnitine intravenously have normal plasmatic
values of carnitine at the end of a dialysis
session. Carnitine washout for 4 months induces a mild reduction of plasmatic values.
The reintroduction of L-carnitine for 4-months
in the dialysate does not increase plasmatic
values.19 The importance of such variations in
plasmatic carnitine values is correlated to
changes in the composition of skeletal muscle
fibers. Indeed, at the end of this period, reduction of diameter of type I fibers was observed.
Type II fibers remained unchanged. For this
reason, it has been concluded that carnitine has
a specific trophic effect on type I fibers, which
are characterized by oxidative metabolism.
Change of carnitine supplementation route,
through the introduction in the dialysate to
prevent the osmotic loss during the dialysis
session, did not improve the ability of skeletal
muscle to determine a normal intake of carnitine. Skeletal muscle needs intravenous route
administration to induce a oxidative functional
phenotype.
RECENT STUDIES ON CARNITINE IN UREMIC
PATIENTS
Several studies have reported the therapeutic
effects of L-carnitine in hemodialysis patients.
The main conditions that have had beneficial
S119
effects from carnitine supplementation are skeletal and cardiac damage, anemia, hypotension,
intradialytic arrhythmia, and dyslipidemia.20-31
Our group showed a reduction of asthenia and
cramps after L-carnitine treatment that was correlated with increased levels of the metabolite in
blood and muscle (Fig 1).21
Brass et al.22 studied the effects of exercise
capacity in patients with end-stage renal disease
after carnitine supplementation. In this randomized, placebo-controlled study, patients were assigned to receive carnitine (20 mg/kg) and a
placebo intravenously for 24 weeks. They found
that patients treated with carnitine showed statistically significant smaller deterioration in VO2max
(P ⫽ .009) and improvement of fatigue domain
(P ⫽ 0.03) using the kidney disease questionnaire (KDQ).
Another study,23 evaluated the concentration
of carnitine and glycogen in the skeletal muscle
of patients in hemodialysis, starting from the
point that plasmatic carnitine concentrations do
not reflect the carnitine tissue content. Comparing the skeletal muscle of normal subjects they
observed (1) similar levels of total carnitine with
reduced levels of free carnitine; (2) skeletal
muscle of total and free carnitine significantly
reduced; (3) negative correlation between total
and free skeletal muscle carnitine and increased
age on dialysis; (4) no correlation between plasmatic and skeletal muscle carnitine concentration; (5) glycogen concentration significantly
higher, probably because of the changes in type
of muscle fibers observed in uremic patients or
lower physical activity.
Matsumoto et al24 studied the effects of 6
months of treatment with L-carnitine (15 mg/kg
intravenously at the end of each dialysis session)
on lipid metabolism, free radicals, and red cell
count. They showed that L-carnitine treatment
induced a significant reduction in plasmatic levels of total and HDL cholesterol (P ⬍ 0.05),
significant increase of plasmatic antioxidant ability (P ⬍ 0.001) associated with a reduction of
malonyl-aldeide (P ⬍ 0.001) plasmatic concentrations, a significant reduction of intrared cell
glutation concentrations (P ⬍ 0.001), and reduced erythropoietin consumption.
In another study, Matsumoto et al25 evaluated
the effects of 3 months of treatment with Lcarnitine (500 mg/d oral) on anemia in a hemodi-
S120
alysis patient resistant to erythropoietin treatment. The results showed an increase in Ht levels
(P ⫽ 0.003) and total ability of iron binding (P ⫽
0.05) together with a significant reduction of
ferritin serum levels (P ⫽ 0.005).
De los Reyes et al18 studied the intrared cell
carnitine and acylcarnitine variations and CPT
activity in uremic patients versus normal subjects. They found the following alterations: higher
concentration of free carnitine, lower proportion
of long-chain acyl-CoA versus free CoA, reduced activity of CPT and glycerophospholipid
acyltransferase, and higher long-chain acyl to
free carnitine ratio. They concluded that Lcarnitine treatment induced a positive effect on
these parameters through an improvement of
acylation and reacylation processes of red cell
membrane.
A defect in sodium transport system has been
shown in uremic patients, which was improved
by L-carnitine supplementation. The average
value of sodium efflux of dialysis patients
(through the Na⫹/K⫹ oubain-sensitive pump),
is significantly reduced, whereas sodium content
is higher, and there are no differences in sodium
passive permeability.26
Matsumura et al27 also showed that the serumfree and total carnitine levels, but not the acylcarnitine, correlate to erythrocyte osmotic fragility
evaluated as a point of maximal emolysis, starting emolysis, and average of final emolysis.
Moreover, both types of carnitine correlate to
erythropoietin dosage. Low serum levels of free
carnitine worsen the condition of erythrocyte
osmotic fragility and negatively influence the
therapeutic efficacy of erythropoietin on anemia.
Nikolaos et al28 showed that 3 months of
treatment with L-carnitine (30 m/kg for dialysis
session) significantly reduces the deformability
of red blood cells (P ⬍ 0.004) and significantly
increases Ht (P ⬍ 0.001).28
Echocardiographic measurements of cardiac
activity have been performed on dialysis patients
to study the effect of chronic oral supplementation of L-carnitine; the results showed a statistically significant improvement of systolic and
diastolic function of left ventricula.29 Sakurabayashi et al.30 performed a myocardial scintigraphy using beta-methyliodophenyl pentadecaonic
acid (BMIPP), which showed improved cardiac
BELLINGHIERI ET AL
Fig 3. Asthenia and cramps in hemodialysis patients. Treatment: oral carnitine (2 g/d), placebo. (Reprinted with permission from Bellinghieri et al.20)
activity connected to lower time of washout of
BMIPP (P ⬍ 0.05).30
Recently, Hurot et al31 performed a systematic
review to determine the effects of L-carnitine in
maintenance hemodialysis patients. They analyzed, from 1978 to 1999, data from 481 patients
in 21 trials in which L-carnitine was used and
examined changes in serum triglycerides, cholesterol fractions, hemoglobin levels, erythropoietin
dose, and other symptoms (muscle function, exercise capacity, and quality of life). In their
conclusion, L-carnitine was not recommended
for treating the dyslipidemia of maintenance hemodialysis patients, but they suggest the Lcarnitine could be used successfully for treating
anemia.
Recently, carnitine supplementation has been
approved by the US Food and Drug Administra-
CARNITINE AND UREMIA
tion not only for the treatment, but also for the
prevention of carnitine depletion in dialysis patients.
Available studies on carnitine supplementation suggest the use of this molecule in dialysis,
especially for those patients with cardiac complications, impaired exercise and functional capacities, lack of energy affecting quality of life, and
increased episodes of hypotension. Moreover, in
some patients, the improved stability of erythrocyte membranes may decrease erythropoietin
requirements, thus, leading to a reduction of
dialytic costs.
REFERENCES
1. Gulewitsch W, Krimberg R: Zur Kenntnis der Extraktivstoffe der Muskeln. Z. Physiol Chem 45:326-330, 1905
2. Wolfgang R: Carnitine: Historical overview, in Seim
H, Loster H (eds): Carnitine Pathobiochemical Basis and
Clinical Applications. Bochum, Germany, Ponte Press Verlags-GmbH, 1996, pp 3-7 (chap 1)
3. Karpati G, Carpenter S, Engel AG, et al: The syndrome
of systemic carnitine deficiency. Clinical, morphologic, biochemical, and pathophysiologic features. Neurology 25:1624, 1975
4. Zammit VA: Carnitine acyltransferase: Functional significance of subcellular distribution and membrane topology. Progress Lipid Res 38:199-224, 1999
5. Bremer J: The role of carnitine in intracellular metabolism. J Clin Chem Clin Biochem 28:297-301, 1990
6. Sidossis LS, Sturt CA, Shulman GI, Lopaschuck GD,
Wolfe RR: Glucose plus insulin regulate fax oxidation by
controlling the rate of fatty acid entry into the mitochondria.
J Clin Invest 98:2244-2250, 1996
7. Peluso G, Nicolai E, Reda E, Benatti P, Barbarisi A,
Calvani M: Cancer and anticancer therapy-induced modifications on metabolism mediated by carnitine system. J Cell
Physiol 182:339-350, 2000
8. Bremer J: The role of Carnitine in cell metabolism, in
de Simone C and Famularo G (eds): Carnitine Today. Heidelberg, Germany, Springer-Verlag, 1997, pp 1-37
9. Ferrari R, Di Mauro S, Shervood G: L-Carnitine and its
Role in Medicine: From Function to Therapy. London,
England, Academic Press, 1992
10. Rubio JC, de Bustos F, Molina JA, et al: Cerebrospinal fluid carnitine levels in patients with Alzheimer’s disease. J Neurol Sci 155:192-195, 1998
11. McGarry JD, Mannaerts GP, Foster DW: A possible
role for malonyl-CoA in the regulation of hepatic fatty acid
oxidation and keratogenesis. J Clin Invest 60:265-270, 1977
12. Evans AM, Faull R, Fornasini G, et al: Pharmacokinetics of L-carnitine in patients with end-stage renal disease
undergoing long-term haemodialysis. Clin Pharmacol Ther
68:238-249, 2000
13. Shaw RD, Li BUK, Hamilton JW, Shug AL, Olsen
WA: Carnitine transport in rat small intestine. Am J Physiol
245:G376-G381, 1983
14. Wanner C, Förster-Wanner S, Rössle C, Furst P,
S121
Schollmeyer P, Horl WH: Carnitine metabolism in patients
with chronic renal failure: Effect of L-carnitine supplementation. Kidney Int Suppl 22:132S:135S, 1987
15. Ohashi R, Tamai I, Yabuuchi H, et al: Na(⫹)dependent carnitine transport by organic cation transporter
(OCTN2): Its pharmacological and toxicological relevance.
J Pharmacol Exp Ther 291:778-784, 1999
16. Zhu Y, Jong MC, Frazer KA, et al: Genomic interval
engineering of mice identifies a novel modulator of triglycerides production. Proc Natl Acad Sci U S A 97:1137-1142,
2000
17. Lennon DL, Shrago E, Madden M, Nagle F, Hanson
P, Zimmerman S: Carnitine status, plasma lipid profiles, and
exercise capacity of dialysis patients: Effects of a submaximal exercise program. Metabolism 35:728-735, 1986
18. De los Reyes B, Navarro JA, Perez-Garcia R, et al:
Effects of L-carnitine on erythrocyte acyl-CoA, free CoA,
and glycerophospholipid acyltransferase in uremia. Am J
Clin Nutr 67:386-390, 1998
19. Spagnoli LG, Palmieri G, Mauriello A, et al: Morphometric evidence of the trophic effect of L-carnitine on human
skeletal muscle. Nephron 55:16-23, 1990
20. Guarnieri G, Situlin R, Biolo G: Carnitine metabolism in uremia. Am J Kidney Dis 38:S63-67, 2001
(suppl 4)
21. Bellinghieri G, Savica V, Mallamace A, et al: Correlation between increased serum and tissue L-Carnitine levels
and improved muscle symptoms in hemodialysis patients.
Am J Clin Nutr 38:523-531, 1983
22. Brass EP, Adler S, Sietsema KE, Hiatt WR, Orlando AM, Amato A: Intravenous L-Carnitine increases
plasma carnitine, reduces fatigue, and may preserve exercise capacity in hemodialysis. Am J Kidney Dis 37:10181028, 2001
23. Debska-Slizien, Kawecka A, Wojanarowsky K, et al:
Correlation between plasma carnitine, muscle carnitine and
glycogen levels in maintenance hemodialysis patients. Int J
Artif Organs 23:90-96, 2000.
24. Matsumoto Y, Sato M, Ohashi H, et al: Effects of
L-carnitine supplementation on cardiac morbidity in haemodialysis patients. Am J Nephrol 20:201-207, 2001
25. Matsumoto Y, Amano I, Hirose S, et al: Effects of
L-carnitine supplementation on renal anemia in poor responders to erythropoietin. Blood Purif 19:24-32, 2001
26. Labonia WD, Morelli OH Jr, Gimenez MI, Freuler
PV, Morelli OH: Effects of levo-carnitine on sodium transport in erythrocytes from dialysed uremic patients. Kidney
Int 32:754-759, 1987
27. Matsumura M, Hatakeyama S, Koni I, Mabuchi H,
Muramoto H: Correlation between serum carnitine levels
and erythrocyte osmotic fragility in haemodialysis patients.
Nephron 72:574-578, 1996
28. Nikolaos S, George A, Telemachos T, Maria S, Yannis M, Konstantinos M: Effect of L-carnitine supplementation red blood cells deformability in hemodialysis patients.
Ren Fail 22:73-80, 2000
29. 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 102:885891, 1999
S122
30. 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 19:480-484, 1999
31. Hurot JM, Cucherat M, Haugh M, Fouque D: Effects
BELLINGHIERI ET AL
of L-carnitine supplementation in maintenance hemodialysis
patients: A systematic review. J Am Soc Nephrol 13:708714, 2002
32. FDA approves Carnitor for dialysis. SCRIP World
Pharmaceutical News 05-06-2000