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Carnitine metabolism in renal disease and dialysis

Author
Alan Wasserstein, MD
Section Editor
Steve J Schwab, MD
Deputy Editor
Alice M Sheridan, MD
Disclosures: Alan Wasserstein, MD Nothing to disclose. Steve J Schwab, MD Nothing to disclose. Alice M
Sheridan, MD Employee of UpToDate, Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed
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All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jul 2014. | This topic last updated: Jan 07, 2014.
INTRODUCTION Carnitine deficiency may be a significant problem in patients with kidney
disease, particularly in those undergoing maintenance dialysis. A discussion of carnitine
metabolism, as well as the role of carnitine supplementation in this patient population, is presented
in this topic review.
ROLE OF CARNITINE IN INTERMEDIARY METABOLISM Carnitine is an important
intermediary in fat metabolism. It is required to shuttle long-chain fatty acids, in the form of
acylcarnitines, into mitochondria for beta-oxidation; carnitine is, therefore, crucial for energy
production in tissues dependent upon fatty acid oxidation, such as cardiac and skeletal muscle.
Reactions of carnitine with activated fatty acids (acyl CoA) are esterifications of the general form
acyl CoA + carnitine -> acylcarnitine + CoASH
and are catalyzed by a family of carnitine acyltransferases.
Besides fatty acid oxidation, functions of carnitine include modulating the concentration of CoA,
scavenging toxic acyl groups, and facilitating their transport out of mitochondria. Impaired fatty acid
metabolism and consequent accumulation of acyl CoA are characteristic of renal failure. Acyl CoAs
inhibit numerous enzymes important in intermediary metabolism and thereby increase insulin
resistance, apoptosis, generation of free radicals, and lipid peroxidation products. Conversion of
acyl CoA to acylcarnitine and transport out of mitochondria constitutes a normal scavenger system
for toxic acyl groups that are generated in excess in renal failure [1-4].
RENAL HANDLING AND METABOLISM OF CARNITINE IN RENAL
FAILURE While carnitine is derived from red meat and dairy products in the diet, biosynthesis in
the liver, kidney, and brain is adequate to meet normal requirements in healthy individuals.
Approximately 95 percent of carnitine is stored in muscle, where it is concentrated by a specific
transporter. Free carnitine is filtered at the glomerulus, and over 90 percent undergoes tubular
reabsorption. By contrast, renal tubular absorption of acylcarnitine is limited, and clearance of
acylcarnitine is four to eight times greater than that of free carnitine [3]. Such differential clearance

is consistent with the concept that esterification with carnitine is a pathway for detoxification and
elimination of toxic acyl groups.
Alterations in chronic kidney dysfunction In chronic kidney dysfunction, clearance of both
free carnitine and acylcarnitine is reduced. Plasma levels of free and total carnitine are unchanged,
but serum acylcarnitine rises in inverse relation to the decline of the glomerular filtration rate (GFR)
[5]. The ratio of acylcarnitine to free carnitine is markedly increased.
Metabolism in hemodialysis In hemodialysis patients, plasma total carnitine concentration is
normal or elevated; the free carnitine concentration is reduced (19.2 to 32.4 micromol/L) and
significantly lower than in healthy controls (40 to 50 micromol/L) or in chronic kidney disease (CKD);
the acylcarnitine concentration is markedly increased, and the ratio of acyl to free carnitine (AC:FC)
is markedly increased (0.77 to 0.96) compared with healthy controls (0.15 to 0.25) [4,6].
Several factors contribute to this abnormal profile [3-5]:
Loss of renal parenchyma removes a source of endogenous carnitine synthesis.
Low dietary intake of meat and dairy products deprives patients of a rich source of carnitine.
Hemodialysis removes free carnitine and acylcarnitine. Although total dialytic removal is
probably comparable to normal urinary excretion, free carnitine clearance by hemodialysis is
greater than that of acylcarnitine. This pattern is the reverse of normal urinary carnitine
excretion.
Fatty acid metabolism is impaired in renal failure. Thus, incompletely metabolized acyl
residues accumulate and drive the formation of acylcarnitine esters.
The normal preferential renal excretion of acylcarnitine is lost in renal failure.
Metabolism in peritoneal dialysis Metabolism of carnitine in peritoneal dialysis patients has not
been sufficiently studied. Available information indicates that total and free plasma carnitine are
normal, and plasma acylcarnitine is elevated.
Carnitine deficiency and dialysis patients An AC:FC ratio >0.4 indicates a disorder of fatty
acid metabolism [4,6]. Excessive generation of acyl moieties because of incomplete fatty acid
oxidation enhances formation of acylcarnitines and uses up free carnitine; thus, a high AC:FC ratio
and free carnitine deficiency may be a consequence as well as a cause of abnormal fatty acid
metabolism. Conversion to intensive (nocturnal) hemodialysis (five to six sessions per week, eight
hours per treatment) reduced free and acylcarnitine levels and improved (reduced) the AC:FC ratio
[7]. This improvement could be due to amelioration of impaired fatty acid oxidation.
Effective carnitine deficiency exists if free carnitine is inadequate to meet metabolic needs; such
carnitine deficiency further impairs fatty acid oxidation. However, the plasma carnitine profile does
not predict whether effective carnitine deficiency exists. The vast majority (95 percent) of
hemodialysis patients have low free plasma carnitine, but neither plasma total, free, or acylcarnitine
nor their ratios predict clinical response to L-carnitine supplements [8,9]. By comparison, tissue
(muscle or erythrocyte) total carnitine levels sometimes correlate with clinically significant endpoints
(see below).
L-Carnitine supplementation increases plasma total, free, and acylcarnitine levels; the AC:FC ratio
falls (improves) only moderately and incompletely, suggesting that carnitine continues to bind acyl
residues that are present in excess in dialysis patients [8].

The decline of free carnitine levels depends on dialysis vintage. In a study of 21 patients, plasma Lcarnitine levels principally decreased within the first few months of beginning hemodialysis, while
levels in muscle continued to decline, even after one year of dialysis [10]. These findings are
consistent with a pharmacokinetic model of L-carnitine in patients receiving hemodialysis [11].
CLINICAL FEATURES OF CARNITINE DEFICIENCY Much of our knowledge of the
consequences of carnitine deficiency comes from inherited cases in children. In these children
without kidney disease, the features of carnitine deficiency include muscle weakness, acute
encephalopathy, hepatic dysfunction, cardiomyopathy, nonketotic hypoglycemia, frequent infections,
and failure to thrive.
Carnitine deficiency in dialysis patients has been termed dialysis-related carnitine deficiency (DCD);
it is distinguished from primary and secondary carnitine deficiency syndromes on the grounds that:
Carnitine deficiency in DCD is relative and due to disparity between carnitine availability and
metabolic needs.
The ratio of acylcarnitine to free carnitine is increased.
Symptomatic improvement requires pharmacologic doses rather than physiologic
replacement.
CARNITINE SUPPLEMENTATION IN DIALYSIS PATIENTS It is difficult to clearly ascribe
benefits with L-carnitine supplementation in dialysis patients because of the following:
The symptoms of carnitine deficiency (including muscle weakness and cardiomyopathy)
overlap with those of dialysis patients, generally.
Laboratory evidence of abnormal carnitine metabolism is ubiquitous in this population.
The response to carnitine supplementation cannot be predicted from plasma carnitine
profiles.
There are numerous studies supporting the view that L-carnitine supplementation improves the
plasma lipid profile, exercise capacity and oxygen utilization, muscle strength, intradialytic
symptoms, sense of well-being, hospitalization rate, inflammatory markers, protein metabolism, left
ventricular hypertrophy and cardiac function, anemia, and response to erythropoietin. In many of
these instances, the physiologic rationale for administration of L-carnitine is appealing.
However, data evaluating these possible benefits of L-carnitine supplementation in hemodialysis
patients are limited, with many trials being uncontrolled and small in size. Although some controlled
prospective studies have been performed, trials have been limited by small size, inclusion of
patients independent of signs and symptoms of carnitine deficiency, and relatively short follow-up
[8,9].
In general, a growing literature supports benefits with L-carnitine supplementation on inflammation
and muscle wasting. However, the evidence is unclear that L-carnitine supplementation in dialysis
patients improves exercise capacity, cardiomyopathy, or intradialytic symptoms.
Protein and muscle catabolism and signs of inflammation The effect of acyl CoA to increase
insulin resistance and generation of free radicals and lipid peroxidation products suggests
that carnitine deficiency may contribute to muscle wasting in dialysis patients [4]. In general, results
from different trials have found that L-carnitine has beneficial effects on inflammation, the oxidative
state, and protein metabolism in dialysis patients [4,9,12-14].

In a controlled trial, L-carnitine supplementation reduced blood urea nitrogen (BUN) and
plasma concentrations of creatinine and phosphate compared with placebo and increased
mid-arm muscle circumference, suggesting a decline in muscle catabolism; however, the
constancy of delivered dialysis and diet was not verified [9].
Two placebo-controlled trials in hemodialysis patients independently demonstrated that
intravenous (IV) L-carnitine (20 mg/kg body weight three times a week for six months) reduced
serum C-reactive protein and increased albumin, transferrin, and body mass index (BMI)
[12,13].
A randomized controlled trial showed that L-carnitine administration reduced serum amyloid
A protein in dialysis patients [15].
L-carnitine supplementation may therefore be considered in the patient with muscle
wasting and/or inflammation, as defined by weight loss that is not otherwise explained, high Creactive protein level, and/or decreasing anthropometric measures (eg, mid-arm muscle
circumference).
Lipid metabolism Since L-carnitine supplementation increases fatty acid oxidation and reduces
myocardial fatty acid retention [4], it is plausible that such supplementation may improve
hyperlipidemia in this population. However, there is no consensus on the effect of L-carnitine on
hyperlipidemia (elevated triglycerides and reduced high-density lipoprotein [HDL] cholesterol) in
hemodialysis patients (see "Lipid abnormalities in nephrotic syndrome"). A 2002 meta-analysis, for
example, found no beneficial effect of L-carnitine on serum lipid profiles [16].
These negative results may be due to the use of different doses and/or route of administration. A
low dose of carnitine (<5 mg/kg) significantly improved the lipid profile [17] or modestly reduced
elevated serum triglyceride levels [18], while a dose of 20 mg/kg IV after each hemodialysis
treatment had no effect [8]. High levels of carnitine may stimulate fatty acid (and hence triglyceride)
synthesis rather than oxidation, which could explain this dose dependence.
Exercise limitation and oxygen consumption The ability of L-carnitine supplementation to
improve exercise performance in patients receiving hemodialysis is unclear [9,19-22]. Some studies
demonstrated that L-carnitine supplementation improved muscle strength, but not endurance
[19,20]. However, when muscle metabolism and function were assessed by magnetic resonance or
near-infrared spectroscopy, L-carnitine supplementation for 16 weeks in patients receiving
maintenance hemodialysis showed no effect [22].
These disparate results for the effect of L-carnitine supplementation on exercise capacity may
reflect a failure to select a severely carnitine-deficient population, such as long-term dialysis
patients. They also suggest that impairment of muscle energetics in some dialysis patients is due
not only to carnitine deficiency, but to other defects in fatty acid metabolism, such as carnitine
palmitoyl transferase deficiency.
Intradialytic complications L-carnitine may improve cardiac and skeletal muscle energy
metabolism, thereby possibly ameliorating intradialytic symptoms [9]. However, a 2008 metaanalysis that included 193 patients found no effect of L-carnitine on intradialytic hypotension and
only a tendency to ameliorate muscle cramps, which did not achieve statistical significance [23]. In
addition, a randomized study that was published after the meta-analysis and included 92

hemodialysis patients showed no effect of L-carnitine supplementation on hypotensive episodes


[24].
Quality of life Evidence examining whether carnitine supplementation improves quality of life is
conflicting [9,19,25,26]. Clinical status and sense of wellbeing, as reported by patients and staff,
were significantly improved in one controlled trial [9], but not in two other studies [19,25]. In a
randomized controlled trial of 50 patients studied for 24 weeks, L-carnitine supplementation
improved short form-36 (SF-36) scores and reduced erythropoietin doses [26]. However, in the
randomized trial cited above, L-carnitine supplementation had no effect on the SF-36 scores and
did not change erythropoietin responsiveness [24]. The effect of carnitine supplementation on
erythropoietin responsiveness is discussed elsewhere. (See "Non-iron pharmacologic adjuvants to
erythropoiesis stimulating agent therapy in dialysis patients", section on 'Efficacy'.)
Hospitalization The effect of carnitine supplementation on rates of hospitalization is unclear.
Review of Centers for Medicare and Medicaid Services (CMS) administrative data for prevalent
hemodialysis patients in the years 1998 to 2003 revealed that infusion of L-carnitine 1 g per session
for at least 10 sessions in a month was associated with a statistically significant reduction of 10.8
percent in subsequent months' hospital days [27]. However, a causal relationship cannot be
inferred. It is important to note that no existing randomized trials have addressed this issue.
Anemia and response to erythropoietin L-carnitine may be effective in patients with chronic
renal disease and anemia. This is discussed in detail separately. (See "Non-iron pharmacologic
adjuvants to erythropoiesis stimulating agent therapy in dialysis patients", section on 'L-carnitine'.)
Cardiovascular effects Observations of benefit from L-carnitine supplementation in trials with
small numbers of patients include partial reversal of cardiomegaly, improvement of left ventricular
ejection fraction, and reductions in cardiac arrhythmias and anginal episodes [28-30]. A multicenter,
randomized controlled trial showed that L-carnitine in large doses ameliorated left ventricular
dilatation after myocardial infarction, but this study was not done in dialysis patients [31].
CONSENSUS STATEMENTS AND GUIDELINES Several consensus conferences as well as the
National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) working
groups that developed guidelines for nutrition and for anemia in chronic renal failure concluded that
routine carnitine supplementation in dialysis patients was not justified by available information [3235]. Several of these groups suggested that L-carnitine supplementation may be considered in the
following settings when standard therapy had not been effective [32,33,35]:
Intradialytic hypotension or muscle cramps
Muscle weakness and lack of functional wellbeing
Decreased exercise capacity or low peak oxygen consumption
Cardiomyopathy and low cardiac output
Anemia of renal failure that is unresponsive to or requires large doses of
erythropoietin (see "Non-iron pharmacologic adjuvants to erythropoiesis stimulating agent
therapy in dialysis patients", section on 'L-carnitine').
In 1999, the Food and Drug Administration (FDA) approved the use of L-carnitine in dialysisrelated carnitine deficiency [36]. In 2003, the Centers for Medicare and Medicaid Services (CMS)
approved reimbursement for use of L-carnitine in the treatment of hemodialysis patients only with

erythropoietin-resistant anemia or intradialytic hypotension [37]. The wisdom of providing


reimbursement for an unproven agent has been challenged [38], while others have questioned why
use of L-carnitine in dialysis patients is not more widespread [4].
TREATMENT There are few, if any, adverse effects of intravenous (IV) administration of Lcarnitine. Thus, the major deterrent to an empiric trial in patients with symptoms compatible
with carnitine deficiency is cost and convenience.
The evidence is not definitive that L-carnitine supplementation in dialysis patients improves exercise
capacity, cardiomyopathy, or intradialytic symptoms. On the other hand, a growing body of work
supports benefit on inflammation and muscle wasting. Since many of the putative benefits of Lcarnitine remain anecdotal and are confined to an unpredictable subset of the dialysis population,
refinement of the definition of carnitine deficiency in dialysis patients is needed to better understand
the use of the agent in this setting.
As response to L-carnitine supplementation cannot be predicted from laboratory evidence
of carnitine deficiency, close follow-up and objective clinical end points are required when Lcarnitine supplements are prescribed. Physicians should be hesitant to add the cost of this
supplement to the high expense of maintenance dialysis if an empiric course of treatment shows no
benefit.
The NKF Carnitine Consensus Conference recommended that the clinical response to Lcarnitine be evaluated at three-month intervals and the agent discontinued if no clinical
improvement has occurred within 9 to 12 months [35]. Measurement of plasma carnitine levels to
predict response or monitor treatment has not been useful. However, CMS has required a
predialysis plasma-free carnitine level <40 micromol/L to qualify L-carnitine administration for
reimbursement.
Despite the recommendations of expert consensus groups and the approval of reimbursement by
the CMS, we do not believe that existing evidence is strong enough to endorse the use of Lcarnitine for any of the indications for which it has been recommended. Potential uses of Lcarnitine in dialysis patients include anemia resistant to erythropoiesis-stimulating agents, dialysisrelated hypotension, muscle wasting, weight loss, biochemical evidence of inflammation, and
cardiomyopathy. The expense of IV administration of L-carnitine is an important reason to
discourage its use, especially if medical resources become increasingly scarce. As an IV
medication, L-carnitine is included in the bundle of reimbursed dialysis services and, therefore, is
not specifically reimbursed. National dialysis chains do not approve L-carnitine for use in their
patients, a decision with which we agree. If L-carnitine is administered, the course should be limited
to three to six months, and objective evidence of benefit should be sought.
L-carnitine dose and route of administration Because of the toxicity of D-carnitine, racemic
mixtures of D- and L-carnitine should not be used. Optimal dosing is not defined for L-carnitine. The
Food and Drug Administration (FDA) approved the use specifically of the IV formulation of Lcarnitine in dialysis patients. A dose of 20 mg/kg IV after dialysis has been employed in several
controlled trials [8,9,12-14] and has been recommended [32,35]. Higher doses (up to
100 mg/kg) have been used, but total doses >3 grams may increase platelet aggregation. Lower
doses (<5 mg/kg) have been used in hyperlipidemias [17,18].
Oral carnitine is not recommended because of the following:

High oral doses are required because of limited bioavailability [39]. In addition, data on the
efficacy of oral L-carnitine are limited.
Toxic metabolites of oral carnitine are generated due to intestinal metabolism; this first results
in trimethylamine (TMA), which is further metabolized in the liver to trimethylamine-n-oxide
(TMNO). These toxic metabolites accumulate between dialysis sessions, even in patients who
are not receiving oral L-carnitine supplements, but are efficiently cleared by dialysis [40]. In
dialysis patients who receive oral L-carnitine 1 g daily, plasma concentrations of TMNO
continue to rise after two weeks [41]. TMA and TMNO may cause cognitive impairment and
malodorous breath characteristic of uremia [42].
SUMMARY AND RECOMMENDATIONS
In hemodialysis patients, plasma total carnitine concentration is normal or elevated, and the
free carnitine concentration is reduced. Although effective carnitine deficiency exists if free
carnitine is inadequate to meet metabolic needs, the plasma carnitine profile does not predict
whether effective carnitine deficiency exists. (See 'Renal handling and metabolism of carnitine
in renal failure' above.)
In children with carnitine deficiency but without kidney disease, the features of carnitine
deficiency include muscle weakness, acute encephalopathy, hepatic dysfunction,
cardiomyopathy, nonketotic hypoglycemia, frequent infections, and failure to thrive. Carnitine
deficiency in dialysis patients (DCD) is distinguished from these carnitine deficiency
syndromes in that DCD is relative and due to the disparity between carnitine availability and
metabolic needs, and symptomatic improvement requires pharmacologic doses rather than
physiologic replacement. (See 'Clinical features of carnitine deficiency' above.)
It is often difficult to ascribe benefits to L-carnitine supplementation in dialysis patients. This
is because the symptoms of carnitine deficiency overlap with those of dialysis patients
generally, laboratory evidence of abnormal carnitine metabolism is ubiquitous, and the
response to carnitine supplementation cannot be predicted from plasma carnitine profiles. It is,
however, safe for long-term administration, at least by the intravenous (IV) route.
(See 'Carnitine supplementation in dialysis patients' above.)
There is no strong evidence that L-carnitine supplementation in dialysis patients improves
muscle wasting or weight loss, exercise capacity, cardiomyopathy, or intradialytic symptoms,
although it appears to be safe. Among dialysis patients, we recommendnot administering oral
L-carnitine (Grade 1A). (See 'Carnitine supplementation in dialysis patients' above.)
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REFERENCES
1.

Hoppel C. The physiological role of carnitine. In: L-Carnitine and Its Role in Medicine: From
Function to Therapy, Ferrari R, DiMauro S, Sherwood G (Eds), Academic Press, London 1992. p.5.

2.

Wanner C, Hrl WH. Carnitine abnormalities in patients with renal insufficiency.


Pathophysiological and therapeutical aspects. Nephron 1988; 50:89.

3.

Ahmad S. Carnitine, kidney and renal dialysis. In: L-Carnitine and Its Role in Medicine:
From Function to Therapy, Ferrari R, DiMauro S, Sherwood G (Eds), Academic Press, London
1992. p.381.

4.

Schreiber BD. Debate forum: levocarnitine therapy is rational and justified in selected
dialysis patients. Blood Purif 2006; 24:128.

5.

Fouque D, Holt S, Guebre-Egziabher F, et al. Relationship between serum carnitine,


acylcarnitines, and renal function in patients with chronic renal disease. J Ren Nutr 2006; 16:125.

6.

Golper TA, Ahmad S. L-carnitine administration to hemodialysis patients: has its time
come? Semin Dial 1992; 5:94.

7.

Hothi DK, Geary DF, Fisher L, Chan CT. Short-term effects of nocturnal haemodialysis on
carnitine metabolism. Nephrol Dial Transplant 2006; 21:2637.

8.

Golper TA, Wolfson M, Ahmad S, et al. Multicenter trial of L-carnitine in maintenance


hemodialysis patients. I. Carnitine concentrations and lipid effects. Kidney Int 1990; 38:904.

9.

Ahmad S, Robertson HT, Golper TA, et al. Multicenter trial of L-carnitine in maintenance
hemodialysis patients. II. Clinical and biochemical effects. Kidney Int 1990; 38:912.

10.

Evans AM, Faull RJ, Nation RL, et al. Impact of hemodialysis on endogenous plasma and
muscle carnitine levels in patients with end-stage renal disease. Kidney Int 2004; 66:1527.

11.

Fornasini G, Upton RN, Evans AM. A pharmacokinetic model for L-carnitine in patients
receiving haemodialysis. Br J Clin Pharmacol 2007; 64:335.

12.

Savica V, Santoro D, Mazzaglia G, et al. L-carnitine infusions may suppress serum Creactive protein and improve nutritional status in maintenance hemodialysis patients. J Ren Nutr
2005; 15:225.

13.

Duranay M, Akay H, Yilmaz FM, et al. Effects of L-carnitine infusions on inflammatory and
nutritional markers in haemodialysis patients. Nephrol Dial Transplant 2006; 21:3211.

14.

Biolo G, Stulle M, Bianco F, et al. Insulin action on glucose and protein metabolism during
L-carnitine supplementation in maintenance haemodialysis patients. Nephrol Dial Transplant 2008;
23:991.

15.

Tabibi H, Hakeshzadeh F, Hedayati M, Malakoutian T. Effects of l-carnitine supplement on


serum amyloid A and vascular inflammation markers in hemodialysis patients: a randomized
controlled trial. J Ren Nutr 2011; 21:485.

16.

Hurot JM, Cucherat M, Haugh M, Fouque D. Effects of L-carnitine supplementation in


maintenance hemodialysis patients: a systematic review. J Am Soc Nephrol 2002; 13:708.

17.

Wanner C, Wieland H, Wckerle B, et al. Ketogenic and antiketogenic effects of L-carnitine


in hemodialysis patients. Kidney Int Suppl 1989; 27:S264.

18.

Elisaf M, Bairaktari E, Katopodis K, et al. Effect of L-carnitine supplementation on lipid


parameters in hemodialysis patients. Am J Nephrol 1998; 18:416.

19.

Fagher B, Cederblad G, Eriksson M, et al. L-carnitine and haemodialysis: double blind


study on muscle function and metabolism and peripheral nerve function. Scand J Clin Lab Invest
1985; 45:169.

20.

Siami G, Clinton ME, Mrak R, et al. Evaluation of the effect of intravenous L-carnitine
therapy on function, structure and fatty acid metabolism of skeletal muscle in patients receiving
chronic hemodialysis. Nephron 1991; 57:306.

21.

Thompson CH, Irish AB, Kemp GJ, et al. The effect of propionyl L-carnitine on skeletal
muscle metabolism in renal failure. Clin Nephrol 1997; 47:372.

22.

Vaux EC, Taylor DJ, Altmann P, et al. Effects of carnitine supplementation on muscle
metabolism by the use of magnetic resonance spectroscopy and near-infrared spectroscopy in endstage renal disease. Nephron Clin Pract 2004; 97:c41.

23.

Lynch KE, Feldman HI, Berlin JA, et al. Effects of L-carnitine on dialysis-related
hypotension and muscle cramps: a meta-analysis. Am J Kidney Dis 2008; 52:962.

24.

Mercadal L, Coudert M, Vassault A, et al. L-carnitine treatment in incident hemodialysis


patients: the multicenter, randomized, double-blinded, placebo-controlled CARNIDIAL trial. Clin J
Am Soc Nephrol 2012; 7:1836.

25.

Semeniuk J, Shalansky KF, Taylor N, et al. Evaluation of the effect of intravenous l-carnitine
on quality of life in chronic hemodialysis patients. Clin Nephrol 2000; 54:470.

26.

Steiber AL, Davis AT, Spry L, et al. Carnitine treatment improved quality-of-life measure in a
sample of Midwestern hemodialysis patients. JPEN J Parenter Enteral Nutr 2006; 30:10.

27.

Weinhandl ED, Rao M, Gilbertson DT, et al. Protective effect of intravenous levocarnitine on
subsequent-month hospitalization among prevalent hemodialysis patients, 1998 to 2003. Am J
Kidney Dis 2007; 50:803.

28.

Romagnoli GF, Naso A, Carraro G, Lidestri V. Beneficial effects of L-carnitine in dialysis


patients with impaired left ventricular function: an observational study. Curr Med Res Opin 2002;
18:172.

29.

Signorelli SS, Fatuzzo P, Rapisarda F, et al. A randomised, controlled clinical trial evaluating
changes in therapeutic efficacy and oxidative parameters after treatment with propionyl L-carnitine
in patients with peripheral arterial disease requiring haemodialysis. Drugs Aging 2006; 23:263.

30.

Signorelli SS, Fatuzzo P, Rapisarda F, et al. Propionyl-L-carnitine therapy: effects on


endothelin-1 and homocysteine levels in patients with peripheral arterial disease and end-stage
renal disease. Kidney Blood Press Res 2006; 29:100.

31.

Iliceto S, Scrutinio D, Bruzzi P, et al. Effects of L-carnitine administration on left ventricular


remodeling after acute anterior myocardial infarction: the L-Carnitine Ecocardiografia Digitalizzata
Infarto Miocardico (CEDIM) Trial. J Am Coll Cardiol 1995; 26:380.

32.

Consensus Group Statement. Role of L-carnitine in treating renal dialysis patients. Dial
Transplant 1994; 23:177.

33.

Clinical practice guidelines for nutrition in chronic renal failure. K/DOQI, National Kidney
Foundation. Am J Kidney Dis 2000; 35:S1.

34.

KDOQI, National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical
Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis 2006; 47:S11.

35.

36.

Eknoyan G, Latos DL, Lindberg J, National Kidney Foundation Carnitine Consensus


Conference. Practice recommendations for the use of L-carnitine in dialysis-related carnitine
disorder. National Kidney Foundation Carnitine Consensus Conference. Am J Kidney Dis 2003;
41:868.
FDA summary of approval for carnitor injection in dialysis. NDA:20-182/s-006, Dec 1999

37.

Medicare Coverage Policy: Levocarnitine for end-stage renal disease decision


memorandum. 2002.

38.

Steinman TI. L-carnitine supplementation in dialysis patients: does the evidence justify its
use? Semin Dial 2005; 18:1.

39.

Brass EP. Pharmacokinetic considerations for the therapeutic use of carnitine in


hemodialysis patients. Clin Ther 1995; 17:176.

40.

Bain MA, Faull R, Fornasini G, et al. Accumulation of trimethylamine and trimethylamine-Noxide in end-stage renal disease patients undergoing haemodialysis. Nephrol Dial Transplant 2006;
21:1300.

41.

Bain MA, Faull R, Milne RW, Evans AM. Oral L-carnitine: metabolite formation and
hemodialysis. Curr Drug Metab 2006; 7:811.

42.

Schreiber B. Safety of oral carnitine in dialysis patients. Semin Dial 2002; 15:71.