Carnitine metabolism in renal disease and dialysis

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Official reprint from UpToDate www.uptodate.com 2011 UpToDate

Carnitine metabolism in renal disease and dialysis

Author Alan Wasserstein, MD Disclosures Last literature review version 19.3: settembre 2011 | This topic last updated: agosto 24, 2011 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 Section Editor Steve J Schwab, MD Deputy Editor Alice M Sheridan, MD

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. About 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 decline of 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 (19.2-32.4 umol/L) and significantly lower than in healthy controls (40-50 umol/L) or in chronic kidney disease (CKD); the acylcarnitine
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concentration is markedly increased and the ratio of acyl to free carnitine (AC:FC) is markedly increased (0.77-0.96) compared to healthy controls (0.15-0.25) [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 greater than 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:
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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 pharmacological doses rather than physiological 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 physiological 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 BUN and plasma concentrations of creatinine and phosphate compared to 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 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 [12,13]. 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 C-reactive 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

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hyperlipidemia in this population. However, there is no consensus on the effect of L-carnitine on hyperlipidemia (elevated triglycerides and reduced 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 [15]. These negative results may be due to the use of different dosages and/or route of administration. A low dose of carnitine (less than 5 mg/kg) significantly improved the lipid profile [16] or modestly reduced elevated serum triglyceride levels [17], while a dose of 20 mg/kg intravenously 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 [9,18-21]. Some studies demonstrated that L-carnitine supplementation improved muscle strength but not endurance [18,19]. However, when muscle metabolism and function were assessed by magnetic resonance or nearinfrared spectroscopy, L-carnitine supplementation for sixteen weeks in patients receiving maintenance hemodialysis showed no effect [21]. 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 that did not achieve statistical significance [22]. Quality of life Evidence examining whether carnitine supplementation improves quality of life is conflicting [9,18,23,24]. 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 [18,23]. In a randomized controlled trial of 50 patients studied for 24 weeks, L-carnitine supplementation improved SF-36 scores and reduced erythropoietin doses [24]. Hospitalization The effect of carnitine supplementation on rates of hospitalization is unclear. Review of CMS administrative data for prevalent hemodialysis patients in the years 1998 to 2003 revealed that infusion of L-carnitine 1 g/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 [25]. 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 [26-28]. CONSENSUS STATEMENTS AND GUIDELINES Several consensus conferences as well as the 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 [29-32]. Several of these groups suggested that L-carnitine supplementation may be considered in the following settings when standard therapy had not been effective [29,30,32]:
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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 approved the use of L-carnitine in dialysis-related carnitine deficiency. In 2003, the Center for Medicare and Medicaid Services (CMS) approved reimbursement for use of L-carnitine in treatment of hemodialysis patients only with erythropoietinresistant anemia or intradialytic hypotension. The wisdom of providing reimbursement for an unproven agent has been challenged [33], 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 administration of L-carnitine. 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 L-carnitine 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 L-carnitine 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 National Kidney Foundation (NKF) Carnitine Consensus Conference recommended that the clinical response to L-carnitine be evaluated at three-month intervals and the agent discontinued if no clinical improvement has occurred within nine to twelve months [32]. 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 below 40 umol/L to qualify L-carnitine administration for reimbursement. The following is our approach to L-carnitine supplementation in dialysis patients: Among patients with symptomatic, recurrent dialysis hypotension that has not responded to other treatments, we suggest the administration of L-carnitine (20 mg/kg intravenously after dialysis). Since benefit for this indication is equivocal [22], improvement (defined as reduced frequency of episodes of symptomatic hypotension at dialysis) should be assessed at threemonth intervals. L-carnitine should be stopped at 9 to 12 months if no benefit is observed. Among patients with muscle wasting (as evidenced by weight loss and anthropometric measurements) and biochemical evidence of inflammation (eg, elevated CRP) that has not responded to standard therapy, L-carnitine administration can be considered (20 mg/kg intravenously after dialysis). Although the use of L-carnitine for this purpose is not reimbursed by CMS, dialysis patients with increased systemic inflammation will in many cases have resistance to erythropoietin; they will therefore qualify for L-carnitine administration on that basis. With regard to protein malnutrition and inflammation, benefits with L-carnitine would include weight gain or at least cessation of weight loss, reduction of elevated CRP levels, and, if
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measured, increase of muscle mid-arm circumference. L-carnitine should be stopped at 9 to 12 months if no benefit is observed. Cardiomyopathy that is unresponsive to standard therapy is another possible indication for intravenous L-carnitine in dialysis patients (20 mg/kg intravenously after dialysis). The negligible risk of L-carnitine and the ominous import of this diagnosis may support a trial of this therapy, but use for this indication is also not reimbursed. Thus, it may not be feasible to give L-carnitine for this indication in practice. If L-carnitine is used for cardiomyopathy, objective response to therapy (eg, by echocardiography) should be measured at three-month intervals. Benefits should include improved NYHA class, improvement of ejection fraction with echocardiography (such as increase by 15 percent), and/or decreased frequency and/or duration of arrhythmias. The drug should be stopped if there is no response within 9 to 12 months. If benefits have been observed, carnitine is continued indefinitely as dialysis depletes carnitine progressively over time and levels are not predictive of response. 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 use specifically of the intravenous formulation of Lcarnitine in dialysis patients. A dose of 20 mg/kg intravenously after dialysis has been effective in several controlled trials [8,9,12-14], and is recommended [29,32]. Higher doses (up to 100 mg/kg) have been used, but total doses above 3 grams may increase platelet aggregation. Lower doses (less than 5 mg/kg) have been used in hyperlipidemias [16,17]. Oral carnitine is NOT recommended because of the following: High oral doses are required because of limited bioavailability [34]. 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 [35]. In dialysis patients who receive oral L-carnitine 1 g daily, plasma concentrations of TMNO continue to rise after two weeks [36]. TMA and TMNO may cause cognitive impairment and malodorous breath characteristic of uremia [37]. 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 pharmacological doses rather than physiological replacement. (See 'Clinical features of carnitine deficiency' above.)
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It is sometimes difficult to clearly 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. (See 'Carnitine supplementation in dialysis patients' above.) 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. (See 'Carnitine supplementation in dialysis patients' above.) Among patients with symptomatic, recurrent dialysis hypotension that has not responded to other treatments, we suggest the administration of intravenous L-carnitine (Grade 2C). Among dialysis patients with muscle wasting (as evidenced by weight loss and decreased anthropometric measurements) and inflammation (elevated C-reactive protein levels) that have not responded to standard therapy, we suggest the administration of intravenous L-carnitine (Grade 2C). Among dialysis patients with cardiomyopathy that is unresponsive to standard therapy, we suggest the administration of intravenous L-carnitine (Grade 2C). If Lcarnitine is administered, objective response to therapy should be measured at three-month intervals and the drug stopped if there is no response within 9 to 12 months of initiating therapy. (See 'Treatment' above.) L-carnitine is administered at a dose of 20 mg/kg intravenously after dialysis. Among dialysis patients, we recommend NOT administering oral L-carnitine (Grade 1A).

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