carnitine in hemodialysis patients - Wiley Online Library

Hemodialysis International 2012; 16:428–434

Review Article

L carnitine in hemodialysis patients Lorenzo A. CALÒ,1 Ugo VERTOLLI,2 Paul A. DAVIS,3 Vincenzo SAVICA4 1 Department of Medicine, Clinica Medica 4, University of Padova, Padova, Italy; 2Division of Nephrology, University of Padova-Azienda Ospedaliera Padova, Padova, Italy; 3Department of Nutrition, University of California, Davis, California, USA; 4Division of Nephrology, University of Messina, Messina, Italy

Abstract Carnitine, 3-hydroxy-4-trimethylaminobutyrate, a small, water soluble molecule that is essential for mitochondrial fatty acid oxidation, is significantly reduced in hemodialysis patients. Uremiainduced carnitine deficiency, which is magnified by dialysis, is associated with symptoms or clinical problems such as anemia hyporesponsive to erythropoietin, cardiovascular diseases, and muscle weakness. This review examines studies dealing with the different clinical aspects of chronic renal failure patients in which carnitine deficiency may play a role and has also examined the studies, which have evaluated the effect of carnitine deficiency treatment. The reports reviewed in this study, including those more recent from our laboratory, have provided data suggesting that chronic renal failure and particularly hemodialysis patients can benefit from carnitine treatment in particular for renal anemia, insulin sensitivity, and protein catabolism. On the other hand, the heterogeneous clinical response to carnitine therapy in dialysis patients, reported by other studies, and the lack of large-scale randomized trials are the rationale for the reluctance regarding a widespread use of carnitine supplements in dialysis patients. Well-designed randomized clinical trials are therefore required to fully address the potentially important carnitine treatment in dialysis patients. Keywords: Carnitine, chronic renal failure, dialysis, anemia, insulin resistance

INTRODUCTION Although discovered in 1905, the crucial role of L-carnitine (LC) in metabolism was not clarified until 1955, and its deficiency was not described until 1972. Carnitine is a trimethylated amino acid which derives its name as a result of its first being found in meat (carnus). It functions as a required cofactor for transport of longchain free fatty acids via their conversion into acylcarnitines (ACs). The ACs are subsequently transported into the mitochondrial matrix to undergo b-oxidation for cellular energy production. Correspondence to: L. A. Calò, MD, PhD, Department of Medicine, Clinica Medica 4, University of Padova, Via Giustiniani 2, 35128 Padova, Italy. E-mail: [email protected]

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Primary and secondary carnitine deficiencies have been widely described in the medical literature. One of the main causes of secondary carnitine deficiency is renal insufficiency and hemodialysis (HD), and LC treatment provides, as recognized, a global approach to these patients.

CARNITINE BIOSYNTHESIS Carnitine in humans is derived from diet with the main dietary sources of carnitine being red meat, fish, and dairy products which supply 2–12 mmol/kg body wt/day. L-carnitine from foods is absorbed in the intestine via both active and passive transport across enterocyte membranes.1 The bioavailability of LC varies depending on diet as increased bioavailability has been reported in individuals consuming low-carnitine diets. Unabsorbed LC is degraded in the colon to trimethylamine which is

© 2012 The Authors Hemodialysis International © 2012 International Society for Hemodialysis DOI:10.1111/j.1542-4758.2012.00679.x

Carnitine and dialysis

absorbed, metabolized to trimethylamine-N-oxide, and excreted in the urine, and gamma-butyrobetaine which is eliminated via the feces.2 Carnitine is also endogenously synthesized using lysine and methionine, a process that provides 1–2 mmol/kg of carnitine.3 Carnitine synthesis occurs mainly in the kidney, liver, and brain and is a multistep process that begins with methylation of the amino acid L-lysine by S-adenosylmethionine (SAMe). The pathway requires magnesium, vitamin C, iron, vitamins B3 and B6, and alpha-ketoglutarate, along with the cofactors responsible for creating SAMe (methionine, folic acid, vitamin B12, and betaine).4 After synthesis, carnitine is transported through the circulation and is then taken up by other tissues through active transport systems. L-carnitine is excreted by the kidneys; however, carnitine excretion by the kidney is normally very low as renal reabsorption is estimated to be 95%. However, elevated LC levels can saturate renal reabsorption leading to increased urinary excretion of LC. Sodium-dependent cationic transporter (OCTN2)5 is the primary known transporter responsible for both the transport of carnitine to other tissues and reabsorption in the kidney.

CARNITINE PHYSIOLOGY It is well established that carnitine is essential for energy production, given its critical role as carrier of activated fatty acids across the inner mitochondrial membrane. Carnitine is also involved in the removal of mitochondrial accumulated toxic fatty acyl-CoA metabolites and helps in buffering the balance between free and acyl-CoA.6 Skeletal muscle and heart tissue are highly dependent upon fatty acid oxidation as a source of energy. In healthy individuals, approximately 98% of total carnitine, the sum of free carnitine (FC) and AC is found in skeletal muscle, less than 1% in plasma with the remainder found in the heart, liver, and kidneys.7 Most of the total carnitine present in plasma exists in the free form, with the remaining as AC. In healthy men, the normal plasma FC concentration is between 40 and 50 mmol/L and is approximately 10% to 20% lower in healthy women.7 An AC to FC ratio ⱕ0.4 is considered normal. Of note, the high concentration of carnitine in skeletal and cardiac muscles is not obtained via synthesis but rather through carrier-mediated transport from the bloodstream. Thus, while synthesis may supply adequate carnitine under healthy conditions, when there is either excess demand for metabolism of fatty acids or abnormal losses of carnitine from the body, such as in HD, exogenous carnitine is required.8 With chronic kidney disease, in the absence of dialysis, free and


total carnitine concentrations increase, as does the AC/FC ratio. An AC/FC ratio >0.4 may indicate insufficient carnitine to buffer accumulation of excess acyl groups within the mitochondria, a condition referred to as carnitine insufficiency.9

CARNITINE DEFICIENCY IN DIALYSIS PATIENTS Hemodialysis patients experience many adverse consequences of kidney disease and often develop clinical conditions such as anemia, cardiovascular diseases, muscle weakness, and intradialytic hypotension, all of which may be associated with dialysis-related carnitine deficiency.10 Carnitine is easily removed by dialysis with subsequent depletion of tissue carnitine stores, inadequate dietary ingestion, and reduced renal synthesis of carnitine. It has been demonstrated that about 95% of dialysis patients have carnitine deficiency.11 Recent studies have confirmed that dialysis patients exhibit a gradual and significant decline in plasma FC concentrations during the months following the initiation of HD.12 Predialysis carnitine concentrations are below the normal range and are reduced further during each dialysis session. During the interdialytic interval, the plasma concentrations gradually rise, reflecting redistribution of LC from tissue stores into plasma. Biopsy studies have confirmed that long-term HD is associated with depletion of muscle carnitine stores, presumably due to redistribution of muscle carnitine into plasma and subsequent loss in dialysate.12 While ACs are also removed from the blood by dialysis, their removal is not as efficient as that seen for FC. Therefore, an increase in the plasma AC/FC ratio occurs. In fact, while in healthy population AC has been reported to be 17.4% of the total carnitine pool, Reuter et al. in HD patients reported that the AC proportion was 42.8%, that dialytic removal of AC was related to carbon chain length of the acyl group with diminished removal of ACs with acyl chain length exceeding eight carbons and no significant removal of the 18-carbon chain length esters.13 Possible clinical implication of the accumulation of ACs such as palmitoyl-Lcarnitine and stearoyl-L-carnitine in chronic dialysis patients is the contribution to the development of ventricular arrhythmias.14

L-CARNITINE TREATMENT IN DIALYSIS PATIENTS The maintenance of or even restoration to a predialysis state of a chronic kidney disease patient’s health

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represents the main goal in the treatment of dialysis patients. Thus, any potential treatment to improve their health and or quality of life is of great interest.

Anemia One of the most convincing therapeutic effects of carnitine is an improvement of uremic anemia,10 in particular in patients who fail to respond to erythropoietin (EPO). In fact, a reduction in erythropoiesis due to a decrease in renal EPO production shortened erythrocyte (RBC) life span, and induction of oxidative stress and apoptosis are important causes of renal anemia in dialysis patients or end-stage renal disease (ESRD) patients.15 L-carnitine has been shown to prolong RBC life span and increases the number of colony-forming unit-erythroid colonies in mouse bone marrow cell cultures, suggesting that LC stimulates erythropoiesis.16 In addition, antioxidant and antiapoptotic effects of LC have also been described both in vitro in endothelial cells in culture and ex vivo in chronic HD patients17–19 as well as by the improvement of inflammatory markers upon carnitine infusion.18–21 That LC may influence erythropoiesis by inhibiting oxidative stress and apoptosis is suggested by the results obtained treating human endothelial cells in culture with LC and its acyl derivatives, which showed increased heme oxygenase-1 (HO-1) mRNA and protein expression.17 HO-1 is a phase II enzyme induced by oxidative stress22 and has been shown to possess potent antioxidant and antiapoptotic activity.22 HO-1 expression in response to oxidative stress is regulated at transcriptional level by phosphatidylinositol 3-kinase (PI3K)/Akt pathway.23 Interestingly, the antiapoptotic action of EPO has been shown to be dependent on JAK2 signaling and PI3K-mediated phosphorylation of Akt which activates multiple targets.24 Given that both EPO and HO-1 antiapoptotic and anti-inflammatory effects occur via activation of the PI3K/Akt pathway and that carnitines induce HO-1, HO-1 induction might play an important role in the antiapoptotic effect of both EPO and carnitines.25 The results of our recent human study further support the importance of HO-1 in the effects of EPO as EPO treatment of chronic HD patients increased mononuclear cell HO-1 gene expression and improved plasma antioxidant levels.18,19 Moreover, there was a high degree of correlation between hemoglobin and HO-1 expression in our study, which suggests a possible direct EPO effect.18 Finally, reports that addition of carnitine improved the response to EPO and the anemia of chronic HD patients who failed to respond to EPO26 and HO-1-related antiapoptotic effects suggest an association between carnitine, EPO, and HO-1 pathways.24,25 Thus, a variety of studies

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show HO-1’s interrelated roles as both an antioxidant and antiapoptotic enzyme and provide a plausible mechanism for the reported LC-induced stimulation of erythropoiesis16 as well as the effects of carnitine on hemopoietic cells in ESRD patients.

Cardiac disease Cardiovascular disease is the most frequent cause of death among dialysis patients. In two open small-sized studies, it has been demonstrated that LC treatment was associated with a significant reduction in both dialysis-induced rise in free fatty acid levels and the frequency of ventricular premature beats and their severity.21,27 In addition, LC treatment has been found to be associated with a significant increase in left ventricular ejection fraction (LVEF), in particular in symptomatic patients with a lower baseline LVEF.28 The effect of LC treatment on LVEF was also studied in a group of patients who had significant impairment of systolic dysfunction. Most of these patients were already receiving standard therapy for congestive heart failure. Eight months of LC therapy was associated with a significant improvement in LVEF.29 Possible explanations for the improvement in LVEF seen with LC treatment include a reduction in cardiomyocyte apoptosis30,31 or an improvement in cardiac energy metabolism.32 Based on these studies, the consensus conference panel10 issued a recommendation for the use of LC in patients with severe cardiomyopathy.

Intradialytic hypotension About 25% of HD patients suffer from intradialytic hypotension, a condition recently recognized as a risk factor of mortality. LC treatment significantly reduced the number of patients experiencing one or more monthly episodes of intradialytic hypotension compared with placebo-treated patients.33 Because LC therapy has been associated with improvement in cardiovascular abnormalities common in hypotensive dialysis patients, its use for dialytic hypotension has also been recommended by the panel of experts.10

Muscle weakness Muscle tissue is highly dependent on the energy generated by b-oxidation of fatty acids and glycogen; therefore, it is important for muscle tissue to have adequate levels of carnitine. Hiatt34 showed that muscle carnitine content correlated inversely with time on HD and correlated positively with peak exercise performance. Hemodialysis patients with muscle symptoms (defined as muscle weak-



ness, fatigue, and cramps/aches) had significantly lower plasma FC levels, and the plasma AC/FC ratio was significantly greater than that in a group of dialysis patients completely free of muscle symptoms, suggesting that these symptoms may be associated with carnitine deficiency.35 Additional studies using either histological or anthropometric studies showed a direct correlation between carnitine level and mean diameter of type 1 fibers when comparing muscle biopsies at the end of the 12-month period of LC treatment and at the end of 4 months of LC added to dialysate. When LC was added to dialysate fluid, a statistically significant reduction in mean diameter and in the coefficient of hypertrophy has been observed in type 1 fibers.36 Another study showed an increase in isometric performance parameters as well as the diameters of type I and IIa fibers and a reduction in number of atrophic fibers after LC treatment.37 The panel of experts suggested that the use of LC should be reserved for those patients in whom other causes have been excluded and who have been unresponsive to standard therapies.10

L-CARNITINE NUTRITIONAL IMPACT L-carnitine treatment has been shown to impact insulin sensitivity and protein catabolism.38,39 Patients with poor insulin sensitivity in the LC group had improved sensitivity as measured by a euglycemic insulin-clamp procedure. Recently, Samocha-Bonet et al.40 have proposed that the relationship between oxidative stress and insulin resistance is mediated in part by a mismatch between lipid supply and mitochondrial oxidation capacity in skeletal muscle. This mismatch results in lipotoxic lipid and lipid peroxides species accumulation in skeletal muscle, which then interfere with insulin signaling. The role of carnitine in lipid transport as well as the efficacy of LC in reducing oxidative stress in dialysis patients16,17 are consistent with this proposed mechanisms and suggest that increased LC is likely to improve nutritional status by reducing insulin resistance.

L-CARNITINE EFFECT ON HOSPITALIZATION RATE AND QUALITY OF LIFE It has been recently demonstrated the efficacy of LC treatment in reducing the rate of hospitalization.41 These results were supported by a follow-up analysis by Weinhandl et al.42 in much larger US database containing data on over 116,000 HD patients in which between 4400


and 10,500 patients had been treated with LC (1 g or more of carnitine per treatment for 10 or more dialysis sessions). Treatment with LC resulted in a reduction of the future risk of hospital stay in the month following treatment, and this is even more remarkable after 1-month treatment. Quality of life, as measured by either the Kidney Disease Questionnaire or the 36-Item Short-Form Health Survey (SF-36) questionnaires, has been shown to improve after treatment with LC. Brass et al.43 showed improvements in the fatigue domain of the kidney disease quality of life and Steiber et al.44 showed significant improvements in the domains of role physical, bodily pain, and a trend toward increased physical composite score with LC treatment of 20 mg/kg of body weight per dialysis session.

RELUCTANCE FOR A WIDESPREAD USE OF CARNITINE The main explanation for the reluctance of nephrologists for a widespread use of carnitine in dialysis patients is essentially the heterogeneous clinical response of these patients to carnitine therapy. Although, in fact, studies reporting positive results and significant beneficial effects of carnitine supplementation are the majority, studies reporting no statistically significant beneficial effects or that LC supplementation was effective only in some subgroup of patients have also been reported. In addition, no large-scale randomized trials are included in the database for carnitine supplements in dialysis patients, which adds further reluctance given the general preference to make treatment decision based on the outcome of randomized trials.

Controversies on treatment with LC supplements in anemia Despite an overall improvement of anemic parameters with LC supplementation, a number of studies have also underlined the possibility of “responders” and “non responders” to such a treatment.45–47 Although in all of these studies, the division of patients into these subgroups was retrospective, a greater benefit was reported in those patients with the higher increase in carnitine plasma levels.46 Kletzmayr et al.47 noted that responders had higher baseline levels of all carnitines compared with nonresponders, suggesting that patients with more severe carnitine depletion might need of a higher dosage or longer period of carnitine supplementation in order to reduce EPO requirement. The apparent subgrouping of patients as responders and nonresponders therefore needs to be further and appropriately investigated.

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LVEF and dialytic hypotension In addition to the evidence in favor of the role of carnitine in the treatment of left ventricular dysfunction, negative results have been reported by other studies,48,49 although the patients in these latter studies had normal baseline ejection fraction. The use of carnitine therapy for the treatment of cardiac arrhythmias also remains a subject of contention. Suzuki et al.21 reported that the administration of carnitine (2 g p.o. prior to dialysis) for 4–8 weeks significantly reduced the incidence and severity of arrhythmias in dialysis patients. No change in the frequency of arrhythmias was instead reported after administration of 20 mg/kg i.v. carnitine for 6 months, after dialysis, compared with a placebo group, although very few dialysis-related arrhythmias were reported in both groups.50 The findings of the available studies in this area therefore indicate that carnitine has a potential for use in the treatment of cardiac dysfunction and in particular in the treatment of dialysis-related hypotension, while the relationship between carnitine and cardiac arrhythmias is less compelling, requiring additional well-designed trials to further investigate this aspect.

ments in improving multiple measures of health in dialysis patients has been reported by many studies. The use of carnitine supplements for many clinical signs and symptoms associated with carnitine deficiency in dialysis patients, and in particular for EPO-resistant anemia, has been, in fact, supported by a number of studies. Based on these studies, the recent National Kidney Foundation clinical consensus panel has recommended the use of intravenous carnitine supplements for these conditions in dialysis patients. There is, however, reluctance between nephrologists for a widespread use of carnitine in dialysis patients due essentially to the heterogeneous clinical response of these patients reported in other studies, in addition to the lack of large-scale randomized clinical trials, which further strengthens this reluctance to make treatment decisions in the absence of data coming from randomized trials. Well-designed randomized, large-scale clinical trials are therefore required to fully address the potentially important carnitine treatment in dialysis patients.

Manuscript received November 2011; revised January 2012.

Symptoms related to dialysis The benefit of carnitine therapy on the evaluation of muscle function as well as muscle weakness appears to be limited.51,52 In the study of Siani et al.,52 it was noted that, although no overall significant effects on muscle activity were found, four of the seven patients who received carnitine treatment showed an improvement of two or more grades in the assessment of muscle activity, pointing toward a subset of patients in whom carnitine administration appears to improve muscle function. The benefit of carnitine treatment on muscle function and muscle weakness therefore does not seem fully established. However, because the muscle weakness and related dialytic symptoms are life altering and, in many cases, debilitating for the numerous HD patients who regularly experience them, carnitine treatment might be justified, in some cases, for its potential on the improvement of these symptoms.

CONCLUSIONS Growing scientific and clinical evidence confirms the likelihood of the development of carnitine deficiency in patients receiving HD for several months. LC’s favorable safety profile and the effectiveness of carnitine supple-

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