L-Carnitine Supplementation in Dialysis: Treatment in Quest of Disease

Abstract

L-Carnitine (LC) administration has been recommended for specific indications in dialysis patients, including epoetin-resistant anemia, intradialytic hypotension, cardiomyopathy, fatigue, muscle weakness, and exercise performance; it may ameliorate insulin resistance, inflammation, and protein wasting. Use of LC for anemia and intradialytic hypotension has been approved for reimbursement by the Centers for Medicare and Medicaid Services. Yet, the data to support these recommendations are inadequate and have not been bolstered over several decades. LC administration continues to appeal to nephrologists because its use in dialysis patients has an attractive rationale, it addresses problems that persist despite dialysis, it is safe, and the existing literature does not refute its use. Nevertheless, definitive trials to justify LC administration have not been conducted and are increasingly unlikely to be funded. In an era of shrinking resources and bundling of dialysis services, the use of LC in dialysis patients will, appropriately, diminish.

There are several reasons to think that carnitine deficiency is endemic in dialysis patients and should be corrected. In the dialysis population, LC levels in blood and muscle are typically low and comparable to those observed in primary (inherited) carnitine deficiency. Dialysis patients exhibit some of the clinical features of primary carnitine deficiency. An appealing rationale can be devised to explain these clinical features on the basis of carnitine deficiency. An abundance of small, heterogeneous, and often uncontrolled studies provide suggestive support for L-carnitine (LC) supplementation. Partly on the basis of one, small randomized controlled trial (RCT) (1,2), the Food and Drug Administration (3), the Centers for Medicare and Medicaid Services (CMS) (4), and several expert consensus panels (5,6) have endorsed its use in dialysis patients. And LC is apparently safe, even in very large, pharmacological doses. The rationale for LC use is attractive, the needs of dialysis patients great, and the intervention safe. The nephrology community continues to dally with this appealing idea, especially as clinical experience and research have not refuted it.

Nevertheless, more than two decades since widespread use of LC supplementation in dialysis patients was suggested, and more than a decade since reimbursement for its use in this population was approved (4), the case for its use has not been bolstered. The lack of definitive evidence might suggest that, despite the plethora of suggestive small RCTs and observational studies, larger studies have been negative. But the large-scale RCTs that would make the case for LC administration have not been conducted. The climate for clinical studies of LC has been adverse and will only worsen.

LC Metabolism in Dialysis Patients

LC plays an essential role in transporting fatty acids into mitochondria for oxidation; it is critical in tissues, such as heart and skeletal muscle, which depend on fatty acids for energy metabolism. LC also transesterifies toxic acyl groups that accumulate in renal failure and that are thought to mediate insulin resistance, free radical generation, and lipid peroxidation (see below). The resulting acylcarnitines are less toxic and are excreted preferentially by the kidney compared to LC (7).

Free LC serum levels, elevated in chronic kidney disease, fall progressively after initiation of dialysis, for multiple reasons:

• 1
   LC is small and not protein-bound and, therefore, highly dialyzable: serum levels fall substantially after each dialysis procedure, to be replenished from muscle stores that are progressively depleted (8)
• 2
   Foods high in LC (meat and dairy products) are not consumed in large amounts by dialysis patients
• 3
   Renal mass, a site of LC synthesis, is reduced
• 4
   Incompletely metabolized acyl groups accumulate in dialysis patients, in whom the rate of fatty acid oxidation in skeletal muscle is 50% of that of healthy controls (9). These fatty acid moieties deplete LC by transesterification to acylcarnitines.

Acylcarnitines are poorly dialyzed compared with LC, while in normal individuals, renal tubular reclamation of filtered LC is greater than that of acylcarnitines. Because of these factors—incomplete fatty acid oxidation, increased transesterifcation of LC, loss of renal function, and reduced dialysance of long-chain acylcarnitines—the ratio of acylcarnitines to free LC is substantially higher in dialysis patients (>0.4) than in healthy controls (0.1–0.2) (7).

Low free LC levels have suggested, quite naturally, that dialysis patients suffer from secondary carnitine deficiency, termed dialysis-related carnitine disorder (DCD). Primary carnitine deficiency is due to an inherited defect of the transporter that concentrates LC in skeletal muscle and reclaims filtered LC from renal tubular fluid (10). Its features include muscle weakness, failure to thrive, cardiomyopathy, nonketotic hypoglycemia, and frequent infections. This array of complaints has a tantalizing overlap with the problems of dialysis patients, but, for the most part, lacks specificity (aside from hypoglycemia, which is not typical of dialysis patients unless they are severely malnourished).

It has been suggested that dialysis patients suffer from relative rather than true carnitine deficiency: LC levels are insufficient to keep up with metabolic demand, e.g. for fatty acid oxidation or for detoxification of acyl groups that accumulate in renal failure. In support of this concept is the observation that, unlike the situation in primary carnitine deficiency, the ratio of acyl- to free carnitine is elevated in dialysis patients. The constellation of elevated acylcarnitine-to-free LC ratio and low free LC constitutes a laboratory definition of relative carnitine deficiency.

LC supplementation lowers the acyl-to-free LC ratio toward normal, but does not normalize it (1). This observation suggests that, despite administration of pharmacological doses, free LC remains insufficient to detoxify all of the acyl groups that accumulate in dialysis patients. It is also consistent with the idea that the primary cause of impaired fatty acid oxidation and excess acyl production in dialysis patients is not, or not exclusively, carnitine deficiency. For example, while LC levels in plasma and skeletal muscle are reduced, they may not be low enough to limit fatty acid oxidation. LC deficiency and elevated LC:acylcarnitine ratio could be a consequence rather than a cause of impaired fatty acid oxidation in dialysis patients.

The use of levels of LC and acylcarnitine to define DCD has a crucial shortcoming: There is no pattern of carnitine metabolites that correlates with the alleged features of the condition, nor predicts response to LC administration. For example, the large majority (95%) of long-term dialysis patients have low serum-free LC (8,11), but the response of dialysis patients to LC supplementation is heterogeneous. It is tautological to define DCD by low serum-free LC level, which has no relation to symptoms or treatment, and it is puzzling that CMS chose to do so (4). A similar argument could be made for skeletal muscle LC, which comprises 98% of the body LC pool and is also depleted in long-term dialysis patients (7–9). Relative carnitine deficiency is a theoretical construct based on an attractive metabolic rationale, a resemblance of nonspecific clinical features to those of primary carnitine deficiency, and a pattern of carnitine metabolites that does not define clinical features or response to treatment.

Trials of LC Administration

Given the high prevalence of abnormal carnitine profile in dialysis patients, response to LC administration is required to prove the significance of carnitine deficiency. But the clinical trial and observational data are unconvincing. Most of the extant studies are uncontrolled. RCTs have been small and have short duration of follow-up, and their study populations were not selected for clinical manifestations that might respond to LC administration. For example, there are few, if any, controlled trials of LC in a study population with erythropoietin resistance. Study endpoints and dosing have been variable. Furthermore, RCTs of LC administration have generally been unregistered, so their results, as well as those of meta-analyses, are susceptible to reporting or publication bias (12).

The clinical manifestations that are thought to be due to relative carnitine deficiency include anemia, intradialytic symptoms, muscle weakness, impaired exercise capacity, cardiomyopathy, hyperlipidemia, inflammatory state, and failure to thrive. Treatment with LC has not been proved efficacious in any of them.

Anemia

The best (though still unconvincing) case for use of LC in dialysis patients is as an adjuvant in treatment of anemia. At least three mechanisms for this benefit have been suggested:

• 1
   Toxic acyl groups may be incorporated into the cell membrane and reduce membrane deformability and stability; accumulation of acyl groups could be corrected by LC administration (13).
• 2
   LC stimulates erythropoiesis in mouse bone marrow cell cultures (14).
• 3
   LC could enhance the response to erythropoietin through its anti-inflammatory and antiapoptotic effects, which may be mediated by stimulation of heme oxygenase 1, a pathway that LC shares with erythropoietin (15,16).

Despite these attractive mechanisms, the clinical trial data are contradictory and unconvincing. In a very small (n = 24) prospective RCT, treatment with LC, 1 g intravenously after each hemodialysis treatment for 6 months, was associated with a 38% reduction in epoetin dose with no change in hematocrit; 6 of 13 patients in the experimental group showed no effect of LC (17). In another small RCT (n = 31), LC administration at the same dose and duration did not increase epoetin response; a post hoc analysis (n = 21) of patients over age 65 did show a significant benefit of LC (18). In a third small RCT (n = 40), LC was administered in doses of 5 mg/kg in 15 patients and 25 mg/kg in five patients; there was no significant effect on epoetin dose (19). In two additional randomized, controlled trials in which anemia and epoetin dosing were not primary endpoints, intravenous LC administration was not associated with significant changes in hemoglobin or epoetin dose from baseline or compared with a control group (20,21). Trials of oral LC in adults (22) and children (23) showed no change in hemoglobin level after 3 (23) or 6 (22) months.

A meta-analysis evaluated the efficacy of LC supplementation in lowering the required dose of epoetin using data from six randomized trials. The epoetin dose was found to be significantly lower among those administered LC, with a beneficial response reported in four of the six studies (24). However, meta-analyses are compromised by reporting bias.

In general, trials of LC in anemia of dialysis patients have been small, showed variable effects on response to epo, did not look at a population of epo-resistant patients, and were not registered. A widely used reference concluded that there is insufficient evidence to recommend the use of LC in epoetin-resistant dialysis patients (25).

Dialysis Hypotension and Cardiomyopathy

The rationale for use of LC in dialysis hypotension includes improved cardiac and vascular smooth muscle function. A proposed mechanism for cardiac benefit is that LC administration stimulates pyruvate dehydrogenase and, therefore, glucose oxidation in cardiac muscle (26). A small, prospective, double-blind, placebo-controlled trial reported benefit on intradialytic hypotension (2), but a meta-analysis that included 193 patients did not confirm this benefit (27). Studies purporting to show a benefit of LC on ejection fraction or cardiac fractional shortening have been small and lacking in controls. A large multicenter RCT showed that long-term LC administration in very large doses ameliorates left ventricular dilatation after anterior wall myocardial infarction, but this study was not conducted in dialysis patients (28).

Exercise Performance and Muscle Metabolism

There is no consistent evidence of benefit of LC administration: Muscle strength was improved in several small studies, but muscle fatty acid metabolism and muscle fiber performance were not improved (9,20,29).

Quality of Life

Studies have been conflicting (9,21,30). Improvements were noted in role-physical and physical component summary score of the SF-36 (30). In an RCT of LC 20 mg/kg after dialysis, there was no benefit on the Kidney Dialysis Questionnaire, nor improvement of muscle cramping, muscle weakness, response to erythropoietin, or intradialytic hypotension (21).

Dyslipidemia

Studies of the effect of LC administration on hyperlipidemia in dialysis patients have been conflicting and a meta-analysis found no benefit (24).

Inflammation, Insulin Resistance, and Muscle Wasting

The effect of acyl CoA to increase insulin resistance and generation of free radicals and lipid peroxidation products suggests a mechanism by which carnitine deficiency could contribute to insulin resistance and muscle wasting in dialysis patients (26). LC administration ameliorated insulin resistance in dialysis patients (31). Two placebo-controlled trials in hemodialysis patients independently demonstrated that intravenous LC (20 mg/kg body weight three times a week for 6 months) reduced serum C-reactive protein and increased albumin, transferrin, and body mass index (32,33); nutrition and adequacy of dialysis were not controlled. In another double-blind RCT, LC administration reduced serum amyloid A (34). These studies suggest a benefit of LC on inflammatory state, muscle wasting, and insulin resistance, but are too small to be definitive.

Why are Definitive RCTs of LC in Dialysis Patients Lacking?

A large, multicenter RCT focused on a specific putative consequence of carnitine deficiency in dialysis patients has not been performed. Why not? The economics of drug development and dialysis do not favor such a trial. LC is a generic drug that is not protected by patent. A drug company that funded a positive trial would not have exclusive rights to the agent and would not profit from it. There can be no doubt that LC would have been appropriately tested if it were patent-protected. In this time of shrinking resources, federally funded large-scale studies in this area are equally unlikely.

Bundling of dialysis services now also militates against carnitine use. Intravenous agents are included in the bundle and are not separately reimbursed. In the absence of striking and proven benefits, the disincentive to LC administration in the US market is strong. Bundling is relatively recent and does not explain the historic paucity of large trials of LC, but bundling will dampen enthusiasm for future trials. Already, dialysis providers in the United States are discouraging LC administration.

Aside from these economic disincentives, the drug has not kindled much enthusiasm in the nephrology community. This reluctance could be due simply to well-informed reading of the existing literature. Perhaps the most dispiriting feature of this literature is the heterogeneity of responses to LC. Many authors divide responders from nonresponders, as if this maneuver could salvage a significant effect from a negative study. Not only is this approach statistically fatuous, it begs the question of which patients would benefit from and should receive LC. This question remains unanswered—there is no a priori test to predict response to LC—and lack of enthusiasm for LC in this context is understandable. Ultimately, we need more basic scientific knowledge about fatty acid metabolism in dialysis patients. Heterogeneous responses and failure to normalize fatty acid oxidation and the acyl:free carnitine ratio in dialysis patients suggest that carnitine deficiency is far from the whole story in their defective fat metabolism. Such knowledge would surely improve the heretofore merely empirical trials of LC administration.

Clinical Role of LC

Despite this unimpressive record of supportive studies, expert consensus groups and federal agencies have recommended LC not for routine use, but for consideration in dialysis patients with specific indications. In 1999, the FDA approved intravenous LC for use in dialysis-related carnitine deficiency, as defined by low LC levels (3). Expert consensus panels of the American Association of Kidney Patients (5) and of the NKF (6) have recommended intravenous LC for treatment of erythropoietin-resistant anemia, dialysis hypotension, cardiomyopathy, and muscle weakness. Use of oral LC was discouraged because of limited bioavailability, paucity of supportive studies, and formation of toxic metabolites (trimethylamine and trimethylamine-n-oxide) via intestinal metabolism (35). The CMS issued a national coverage determination for intravenous LC for treatment of epoetin-resistant anemia and dialysis hypotension (4). The wisdom of this determination has been vigorously questioned (36). Among other things, the requirement for low LC level is subject to variations due to dialysis, and the expense of LC in the absence of definitive studies is hard to justify.

Conclusion

What does the future hold for use of LC in dialysis patients? It is hard to argue, in an age that will have to come to terms with scarcity of medical resources, that an unproven agent should be reimbursed at great expense to the already expensive ESRD program. On the other hand, LC is an answer to intractable problems in dialysis patients that have no other solutions.

Dialysis is an imperfect, “halfway” technology for patients with stage 5 chronic kidney disease, and they are left with many problems that we are desperate to solve. Epoetin-resistant anemia is one of these: none of the adjuvants used to enhance response to ESAs has strong scientific support (25). The malnutrition–inflammation–atherosclerosis complex is another such problem, and because patients with this disorder are likely to be epoetin-resistant, LC may be reimbursed for them.

LC has an attractive theoretical rationale, suggestive but not definitive supportive studies, and with minimal, if any, toxicity. Its modest expectation of benefit exceeds its minimal risk, so it qualifies as worth trying in some difficult clinical scenarios. For the present, we are reimbursed to try LC, but dialysis providers are—appropriately—discouraging its use. Whether our health system can afford profligate spending on treatments that do not work is a risk as well, not a medical, but a societal and economic one. Forces external to science and medicine may soon put an end to the prolonged and tepid romance of the nephrology community with LC.