Debate Forum: Levocarnitine Therapy Is Rational and Justified in Selected Dialysis Patients
- 1 December 2005
- journal article
- review article
- Published by S. Karger AG in Blood Purification
- Vol. 24 (1), 128-139
- https://doi.org/10.1159/000089449
Abstract
Carnitine is a metabolic cofactor which is essential for normal fatty acid metabolism. Patients with chronic kidney disease on dialysis have been shown both to suffer from disordered fatty acid metabolism and to have a significant deficiency in plasma and tissue carnitine. Aberrant fatty acid metabolism has been associated with a number of cellular abnormalities such as increased mitochondrial permeability (a promoter of apoptosis), insulin resistance, and enhanced generation of free radicals. These cellular abnormalities have, in turn, been correlated with pathological clinical conditions common in dialysis patients including cardiomyopathy with attendant hypotension and resistance to the therapeutic effect of recombinant human erythropoietin (EPO). In 1999, the Food and Drug Administration approved levocarnitine injection for the prevention and treatment of carnitine deficiency in patients on dialysis based on documentation of free plasma carnitine levels in dialysis patients similar to other serious carnitine deficiency states for which treatment was required. Data analysis performed by expert panels convened by both the American Association of Kidney Patients and, subsequently, the National Kidney Foundation recommended a trial of levocarnitine therapy for specific subsets of dialysis patients including those with EPO resistance, dialysis-related hypotension, cardiomyopathy and muscle weakness. In 2003, the Centers for Medicare and Medicaid services convened a Medical Advisory Committee which established reimbursement on a national level for carnitine-deficient dialysis patients who had either dialysis-related hypotension or EPO resistance. Recently, a correlation between reductions in hospitalization rates of dialysis patients receiving levocarnitine therapy has been demonstrated in a large retrospective study. Despite data-based recommendations and national reimbursement, only a small minority of dialysis patients have been prescribed a therapeutic trial of levocarnitine. Whereas the reasons for the reluctance of nephrologists to prescribe this therapeutic trial are unclear, possible explanations include a lack of appreciation of the pivotal role played by carnitine in cellular metabolism and the strength of evidence for a substantial deficiency of carnitine in dialysis patients, an underestimation of the prognostic import of EPO resistance and dialysis-related hypotension, inadequate dissemination of the clinical trial data supporting the use of levocarnitine in dialysis patients, and the heterogeneous clinical response of dialysis patients to levocarnitine therapy. Difficulties in documenting both initial eligibility and evidence of improvement as a result of therapy may also be a contributing factor. This paper discusses the biological role of carnitine and its particular relevance to dialysis patients. Clinical trial data concerning an effect of therapy on EPO resistance and dialysis-related hypotension are summarized along with a discussion of the logic behind the use of levocarnitine in dialysis. Finally, the difficulties posed by a reimbursement policy based on clinical as opposed to laboratory endpoints and a heterogeneous response to therapy are addressed.Keywords
This publication has 61 references indexed in Scilit:
- Epoetin requirements predict mortality in hemodialysis patientsAmerican Journal of Kidney Diseases, 2004
- Impact of hemodialysis on endogenous plasma and muscle carnitine levels in patients with end-stage renal diseaseKidney International, 2004
- Hemodialysis-associated hypotension as an independent risk factor for two-year mortality in hemodialysis patientsKidney International, 2004
- Effect of L-Carnitine on Mitochondrial Acyl CoA Esters in the Ischemic Dog HeartJournal of Molecular and Cellular Cardiology, 1994
- Fatty acid oxidation disorders: A new class of metabolic diseasesThe Journal of Pediatrics, 1992
- Primary Carnitine Deficiency Due to a Failure of Carnitine Transport in Kidney, Muscle, and FibroblastsNew England Journal of Medicine, 1988
- Plasma and muscle free carnitine deficiency due to renal Fanconi syndrome.JCI Insight, 1985
- Carnitine and left ventricular function in haemodialysis patientsScandinavian Journal of Clinical and Laboratory Investigation, 1985
- Effects of L-carnitine on arrhythmias during hemodialysis.Japanese Heart Journal, 1982
- CARNITINE DEFICIENCY INDUCED DURING INTERMITTENT HÆMODIALYSIS FOR RENAL FAILUREThe Lancet, 1978