Differential effects of oral and intravenous l-carnitine on serum lipids: is the microbiota the answer?

L‐carnitine (free carnitine) transports cytosolic long‐chain fatty acids as acylcarnitines across the inner mitochondrial membrane for β‐oxidation and subsequent ATP production in the mitochondria. The endogenous carnitine pool comprises free L-carnitine as well as short-, mediumand long-chain fatty acid esters (acyl-carnitines) and depends on absorption of L-carnitine from dietary sources, endogenous biosynthesis and renal tubular reabsorption from glomerular filtrate [1]. More than 99% of the carnitine pool is located outside of plasma. Carrier-mediated transport ensures high tissue-to-plasma concentration ratios in tissues that depend critically on fatty acid oxidation, such as heart and muscle. Myocytes have one of the highest intracellular carnitine concentrations in the body, and red meat is a rich source of dietary carnitine. Absorption of orally administered L-carnitine is very variable and ranges from 5 to 18% for pharmacological doses of up to 75% for dietary L-carnitine. The low bioavailability depends both on transport kinetics and on L-carnitine metabolism by intestinal bacteria [1, 2]. The renal clearance of L-carnitine (1–3 mL/min) is much lower than the glomerular filtration rate because of extensive (98–99%) tubular reabsorption. The lack of reabsorption during the haemodialysis procedure results in large losses of L-carnitine in dialysate. The existence of a threshold concentration for tubular reabsorption results in much higher renal clearances after intravenous administration of high doses [3]. In 1978 a dramatic reduction in carnitine concentration in muscle and plasmawas observed after the haemodialysis session due to loss of carnitine into the dialysate [4]. By 1980 it was reported that intravenous L-carnitine for 14 weeks decreased serum triglycerides [5], and oral D,L-carnitine for 30 days decreased serum triglycerides and returned HDL cholesterol to normal in chronic haemodialysis patients with hypertriglyceridaemia [6]. Potential benefits of carnitine supplementation on cardiomyopathy, cardiac failure and atherosclerosis in renal failure patients were envisioned. By 2003, National Kidney Foundation practice recommendations offered an expert opinion on the use of L-carnitine in dialysis patients with disorders potentially related to carnitine deficiency, such as erythropoietinresistant anaemia, intradialytic hypotension, cardiomyopathy and fatigability [7]. L-Carnitine administration may also ameliorate insulin resistance, hypertriglycedaemia, inflammation and protein wasting [8, 9]. Reimbursement for the intravenous and oral administration of L-carnitine for chronic renal failure anaemia and intradialytic hypotension was approved by the US Centers for Medicare & Medicaid Services in 2004 and 2012, respectively [10]. Even intraperitoneal supplementation in peritoneal dialysis fluid has been tested and reported to be associated with improving insulin sensitivity in nondiabetic peritoneal dialysis patients [11]. However, 35 years after the first reports on L-carnitine deficiency in haemodialysis patients, routine L-carnitine supplementation is not recommended by KDIGO or KDOQI clinical guidelines covering several aspects of the renal failure patient, based on lack of definitive evidence of benefit [8, 9, 12–14]. Chronic haemodialysis may lead to progressive L-carnitine deficiency through a combination of loss of L-carnitine in dialysate and decreased L-carnitine synthesis by the injured kidney. L‐carnitine deficiency develops over time in haemodialysis patients and serum levels may not differ from controls in incident patients [15]. In a recent clinical trial, pre-dialysis serum carnitine levels decreased by ∼22% during the first year of haemodialysis in the placebo arm and carnitine deficiency developed in 30% of patients [16]. Furthermore, low renal clearance of short‐chain acylcarnitines results in a high acylcarnitine:L‐carnitine ratio in chronic kidney disease patients. In addition, a metabolomics approach identified higher concentrations of long-chain acylcarnitines in incident dialysis patients, and these high concentrations were a marker of cardiovascular mortality after multivariable adjustment [15]. While the haemodialysis session induces a decline in free, short-chain, medium-chain and dicarboxylic acylcarnitines, it does not affect long-chain acylcarnitines [17]. Thus, dialysis patients, especially those on haemodialysis, may present two abnormalities regarding carnitine levels: a carnitine deficiency and a high acylcarnitine/free carnitine ratio that may further limit free carnitine availability. The 2000 KDOQI Clinical Practice Guidelines for Nutrition in Chronic Renal Failure Work Group extensively reviewed the evidence regarding L-carnitine supplementation