Potentially Nephroprotective Effects of Carnitine and Phosphodiesterase Type 5 (PDE5) Inhibitor Agent Against Contrast Media-induced Nephropathy (CMN): A Double Blind Randomized Study

Hypothesis 1: More studies are focusing now on strategies to preserve tissue mitochondria and subsequently to maintain normal organ functioning [62]. One of these strategies is the use of Carnitine. Carnitine was first described in the early beginnings of the 20th century. In humans, 75% of carnitine is obtained from diet [63], whereas the rest is synthesized from two essential amino acids, lysine and methionine in kidney, liver and brain [64]. Carnitine transports long-chain acyl groups from fatty acids into the mitochondrial matrix, so they can be broken down through β-oxidation to acytl-coenzyme-A to obtain energy balance across cell membranes of tissues that derive much of their energy from fatty acid oxidation such as cardiac and skeletal muscles [66,67].

Plasma concentration of free carnitine is in dynamic balance with acylcarnitines with the acyl to free carnitine ratio of ≤ 0.4 being considered normal [65], however, in uremic patients, this balance is disrupted, and this ratio is altered because of a larger amount of free carnitine is esterified to acyl-carnitine to "buffer" the excess of acyl groups, modulating the bound CoA to free CoA [68]. This may cause several metabolic disturbances at the cellular level, including impaired mitochondrial fatty acid oxidation and energy production, accumulation of toxic acyl moieties, and inhibition of key enzymes of metabolic pathway [69]. These metabolic abnormalities may lead to the several clinical alterations often observed in these patients, such as muscle weakness and myopathy, loss of body protein and cachexia, insulin resistance and glucose intolerance, plasma lipid abnormalities, anemia refractory to erythropoietin (EPO) treatment, cardiomyopathy, and intradialytic symptoms [70,71,72]. Thus, the imbalanced in acyl/free carnitine ratio may explain the higher risk of patients with chronic renal failure to CIAKI. However, Carnitine supplementation may contribute to the regeneration of sequestrated free CoA and to maintain normal metabolic processes [66,67].

Experimental studies shows that L-propionylcarnitine, a propionyl ester of L-carnitine, was able to prevent cyclosporine (immunosuppressive agent following organ transplantation) induced acute nephrotoxicity, reducing lipid peroxidation and significantly lowering blood pressure. L-propionylcarnitine prevented the decline in creatinine clearance in cyclosporine chronically treated animals [73]. Patients treated with carnitine displayed improved physical performance and treatment-related chronic fatigue, cardiovascular disease, cancer, diabetes, and other chronic syndromes, caused by impaired carnitine production in kidney disease [36-38]. In the last decade there are increasing reports describing the beneficial use of carnitine for a better energy metabolism (mitochondrial metabolism). Carnitine increases albumin and protein levels, restores antioxidant defenses, and improves nutritional status, cardiac, vascular smooth muscle, and muscular function [39-42]. The postulated beneficial effect of carnitine treatment is by directing lipids towards oxidation and ATP production. Another possible protective effect of carnitine on contrast media induced lesions is its ability to suppress the development of oxidative stress and free radical generation [74]. Free radicals, and in particular hydroxyl radical, lead to lipid peroxidation of cell membranes, causing degradation of phospholipids, resulting in increased production of renal vasoconstrictors [75].

It should be emphasized that carnitine is available as a medication and is approved by the FDA for treating secondary deficiency due to metabolic diseases. Intravenous administration of carnitine is safe, and its pharmacokinetics can be analyzed just by knowing the pre-dose level in plasma [76]. Further, after single-dose intravenous administration of (0.5 g) of acetyl-L-carnitine, its rapidly, but not completely hydrolyzed, and acetyl-L-carnitine and L-carnitine concentrations return to baseline within 12 hours. Even in high doses; intravenous doses as high as 300 mg/kg have been administered with no apparent toxicity. However, the most commonly reported adverse effects are few and nonserious including gastritis, diarrhea, and body odor.

The beneficial carnitine supplies have been extensively evaluated in animals and humans during the last 20 years. As a result, several experts have already aimed to revise the clinical evidence supporting its therapeutic use. In Addition to the light of the growing experimental evidences for the beneficial effects of carnitine as an antioxidant and as a beneficial modulator of mitochondrial energy expenditure, it is tempting to explore the possibility that carnitine may exert nephroprotective effects in CIAKI.