Contrast Media Induced Nephropathy Clinical Trial
Official title:
Potentially Nephroprotective Effects of Carnitine and Phosphodiesterase Type 5 (PDE5) Inhibitor Agent Against Contrast Media-induced Nephropathy (CMN): A Double Blind Randomized Study
CIAKI is a common iatrogenic. Up to date the suggested treatments for CIAKI are partially effective and have not been approved by the Food and Drug Administration yet. The lack of effective nephroprotective drug for CIAKI, emphasizes the need not only for additional new drugs but also for new strategies that might also clarify CIAKI pathophysiology. To the best of our knowledge, the potentially beneficial effect of carnitine and PDE5 inhibitors on CIAKI prevention has not been examined, so far.
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.
Hypothesis 2: Another new upraising strategy that has been used in attenuating renal injury
in experimental studies is the use of phosphodiesterase type 5 (PDE5) inhibitor agents [77,
78]. PDE5 inhibitors are approved by the FDA for erectile dysfunction and pulmonary
hypertension. The latter have been found to exert a significant antiapoptotic effect on
renal tubular cells exposed to partial unilateral ureteral obstruction [79]. Part of the
physiological process of PDE5 inhibition involves the release of nitric oxide (NO). Brando
et al. linked the increase in available pool of cyclic 3,5 guanosine monophosphate (cGMP) by
phosphodiesterases inhibitors to prevention and ameliorating chronic renal damage mainly by
attenuating hypertension and retarding progression of renal disease [80]. Furthermore a PDE
5 inhibitor has been demonstrated to be able to ameliorate nephrotoxicity. Noami H. et al.
have shown that FR226807, a selective PDE5 inhibitor, ameliorates cyclosporine A
nephrotoxicity with further increases in cGMP content [81]. These observations may be of
relevance for contrast media induced renal injury and suggest PDE5 inhibition as a potential
therapeutic approach to this clinical entity.
In sum, CIAKI is a common iatrogenic. Up to date the suggested treatments for CIAKI are
partially effective and have not been approved by the Food and Drug Administration yet. The
lack of effective nephroprotective drug for CIAKI, emphasizes the need not only for
additional new drugs but also for new strategies that might also clarify CIAKI
pathophysiology. To the best of our knowledge, the potentially beneficial effect of
carnitine and PDE5 inhibitors on CIAKI prevention has not been examined, so far.
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Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Supportive Care