Allopurinol and Trimetazidine as a Preventive of Contrast-associated Acute Kidney Injury in Patients Undergoing Percutaneous Coronary Intervention

I. Introduction Contrast-associated acute kidney injury (CA-AKI) is a common complication of procedures with intravascular contrast. Generally, CA-AKI is defined as serum creatinine (Scr) ≥ 25 to 50% or Scr rise around 0.3 to 0.5 mg/dl. The initial rise in SCr is typically seen within 48 to 72 h of contrast exposure . The incidence of CA-AKI varies from 3% to 30% depending on the type of contrast media administered, mode of delivery, intra-arterial , intra-venous, and underlying comorbidities . According to contrast induced nephropathy (CIN) Mehran Risk Score, specific factors that increase the risk of developing CA-AKI include hypotension, the use of an intra-aortic balloon pump, chronic heart failure, a serum creatinine level > 1.5 mg/dl, age > 75 years, anemia, diabetes mellitus, estimated glomerular filtration rate less than 60 ml/min and contrast media volume . CA-AKI has been associated with increased hospital length of stay and excess costs Therefore, the prevention of CA-AKI is beneficial for minimizing hospital costs, mortality and morbidity.

Till now, what is clearly beneficial in CIN is adequate hydration before and after coronary angiography However, further measures are trialed, aiming to reduce more morbidity and mortality. There is a great deal of publications pertaining to the causes, risk factors, outcomes, and possible therapeutic interventions to avoid the ultimate outcome of complete kidney failure requiring dialysis. Over the decades many proposed preventative strategies and treatments have failed to produce a reliable outcome One of the targets of antioxidants trialed in the prevention of CIN is to reduce the release of oxygen free radicals which are promoting CIN .

Allopurinol, as an inhibitor of xanthine oxidase (XO), has been widely used to treat gout and hyperuricemia. Studies have demonstrated the presence of a strong association between serum uric acid (SUA) and acute kidney injury (AKI) . In humans, uric acid acts as an antioxidant in the extracellular environment and as a prooxidant in the intracellular environment. For centuries, the biological significance of uric acid is that it crystallizes and in the urinary tract to cause kidney Stones. High SUA has been associated with hypertension, cardiovascular diseases, stroke, diabetic nephropathy, and acute kidney injury (AKI) . Moreover, allopurinol has been shown to decrease the fall in the glomerular filtration rate (GFR) following exposure to contrast media by inhibiting oxygen free radical release, adenine nucleotide degradation, and limiting vasodilator reaction to intra-renal adenosine.

Accordingly, allopurinol has been suggested as a promising measure for the prevention of acute kidney injury after coronary angiography through protecting the kidney by inhibiting XO activity and blocking the generation of oxygen radicals and the production of uric acid However, studies have shown conflicting results Trimetazidine is cellular anti-ischemic drug which has been shown to protect against free radical damage due to its antioxidant activity through inhibiting the excessive release of oxygen-free radicals, shifting energy metabolism from fatty acid oxidation to glucose oxidation preserving adenosine triphosphate stores, diminishing intracellular acidosis, limiting the peroxidation of membrane lipids and inhibiting the infiltration of neutrophils after ischemia-reperfusion. Thus, may attenuate renal ischemic-reperfusion injury. A recent meta-analysis showed that Trimetazidine administration decrease the risk of CIN in patients undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) in some studies. However, it is worth mentioning that studies evaluating trimetazidine under presented patients with high estimated glomerular filtration rate (eGFR). Zhang .found that trimetazidine reduced CIN occurrence in patients with moderate and high-risk populations based on Mehran score, but not in low-risk patients . Accordingly, further RCTs are required to confirm whether the effect is demonstrable in patients with normal renal function.

Hence, using allopurinol or trimetazidine for the prevention of CIN beside adequate hydration do not have sufficient evidence to justify a recommendation in favor or against in patients with different risk stratification and normal GFR. Moreover, no studies to date evaluated the combined effect of using both agents in preventing CA-AKI. Accordingly, we aimed to evaluate the combination of trimetazidine with allopurinol versus using trimetazidine alone to define the most effective strategy to be implemented in the clinical setting in patients with diverse risk factors II. Aim The aim of this study is to compare trimetazidine alone versus trimetazidine plus allopurinol as a preventive of CA- AKI in patients undergoing elective PCI.