… you’d think that by now I’d know ‘Cause here we go go go go again
Cardiac catheterization associated contrast-induced nephropathy (CIN) is an enigma that has troubled interventional cardiologists, radiologists and nephrologist for over two decades. CIN is diagnosed by increased serum creatinine concentration within <72 h of administration of contrast media and has significant impact on patient outcomes and the medical system as a whole . CIN has been shown to be associated with progression of chronic kidney disease , increased risk of dialysis , higher risk of future cardiovascular disease , longer length of stay , and more 30 day readmissions . Furthermore, recent data from the national inpatient sample demonstrate incidence of post-cardiac catheterization acute kidney injury (AKI) to be increasing nationwide . Minimizing post-cardiac catheterization creatinine rise or drop in the glomerular filtration rate has manifested into being a quality metric among review agencies. However, unlike acute coronary syndromes and troponins, we do not yet have consensus or approved biomarkers to measure or define post-cardiac catheterization AKI. Investigational biomarkers such as cystatin-c, urine neutrophil gelatinase-associated lipocalin (u-NGAL) and phosphatidylserine receptor kidney injury molecule-1 (KIM-1) have brought forth encouraging results in recent years as markers of ischemic, septic or nephrotoxic injury to the kidneys . Nevertheless, the field continues to utilize serum creatinine, a surrogate for renal function, and the estimated glomerular filtration rate (eGFR) to identify CIN associated AKI. Such a case is analogous to a patient having an infarcted diagonal branch but believing there was no cardiac injury because the left ventricular ejection fraction remains preserved.
Given that no specific treatment currently exists for CIN, the focus rests on prevention. A variety of preventive measures may reduce the risk of CIN, such as low contrast dose, avoiding volume depletion or the use of non-steroidal anti-inflammatory drugs, the administration of intravenous saline or sodium bicarbonate and the use of low- or iso-osmolal nonionic contrast agents. Current evidence does not support the routine use of N -acetylcysteine, IV sodium bicarbonate, statins or ascorbic acid for the prevention of CIN.
The present study by [XX et al.] , in this issue of CRM assesses the role of trimetazidine with intravenous hydration for the prevention of CIN among patients with CKD undergoing cardiac catheterization. Trimetazidine has previously been studied as an anti-ischemic agent, functioning as an intracellular modulator shifting ATP production from free fatty acids to glucose oxidation and thus inhibiting myocyte oxidative phosphorylation . XX and colleagues randomized a total of 100 patients with mild to moderate chronic kidney disease (creatinine clearance 30–90 mL/min) undergoing cardiac catheterization in a 1:1 fashion to receive either oral trimetazidine 35 mg twice daily or placebo with intravenous normal saline before and after cardiac catheterization. The authors defined CIN as increase in serum creatinine by 0.5 mg/dl, or a relative increase of 25% in serum creatinine or a decrease in the estimated creatinine clearance at 24 or 72 h post-cardiac catheterization compared to pre-procedure levels. There was a significantly lower estimated creatinine clearance at 24 h and 72 h in the control arm when compared to the trimetazidine group ( Fig. 1 ), but there was no statistical difference in serum creatinine levels between the two groups. XX and colleagues also looked at all patients that developed CIN within the study’s cohort. Importantly, there was no difference in baseline serum creatinine and creatinine clearance levels among those that developed CIN and those that did not. However, nearly one-third of patients that received trimetazidine also developed CIN. Importantly, a higher volume of contrast was utilized among those that developed CIN compared to those that did not (165.0 mL ± 108.4 mL vs 89.9 mL ± 38.6 mL, p < 0.001, respectively) and only one-third of the patients that developed CIN received low-osmolar contrast. The study showed similar results to that of Onbasili et al. ; however, they utilized trimetazidine at 35 mg twice a day as opposed to 20 mg three times a day as done in the former. The authors of the current study failed, however, to delineate in-hospital adverse event rates (myocardial infarction, shock, heart failure exacerbation) which can affect serum creatinine and creatinine clearance levels. It is important to remember that post-cardiac catheterization AKI is not always CIN. Like other investigators, the authors have put forward interesting positive data on the utilization of trimetazidine for the prevention of cardiac catheterization-associated CIN . There are important limitations within the current trial, most notably the small sample size and single-center approach, which affect the broader scale impact of their results. Importantly, the only modifiable risk factor in this study, contrast volume and type, was not adequately controlled for. As Demi Lovato’s song says, here we go again, as we saw with acetylcysteine, there were more than 61 randomized controlled trials, 42 not randomized trials, and countless meta-analysis trying to prove the benefit of acetylcysteine for the prevention of CIN since the original report by Tepel and colleagues in 2000. Larger, multicenter, randomized, superiority based clinical trials, controlling for contrast utilization need to be developed before we consider trimetazidine as a genuine agent for the prevention of CIN. Moreover, it may be equally important for the cardiology, radiology and nephrology communities to consider and agree upon a more contemporary definition of CIN based on biomarkers that assess for true and objective renal injury.
