PrevenTion of Contrast-inducEd nephroAThy With urinE Alkalinization

Overview

Intravascular administration of iodinated contrast media is an essential tool for cardiovascular imaging and percutaneous coronary interventions. Nonetheless, the increasing incidence of contrast-induced nephropathy (CIN) has become an important and prognostically relevant problem along with the spreading of diagnostic and interventional procedures. CIN is largely dependent on oxidative damage and represents a considerable cause of renal failure, being associated with prolonged hospitalization and significant morbidity/mortality. The most effective treatment strategy of this serious complication remains prevention, and several preventive measures have been extensively investigated in the last few years. Pre-procedural hydration is the best known and mostly accepted strategy. The administration of sodium bicarbonate (HCO3) has controversial effects, and is likely to be ineffective when the infused dose is unable to achieve adequate urine alkalinization. Since alkaline pH suppresses the production of free radicals, increasing urine pH would be an attractive goal for CIN prevention. In a randomized clinical trial the investigators will test the hypothesis that urine alkalinization with either oral or i.v. bicarbonate on top of hydration alone is the main determinant of CIN prevention in a population of patients with moderate or severe chronic kidney disease scheduled for coronary angiography and/or angioplasty. If the investigators, demonstrate non-significant differences in urine alkalinization (primary endpoint) and incidence of CIN (secondary endpoint) between the bicarbonate groups, a practical implication will be that oral administration is preferable for practical reasons over the administration of i.v. bicarbonate.

Contrast medium-induced nephropathy (CIN) is a recognized complication in coronary diagnostic and interventional procedures, and is associated with prolonged hospitalization and adverse clinical outcomes. The frequency of CIN ranges from 2% in low-risk patients to 50% in high-risk patients. The most important risk factors for CIN development are pre-existing renal failure, diabetes, age, volume and type of contrast medium. There are two main pathogenetic mechanisms postulated to cause CIN: 1. a direct toxic action of contrast medium on kidney tubule cells, causing a disruption of mitochondrial function, the generation of reactive oxygen species, and subsequent cell injury and apoptosis; 2. vasoconstriction, reducing the blood flow through the renal medulla and causing ischemia with cell damage The treatment of CIN is exclusively supportive. Treatment is particularly recommended in patients with chronic kidney disease (CKD - mild, moderate or severe, according to estimated glomerular filtration rate - eGFR). Several approaches have been tested in the prevention of CIN with variable success. Adequate hydration is widely accepted as the best method for prevention of CIN, and is today the only strategy generally accepted by international guidelines (class of recommendation I, level of evidence A). The use of N-acetyl cysteine, recommended even in the recent past, is not supported by a recent randomized trial14 and a meta-analysis. Hemodialysis and hemofiltration may be effective in preventive CIN, but are reserved to high-risk patients. Attempts at preventing CIN with various medications, such as furosemide, vitamin C, statins and numerous other, have been largely unsuccessful. The efficacy of bicarbonate in the prevention of CIN has been extensively tested; the rationale is here that urine alkalinization suppresses the formation of free radicals. Actually, studies on bicarbonate have been controversial, varying from beneficial to toxic effects; this could bring into question the role of alkalinizing procedures in preventing CIN. Nevertheless, favorable results of prevention protocols using bicarbonate have been noted in studies also documenting a significant alkalinization of urines; while a similar protocol did not prove to be effective when the dose of bicarbonate was insufficient to such aim. Moreover, Markota et al., in a recent study on patients with estimated eGFR \>15 mL/min/1.73 m2 and scheduled for coronary angiography, after documenting that Na/K citrate significantly reduced the incidence of CIN when compared with hydration alone, have shown that patients having a urine pH \<6 had a more than ten-fold higher incidence of CIN compared with patients whose urine pH was \>6.28 These results confirm the potential role of urine alkalinization in preventing CIN and place the oral administration of alkalinizing drugs as an attractive method compared to the more complex, and not always effective, i.v. infusion of bicarbonate. Finally, oral doses of bicarbonate may be sufficient to alkalinize the urine and thus to prevent CIN. In a study recently published, an oral dose of 4 g was sufficient to obtain, two hours after administration, an adequate urinary alkalinization with a pH \>7 in all participants without side effects. This value was maintained and even magnified nearly 8 hours after the last dose. Interestingly, the Authors observed an additive effect after the second dose, showing a nondepleting urine pH, despite the reported short half-life of sodium bicarbonate. Against this background, the investigators will here test the hypothesis that both oral and i.v. bicarbonate are adequate strategies for CIN prevention in patients after coronary angiography. Comparing the incidence of CIN according to urine pH achieved immediately before angiography, the investigators aim at demonstrating that urine alkalinization is the real goal, and that results are here largely independent from the strategy adopted to achieve it. The investigators will therefore compare the efficacy in alkalinizing urine and preventing CIN of three different strategies: hydration alone; hydration plus i.v. sodium bicarbonate; and hydration plus oral bicarbonate. Favorable results of the bicarbonate groups compared to the control group could increase the evidence supporting the use of alkalinizing strategies to prevent CIN; at the same time, non-inferiority results of the oral group compared to i.v. bicarbonate group could suggest the more practical oral administration as the preferred prevention strategy.