NITRATE-OCT-CIN (Sub-Study of NITRATE-OCT)

Contrast induced nephropathy (CIN) refers to a form of acute kidney injury (AKI) that occurs after parenteral administration of radio-contrast agent in the absence of other identifiable causes. It is the third most common cause of hospital-acquired renal failure, after decreased renal perfusion and use of nephrotoxic medications. It is generally defined as an increase in serum creatinine concentration of 44 mol/L (0.5 mg/dl) or 25% above baseline within 48 hours after contrast administration. More than 70 years after the first description of a fatal renal function impairment following the use of radiographic contrast media, CIN still represents a major and unmet clinical challenge, as this potential complication is associated with a prolonged hospital stay, a higher hospitalization cost, and a significant increase in morbidity and mortality.

Data suggest that CIN is due to an acute tubular dysfunction, however mechanisms underlying such acute tubular dysfunction in the context of CIN are rather poorly understood. Acute tubular dysfunction seen in settings of CIN is generally less severe and tends to recover more quickly when compared with other forms of acute tubular necrosis. Previous studies have suggested that CIN may be caused by either renal vasoconstriction resulting in medullary hypoxemia or direct cytotoxic injury caused by the contrast agents. Both mechanisms are known to decrease nitric oxide (NO) synthesis and, therefore, may contribute to renal injury. Importantly studies in animal models of contrast induced nephropathy have suggested that decreased levels of NO contributes to this renal injury. Thus the replacement of this 'lost' NO represents an approach that might offer therapeutic benefit.

Patients with chronic renal failure, diabetes mellitus, and heart failure all have a common phenotype of reduced bioavailability of NO, and it is possible that this state accounts for their increased susceptibility to develop contrast media nephrotoxicity. There have been several approaches taken in an attempt to restore NO biovailability in order to prevent development of CIN. N-acetylcysteine has been the most studied, and the most promising compound in this regard. The proposed mechanism of action of N-acetylcysteine is stimulation of NO synthase and increased production of NO. However, in patients with already impaired NO bioavailability due in part to dysfunction of the NO synthase pathways, activation of NO synthase may not generate amounts of sufficient for kidney protection.

A potential solution for elevating endogenous NO levels lies in the chemical reduction of inorganic nitrite (NO2-) to NO. For several decades, NO2- was considered primarily an oxidative product of NO metabolism and possibly a deleterious substance with reputed carcinogenic properties. However, evidence indicates that NO2-, which is abundant in blood and tissues, represents a significant stable intravascular endocrine reservoir and tissue storage form of NO that exerts a number of beneficial effects. Indeed, NO2--derived NO protects against myocardial ischaemia/reperfusion injury in pre-clinical models, protects against experimentally-induced endothelial dysfunction and attenuates platelet reactivity in healthy volunteers and improves endothelial function in hypertensive patients with endothelial dysfunction. In addition, of specific relevance to this project, NO2--derived NO has been shown to be reno-protective in pre-clinical models of renal injury. Since the ingestion of dietary inorganic nitrate (NO3- ) increases endogenous NO levels, the investigators suggest that potential therapeutic benefit could be derived from the use of dietary NO3- in the prevention of CIN.

There is no data assessing the impact of inorganic nitrite/nitrate treatment on CIN in patients undergoing PCI. However, in one small study, post-procedural renal function was compared between 112 patients who received organic nitrates prior to coronary intervention and 87 who did not. Baseline characteristics were similar between the 2 groups. Overall, 43 (21.6%) patients developed CIN post-PCI. Of the patients who received organic nitrates, 15.2% developed renal impairment when compared to 29.9% in those who did not (odds ratio [OR] = 0.42, 95% confidence interval [CI] 0.21-0.84, P = .014). Multivariate logistic regression analysis demonstrated that nitrate use was independently correlated with a reduction in the development of contrast nephropathy (OR = 0.334, 95% CI 0.157-0.709, P = .004). Importantly this study used a single dose of organic nitrate, in part it is likely that this approach was taken due to the major complications with the organic nitrates of the development of tolerance. Indeed, it is this characteristic of these drugs that has profoundly limited their clinical utility. Inorganic dietary nitrate, in contrast, is superior in this respect in that there is no evidence of tolerance with prolonged administration and it possesses a much longer half life (~8 hours) as opposed to minutes with the organic nitrates. The investigators therefore propose to evaluate the effects of dietary NO3- administration on the incidence of CIN in patients undergoing percutaneous coronary intervention.

Specifically with respect to the study of NO2- and CIN; preliminary data from the NITRITE-AMI study performed by the investigators showed that a single bolus of intracoronary NO2- given during primary PCI for ST-elevation MI lead to a significant rise in circulating NO2- levels which lead to a suggestion of reduced CIN. During the first 48 hours after reperfusion, 12.5% of patients in the control group developed CIN, compared to 2.5% patients in the nitrite group (p=0.108). With respect to change in eGFR, from baseline to 48 hours, there was a reduction in eGFR in the placebo group with a trend to an increase in the nitrite group with a significant difference between the change in eGFR over time between the 2 groups (Nitrite group: 5.98 ± 1.99 vs Placebo: -10.15 ±3.69, p=0.002).

Thus, together all of the above issues coupled with preliminary data support the rationale for further exploration of potential approaches based upon elevation of circulating NO2- levels that might reduce the burden of CIN on the NHS.