Improving outcomes after invasive coronary angiography: the role of inorganic nitrate

The staggeringly high prevalence of cardiovascular disease (CVD) amongst people with chronic kidney disease (CKD) is well-recognised, as is its contribution to premature mortality in this population. CVD not only causes deaths, however, but also substantial morbidity. CVD events commonly result in acute deteriorations in kidney function and/or accelerated progression of CKD. Following an acute coronary syndrome (ACS), for example, approximately 20% of individuals are believed to experience acute kidney injury (AKI).^1,2 AKI is associated with prolonged hospitalisation, greater risk of future CKD and increased mortality.³

Acute kidney injury following ACS is almost certainly multifactorial. Haemodynamic instability, changes in volume status, drugs and atheroemboli must all play a part. Some individuals also receive intra-arterial iodinated contrast during cardiological investigation and/or treatment, which may be nephrotoxic. There has been extensive research into reducing rates of contrast-induced nephropathy (CIN), without much success. This may, in part, be due to our inability to differentiate individuals with CIN, who might benefit, from other causes of AKI after ACS.

There is increasing interest in the role of nitric oxide (NO) in the pathogenesis of cardiovascular–kidney–metabolic spectrum disorders, and its potential therapeutic applications. NO relaxes smooth muscle in coronary and renal vessels, and has anti-thrombotic and anti-inflammatory properties. In the kidney, NO is involved in the modulation of renal sympathetic neural activity, regulation of renal haemodynamics, maintenance of medullary perfusion, and salt and water homeostasis.^4,5 Reduction in renal NO levels secondary to the release of free radicals is believed to be implicated in contrast nephrotoxicity. Early results suggest NO donors may reduce AKI after cardio-pulmonary bypass⁶ and attenuate ischaemic-reperfusion injury following kidney transplantation.⁷ 

In this month’s European Heart Journal, Jones and colleagues report a randomised controlled trial in which inorganic nitrate (a NO donor) was found to improve cardiovascular and kidney outcomes following invasive coronary angiography for ACS.⁸ In this double-blinded, single-centre trial, 640 individuals undergoing coronary angiography for non-ST-elevation ACS (NSTE-ACS), and rated as “at risk of CIN”, were randomised to five days of oral potassium nitrate versus placebo. Risk of CIN was defined as an eGFR <60 mL/min/1.73 m² or ≥2 of diabetes, liver cirrhosis, age >70 years, exposure to contrast in the last seven days, heart failure and/or concomitant renally active drugs (e.g. diuretics). As is sadly standard in cardiovascular research, those with an eGFR <20 mL/min/1.73 m² were excluded. The primary outcome was CIN, with secondary outcomes of rates of procedural myocardial infarction (MI), kidney function at 3 months, serum NO levels and major adverse cardiovascular (MACE) or kidney events (MAKE) at 12 months.

The trial results are remarkable. Of the 556 patients that could be assessed for the primary outcome, 9.1% developed AKI in the intervention group versus 30.5% of those in the control arm (91.9% of these were stage 1 AKI). At 3 months, compared to the trial arm, the average eGFR in the placebo group had declined by 5.17 mL/min/1.73 m² (95% CI, 2.94–7.39; P<0.001). 

Remarkably, procedural MI was also significantly less common in the trial arm (2.7% vs 12.5% of those receiving placebo), despite individuals having received a single dose of the trial drug only prior to angiography. Benefits persisted in subgroups by both diabetes and Mehran status (which predicts risk of CA-AKI after percutaneous coronary intervention). At one year, MACE was significantly lower in the active compared to the placebo arm (9.1% vs 18.1%; interaction P-value, 0.001), driven by reduced all-cause mortality, non-fatal MI and unscheduled revascularisation. The composite MAKE outcome was also reduced in the NO arm (11% vs 29.4%), again due to reduced all-cause mortality, but also persistent kidney dysfunction.

Although derived from a small study, these are impressive results. The improvements in cardiovascular and renal outcomes are worthy of further investigation, especially given the benefits of NO donors demonstrated elsewhere. My concern, however, is with the terminology. Throughout the paper the authors refer to CIN and contrast-associated AKI (CA-AKI) interchangeably, although choosing to use CIN in the title and with reference to the primary outcome. The two are not the same. CIN refers to kidney impairment resulting from contrast media. CA-AKI is a catch-all term for any AKI occurring within a few days of receipt of contrast.⁹ Although the authors were interested in the potential for inorganic nitrate to reduce CIN, they were only able to measure the impact on rates of CA-AKI. Equally plausible mechanisms exist by which pre-renal AKI, as well as CIN, may be reduced by NO supplementation.¹⁰ I would be very interested, therefore, to see how different the results would be if we randomised people with NSTE-ACS not undergoing angiography.

Although seemingly pedantic, incorrectly classifying all AKI as CIN in this (and other) studies, is likely to perpetuate the cycle of fear relating to contrast use amongst clinicians. Undue concern about kidney toxicity risks drives underuse of standard investigations and treatments for CVD in people with CKD.^11–13 A multidisciplinary consensus on the true risk of CIN could assist in overcoming this barrier. Not only would we need to extensively publicise such a consensus, but also remove all subliminal messaging contradicting the message from clinical systems, guidelines and research. Without this, interventional cardiologists will continue to be burdened by a disproportionate level of fear, and the high-risk CKD community will remain at risk of inequitable access to treatments that could improve not only survival, but also quality of life.

So, in summary, yes, we should certainly further investigate the potential for oral inorganic nitrate to improve cardiorenal outcomes following ACS. However, we should keep an open mind regarding how any benefits may occur. Furthermore, to achieve maximal benefit from any advances in such therapies, the renal and cardiology communities must achieve consensus on the research priorities regarding CA-AKI and CIN. Agreement on the terminology would be a lovely start.

A digest of the study can be read here.

1. Parikh CR, Coca SG, Wang Y et al (2008) Long-term prognosis of acute kidney injury after acute myocardial infarction. Arch Intern Med 168: 987–95
2. Yang Y, George KC, Luo R et al (2018) Contrast-induced acute kidney injury and adverse clinical outcomes risk in acute coronary syndrome patients undergoing percutaneous coronary intervention: a meta-analysis. BMC Nephrol 19: 374 
3. James MT, Samuel SM, Manning MA et al (2013) Contrast-induced acute kidney injury and risk of adverse clinical outcomes after coronary angiography: a systematic review and meta-analysis. Circ Cardiovasc Interv 6: 37–43
4. Baylis C, Qiu C (1996) Importance of nitric oxide in the control of renal hemodynamics. Kidney Int 49: 1727–31 
5. Lee J (2008) Nitric oxide in the kidney : its physiological role and pathophysiological implications. Electrolyte Blood Press 6: 27–34 
6. Hu J, Spina S, Zadek F et al (2019) Effect of nitric oxide on postoperative acute kidney injury in patients who underwent cardiopulmonary bypass: a systematic review and meta-analysis with trial sequential analysis. Ann Intensive Care 9: 129
7. Dugbartey GJ (0223) Nitric oxide in kidney transplantation. Biomed Pharmacother 167: 115530
8. Jones DA, Beirne AM, Kelham M et al (2024) Inorganic nitrate benefits contrast-induced nephropathy after coronary angiography for acute coronary syndromes: the NITRATE-CIN trial. Eur Heart J 21 Mar [Epub ahead of print] 
9. Mehran R, Dangas GD, Weisbord SD (2019) Contrast-associated acute kidney injury. N Engl J Med 380: 2146–55
10. Liu ZZ, Schmerbach K, Lu Y et al (2014) Iodinated contrast media cause direct tubular cell damage, leading to oxidative stress, low nitric oxide, and impairment of tubuloglomerular feedback. Am J Physiol Renal Physiol 306: F864–72
11. Bagai A, Lu D, Lucas J et al (2018) Temporal trends in utilization of cardiac therapies and outcomes for myocardial infarction by degree of chronic kidney disease: A report from the NCDR Chest Pain-MI Registry. J Am Heart Assoc 7: e010394
12. Bhatia S, Arora S, Bhatia SM et al (2018) Non-ST-segment-elevation myocardial infarction among patients with chronic kidney disease: A propensity score-matched comparison of percutaneous coronary intervention versus conservative management. J Am Heart Assoc 7: e007920
13. Shaw C, Nitsch D, Lee J et al (2016) Impact of an early invasive strategy versus conservative strategy for unstable angina and non-ST elevation acute coronary syndrome in patients with chronic kidney disease: A systematic review. PloS One 11: e0153478