Dietary Nitrate Dramatically Cuts Contrast-Induced Nephropathy: NITRATE-CIN

AMSTERDAM, the Netherlands—A 5-day course of dietary inorganic nitrate given to patients undergoing invasive angiography for acute coronary syndromes dramatically slashes the risk of contrast-induced nephropathy (CIN) and reduces the risk of subsequent cardiovascular and renal events, the NITRATE-CIN study shows.

Overall, the administration of potassium nitrate a day before angiography and for 4 days afterwards lowered the risk of CIN by 70% compared with placebo, while the risks of MACE and major acute kidney injury were cut by 50% and 60%, respectively, by 12 months.

“We feel that dietary inorganic nitrate shows huge promise,” lead investigator Dan Jones, MBBS, PhD (Queen Mary University of London/Barts Health National Health Service [NHS] Trust, England), told the media during a press conference at the European Society of Cardiology Congress 2023. “These findings could have important implications in reducing the burden of contrast nephropathy on healthcare systems worldwide, including the NHS.”  

CIN is associated with longer hospital stays, impaired long-term kidney function and need for dialysis, an increased incidence of recurrent events, and higher all-cause mortality. The incidence varies depending on patient population and definition of CIN used, “but we know that up to 50% of high-risk individuals can develop contrast-induced nephropathy at the time of angiography,” said Jones. “High-risk features include heart failure, older age, diabetes, preexisting kidney disease—things that we’re increasingly seeing as we treat patients.”

The pathophysiologic mechanisms of CIN aren’t fully understood, but preclinical and early-phase studies suggest it may be the result of decreased nitric oxide, said Jones. The present study, he added, was designed with the intention of “replacing” the depleted nitric oxide by administering dietary inorganic nitrate.

The NITRATE-CIN Trial

NITRATE-CIN, which was presented during Monday’s Hot Line session, was a double-blind, randomized, placebo-controlled trial testing potassium nitrate (12 mmol/744 mg nitrate) against placebo in 640 patients (mean age 71 years; approximately 25% female) undergoing invasive angiography for NSTE ACS. Researchers enrolled a high-risk population, with patients required to have either eGFR < 60 mL/min/1.73 m² or two of the following high-risk features: diabetes, liver cirrhosis, age > 70 years, heart failure, use of renally active drugs, or exposure to contrast in the past 7 days.

The product used in NITRATE-CIN—a formulation of inorganic nitrates in capsule form—isn’t commercially available, as it was made for this trial. Dietary sources of inorganic nitrate include beets or green leafy vegetables, such as spinach. Jones said it’s possible to buy beetroot shots, and that each shot contains 7 mmol of nitrates. Two shots would be roughly equivalent to the dose of capsule used in the trial, but shots of beet juice before angiography didn’t seem prudent or possible logistically, he said.

The incidence of CIN, the study’s primary endpoint defined using the KDIGO criteria, occurred in 9.1% of patients treated with inorganic nitrate versus 30.5% of those treated with placebo (P < 0.0001).

Renal function, assessed by the change in creatinine and eGFR from baseline to 3 months, was significantly improved with treatment. At 12 months, the composite risk of all-cause mortality, MI, or unplanned revascularization was also lower in those treated with inorganic nitrate (9.1% vs 18.1%; P < 0.0001). Similarly, major adverse kidney events, a composite of all-cause mortality, need for renal replacement therapy, and persistent renal dysfunction, was much more favorable in the nitrate arm (10.7% vs 28.4%; P < 0.0001).

‘Too Good to Be True?’

Roxana Mehran, MD (Icahn School of Medicine at Mount Sinai, New York), the discussant following the presentation, pointed out that multiple trials of different agents have all failed to prevent contrast-associated acute kidney injury. She questioned, however, whether the new results from this single-center study were “too good to be true.”

NITRATE-CIN has several limitations, she said, noting that patients were treated with a relatively large volume of contrast media (mean 181 and 169 mL in the placebo and nitrate groups, respectively) even though 50% only underwent diagnostic catheterization. A larger multicenter trial is needed to confirm the findings, one specifically powered for MACE and major kidney events, and further research into the “causative role” of CIN on mortality is also needed, said Mehran.

To TCTMD, Jones said the trial was powered to assess differences in CIN, but the reduction in risk was larger than anticipated. “We saw a greater incidence in the control group than we were expecting, possibly suggesting a higher-risk cohort than we powered the study on,” he said. “We weren’t powered for that reduction in major adverse cardiac events, but there clearly was significant reduction and it was across all measures of that endpoint: mortality, MI, and recurrent revascularization.”

A larger trial is in the works, say investigators.