NITRATE-CIN: Inorganic Nitrate to Prevent Contrast Nephropathy in Acute Coronary Syndromes

Abstract

Contrast-induced nephropathy (CIN) is a significant complication following coronary angiography, particularly in high-risk patients with acute coronary syndromes (ACS). The NITRATE-CIN trial sought to evaluate the efficacy of inorganic nitrate, a precursor of nitric oxide, in preventing CIN and improving long-term renal and cardiac outcomes in this vulnerable population. This double-blind, randomized, placebo-controlled trial enrolled 640 participants, comparing inorganic nitrate treatment to placebo over a 5-day period. The trial demonstrated that inorganic nitrate significantly reduced CIN rates, improved renal function at three months, and lowered the incidence of major adverse cardiac events (MACE) at one year. These findings support the renoprotective and cardioprotective potential of inorganic nitrate in patients undergoing coronary angiography for ACS, offering a promising therapeutic avenue for mitigating the risks associated with contrast-induced kidney injury.

Introduction

Contrast-induced nephropathy (CIN), also known as contrast-associated acute kidney injury (CA-AKI), remains a critical concern for patients undergoing coronary angiography, particularly those presenting with acute coronary syndromes (ACS). Despite advances in interventional cardiology and preventive strategies, CIN continues to contribute to substantial morbidity and mortality, particularly in high-risk patients with underlying conditions such as diabetes and chronic kidney disease (CKD). The pathophysiology of CIN involves complex mechanisms, including endothelial dysfunction, oxidative stress, and impaired renal perfusion, which collectively result in acute kidney injury (AKI).

The unmet need for effective preventive strategies against CIN has driven extensive research into novel therapeutic interventions. Among these, inorganic nitrate has emerged as a potential candidate due to its ability to enhance nitric oxide (NO) bioavailability in the body. Nitric oxide plays a pivotal role in maintaining vascular homeostasis, promoting vasodilation, and reducing oxidative stress—mechanisms that are critical in protecting the kidneys from contrast-induced damage.

Pre-clinical studies have demonstrated the renoprotective effects of inorganic nitrate in models of acute kidney injury, particularly through its conversion to nitric oxide via the nitrate-nitrite-NO pathway. This pathway is distinct from the classical endothelial NO synthase (eNOS)-dependent pathway and provides an alternative mechanism for NO production, especially under conditions of hypoxia and endothelial dysfunction—common scenarios in patients with ACS. However, the clinical translation of these pre-clinical findings has been limited, with few studies investigating the efficacy of inorganic nitrate in preventing CIN in the clinical setting.

The NITRATE-CIN trial was designed to address this gap by evaluating the efficacy of inorganic nitrate in preventing CIN in high-risk patients undergoing coronary angiography for ACS. This double-blind, randomized, placebo-controlled trial represents a significant step forward in understanding the potential benefits of inorganic nitrate in the clinical setting, offering insights into its renoprotective and cardioprotective effects.

Literature Review

The prevention of contrast-induced nephropathy (CIN) has been a topic of intense research and debate, with multiple preventive strategies being explored over the years. The incidence of CIN varies widely depending on the population studied, the definition used, and the preventive measures employed. High-risk patients, particularly those with underlying chronic kidney disease (CKD), diabetes mellitus, or both, are at a significantly increased risk of developing CIN after exposure to iodinated contrast media. In this context, preventive measures are of paramount importance to reduce the incidence of CIN and its associated complications.

Current Preventive Strategies for CIN

Current preventive strategies for CIN primarily focus on optimizing hydration status, using low- or iso-osmolar contrast agents, and minimizing contrast volume. Intravenous hydration with normal saline or sodium bicarbonate remains the cornerstone of CIN prevention, as it helps to maintain renal perfusion and dilute the contrast medium. Additionally, the use of iso-osmolar or low-osmolar contrast agents has been shown to reduce the risk of CIN compared to high-osmolar agents, particularly in high-risk patients. Minimizing contrast volume, whenever possible, is also a critical component of CIN prevention.

Pharmacological interventions aimed at preventing CIN have yielded mixed results. N-acetylcysteine (NAC), a thiol-containing antioxidant, has been extensively studied for its potential to reduce oxidative stress and prevent CIN. However, the results from clinical trials have been inconsistent, with some studies demonstrating a protective effect while others showing no significant benefit. The use of statins, particularly high-dose atorvastatin, has also been investigated in the context of CIN prevention. Several studies have suggested that statins may reduce the incidence of CIN by improving endothelial function and reducing inflammation, although the evidence remains inconclusive.

More recently, attention has turned to novel therapeutic interventions that target the underlying pathophysiological mechanisms of CIN. Among these, inorganic nitrate has gained considerable interest due to its potential to enhance nitric oxide (NO) bioavailability and improve renal outcomes. Nitric oxide is a key regulator of vascular tone, renal blood flow, and tubular function, all of which are critical in the prevention of CIN. Pre-clinical studies have shown that inorganic nitrate can protect against acute kidney injury (AKI) by enhancing NO production through the nitrate-nitrite-NO pathway. However, clinical data on the use of inorganic nitrate in the prevention of CIN remains limited.

The Nitrate-Nitrite-NO Pathway

The nitrate-nitrite-NO pathway represents an alternative mechanism for nitric oxide production, distinct from the classical endothelial NO synthase (eNOS)-dependent pathway. This pathway becomes particularly important under conditions of hypoxia or reduced eNOS activity, as it provides a source of NO that does not rely on oxygen availability. In this pathway, inorganic nitrate is reduced to nitrite by oral bacteria and subsequently converted to NO in tissues. The bioactivation of nitrate and nitrite is facilitated by various enzymes and reductases, including xanthine oxidoreductase, aldehyde oxidase, and cytochrome P450.

Nitric oxide produced via the nitrate-nitrite-NO pathway exerts its effects by promoting vasodilation, inhibiting platelet aggregation, and reducing oxidative stress. These actions are critical in maintaining renal perfusion and protecting the kidneys from contrast-induced injury. In pre-clinical models of AKI, inorganic nitrate has been shown to improve renal blood flow, reduce oxidative stress, and mitigate tubular damage. These renoprotective effects are thought to be mediated by the enhanced NO bioavailability provided by the nitrate-nitrite-NO pathway.

Clinical Translation of Inorganic Nitrate for CIN Prevention

The clinical translation of inorganic nitrate as a preventive strategy for CIN has been limited, with few studies investigating its efficacy in the clinical setting. Early clinical trials evaluating the use of inorganic nitrate in cardiovascular disease have shown promising results, particularly in improving endothelial function and reducing blood pressure. However, its role in preventing CIN remained unexplored until the NITRATE-CIN trial.

The NITRATE-CIN trial was designed to assess the efficacy of inorganic nitrate in preventing CIN in high-risk patients undergoing coronary angiography for ACS. This trial represents a significant advancement in the field, as it provides clinical evidence supporting the renoprotective and cardioprotective effects of inorganic nitrate in this vulnerable population. The trial's findings suggest that inorganic nitrate may offer a novel therapeutic option for preventing CIN, particularly in patients with underlying CKD and diabetes who are at the highest risk of developing this complication.

In addition to its potential benefits in CIN prevention, inorganic nitrate has been shown to improve renal function and reduce the incidence of major adverse cardiac events (MACE) at long-term follow-up. These findings underscore the broader cardioprotective effects of inorganic nitrate, which may extend beyond its role in preventing contrast-induced kidney injury. By enhancing NO bioavailability, inorganic nitrate may help to mitigate the cardiovascular risks associated with ACS and improve overall patient outcomes.

Implications for Clinical Practice

The findings from the NITRATE-CIN trial have important implications for clinical practice, particularly in the management of high-risk patients undergoing coronary angiography. The use of inorganic nitrate as a preventive strategy for CIN represents a novel approach that targets the underlying pathophysiological mechanisms of contrast-induced kidney injury. By enhancing nitric oxide bioavailability, inorganic nitrate offers a promising therapeutic avenue for reducing the incidence of CIN and improving renal outcomes in this vulnerable population.

Moreover, the broader cardioprotective effects of inorganic nitrate, as demonstrated by the reduction in MACE events at long-term follow-up, suggest that this intervention may offer additional benefits beyond CIN prevention. The ability of inorganic nitrate to improve renal function, reduce oxidative stress, and enhance vascular function may help to mitigate the cardiovascular risks associated with ACS, leading to improved overall patient outcomes.

Future studies are needed to further elucidate the mechanisms underlying the renoprotective and cardioprotective effects of inorganic nitrate, as well as to explore its potential role in other clinical settings. The integration of inorganic nitrate into existing preventive strategies for CIN represents an exciting development in the field, with the potential to significantly improve patient outcomes in high-risk populations.

Inorganic nitrate offers a promising new approach to the prevention of contrast-induced nephropathy (CIN) in high-risk patients undergoing coronary angiography for acute coronary syndromes (ACS). The NITRATE-CIN trial demonstrated the efficacy of inorganic nitrate in reducing CIN incidence, improving renal function, and lowering major adverse cardiac events (MACE) rates at long-term follow-up. These findings support the potential for inorganic nitrate to be integrated into existing CIN prevention strategies, providing a novel therapeutic option that targets the underlying mechanisms of contrast-induced kidney injury. The broader cardioprotective effects of inorganic nitrate further underscore its potential as a valuable intervention for improving patient outcomes in the context of ACS.

Methodology

The NITRATE-CIN trial was a rigorously designed, double-blind, randomized, placebo-controlled study aimed at evaluating the efficacy of inorganic nitrate in preventing contrast-induced nephropathy (CIN) in high-risk patients undergoing coronary angiography for acute coronary syndromes (ACS). Here is an in-depth overview of the methodology employed in this trial.

Study Design

The NITRATE-CIN trial was conducted as a single-center study, which allowed for standardized procedures and consistent management of participants. The trial's design ensured robust evaluation of the intervention by minimizing biases and controlling variables that could influence the outcomes. The trial was registered with ClinicalTrials.gov under the identifier NCT03627130.

Participants

The study enrolled 640 participants who were at high risk for developing CIN. High-risk criteria included patients with diabetes, chronic kidney disease (CKD), or both, as well as those with acute coronary syndromes (ACS). Participants were randomly assigned in a 1:1 ratio to receive either inorganic nitrate or placebo. The median age of participants was 71 years, and the cohort was predominantly male (73.3%) and Caucasian (75.2%).

Intervention

Participants were randomized to receive either potassium nitrate (12 mmol) or placebo (potassium chloride) capsules once daily for a period of 5 days. The dosage of potassium nitrate was chosen based on pre-clinical studies and prior research demonstrating its efficacy in enhancing nitric oxide (NO) bioavailability and renal protection. The placebo was matched in appearance to the nitrate capsules to maintain blinding.

Primary and Secondary Endpoints

The primary endpoint of the trial was the incidence of CIN, defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. This included an increase in serum creatinine levels or a decrease in estimated glomerular filtration rate (eGFR) following exposure to contrast media. Secondary endpoints included:

• Kidney Function: Assessments of eGFR at 3 months post-intervention to determine the long-term impact of inorganic nitrate on renal function.

• Procedural Myocardial Infarction: Incidence of myocardial infarction occurring during the procedure or shortly thereafter.

• Major Adverse Cardiac Events (MACE): A composite of death, non-fatal myocardial infarction, and stroke occurring within 12 months post-intervention.

Data Collection and Analysis

Data were collected at multiple time points: before the intervention, immediately after the angiography, and at follow-up visits. Serum creatinine levels and eGFR were measured to assess renal function, while myocardial infarction and MACE were monitored through clinical assessments and patient reports. The analysis aimed to compare the incidence of CIN, changes in renal function, and rates of myocardial infarction and MACE between the inorganic nitrate and placebo groups.

Results

The NITRATE-CIN trial provided valuable insights into the efficacy of inorganic nitrate in preventing CIN and improving long-term outcomes for patients undergoing coronary angiography. Here is a detailed summary of the results.

Participant Demographics

Out of the 640 patients randomized, 319 received inorganic nitrate, and 321 received the placebo. The mean age of participants was 71 years, with a substantial portion having underlying conditions that predispose them to CIN, such as diabetes (45.9%) and chronic kidney disease (56.0%). The mean Mehran score, a risk assessment tool for CIN, was 10, indicating a high-risk population.

Primary Endpoint

The incidence of CIN was significantly lower in the inorganic nitrate group compared to the placebo group. Specifically, 9.1% of patients in the inorganic nitrate group developed CIN, compared to 30.5% in the placebo group. This difference was statistically significant, with a P-value of <.001. After adjusting for baseline creatinine levels and diabetes status, the odds ratio for CIN in the nitrate group was 0.21, with a 95% confidence interval of 0.13-0.34, indicating a strong protective effect of inorganic nitrate.

Secondary Endpoints

• Kidney Function: At the 3-month follow-up, patients in the inorganic nitrate group demonstrated a significant improvement in renal function compared to those in the placebo group. The between-group change in eGFR was 5.17, with a 95% confidence interval of 2.94-7.39, reflecting better preservation of kidney function in the nitrate group.

• Procedural Myocardial Infarction: The rate of procedural myocardial infarction was lower in the inorganic nitrate group (2.7%) compared to the placebo group (12.5%), with a P-value of .003. This suggests that inorganic nitrate may also have a beneficial effect on reducing myocardial infarction rates during or immediately after the procedure.

• Major Adverse Cardiac Events (MACE): The incidence of MACE was significantly lower in the nitrate group (9.1%) compared to the placebo group (18.1%), with a P-value of .001. This finding underscores the potential for inorganic nitrate to provide broader cardiovascular benefits beyond CIN prevention.

Conclusion

The NITRATE-CIN trial has provided compelling evidence for the efficacy of inorganic nitrate in preventing contrast-induced nephropathy (CIN) in high-risk patients undergoing coronary angiography. The trial's findings reveal that a short course of inorganic nitrate significantly reduces CIN rates, improves renal function, and decreases major adverse cardiac events (MACE) compared to placebo. These results support the integration of inorganic nitrate into clinical practice as a valuable preventive measure for CIN.

The trial's robust methodology, including a double-blind, randomized, placebo-controlled design, ensured high-quality data and minimized biases. The significant reduction in CIN rates, coupled with improvements in long-term kidney and cardiovascular outcomes, underscores the therapeutic potential of inorganic nitrate. Furthermore, the favorable safety profile of inorganic nitrate adds to its appeal as a feasible and effective intervention for high-risk patients.

Discussion

The results of the NITRATE-CIN trial are significant for several reasons. First, they highlight the potential of inorganic nitrate to address a major clinical challenge: CIN, a common and serious complication following coronary angiography. Current preventive strategies, such as hydration and contrast management, do not fully eliminate the risk of CIN, particularly in high-risk patients. Inorganic nitrate offers a novel approach by enhancing nitric oxide (NO) bioavailability, which helps protect renal function during contrast exposure.

The observed reduction in CIN rates from 30.5% in the placebo group to 9.1% in the nitrate group represents a substantial improvement. This significant difference is supported by a strong statistical significance and an odds ratio of 0.21, indicating a robust protective effect. Additionally, the improvement in eGFR at 3 months and the reduction in MACE at 1 year further demonstrate the broader benefits of inorganic nitrate, not only in preventing CIN but also in enhancing long-term renal and cardiovascular outcomes.

The trial's safety profile is also noteworthy. With no trial-drug interruptions or discontinuations due to adverse events in the nitrate group, inorganic nitrate appears to be well-tolerated. The incidence of adverse events related to the trial drug was low, supporting the feasibility of incorporating inorganic nitrate into routine clinical practice.

Future Prospects

The promising results of the NITRATE-CIN trial open several avenues for future research and clinical development:

1. Long-Term Outcomes: Further studies are needed to evaluate the long-term impact of inorganic nitrate on kidney function, cardiovascular health, and overall patient survival. Long-term data will help determine the sustainability of its benefits and its potential role in chronic renal protection.

2. Mechanistic Understanding: Research into the precise mechanisms by which inorganic nitrate exerts its protective effects will enhance our understanding of its action. This knowledge can guide optimal dosing strategies and identify patient subgroups that may benefit most from treatment.

3. Comparative Studies: Comparative trials with other emerging therapies for CIN prevention will help establish the relative efficacy of inorganic nitrate. This includes assessing its performance against novel renal-protective agents or anti-inflammatory drugs.

4. Broader Applications: Investigating the use of inorganic nitrate in other clinical settings, such as patients with chronic kidney disease or those undergoing different types of interventional procedures, could expand its therapeutic indications and confirm its broader applicability.

5. Clinical Integration: To facilitate the adoption of inorganic nitrate into clinical practice, updated guidelines should reflect its benefits based on ongoing research. Additionally, healthcare providers should receive training on the use of inorganic nitrate, including its dosing, potential side effects, and monitoring requirements.

6. Patient Selection: Identifying and characterizing patient populations that would benefit most from inorganic nitrate therapy is crucial. Factors such as baseline renal function, comorbidities, and procedural risks should be considered to ensure the optimal use of this intervention.

Conclusion

The NITRATE-CIN trial has demonstrated that inorganic nitrate is an effective and well-tolerated intervention for preventing contrast-induced nephropathy (CIN) in high-risk patients undergoing coronary angiography. By significantly reducing CIN rates, improving renal function, and lowering major adverse cardiac events, inorganic nitrate represents a promising addition to current preventive strategies. The trial's robust findings support further investigation and integration of inorganic nitrate into clinical practice, with potential benefits extending beyond CIN prevention to broader renal and cardiovascular health. Future research will continue to refine its role and optimize its use in patient care.

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