Author + information
- †Department of Medicine, Sections of Cardiology and Nephrology, Providence Hospitals and Medical Centers, Southfield and Novi, Michigan
- ‡St. John Hospital and Medical Center, Detroit, Michigan
- ↵∗Reprint requests and correspondence:
Dr. Peter A. McCullough, St. John Providence Health System, Providence Park Heart Institute, 47601 Grand River Avenue, Suite B-125, Novi, Michigan 48374.
Fortunately, as result of greater awareness, avoidance of dehydration, smaller catheters, and less nephrotoxic contrast, rates of contrast-induced acute kidney injury (CI-AKI) after coronary angiography and percutaneous coronary intervention are decreasing (1). Additionally, there have been enough published data to form the foundation for the first set of AKI guidelines by the Kidney Disease Improving Global Outcomes Group, of which, a portion is dedicated to CI-AKI (2). These guidelines mention the use of N-acetylcysteine (NAC) but not ascorbic acid as a possible preventive approach. This having been said, it is possible to miss a treatment effect that actually exists from small randomized, controlled trials (RCTs). In this issue of the Journal, Sadat et al. (3) summarize the RCTs using short-term ascorbic acid (vitamin C) treatment in the prevention of CI-AKI in a formal meta-analysis.
Ascorbic acid or vitamin C is an essential micronutrient naturally occurring in the human diet that has been studied for decades in the prevention and treatment of the common cold, neurodegenerative diseases, malignancies, preeclampsia, atherosclerosis, and anemia. In virtually every application, with the exception of the treatment of macular degeneration (in combination with beta-carotene and vitamin E) and anemia, ascorbic acid has failed to have a treatment effect when evaluated with the best sources of evidence (4–10). When given in high doses to animals, ascorbic acid appears to amelioriate acute ischemic AKI, which probably plays an initial and minor role in CI-AKI (11). Other basic science studies suggest that ascorbic acid improves nitric oxide (NO) availability in vascular smooth muscle cells (12). Intrarenal NO is crucial for maintaining perfusion and oxygen supply in the renal medulla (13). Reduced production of NO has been implicated in CI-AKI. Additionally, malondialdehyde, an oxidative stress marker, is inversely related to renal production of NO. Thus, ascorbic acid may promisingly augment NO supply and mitigate the oxidative stress and tissue lipid peroxidation in the renal tubules and peritubular capillary network that occur with CI-AKI (14). Finally, ascorbic acid in doses of at least 500 mg orally does have a hemodynamic effect and results in lowering systemic blood pressure in humans (15). Of interest, vitamin C does not seem to influence measures of urine acidity in the majority of studies published. For example, 2 g of intravenous ascorbic acid (equivalent to the dose range applied in most of the studies in this meta-analysis) does not decrease urine pH at 2 h; conversely, urine pH goes up after administration (16).
In the present meta-analysis by Sadat et al. (3), ascorbic acid was given before and after contrast exposure in 9 RCTs (6 orally and 3 intravenously) in 1,536 patients, and the overall pooled treatment effect was a 33% reduction in CI-AKI (p = 0.034) using a random-effects model. The data appeared to be both internally and externally consistent without an impact of publication bias or temporal treatment bias. There was no formal assessment of safety, but the individual trials demonstrated that the therapy was generally safe and well tolerated. Other studies have shown only rare cases of renal oxalosis with intravenous vitamin C (17). However, as the authors point out, a relatively small study (n = 250 subjects) with a neutral or negative result for vitamin C would overturn the results of this meta-analysis in the future. Thus, this paper has helped the field advance and appropriately framed ascorbic acid, perhaps in the higher doses and possibly for a longer duration of time, as a potential therapy to be tested in large-scale clinical trials. Such a large trial (N = 8,680) is now moving forward with NAC to help answer a question concerning the preventive effectiveness of this agent, which has been both used and questioned for decades (18).
In conclusion, as CI-AKI rates are decreasing and guidelines now suggest formal approaches for risk stratification and detection, we remain in need of bona fide preventive approaches until less toxic iodinated contrast can be commercialized. The penultimate question remains: if we prevent or lessen CI-AKI as determined by serum creatinine, will we reduce the rates of clinical outcomes including end-stage renal disease, and mortality and more secondary events including the development of heart failure, recurrent acute coronary syndromes, and stroke? Only large-scale trials with effective therapies and adequate follow-up for these outcomes will answer this pivotal question.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- ↵(2012) KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl 2:2.
- Sadat U.,
- Usman A.,
- Gillard J.H.,
- Boyle J.R.
- Casino P.R.,
- Kilcoyne C.M.,
- Quyyumi A.A.,
- Hoeg J.M.,
- Panza J.A.
- Juraschek S.P.,
- Guallar E.,
- Appel L.J.,
- Miller E.R. 3rd.
- Weisbord S.D.,
- Gallagher M.,
- Kaufman J.,
- et al.