NephrologyNow The Ultimate Guide to Kidney Disease Research

With respect to the article by From et al (1), we have concerns about the conclusion that bicarbonate therapy may promote rather than ameliorate contrast nephropathy (CN). There are theoretical reasons to suspect that bicarbonate prophylaxis may be beneficial for patients receiving iodinated intra-venous contrast. In addition to the non-specific benefit of the maintenance of euvolemia, there may also be a specific effect by reducing the impact of contrast on renal free radical production.

The evidence for the therapeutic efficacy of bicarbonate prophylaxis largely comes from one randomized trial (2), a relatively small study from a single centre with a small number of events and an unexpectedly large treatment effect. A similarly large treatment effect has been found with hemofiltration as prophylaxis against CN which may also in part be an effect of the bicarbonate infusion (3;4). However, the superiority of bicarbonate prophylaxis is by no means established.

How might one reconcile these results with the putative toxic effect of bicarbonate observed in the present study? Given its retrospective nature, patients were not allocated to the various pre-exposure treatments randomly but, rather, they were selected for prophylaxis by their physicians. The effect of selection for a higher risk subpopulation for contrast nephropathy is evident in tables 1 and 2 in the paper. Compared to those patients who did not receive prophylaxis, those who did were, on average, older, had higher pre-contrast creatinine values (and therefore tended to have a higher CKD stage), had a higher proportion of previous contrast exposure, and were more likely to have diabetes, to have congestive heat failure, and to be hypertensive. The prophylaxis group also were more likely to have been previously treated with ACE inhibitors and diuretics.

Given a selection effect, notwithstanding the limited positive results for bicarbonate prophylaxis mentioned above, one possible alternate explanation for the observed results is that N-acetylcysteine (NAC) therapy is effective in reducing the primary outcome whereas bicarbonate infusion is less so. The selection effect would therefore be more fully evident in the patients only given bicarbonate prophylaxis but would be offset by the protective effect of NAC. One cannot distinguish between the latter, plausible, hypothesis and the possibility that bicarbonate therapy is actually toxic. Given that uncertainty, the robustness of the author’s conclusions must be questioned.

NAC has an effect to increase creatinine clearance and therefore to reduce the frequency of the primary outcome. The mechanism underlying this effect is uncertain: it may have a true beneficial effect by increasing GFR or it may simply increase tubular secretion of creatinine without improving GFR.

The literature regarding contrast nephropathy prophylaxis is littered with small studies with major methodologic flaws as demonstrated in a recent review(5). Unfortunately, the current study has not remedied this problem.

David MJ Naimark
Michelle Hladunewich
Reem A.Asad
Sheldon W Tobe

Division of Nephrology,
Sunnybrook Health Sciences Centre
University of Toronto
Toronto, Ontario
Canada

1. From AM, Bartholmai BJ, Williams AW, Cha SS, Pflueger A, McDonald FS: Sodium bicarbonate is associated with an increased incidence of contrast nephropathy: a retrospective cohort study of 7977 patients at mayo clinic. Clin J Am Soc Nephrol 3:10-18, 2008

2. Merten GJ, Burgess WP, Gray LV, Holleman JH, Roush TS, Kowalchuk GJ, Bersin RM, Van Moore A, Simonton CA, III, Rittase RA, Norton HJ, Kennedy TP: Prevention of Contrast-Induced Nephropathy With Sodium Bicarbonate: A Randomized Controlled Trial. JAMA 291:2328-2334, 2004

3. Marenzi G, Lauri G, Assanelli E, Campodonico J, De Metrio M, Marana I, Grazi M, Veglia F, Bartorelli AL: Contrast-induced nephropathy in patients undergoing primary angioplasty for acute myocardial infarction. Journal of the American College of Cardiology 44:1780-1785, 2004

4. Marenzi G, Marana I, Lauri G, Assanelli E, Grazi M, Campodonico J, Trabattoni D, Fabbiocchi F, Montorsi P, Bartorelli AL: The Prevention of Radiocontrast-Agent-Induced Nephropathy by Hemofiltration. N Engl J Med 349:1333-1340, 2003

5. Pannu N, Wiebe N, Tonelli M, Alberta Kidney DN: Prophylaxis strategies for contrast-induced nephropathy. [Review] [130 refs]. JAMA 295:2765-2779, 2006

I think the best way to put it is what is mentioned under the conclusion of the study. It tells me that may be we shouldn’t give bicarb to everyone and shouldn’t make it standard of care until we have larger RCTs. It is important to keep in mind that this is an observational study and can not prove causality. The HRT observational studies are the best example where they showed a significant health benefit of HRT but when RCTs were performed, they showed the opposite.

I found this article very interesting. At my institution, the cardiologists are especially proactive in giving patients sodium bicarbonate prior to angiograms. I wonder what others physicians thought about this article and whether it would change their management.