Contrast-induced kidney injury. Deal with it.


 

Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial, by Estelle C Nijssen et al [1].

 

When I was thinking about a title for this post KKK came to my mind. Something like: Kontrast, the kidney killey! Catchy, right? But I realized we are a serious blog and there is no room for stupid jokes here. Beforehand, I’ll tell you again, I hate non-inferiority trials! Not because sometimes they have conceptual flaws, but because, time and again, people think non-inferiority is equal to equivalence, and boy, that I cannot take! Moving on.

Background

Contrast induced acute kidney injury (CI-AKI). Probably all of us spent some time thinking about it, how to prevent it, how dangerous CI-AKI really is, and some of us, myself included, might have came to, let’s say, unorthodox conclusions. First, does it really exist? Yeah, it does, but it would be naive to think all exams impose the same risk of CI-AKI. Of course, exams with intra-arterial injection of contrast media (like angiography, or PCI) impose greater risks of CI-AKI. But how about contrast computed tomography(CT)? Which is, among the contrasted exams, the one we use most. Well, to play safe, good quality evidence is still lacking. That being said, in my personal unorthodox opinion, CI-AKI after contrast enhanced CT might not even exist[2,3]. However, if we consider only exams with intra-arterial injection of contrast, CI-AKI might be a reality. Yet, even if we assume this scenario, affirmations that CI-AKI increases mortality is, at best, a conclusion based on a weak foundation.

Although I might think this way, I do also have my share of guilty. More than once, driven by the fear of an uncontrollable rising BUN, I also prescribed some form of prophylaxis for my high risk patients before a contrasted exam. If there were no contra indications, hydration with a bicarb solution was my choice. However, I rather die right now than prescribe N-acetylcysteine for my patients. This idea that hydration might protect the kidney against contrast is based on expert consensus, meaning, a bunch of old guys traveled to a 5-star hotel, to discuss and impose what they think. Again, what they think! What could go wrong? To fulfill this gap, the AMACING trial [1] was designed. It was a prospective, single center, randomized, open-label, non-inferiority trial with the objective of assessing the safety and cost-effectiveness of hydration on the prevention of CI-AKI. Wait a second, let’s read it again with SAP on: Prospective = good, single center: no good, randomized = good, open-label = fuck! but right now I cannot see another way; And the real winner: non-inferiority (NI)! You know what is funny? The idea behind a NI trial is that the new drug/intervention is not “unacceptably worse” than the placebo/active control, but here, the standard treatment (prophylactic hydration) was compared to placebo (no intervention), this is odd. The active control in this study was prophylactic hydration, however, this premise undermines the study’s assay sensitivity, which is one of the NI trials’ cornerstones.

-Assay sensitivity: The property of clinical trial to distinguish an effective treatment from a less effective or ineffective treatment. Active treatment intended for use as the active control was reliably found superior to placebo [4].

What they did

OK, maybe I’m being too sensitive. Maybe not. Either way, despite design, they were trying to answer a really important question, and that is praiseworthy. They screened all adult patients with known estimated glomerular filtration rate (eGFR) < 60mL per min/1,73 m2 and were included if:

– eGFR between 45-60mL per min/1,73 m2 combined with diabetes or two of the following: age >75y/o, anemia, cardiovascular disease, use of nephrotoxic medication; or

– eGFR between 35-45mL per min/1,73 m2; or

– multiple myeloma or lymphoplasmacytic lymphoma with small chain proteinuria;

The exclusion criteria were: eGFR <30mL per min/1,73 m2, renal replacement therapy, emergency procedure, ICU patients, among others. It’s a shame that such high risk patients as ICU, emergency patients and patients with eGFR <30 were excluded.

Patients were randomized to a 1:1 ratio to either prophylactic intravenous hydration (PH) or no prophylaxis (NP), stratified by diabetes, eGFR, contrast administration route, and procedure type. The authors also said that: “minimisation ensured that allocated treatment was unpredictable”. What the f***? Did they use minimization or stratified randomization? The PH protocol was: IV 0,9% NaCl 3-4 mL/kg/h during 4 h before and 4 h after contrast administration; or intravenous 0,9% NaCl 1 mL/kg per h during 12 h before and 12 h after contrast administration (long protocol). Only non-ionic, low osmolar iodinated contrast was used. The primary endpoint was: CI-AKI, defined as an increase in serum creatinine  by more than 25% or 44 μmol/L within 2-6 days of contrast exposure and cost-effectiveness of no prophylaxis compared with intravenous prophylactic hydration. They calculated a sample size of 1300 patients, to detect an absolute difference between groups of 2,1% (NI margin), with 80% power, and one-sided alpha of 5%. Due to feasibility issues, they decided to include only 660 patients. Both intention-to-treat and per-protocol analysis were planned.

Results

After randomization, the PH group ended with 328 patients and the NP with 332 patients. The table below shows the baseline characteristics of the patients.

As you can see, patients were old, had multiple risk factors, and almost 50% of them received intra-arterial contrast. In the PH group, 48% of patients received the long hydration protocol. The mean IV hydration volume was ~1600ml. A total of 57 patients were excluded from the primary endpoint analysis, mostly, due to logistical issues. The 2-6 day mean change in creatinine was 0,31 μmol/L in the PH group vs 1,3 μmol/L in the NP group (p=0.4).  Regarding the primary endpoint, an increase  of more than 25% or 44 μmol/L from the baseline, no difference was found ( PH 2,7% vs NP 2,6 %; absolute difference in proportions –0,10%; one-sided 95% CI –2,25 to 2,06; one-tailed p=0,471). The figure below shows the results of the primary analysis and subgroup analysis:

Since a cost-effectiveness analysis were planned, the results showed a reduction in overall costs for the NP group, with the largest savings been due reduced hospitalization. None of the patients required dialysis or were admitted to ICU. Even if we consider the mean hydration volume received small (which I don’t think it is), 4% of PH patients experienced complications which led to a premature stop of hydration.

One thing I think worth mentioning is that all trials use creatinine as a marker of renal failure, ok, I know, but at the moment it’s what we got. Nevertheless, there is one specific aspect that wasn’t take into account, as far as I know, in all those trials. Most of the time, the creatinine was measured between day 2-5, and this value was used in the primary analysis, however, was the fluid balance between groups different at the time of measurement? I suppose it was, specially for in-patients, just by considering the amount of hydration fluid received. And here is the tricky part. We know that creatinine is affected by a lot of factors, including its volume of distribution. In other words, if I increase the volume of distribution I’ll see a fall in creatinine. And an easy way to increase you volume of distribution is, guess what? By giving you some volume. So, as you increase your fluid balance, you should expect a fall in creatinine, masking a possible AKI [5,6]. Well, since the intervention in all those trials were volume vs no-volume, it makes sense that the volume group had a more positive fluid balance. You can correct the creatinine for fluid balance using this formula [7]:

-Adjusted creatinine = sCr x correction factor

-Correction factor = {hospital admission weight (kg) x 0.6 + Σ [daily cumulative fluid balance (L)]} / hospital admission weight x 0.6

Do I do this on daily basis? No, I don’t. Either way, for a trial using creatinine as primary endpoint, and your intervention being hydration, I think it would be appropriated. Anyhow, despite the decision of a non-inferiority trial, as we discussed, I think the Nijssen’s trial is a fairly honest trial adding new perspectives on CI-AKI prevention. Although the trial didn’t include ICU or emergency department patients, I wouldn’t be surprised if the results in those populations were the same as found here. Hydraton for CI-AKI prophylaxis? No way, Jose!

My final thoughts doesn’t have anything to do with CI-AKI. I’m amazed to see (not in a good way) how strategies, based on crappy evidence, become standard care or the usual practice, to the point of a non-inferiority trial being designed to compare an unproven evidence as active control of placebo. Of course the idea behind the trial was different, but I ended up with that feeling that something is not right. It’s disgusting, and it reminds me of the new Surviving Sepsis Guidelines, which make me sick. I’m gonna throw up now. See ya!

 

 

1.     Nijssen EC, Rennenberg RJ, Nelemans PJ, et al. Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial. Lancet. 2017.

2.     McDonald RJ, McDonald JS, Bida JP, et al. Intravenous contrast material-induced nephropathy: causal or coincident phenomenon? Radiology. 2013;267(1):106-118.

3.     Hinson JS, Ehmann MR, Fine DM, et al. Risk of Acute Kidney Injury After Intravenous Contrast Media Administration. Ann Emerg Med. 2017.

4.     Food and Drug Administration, HHS. International Conference on Harmonisation. Guidance E10: Choice of Control Group and Related Issues in Clinical Trials. Fed Regist. 2001 May 14;66(93):24390-1

5.     Pickering JW, Ralib AM, Endre ZH. Combining creatinine and volume kinetics identifies missed cases of acute kidney injury following cardiac arrest. Crit Care. 2013;17(1):R7.

6.     Macedo E, Bouchard J, Soroko SH, et al. Fluid accumulation, recognition and staging of acute kidney injury in critically-ill patients. Crit Care. 2010;14(3):R82.

7.     Moran SM, Myers BD: Course of acute renal failure studied by a model of creatinine kinetics. Kidney Int 1985, 27:928-937.

 

 

Photo credit

Kylie


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Contrast-induced kidney injury. Deal with it.

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