Case of the Month 15: Contrast-induced Nephropathy

This is an anion gap (21) metabolic acidosis in a patient who takes metformin with an acute kidney injury and elevated lactate. Could this be metformin-associated lactic acidosis (MALA)? In order to diagnose MALA, you first have to believe it exists. The mechanism of metformin is complex and not fully understood. It is believed to work in 2 ways. Firstly, it converts glucose into lactate. Secondly, metformin decreases gluconeogenesis inhibiting lactate and pyruvate conversion back to glucose. Metformin is eliminated via the kidneys, and the concern is that in patients with ESRD, it may accumulate to toxic doses. After reviewing the literature, it appears this is unlikely. Yes, it is cleared by the kidney, but does not result in toxic blood levels of metformin (Frid et al, 2010). Additionally, research shows that it leads to increased blood lactate levels but does not translate to an increase in lactic acidosis. This fear of metformin stems from the original biguanide, phenphormin. Ultimately removed from the market in 1970s, it has been shown to cause significant lactic acidoses, because it is both hepatic and renally cleared, more lipophilic, and a stronger binder to the mitochondrial wall. In a Cochrane review from 2010, the authors concluded there is no evidence to support that metformin is associated with increased levels of lactate or an increased risk of lactic acidosis as compared to other anti-hyperglycemic agents (Saltpeter et al 2010). Though most of the research points away from MALA, in actuality, the research is somewhat limited. Largely due to concern from Phenphormin, prescribers stayed away from using metformin in patient with CKD. More research is needed, specifically in the stage 4 and 5 CKD populations. Nevertheless, the FDA has considered the use of metformin for patients with GFR <30mL/min a contraindication. More clinical research is needed but the likelihood that MALA is a real entity appears to be small.

What this question is asking you to think about is contrast-induced nephropathy (CIN). That is, will this patient’s CT with contrast lead to acute kidney injury? The mechanism behind CIN is unclear. Many hypotheses have been generated, but leading theories include damage to tubules from contrast-induced vasoconstriction or oxidative stress from toxic effects of the contrast material itself. On the other hand, some argue that contrast-induced nephropathy is also not a real entity. In a recent study, Mcdonald interestingly found that patients are less likely to have acute kidney injury when they receive IV contrast compared with those patients that don’t (Mcdonald et al 2013).

Is the contrast load too high? Consider that not all contrast loads are the same. In the past, the earlier generation contrast mediums were high-osmolar and shown to be nephrotoxic. However, more recently, low-osmolar or even iso-osmolar mediums have been created that minimize nephrotoxicity.

Can we attribute contrast-induced nephropathy to mediums of the past? Maybe. For now, skepticism has begun to rumble, and ultimately, more research needs to be done on this topic.

Though Mcdonald questions the existence of contrast-induced nephropathy, it was no means conclusive. Therefore, many still attempt prophylaxis against CIN. Generally, few therapies have been shown to be of any benefit, but many have been tried. In a recent systematic review and meta-analysis published in March 2016 (Subramaniam et al 2016) the following therapies were analyzed:

N-acetylcysteine (NAC) + IV saline vs. Saline alone.  
NAC is a direct scavenger of free radicals and improves blood flow through vasodilation. In 54 RCTs analyzed, there was a small benefit although not statistically significant. However when low-dose NAC was analyzed, there was a small and significant reduction in contrast-induced nephropathy (RR 0.75 [CI 0.63–0.89]). However, regardless of dose, when given before low osmolar contrast media, NAC did reduce the risk (RR 0.69 [CI 0.58–0.84]).

IV bicarbonate vs. IV saline.
Bicarbonate alkalinizes the tubular fluid and will decrease production of free radicals. However, in 19 RCTs, there was no evidence to suggest IV sodium bicarbonate was superior to IV saline.

N-acetylcysteine + IV Saline Versus vs Sodium Bicarbonate

In 7 RCTs, there was no benefit (RR, 1.11 [CI, 0.51 to 2.41])

Statin plus IV saline vs. IV saline

The mechanism is a bit unclear, but the belief is that in a cholesterol-independent mechanism, statins stabilize endothelium and reduce free radicals. Eight studies were used in this comparison, and they showed no significant difference (RR 0.68 [CI, 0.39–1.20]).

However,…

Statins + N-acetylcysteine and IV saline vs N-acetylcysteine plus IV saline or sodium bicarbonate showed a significant reduction in contrast-induced nephropathy. RR, 0.52 [CI, 0.29 to 0.93].

Ascorbic Acid

Vitamin C acts as a scavenger for free radical species. Overall, Ascorbic Acid has not been shown to have a significant benefit. When compared vs. IV saline (0.72 [CI 0.48–1.01]) or NAC (0.89 [CI 0.34–2.30]), no significant difference was found.

The bottom line is that many interventions have been tried with limited success. This could in part be due to sample size, confounders such as osmolar agent used, or some other reason that isn’t exactly clear. The search for a prophylaxis will likely continue. However for those such a Mcdonald that don’t believe in CIN, the lack of evidence for prophylaxis might not be because we haven’t discovered the right regimen. It might simply be a reminder that contrast-induced nephropathy doesn’t actually exist.