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Contrast Induced Nephropathy - 2/12/2013

posted Feb 12, 2013, 8:11 AM by Rohit Das   [ updated Feb 12, 2013, 1:58 PM by Purnema Madahar ]

Iodinated radiocontrast-Induced Nephropathy (which I shall abbreviate as CIN) is an issue we very commonly encounter when thinking about the risks and benefits about imaging studies and angiographic procedures. Such was the case in a patient presented at resident report today – a woman with quite a cardiovascular history who presented with a NSTEMI, high TIMI score, but didn’t have invasive intervention primarily because of a high risk for CIN, and CIN-associated dialysis. So, thought I’d write about the following:

·         What’s the pathophysiology behind CIN?

·         What’s the epidemiology of CIN, and which patients are at risk? What’s the usual clinical course?

·         How can we prevent it, and what’s the evidence behind commonly used preventative measures?

What’s the pathophysiology behind CIN?

·         Most of the studies looking at this have been in animal models. Though histology depicts “ATN” type mechanisms, the course of CIN is markedly different and characterized generally by rapid recovery. The pathophysiology isn’t completely clear, but there are two accepted mechanisms: renal vasocontstriction and tubular damage.

·         Renal vasoconstriction – this occurs primarily in the outer medulla, which is particularly susceptible to decreased blood flow due to an already baseline hypoxic environment. The vasa recta, the vascular bed that feeds the renal medulla, is dependent on a low viscosity system to maintain adequate blood flow. Contrast media leads to high viscosity blood flow, medullary ischemia, free radical production and oxidative damage badness. It’s also been proposed that oxidative species inactivate nitric oxide (which maintains local vasodilatation), further compounding the issue.

·         Tubular Injury – this is kind of along the same lines; free radicals are cytotoxic to tubular cells, and thus, medullary vasoconstriction and tubular injury work synergistically.

So, overall, the mechanism is similar to ATN in many respects – the induced hyperosmolar environment leads to localized vasoconstriction, ischemic tubular injury, and unsurprisingly – renal failure.


What’s the epidemiology of CIN, and which patients are at risk? What’s the usual clinical course?

·         The literature defining the risk factors for CIN has largely been in the context of angiography. Generally, the risk related to CT contrast imaging is much lower, even among high risk patients. For example, in one study of 420 patients with estimated GFR < 40, only 2% had a creatinine increase of >0.5 mg/dL 2-4 days post-procedure.

·         The epidemiology for angiography-related CIN is very dependent on the patient population one is looking at it. In patients with no risk factors, the risk is negligible; in high-risk patients the incidence can be as high as what are the risk factors?

·         In a nice study by Mehran et. al. in 2004 (attached), about 5000 patients undergoing PCI were used to develop a clinical risk score, which was then subsequently validated in a prospective cohort of around 3,000 patients. The overall incidence of CIN, defined as ≥25% or ≥0.5 mg/dL increase in pre-PCI creatinine at 48h post-PCI, was 13.1%. Of further note:

o   After multivariate analysis, the following were shown to be independent risk factors of CIN (with associated “integer” allocation): hypotension (5), Intra-aortic balloon bump (5), CHF (5), creatinine > 1.5 mg/dL (4), age > 75 (4), anemia (defined as hematocrit <39% in men, <36% in women; 3), DM (3) and contrast volume (1 point for every 100cc injected…the mean volume of contrast during a diagnostic cath is around 100-200cc; that number increases if intervention is performed, and increases further depending on the number of lesions intervened on).

o   Figure 5 gives a nice layout of how they then stratified the cohort based on their integer score; the highest subgroup, with a score ≥ 16, had an incidence of around 60%, with an associated 12% risk of requiring HD. Pretty crazy…

·         So…how does it present clinically? Serum creatinine usually rises within 24-48 hours after creatinine exposure, and decreases back to pre-contrast levels within a week. Most patients are not oliguric. Further studies may show an ATN-like urine sediment, FeNa usually <1% (in contrast to ATN – don’t totally get why, sorry L) and little to no proteinuria. Overall, CIN is benign and rarely leads to renal replacement therapy, but it is certainly an important consideration among high-risk subgroups, as mentioned above.


How can we prevent it, and what’s the evidence behind commonly used preventative measures?

·         First point I want to make…what are we actually preventing? As mentioned, CIN has a relatively benign natural history in most cases, and the incidence of CIN leading to dialysis is rare for most patients (<1%), BUT, can be as high as 10% in certain subgroups. Importantly, studies have shown that the in-hospital mortality for those patients who require dialysis for CIN is very high (20-30%) and also associated with low long-term survival (20% at 2 years). How much of this is confounded by various co-morbids requires more in-depth examination of these studies, but the other important point – the preventative treatments we CAN give are pretty harmless. Ok, so what can we do prevent CIN?

·         Numero Uno – give low osmolal or iso-osmolal agents. As described, the hyperosmolar nature of iodinated contrast is central to the pathophysiology of CIN, and administration of lower osmolarity or iso-osmolar agents clearly leads to a lower incidence of CIN. This is now the standard of care and part of several society guidelines, so not to fret…safe to say that cardiologists and radiologists have this one covered.

·         Number Two – volume. Makes sense hopefully – ensuring adequate volume helps to maintain adequate renal blood flow, which would otherwise be worsened by iodinated contrast. It’s pretty clear that IV volume is better than oral volume replacement, but there is a lot of controversy over what TYPE of fluid (isotonic NaBicarb vs. isotonic saline) to give…

o   Data supporting bicarbonate include the REMEDIAL trial (attached), in which patients were randomized to NaBicarb + NAC, saline + NAC, or saline + NAC + ascorbic acid. Long-story short, and I’ll talk about NAC in a bit, but the incidence in the NaBicarb arm was 2%, as compared to around 10% in both saline arms. On the other side of the coin, there also have been randomized trials supporting the use of isotonic saline. FINAL TAKE – can’t really go wrong either way; kidney society guidelines recommend isotonic NaBicarb over isotonic saline.

o   How does one administer fluids to prevent CIN? For isotonic NaBicarb, studies have used brief infusions – bolus of 3 ml/kg 1h prior to the procedure, continued at a rate of 1 ml/kg until 6 hours after. For saline, longer, maintained infusions have been best studied – 1 ml/kg/h for 12 hours prior and post procedure. Suppose either one works…

·         Number Three – N-acetylcysteine. Thought here is that NAC has both antioxidant and vasodilatory properties. There has been a TON of literature looking into this fairly harmless, inexpensive intervention.

o   One of the earliest was the attached NEJM trial, which randomized 80 pretty high-risk patients (mean age of 65, 30% prevalence of DM, mean creatinine of around 2.5) to saline + NAC or placebo. The control group had a CIN incidence of 21%, and the NAC group of 2%, giving a relative risk of 0.1, absolute risk reduction of 19%, and thus a NNT of around 5-6…wicked numbers.

o   Bigger trials have not shown the same benefit. The ACT trial in 2011, for example, randomized 2300 patients (majority of whom received low-osmolar contrast and hydration) to NAC or placebo. In summary, it was a negative study, even among several high-risk subgroups. However, the cohort overall was relatively low-risk as compared to the 2000 study – the mean creatinine was 1.2 mg/dL, and only about 16% of patients had a creatinine higher than 1.5 mg/dL. So, the study at initiation may have been biased to not show a difference…hard to say…

o   Overall take on this – NAC is cheap, harmless, given short-term and has some data to support its use in high-risk patients, particularly those with established CKD. It’s recommended to give it at a dose of 1200mg, twice a day, on the day of and the day after the procedure. Try it out some time….


Attached is a brief review on CIN, and the trials that I mentioned above. One of those things that’s common enough where it’s useful to be familiar with some of the literature…Till next time…

Contrast-Induced Nephropathy: A Review
Sanaei-Ardekani et. al., Card Revasc Medicine 2005, Volume 6(2): 82-88

Mehran et. al., J Am Coll Cards 2004, Volume 44: 1393-99

Briguori et. al., Circulation 2007, Volume 115: 1211-17

Tepel et. al., NEJM 2000, Volume 343: 180-184

ACT Investigators, Circulation 2011, Volume 124: 1250-1259