Contrast-Associated Acute Kidney Injury Is a Meaningless Endpoint

In 2006, The New England Journal of Medicine ran a review on the renal dangers of radiographic contrast, titled, "Preventing Nephropathy Induced by Contrast Medium." When the journal revisited the topic in 2019, the kidney damage was no longer induced by the contrast but merely associated with the contrast. This change in language indicates a loss of confidence in the long-standing belief that radiographic contrast causes the kidney injury. However, two recent additions to the contrast-associated acute kidney injury (CA-AKI) literature refuse to accept this change and bring us back to adjudicating meaningless wanderings in serum creatinine.

Intravenous Contrast and Kidney Injury

Some of the first observations to shake confidence in the causal relationship between contrast and AKI were retrospective comparisons of patients who had contrasted CT scans with those who didn't receive contrast. These repeatedly found higher rates of AKI in the patients who did not receive contrast

The problem is that the people who developed CA-AKI look completely different from those who did not. The 6.5% of patients who developed CA-AKI were older and had more peripheral artery disease, heart failure, diabetes, hypertension, chronic kidney disease, and anemia. Multivariable adjustment attempts to account for these confounding factors, but the authors' decision to use dichotomous variables diminishes its power to squash residual confounding. For example, they measured GFR but then use CKD or no CKD in their multivariable adjustment. The 30-year-old with a GFR of 31 mL/min is wildly different from the 67-year-old with a GFR of 57 mL/min, yet this analysis treats them the same. Similarly for hypertension: 137/84 mm Hg does not equal 188/104 mm Hg, and so on.

I believe that these latest papers and others that show an association between CA-AKI and adverse outcomes are examples of reverse causality. We know that diabetes, heart failure, and CKD are risk factors for CA-AKI, and that CA-AKI is associated with all kinds of devastating outcomes, but the jump from association to causation is a bridge too far.

Do you think a creatinine bump from 1.1 mg/dL to 1.4 mg/dL that returns to normal within a week of cardiac catheterization is a more important cause of mortality than the fact that the patient had heart failure or diabetes? Instead of thinking of the heart failure being a risk factor for CA-AKI, think of the CA-AKI as a convoluted way to find patients with heart failure, diabetes, and peripheral artery disease. The CA-AKI is not the cause of the devastating outcomes but a indicator of patients at high risk for those outcomes.

We can't get a definitive answer from the CA-AKI trials because they were not powered for mortality and we have yet to identify effective therapies to prevent CA-AKI. But we do have trials on interventions that cause acute, mild to moderate, and often temporary elevations in sCr. Coca and colleagues looked at 14 such trials to see if the spread in AKI between the intervention and control group predicted future mortality. It did not. This is further evidence that spending time worrying about tiny changes in serum creatinine is a fool's errand that does not benefit patients.

Could Subclinical Cholesterol Emboli Be a Factor?

If contrast is not the cause of AKI during cardiac catheterization, what could be? I wonder if subclinical cholesterol emboli syndrome may be the true culprit.

Cholesterol emboli syndrome is a rare complication of arterial catheterization where the fibrous caps of plaques are disrupted and cholesterol emboli are showered downstream. These bits of cholesterol cause ischemic damage wherever they finally lodge. They can cause ischemic colitis, purple toes, and AKI. While cholesterol emboli are reported following 1%-2% of cardiac catheterizations, I suspect that subclinical cholesterol emboli syndrome is more common and may be responsible for some, perhaps many, cases of so-called CA-AKI.

Supporting my hunch is a study looking at AKI following transcatheter aortic valve replacement (TAVR). AKI is relatively common following TAVR, occurring in 10%-30% of interventions. Shishikura and colleagues looked at risk factors for AKI, and while the usual suspects of low GFR and anemia were found to be significant predictors, contrast volume was not. The investigators then used CT to estimate aortic atherosclerotic burden and found that increased plaque volume above the renal arteries was a powerful predictor of AKI, while aortic plaque volume below the renal arteries was not. The authors suggest that cholesterol emboli could be an underrecognized but important cause of AKI.

Cholesterol emboli from aortic plaques would also explain the decreased CA-AKI found with radial catheterizations in the MATRIX study.

Stop Chasing Creatinine

Nephrology, cardiology, and radiology have been trying to reduce and prevent contrast from damaging kidneys for decades. I had hoped that the PRESERVE trial would lead to a change in how people evaluated contrast and other nephrotoxins. Or that the cholesterol emboli theory would get more attention. However, looking at the two most recent additions to this field, we are back to adjudicating meaningless wanderings in serum creatinine.

Joel Topf, MD, is a partner at St. Clair Nephrology and on faculty at Ascension St. John Hospital in Michigan. He is a co-creator of NephMadness and NephJC, and hosts the Freely Filtered podcast.

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