High Homocysteine Levels Linked with Contrast Nephropathy

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High levels of homocysteine, a known risk factor for cardiovascular disease, also independently predict contrast-induced nephropathy (CIN) in patients undergoing percutaneous coronary intervention (PCI). It is not clear whether the findings represent just an association or a more causal relationship, according to a report appearing online July 26, 2011, ahead of print in the American Journal of Cardiology.

Researchers led by Tae-Hyun Yoo, MD, PhD, of Yonsei University College of Medicine (Seoul, South Korea), looked at 572 patients who underwent PCI at a single South Korean hospital during 2009, analyzing them according to tertile of plasma homocysteine level. Patients with higher homocysteine levels were older and tended to be male. Also, blood urea nitrogen (BUN) and creatinine levels were greater in the third tertile, while eGFR was significantly lower. All other biochemical parameters, comorbidities, and procedural characteristics were similar among the groups.

CIN, defined as an absolute increase of at least 0.5 mg/dL or a relative increase of at least 25% in serum creatinine at 48 hours after PCI, developed in 69 (12.1%) of the patients and was more common in the third homocysteine tertile (from lowest to highest: 4.7%, 7.3%, 24.2%; P < 0.001). In addition, plasma homocysteine levels were greater in patients with CIN compared to those without the condition (16.9 ± 4.9 µmol/L vs. 13.5 ± 4.2 µmol/L; P < 0.001). Serum BUN, creatinine, and blood glucose levels were also higher in patients with CIN, while eGFR, serum albumin, and hemoglobin levels, as well as LVEF, were lower in this group.

Results Consistent Across Subgroups

On subanalysis, stepwise associations were found between increasing homocysteine levels and CIN incidence in groups defined by diabetes (P < 0.001) and nondiabetes (P = 0.039), ACS (P < 0.001) and stable angina (P = 0.02), and eGFR less than 60 mL/min/1.73 m² (P = 0.044) or at least 60 mL/min/1.73 m² (P < 0.001). There was a significant positive association between homocysteine level and CIN on univariate analysis that remained consistent on multivariate analysis (OR 1.70 for each 4.44 µmol/L increase; 95% CI 1.07-2.71; P = 0.025). Diabetes, eGFR, and use of intraaortic balloon pump were also independent risk factors for the development of CIN.

On receiver operating characteristic curve analysis, homocysteine level was an accurate predictor for the development of CIN, with an area under the curve of 0.73 for baseline homocysteine level (95% CI 0.66-0.79; P < 0.001).

“We found that the incidence of CIN was increased in patients with higher plasma homocysteine levels and that hyperhomocysteinemia was an independent predictor for CIN in patients who underwent PCI,” the researchers write, cautioning that they “were not able to confirm a causal relation” due to the study’s observational nature. “Future clinical trials are needed to clarify whether lowering the homocysteine level reduces the incidence of CIN,” they add.

Oxidative Stress May Link Homocysteine, CIN

In terms of a possible mechanism, the researchers explain that elevated homocysteine levels are associated with generation of free radicals and increased oxidative stress, factors thought to play a central role in the kidney injury caused by contrast media.

In an e-mail communication with TCTMD, Peter A. McCullough, MD, MPH, of the Providence Park Heart Institute (Novi, MI), agreed with that assessment, adding that he doubts the association is causative. “Elevations in homocysteine probably reflect minor degrees of chronic kidney disease or renal vulnerability to acute kidney injury after contrast. Homocysteine is not known to be directly pathogenic,” he said. “Impaired remethylation in the metabolism of methionine and ultimately higher levels of homocysteine may be a surrogate for higher levels of baseline oxidative stress, and thus, the lack of recovery of renal function after contrast exposure.”

Whatever the mechanism, “it’s a real association,” Richard J. Solomon, MD, of the University of Vermont (Burlington, VT), told TCTMD in a telephone interview. “The study is supportive of there being something with homocysteine levels that is associated with the incidence of acute kidney injury related to contrast media that’s not explained by just having chronic kidney disease.”

The question, though, “is whether it’s a modifiable risk factor,” Dr. Solomon said. “We don’t know. The only way to prove causation is to try and modify it and show that doing so alters the incidence of CIN.”

This should prove relatively easy given the current in vitro models used to study the condition, he noted. “One could just imagine adding some homocysteine into the culture media, for example, of renal cells and see if that enhances the injury when you then incubate them in contrast,” Dr. Solomon added. “That’s exactly the kind of experiment that this observational data should prompt.”

Modifying Risk Factor Not So Simple

However, even if homocysteine is found to play a significant role in CIN risk, lowering levels of the amino acid poses some challenges, Dr. Solomon noted. For instance, in the large trials investigating homocysteine and CVD, efforts to decrease concentrations of the substance failed to cause a reduction in risk, even though homocysteine was proven to be an independent risk factor. Also, lowering homocysteine in the first place might not be so easy in the context of patients undergoing PCI.

“Those trials tried to give folate to see if you lowered homocysteine levels, would that modify outcomes, and it didn’t. But that was for chronic conditions,” Dr. Solomon said. “Whether in this acute setting you might see an effect, we don’t know. Somebody’s got to have an acute way to lower homocysteine levels.”

Even testing for the substance presents challenges. “Yes, you can measure it, but whether you can get that measurement back in a timely fashion that would allow you to do anything, I don’t know. For STEMI, for instance, that’s not going to happen,” Dr. Solomon said. “You could measure it and get the answer by the next day for elective PCI, for instance. But you still need to have a way to get it down acutely. I’m not sure if anyone has ever looked at that.”

Regardless, the current study should encourage future research. “The fact remains that we don’t fully know the mechanism of action of contrast agents in causing injury,” Dr. Solomon pointed out. “We certainly haven’t got a therapy that has stopped the injury, and every effort to better understand the things that contribute to that injury, of which homocysteine may be one, advances the field.”

Study Details

Homocysteine levels in the 3 tertiles from lowest to highest were 9.7 ± 1.6 µmol/L, 13.3 ± 1.0 µmol/L, and 18.7 ± 3.8 µmol/L (P < 0.001). Rates of AMI across the 3 tertiles from lowest to highest were 40%, 35%, and 42%, while rates of unstable angina were 14%, 16%, and 16%, respectively.

 

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Source:
Kim SJ, Choi D, Ko Y-G, et al. Relation of homocysteinemia to contrast-induced nephropathy in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2011;Epub ahead of print.

 

 

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