Inflammatory biomarkers foreshadow CKD, study finds

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Dr. Lopes-Virella

Says Dr. Lopes-Virella: “Our idea was to see if some biomarkers could help us choose patients who start with more of a chance of having the event. Then, if you are looking at a drug and the effects of a drug, you can see more easily if some do not develop the disease when they are treated.” The study team also wants to help other trials expose fewer patients to the drugs being studied, Baker says. “You can do that if you can choose patients for your study pool who are more likely to acquire the disease.”

The researchers chose to study short-term and long-term time frames because they have different purposes, Dr. Lopes-Virella says. “The short term was mostly to help in recruitment of patients if you are doing clinical studies. Those patients are in more immediate need of treatment because they are not doing well. But the long term, in my opinion, is more important because they are the ones who tell you which patients need help and need to be treated more intensively to prevent the development of complications.”

With most clinical trials funded by the National Institutes of Health, Baker notes, “you don’t get 10 or 20 years of follow-up data. You get three. So being able to use biomarkers to identify at-risk patients is very important.”

But he is interested not only in how the biomarker works to help but also in how the biomarker represents one of the mechanisms of the disease. “I personally don’t like biomarkers that I don’t think are somehow related to the pathophysiology of disease,” he says. As the study notes, identifying biomarkers associated with long-term disease progression helps illuminate the underlying mechanism of disease development.

“There are a lot of publications and a lot of data to suggest that the pathogenesis of diabetes complications has a strong link to the complement system, and also indicators of signaling operations in membrane structures that lead to different signal pathways. All of that seems to be very much involved in the complications of diabetes. So we were looking partly at what we know was involved in the complications and trying to figure out the biomarkers,” Baker says.

Baker and Dr. Lopes-Virella note that this study does not provide added clinical utility for disease prediction beyond the traditional risk factors, and that further classification analysis, including prediction models, should be conducted.

“In a sense, many of the clinical implications depend a lot on which pathway is implicated in the disease process,” Dr. Lopes-Virella says. Clinicians do not want, when trying to prevent one problem, to create another, she points out. For example, with inflammation, “you need to be very careful with your conclusions because inflammation is a necessary process in the body.” Since inflammation is part of a protective immune response, “if you attack inflammation, you may have unwanted side effects.” Sometimes researchers can find very specific pathways that do not have general effects. “Targeting these pathways, I think, may have clinical implications and help with the discovery of drugs to treat the disease.”

“I think as we work toward a more discriminative model, a panel-type model” for predicting kidney dysfunction, “we’ll get closer to clinical utility,” Baker says. “But with individual biomarkers, we are still kind of exploring the relationship not just to CKD but to the heart as well. Once we get a panel together, we will have a lot more clinical utility from our findings.”

That milestone is still a step or two away. “We are talking about building a full panel and possibly developing a risk score that will help assess patients with additional biomarkers. But we haven’t yet concluded which ones,” Baker says. “In this study, we were looking at sE-selectin and sTNFR-1/2 because they seem to have a tremendous impact in the kidney.”

The biomarkers study had a well-defined population that was followed for a significant time, but limitations of the study do temper the results, the authors note. The number of events in the cohort studied was relatively small in the three-year follow-up window, detracting from its statistical significance. There were variations in testing, including participant albumin excretion rate values that were measured annually during DCCT but only every other year during EDIC, making it difficult to measure persistent macroalbuminuria in the presence of treatment with ACE/ARB medications.

The NIH and pharmaceutical companies are paying attention to different biomarkers and how they could help in treating and preventing complications in diabetes and other diseases, Dr. Lopes-Virella says. “They want to use, as much as possible, plasma/serum/urine biomarkers and avoid invasive procedures to identify patients at high risk. That way you can more easily identify patients who are at high risk and really need treatment. You cannot treat everyone, but it helps if you considerably reduce the number of patients who will progress if left untreated.”

A population of only type 1 diabetes patients was the subject of the study. But could the study’s findings be helpful in predicting type 2 diabetes? Maybe, says Baker. “Diabetes is a very interesting disease. With type 2, I don’t think we really know when the disease starts. It’s a continuum from metabolic syndrome to prediabetes to diabetes. So I think these biomarkers are definitely something that could be helpful.” But, he says, since the population of patients in this study all had diabetes and various stages of kidney disease, the biomarkers were not predicting progression to diabetes.

Dr. Lopes-Virella believes the biomarkers shown to be correlated with renal function deterioration in patients with diabetes could potentially help with prediction of prediabetes. “These biomarkers will probably help identify patients at risk. Could they help more than the traditional markers we already know? I don’t know. But there are studies looking at this question.”
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 Anne Paxton is a writer and attorney in Seattle.