Nephropathy is one of the most significant complications of diabetes. Glycemic control—measured by HbA1c—and albuminuria are long-established risk factors for this condition, but a growing body of evidence also points to inflammatory markers. Researchers recently evaluated 10 such analytes and their findings are the subject of this issue of Strategies.

How quickly and how severely diabetes-related nephropathy develops varies significantly from person-to-person, yet being able to identify individuals most at-risk for this condition could lead to early interventions that might slow the effects of nephropathy. Many studies have implicated endothelial dysfunction and inflammation as early events in the run-up to diabetes-related renal disease, although the pathological mechanisms underlying these findings are unclear. Based on their prior findings, researchers with the Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) study sought to further examine whether baseline levels of markers of inflammation and endothelial dysfunction would be associated with subsequent development of albuminuria (Diabetes Care 2013 doi: 10.2337/dc12-2521).

“Although we don’t completely understand the mechanisms, we know diabetic complications are related to levels of modified lipoproteins, which are pro-atherogenic, pro-inflammatory, and immunogenic. These modified lipoproteins probably are enhanced by antigen-antibody immunocomplexes,” explained the study’s first author, Maria Lopes-Virella, MD, PhD, a professor of medicine and pathology at the Medical University of South Carolina in Charleston. “We were interested to know if inflammatory markers per se were as good markers as immunocomplexes because, of course, they’re easier to measure and it’s not very difficult to look at several of them. If they prove to be equally predictive and indicative of disease, this would help us to identify patients who are at a high risk of complications. That clinically would be a very useful, practical way to go.”

The DCCT was a randomized controlled trial of more than 1,400 type 1 diabetics who, at the time of enrollment, were between 13–39 years and had had the disease 1–15 years. Subjects were randomized to intensive or conventional insulin therapy and followed for an average of 6.5 years before the study was stopped in 1993 because of the clear effect of intensive therapy on microvascular complications. In 1994, nearly all DCCT participants enrolled in EDIC, an observational study designed to assess development of more advanced micro- and macrovascular complications. In the current study, the investigators measured 10 biomarkers associated with inflammation, ranging from C-reactive protein and interleukin-6 to fibrinogen and soluble tumor necrosis factor receptors (sTNFR)-1 and-2. They did so by accessing aliquots of baseline DCCT samples that had been archived for future research.

“These patients have been followed successfully for more than 20 years, so we have all the parameters on the complications they are developing. When they were first enrolled, the mean age was 20-something, and the patients were very clean from a complications stand-point,” said Lopes-Virella. “Our idea was to see if we could readily in the beginning of the disease identify those individuals who are at risk to develop complications later on. We were lucky enough to have access to samples that were collected 20 years before; otherwise it would have been very difficult to do this study.”

Lopes-Virella and her colleagues found, after design- and covariate-adjustment, that three markers remained significantly associated with abnormal albuminuria: soluble E-selectin (sE-selectin), sTNFR-1, and -2. In design-adjusted regression models which took into account DCCT treatment assignment, baseline albumin excretion rate, and use of ACE/angiotensin receptor blocker drugs, one unit increases in sE-selectin, sTNFR-1, and -2, respectively, were associated with 87%, 32%, and 52% increases in the risk of developing macroalbuminuria. After a second adjustment for covariates, which took into account baseline DCCT retinopathy cohort, sex, and baseline age, HbA1c percentage, and duration of diabetes, these biomarkers remained significant, with respective odds ratios of developing macroalbuminuria of 1.42 for sE-selectin, 1.33 for sTNFR-1, and 1.43 for sTNFR-2. At the same time, soluble vascular cell adhesion molecule-1 was associated with lower risk of developing macroalbuminuria, with 0.54 and 0.62 design- and covariate-adjusted odds ratios, respectively.

Several of the authors’ findings correspond with those of other investigators, including the Joslin Kidney Study conducted by researchers at the Joslin Diabetes Center in Boston. The study results also underscore that much more remains to be elucidated about the pathology of diabetic nephropathy, according to Monika Niewczas, MD, PhD, a research associate at Joslin Diabetes Center and an instructor in medicine at Harvard Medical School.

“This was a very nice study by a very well-known, established group. In this prospective cohort study, they carefully evaluated albuminuria, which is very important for the progression of diabetic nephropathy. Their findings speak again to the concept that the specific markers rather than generalized inflammation are relevant and that some of those markers may have value as a diagnostic test in the future,” she said. “We don’t really know what these markers stand for because we don’t know exactly the mechanism of action. If it were just general inflammation, all the other inflammatory markers should also be showing associations with progression of macroalbuminuria. But they aren’t, so it is reasonable to think these markers might have a role that was not elucidated here.” Niewczas was not associated with the study.

Both Niewczas and Lopes-Virella agreed that more investigation needs to be done about the putative role of inflammation in diabetic nephropathy, and both are involved in research seeking to do just that. Niewczas elaborated on the effect having better predictors of nephropathy could have on patient care. “At this moment the clinical markers which are available in the doctor’s office or from the clinical laboratory are not sufficient determinants for identifying or distinguishing those people who will progress, that is definitely develop kidney failure versus those who will not. To make clinical care efficient and also to focus on those people who are at risk it’s very important to search for new markers,” she said.

Both Lopes-Virella and Niewczas also agreed that because of the complex and still incompletely understood mechanisms underlying diabetic-related nephropathy, selected markers of inflammation might one day be considered along with standard risk factors like HbA1c and glomerular filtration rate to paint a more complete risk picture.