Marker May Show Kidney Disease in Diabetics
High levels of certain inflammatory markers may foretell of the development of macroalbuminuria in patients with type 1 diabetes, researchers found.
In an analysis of data from a prospective study, higher baseline levels of soluble E-selectin and soluble tumor necrosis factor receptors (sTNFR) -1 and sTNFR-2 were associated with an increased risk of developing macroalbuminuria over about 6 years, Maria Lopes-Virella, MD, PhD, of the Medical University of South Carolina, and colleagues reported online in Diabetes Care.
An abnormal albuminuria level “is associated not only with risk of developing renal insufﬁciency but also cardiovascular disease in patients with diabetes,” the authors explained. “There is considerable interest in determining the mechanisms responsible for albuminuria and in identifying early biomarkers that may be predictive of this complication of diabetes.”
The mechanisms behind the development of albuminuria in patients with type 1 diabetes aren’t clear, so Lopes-Virella and colleagues assessed whether markers of inflammation and endothelial dysfunction would be associated with the development of protein in the urine.
They looked at data from the Diabetes Control and Complications Trial (DCCT), in which 1,237 of the 1,441 patients, who were free of albuminuria and cardiovascular disease at baseline, and had diabetes for 1 to 15 years. These patients were in the primary prevention DCCT cohort and were retinopathy-free.
There also was a secondary intervention cohort that had mild to moderate nonproliferative diabetic retinopathy and albumin excretion rates of ≤200 mg/24 hours.
All patients had markers of inflammation and endothelial dysfunction assessed at that time.
Overall, they saw increased levels of sE-selectin, interleukin-6 (IL-6), plasminogen activator inhibitor 1 (PIA-1), and sTNFR-1 and -2 in patients who developed macroalbuminuria, compared with those who had normal urine during 6.5 years of follow-up.
They also saw a pronounced decrease in soluble vascular cell adhesion molecule 1 (sVCAM-1) levels in those who progressed to macroalbuminuria.
In adjusted models, the researchers found that a 1-unit increase in the standard level of sE-selectin was associated with a significant increase in the risk of developing macroalbuminuria (odds ratio 1.87, 95% CI 1.42 to 2.47).
And 1-unit increases in the levels of several other hormones were also tied to an increased risk of macroalbuminuria:
- IL-6: OR 1.28 (95% CI 1.04 to 1.56)
- PAI-1: OR 1.27 (95% CI 1.04 to 1.56)
- sTNFR-1: OR 1.32 (95% CI 1.02 to 1.71)
- sTNFR-2: OR 1.52 (95% CI 1.16 to 2.00)
After further adjustment for baseline retinopathy status, age, sex, HbA1c, and duration of diabetes, associations remained for only three of the biomarkers:
- sE-selectin: OR 1.42 (95% CI 1.06 to 1.91)
- sTNFR-1: OR 1.33 (95% CI 1.01 to 1.76)
- sTNFR-2: OR 1.43 (95% CI 1.07 to 1.91)
While the associations did not remain for IL-6 or PAI-1, they reported, there was a signiﬁcant interaction between PAI-1 total levels and baseline retinopathy (P=0.009). This indicated that there was a relationship between total levels of PAI-1 and progression to micro- or macroalbuminuria in patients without any retinal complications at baseline, but no relationship in those with early retinopathy and longer duration of type 1 diabetes mellitus at baseline, they stated.
The researchers also found each 1-unit increase in standard levels of sVCAM-1 was associated with a drop in the risk of progression to macroalbuminuria in two different adjusted models (OR 0.54, 95% CI 0.37 to 0.78 and OR 0.62, 95% CI 0.42 to 0.93).
They concluded that measurement of sE-selectin, sTNFR-1, sTNFR-2 levels “provides valuable information concerning the risk for development of macroalbuminuria in patients with type 1 diabetes.”
The study suggests that vascular dysfunction and other effects of sTNFRs are “either directly responsible or more closely related to the development of diabetic nephropathy than other markers of inflammation.”
Ultimately, the findings could be used as the basis for therapeutic interventions aimed at slowing the rate of progression to kidney disease, they wrote.
The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases and Veterans Affairs Medical Center.