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Collagen biomarkers may clarify prognosis of renal complications in type 1 diabetes
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Adults with type 1 diabetes may be at greater risk for adverse cardiovascular and renal outcomes when elevated measures of certain collagen biomarkers are also present, according to findings published in Diabetes Care.
“Collagens are an essential part of the fibrotic structure, acting as a scaffold for a range of [extracellular matrix] molecule interactions and cell adhesion,” Sascha Pilemann-Lyberg, MD, PhD, a postdoctoral researcher at Steno Diabetes Center Copenhagen in Gentofte, Denmark, and colleagues wrote. “Because increased collagen formation and reduced degradation are closely linked with the development of fibrosis, assessment of collagen formation and degradation may identify patients with active fibrosis at higher risk of CV [events] and heart failure, mortality, and rapid deterioration of kidney function.”
Pilemann-Lyberg and colleagues focused on the biomarkers PRO-C6 and C3M, which are linked to the formation of collagen type VI and the degradation of collagen type III, respectively, they wrote. The researchers measured serum and urinary levels of these biomarkers in three urine samples taken between 2009 and 2011 from 663 adults with type 1 diabetes (mean age, 54.6 years; 44% women) at the Steno Diabetes Center in Copenhagen. The participants were then followed until the end of 2016. During follow-up, the researchers identified instances of CV and renal death, nonfatal acute myocardial infarction, nonfatal stroke, coronary interventions, end-stage renal disease, chronic dialysis and kidney transplant as well as measures of estimated glomerular filtration rate from medical records.
Based on median cutoffs, serum PRO-C6 measures of 7.5 ng/mL or more were associated with reduced eGFR (P .001), increased urinary albumin excretion rate (P .007) and greater diabetes duration (P < .001), the researchers wrote. Mortality risk was twice as high for adults with type 1 diabetes who had serum PRO-C6 measures of 7.5 ng/mL or more (HR = 2.26; 95% CI, 1.31-3.87) in fully adjusted models. The researchers noted that this increased mortality risk was present but only for participants with a urinary albumin excretion rate of less than 30 mg per 24 hours (P = .002). In addition, an association between serum PRO-C6 and a worsening of 30% or more in eGFR was observed only in participants who had a baseline eGFR of more than 30 mL/min/1.73 m2 (P .009), according to the researchers, who noted that ESRD was 8.45 times more likely to develop in participants with serum PRO-C6 measures of at least 7.5 ng/mL (HR = 8.45; 95% CI, 1.75-40.9).
“This could indicate that [serum] PRO-C6 is of more prognostic value in patients with mild kidney disease as opposed to patients with severe kidney disease,” the researchers wrote. “It could also be due to the fact that we have limited events in our cohort, and this should be reproduced in a larger cohort.”
Serum measures of PRO-C6 were considered elevated at 7.5 ng/mL, but urinary measures of the biomarker were considered increased if they were more than 0.211 ng/µmol creatinine. This elevated urinary mark shared similar associations with the serum measure in terms of decreased eGFR (P .001) and increased urinary albumin excretion rate (P .007), but the researchers wrote that there was an association between increased urinary PRO-C6 and decreased chances for a 30% or greater reduction in eGFRin fully adjusted models (P = .004).
Serum C3M greater than 8.5 ng/mL was correlated with decreased eGFR (P .001) and greater urinary albumin excretion rate (P .007). Conversely, when using urinary C3M measures of 5.58 ng/µmol of creatinine as the threshold for elevated C3M, the researchers found an association with increased eGFR (P < .001).
“We were able to demonstrate that [collagen type VI] formation and [collagen type III] degradation act as an early marker for poor prognosis,” the researchers wrote. “This is important because therapeutic interventions are more likely to be effective during the early period of kidney disease because the reversibility of fibrosis in advanced stages becomes doubtful as a result of varied processes, such as crosslinking of the [extracellular matrix].” – by Phil Neuffer
Disclosures: Pilemann-Lyberg reports no relevant financial disclosures. Please see study for all other authors’ relevant financial disclosures.
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