Urine transferrin as an early endothelial dysfunction marker in type 2 diabetic patients without nephropathy: a case control study

Abstract

Background Albumin, along with other proteins, is abnormally eliminated via the urine during early stages of diabetic nephropathy. Moreover, endothelial dysfunction (ED) accompanying early diabetic nephropathy may develop even before microalbuminuria is detectable. Transferrin has a molecular weight comparable to albumin, whereas transferrinuria and microalbuminuria in a 24-h urine sample may comparably reflect early diabetic nephropathy. Whereas transferrin metabolism is related with ED during very early diabetic nephropathy has not been elucidated yet. This case–control study aimed to evaluate the relation between ED and urine transferrin, even before early diabetic nephropathy is present. Methods Patients were enrolled from two study sites in Mexico City: Ticomán General Hospital (healthy controls); and a Specialized Clinic for the Management of the Diabetic Patient (cases). All patients provided written informed consent. The primary endpoint was the correlation between urinary transferrin concentration and ED measured in type 2 diabetic patients without albuminuria. ED was evaluated by ultrasonographic validated measurements, which included carotid intima-media thickness (CIMT) and flow mediated dilation (FMD). Plasma biomarkers included glycated hemoglobin, creatinine, cholesterol and triglycerides, as well as urine albumin, transferrin and evidence of urinary tract infection. Results Sixty patients with type 2 Diabetes Mellitus (t2DM; n = 30) or without t2DM (n = 30), both negative for microalbuminuria, were recruited. The group with t2DM were older, with higher values of HbA1c and higher ED. This group also showed significant differences in urine transferrin and urine/plasma transferrin ratio, as compared with healthy controls (14.4 vs. 18.7 mg/mL, p = 0.04, and 74.2 vs. 49.5; p = 0.01; respectively). Moreover, urine transferrin correlated with higher CIMT values (r = 0.37, p = 0.04), being particularly significant for t2DM population. CIMT also correlated with time from t2DM diagnosis (r = 0.48, p < 0.001) and HbA1c (r = 0.48; p < 0.001). Conclusion Urine transferrin correlated with subclinical atherogenesis in patients with t2DM without renal failure, suggesting its potential to identify cardiovascular risk in patients at very early nephropathy stage without microalbuminuria.

Urinary Transferrin as a Marker of Renal Injury in Diabetic Individuals: An Integrative Review

“…Urinary transferrin is correlated with subclinical atherogenesis in type 2 DM patients without renal failure, suggesting its potential to identify cardiovascular risk in patients at an early stage of nephropathy without microalbuminuria [37].…”

Iron metabolism and chronic inflammation in IgA nephropathy

“…In addition, urinary transferrin can predict the severity of mesangial cell proliferation and glomerulosclerosis in the early stages of potentially progressive glomerular disease [ 97 ]. Urinary Tf can be evaluated to assess cardiovascular risk [ 98 ]. A cohort study showed significant differences in urinary Tf and the urinary/plasma Tf ratio in patients with type 2 diabetes compared to healthy controls, and urinary Tf was correlated with higher carotid intima-media thickness values [ 98 ].…”

“…Urinary Tf can be evaluated to assess cardiovascular risk [ 98 ]. A cohort study showed significant differences in urinary Tf and the urinary/plasma Tf ratio in patients with type 2 diabetes compared to healthy controls, and urinary Tf was correlated with higher carotid intima-media thickness values [ 98 ]. In a retrospective study of 514 IgAN patients, urinary Tf was positively correlated with mesangial cell hyperplasia, endothelial cell hyperplasia, tubular atrophy or interstitial fibrosis in the Oxford classification of IgAN [ 99 ].…”

Early renal structural changes and potential biomarkers in diabetic nephropathy

“…( Wellen and Hotamisligil, 2005 ). Processes closely associated with the persistent early elevation of blood glucose, such as increased ion transport-related proteins transferrin and ceruloplasmin, reflect endothelial cell dysfunction and increased intra-glomerular pressure ( Narita et al, 2006 ; Sánchez-Hidalgo et al, 2021 ), and upregulated expression of VEGF promotes angiogenesis ( Aly et al, 2019 ), as well as increased collagen IV are also closely associated with the fibrotic process ( Kotajima et al, 2000 ). A recent study showed a detailed interpretation of the progression of DN by combining proteomics and peptidomics in the urine of diabetic subjects, and the results of our analysis have similarities to this study ( Van et al, 2017 ).…”