The key finding of the present study states that urinary transferrin was significantly related with subclinical atherogenesis, particularly in patients with diagnosis of t2DM, who had not developed renal disease yet. This was primarily evidenced by a positive correlation between urinary transferrin measurement and CIMT value, being particularly significant for subjects with t2DM. Such correlation results in a potentially useful tool for clinical assessment of a very early endothelial damage to the kidney.
Microalbuminuria has been traditionally used for the assessment of early renal damage in patients with T2DM. However, approximately 30 to 45% of t2DM patients may show a diminished glomerular filtration rate, even in the absence of albuminuria. Therefore, clinical characterization of new biomarkers is required 9. To date, there has not been described the correlation between transferrinuria in a random urinary sample and incipient nephropathy with t2DM as an early endothelial damage biomarker in patients without known renal disease.
Urinary transferrin, as well as several urine biomarkers such as ceruloplasmin, immunoglobulin G, podocalyxin, neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-beta-glycosaminidase, α-1-microglobulin, 8-hydroxy-deoxyguanosine, tumor necrosis factor-alpha (TNF-α), interleukin-18 and cystatin C, have shown to reflect early renal damage progression when assessed altogether with microalbuminuria 10. However, urinary transferrin alone may also correlate with early vascular damage reflected by ED and subclinical atherogenesis, leading to arterioles inability of adaptive vasodilation and to progressive increase of vascular stiffness 11. This indicates that urinary transferrin is an early marker of vascular disease, occurring even before overt microalbuminuria in patients with t2DM.
While the relation of urinary transferrin with early renal damage and subclinical atherogenesis is not completely clear, possible explanation is acting through different pathological mechanisms. Although the underlying problem often cannot be treated, extensive studies in experimental animals and humans suggest that progressive CKD may be largely due to secondary factors that are sometimes unrelated to the activity of the initial disease 12. Some of these secondary factors include compensatory response to nephron loss to maintain the total glomerular filtration rate (GFR); direct endothelial cell damage, like that induced by systemic hypertension; and marked tubulointerstitial injury (tubular dilatation, interstitial fibrosis), even if the primary process is a glomerulopathy 13.
Zylka et al found the highest relationship between biomarkers associated with glomerular damage (in comparison to albuminuria) and diminished glomerular filtration rate that were evaluated in a population similar to the present study, in which it stands for transferrin, immunoglobulin G, ceruloplasmin, type IV collagen, glycosaminoglycans, prostaglandin D synthase lipocalin type, fibronectin, vascular endothelial growth factor, cystatin C, and nefinina 14. Besides, Kim et al described a correlation between tubulointerstitial damage in t2DM with nephropathy, including different biomarkers such as urinary transferrin, that could lead to evaluate histopathological damage 15. Therefore, the correlation of urinary transferrin with ED suggests that glomerular and tubulointerstitial damages are related with vascular dysfunction, and urinary transferrin may be a useful marker of such dysfunction.
In addition, our results suggest that either the urinary transferrin or the urinary/serum transferrin index are useful to identify patients with diabetic nephropathy at early risk for ED and subclinical atherogenesis. These finding suggests the dynamic participation of the whole transferrin metabolism as related with early renal and vascular damages. The clinical usefulness of transferrinuria/transferrinemia index in the evaluation of early renal damage and subclinical atherogenesis, as a part of a routine test to identify high risk population with t2DM, are to be developed, and merits further evaluation by developing the specific concentration that could lead the patient at high risk, develop diabetic nephropathy.
The main limitation of our study was the heterogeneous characteristics between cases and controls within the study population, particularly in terms of age. However, no significant association was found between age and FMD nor CIMT values that could affect the study results. Another limitation was the determination of albuminuria with a bedside urine dipstick test in a urine single sample. Since this method is more sensitive for albumin (even with the false positive, false negative results that can occur), it resulted adequate for our analysis l. Finally, we used urine transferrin measured in a single morning urine sample, which did not show significant difference with 24h urine transferrin.
In conclusion, urine transferrin may be related with early endothelial dysfunction and subclinical atherogenesis in patients with t2DM and very early renal damage. This relation may be useful to stratify patients at higher vascular risk as well as early nephropathy, even before microalbuminuria becomes evident.