Challenging the conventional wisdom on diabetic nephropathy: Is microalbuminuria the earliest event?

Microalbuminuria, urine albumin-to-creatinine ratio >30 and less than <300 mg/g has widely been accepted as biomarker of early diabetic kidney disease (DKD). Based on absence of beta-2 microglobulinuria in earlier studies on microalbuminuria, its possible tubular origin has been dismissed. Microalbuminuria has been assumed as a marker of endothelial injury. Low-molecular-weight (LMW) proteins are smaller than albumin and less restricted by the glomerular filtration barrier. Normal individuals excrete no >10 to 20 mg/day low-molecular-weight proteins in urine, as they are absorbed in the proximal tubules. Thus, LMW proteinuria, or non-albumin proteinuria (NAP) is a reliable marker of tubular dysfunction in patients without glomerular involvement. In some cohorts of patients with diabetes (DM), tubular proteinuria preceded microalbuminuria, and similar to the findings reported by Han et al. in this issue of the journal, the tubular origin of these proteins was confirmed through correlations with the increased urinary concentrations of N‑Acetyl‑β‑d‑Glucosaminidase (NAG), a marker of tubular-lysosomal injury. Observations show significant NAP in the urine of DM patients without microalbuminuria; and that NAP correlates with NAG. In many studies it appears that NAP often precedes microalbuminuria, and is likely not the earliest biomarker of diabetic kidney disease. The conclusion that microalbuminuria is a biomarker of glomerular endothelial injury and that it is the earliest finding in DKD requires a re-appraisal. Data increasingly suggest that in early stages of DKD, NAP precedes microalbuminuria, and that microalbuminuria itself may be a consequence of impaired tubular reabsorption.