Obesity-Related Glomerulopathy: Hyperfiltration May Contribute to Early Proteinuria.

To the Editor:

We read with great interest the paper on Obesity-Related Glomerulopathy (ORG) and Single-Nephron GFR (SNGFR) by Okabayashi et al. and Denic and Glassock’s editorial., Clinicopathological features of ORG include initial glomerulomegaly, podocyte failure and glomerulosclerosis. Marked proteinuria occurs even in early ORG, 874±770 mg/day compared with 29±41 in obese renal donors, an approximately 30-fold increase (CKD Stages 1 and 2, Table 2). Corresponding SNGFR values are 97±43 nl/min and 64±21 nl/min. We recently described a human model of the handling of multiple proteins by the proximal renal tubule, assuming a normal SNGFR value of 80±40 nl/min as determined by Denic et al., This model suggests that hyperfiltration itself may cause proteinuria, since renal protein excretion appears very sensitive to SNGFR. This agrees with a previous albumin-handling model in rats. Increased SNGFR decreases the time glomerular filtrate proteins are available for proximal tubular endocytosis so protein reabsorption decreases and proteinuria develops. Our model predictions of the urinary excretion of the four major proteins in the glomerular filtrate (albumin; α1-microglobulin; retinol-binding protein 4 and β2-microglobulin) indicate that hyperfiltration may be a key determinant of the proteinuria in early ORG found by Okabayashi et al. We estimate that the change in SNGFR observed by Okabayashi et al. will per se increase albumin excretion approximately five-fold. So hyperfiltration may make a substantial contribution to the proteinuria of early ORG before major podocyte damage increases proteinuria further. Measurements of individual urinary proteins from early ORG patients might confirm this suggestion.