Response to Obesity-Related Glomerulopathy: Hyperfiltration may Contribute to early Proteinuria.

The Authors Reply:

We thank Edwards et al. for their letter regarding our article reporting the single-nephron GFR in patients with obesity-related glomerulopathy (ORG). Glomerulomegaly with focal segmental glomerulosclerosis of perihilar location is a typical renal histopathological finding in ORG, which has long-been considered to represent a state of single-nephron glomerular hyperfiltration. Our results demonstrated single-nephron hyperfiltration in ORG patients and were consistent with the hypothesis of podocyte failure due to intraglomerular hypertension. Another important aspect of glomerular hyperfiltration is the tubular reabsorption function, which is linked to sugar and salt loading. Changes in the tubular protein reabsorption in response to changes in the single-nephron GFR as suggested by Edwards’ mathematical models may be quite important for the maintenance of systemic protein homeostasis. Failure of glomerulotubular and tubuloglomerular interactions may be fundamentally important in the pathogenesis of glomerular hyperfiltration due to obesity.

Edwards’ suggestions may help resolve an important question. ORG typically shows an insidious onset with varying degrees of moderate to massive amounts of proteinuria and rarely accompanies an apparent decrease in the serum albumin concentration. These clinical features are in marked contrast to those found in patients with primary focal segmental glomerulosclerosis, in which massive proteinuria and hypoalbuminuria acutely occurs following diffuse and global podocyte foot process effacement. These differences in clinical presentations may represent not only different pathological mechanisms in podocyte failure but also the involvement of dysfunction in glomerulotubular and tubuloglomerular interactions. Edwards’ mathematical models may help clarify the pathophysiology underlying proteinuric kidney diseases, including ORG.