Figure 1. Panel A. The podocyte depletion paradigm.

a. Each glomerulus has a filtration surface that must be completely covered by podocyte foot processes to maintain the filtration barrier. b. Podocytes can adapt to glomerular enlargement or podocyte loss by hypertrophy. c. If hypertrophic stress exceeds the podocytes' adaptive capacity they detach into the filtrate where they can be measured in urine. d. Loss of a critical number of podocytes results in bare areas of GBM that leak protein and become patched by scar tissue (focal sclerosis). e. When >80% of podocytes are lost global sclerosis supervenes.

Panel B. Podocyte dynamics as a zero-sum game. Biopsy podometrics can be used to estimate glomerular volume (reflecting the filtration surface area), the number of podocytes remaining per glomerulus (podocyte number) and the average podocyte size (podocyte size). Proteinuria is in part a measure podocyte function and detachment (see text for qualifications). Podocyte replacement capacity (either from de novo podocytes or from podocytes stored on the inner surface of Bowman's Capsule) is very limited in the adult and is probably a minor contributor even in young glomeruli. Urine podometrics noninvasively estimates the rate of podocyte detachment assumed to be directly proportional to the rate of podocyte loss from glomeruli over time. Since podocyte replacement capacity can be assumed to be zero, the net glomerular podocyte complement must be balanced by the rate of podocyte detachment over time. In other words with various assumptions as outlined above podocyte dynamics can be considered as a zero-sum game where the key variables can be directly measured.