Markers that identify risk for End Stage Kidney Disease (ESKD) and accurately report treatment efficacy will place glomerular diseases into a new paradigm of logical decision-making that improves outcome and efficient testing of new drugs. The Wiggins laboratory (supported by NIDDK) has used model systems to prove that podocyte depletion is the underlying mechanism responsible for progression of glomerular diseases to ESKD, and to demonstrate that urine podocyte mRNA markers non-invasively monitor accelerated podocyte detachment common to all progressive glomerular diseases in man and model systems. We have now developed novel automatable technology that allows high throughput measurement of podocyte density, number per tuft, size and other parameters in routine kidney biopsies. Application of these quantitative approaches to archival human biopsies shows a remarkable age-dependent decrease in podocyte density that can in part explain age-associated kidney failure in man (Aim 1). The kidney transplant setting (where protocol biopsies are routinely done prior to and following transplantation and where patients are closely followed long term) will be used to test the hypotheses that transition from the 2 kidney to the 1 kidney state is associated with hypertrophic podocyte stress that results in accelerated podocyte depletion long term, and that transplant glomerulopathy occurs in those individuals with high level prolonged podocyte depletion (Aim 2). Recurrent FSGS in the allograft will be used as a model system to test the hypothesis that FSGS supervenes when the podocyte density falls below a critical threshold (100 per 106 um3) (Aim 3). The relationship between the rate of podocyte detachment (as measured by the non-invasive urine pellet podocyte marker) and the rate of loss of podocytes from glomeruli (measured morphometrically as the decrease in podocyte number per glomerular tuft and density in relation to glomerular volume) will be defined. The insights developed and principles established will be applicable to prevention of progression in human glomerular diseases.
New technologies now allow us to measure podocyte number, size and rate of loss from the glomerular filter of the kidney. We use these new tools to investigate (i) why older people develop kidney failure so frequently, (ii) why kidney transplants fail after a shorter-than expected life, and (iii) why recurrent FSGS happens after kidney transplantation.
