Podocyte Density, Rather than Podocyte Number per Glomerulus, Is Associated with Kidney Outcomes in Obesity-Related Glomerulopathy

Background: Obesity-related glomerulopathy (ORG) is a slowly progressive glomerular disease occurring in obese individuals. Podocyte injury and subsequent podocyte depletion are regarded as key processes in ORG progression. However, no previous study has assessed the longitudinal association between podometrics and longterm kidney outcomes in ORG. Methods: Podocyte number per glomerular volume (podocyte density) and podocyte number per glomerulus (podocyte number) in ORG patients were estimated using modelbased stereology. The associations between these podometrics at the diagnostic biopsy and subsequent kidney outcomes (30% decline in eGFR) were examined by log-rank tests and Cox proportional hazard analyses. Results: Forty-one ORG patients with median age of 47 years, eGFR 63 mL/min/1.73m2 were analyzed. At biopsy diagnosis, ORG patients with podocyte density below the median value were older, predominantly male, and had larger body surface area, higher proteinuria, larger glomeruli, and lower podocyte number than ORG patients with higher podocyte density. During a median follow-up period of 3.9 years, 16 (39%) ORG patients reached a 30% decline in eGFR. Kidney survival in patients with lower podocyte density was significantly worse than in patients with higher podocyte density (P = 0.001), but there was no significant association between kidney survival and lower vs higher podocyte number (P = 0.3). Cox hazard analyses showed that podocyte density, but not podocyte number, was associated with kidney outcome after adjustment for clinical factors, including age, sex, proteinuria, and eGFR. Conclusions: Our results indicate that lower podocyte density, rather than lower podocyte number, is a high-risk factor for progression of ORG. Confirmation in other ORG cohorts and potential generalizability to other glomerular diseases will require further studies. Funding: Government Support - Non-U.S.