[1636] Podocyturia (PCU) and Biopsy (Bx) Podocyte (PC) Globotrioasylceramide (GL-3) Accumulation Correlate with Proteinuria in Patients with Fabry Disease (FD)

Cecilia Ponchiardi, Brent Fall, Ronald Scott, Stefanie Uhrich, Michael Mauer, Chester Whitley, Jeffrey Pippin, Stuart Shankland, Jonathan Jefferson, Behzad Najafian. University of Washington, Seattle, WA; University of Minnesota, Minneapolis, MN

Background: Renal failure is a major FD complication. BX studies suggested that PC injury parallels age and urine protein/creatinine ratio (UPCR) in young FD patients. We hypothesized that PCU may correlate with proteinuria and likely of pathogenetic significance. We studied PCU and PC GL-3 accumulation in two cohorts of FD patients with a wide range of age and renal function.
Design: Urine from 12 FD patients (M/F=7/5), age 34[14-66] years, median[range], were processed to prepare cytospin slides and stained for PC (Podocalyxin, PCX) and parietal cell (Claudin 1, CL1) markers. PCX+/CL1- cells were identified as PCs and PCX+/CL1+ cells as parietal cells with PC phenotype. Cells with small/apoptotic and normal size nuclei were counted separately. TUNEL staining was performed for apoptosis. All counts were corrected for urine creatinine (Cr). The findings were correlated with age, UPCR, urine albumin/creatinine ratio (UACR) and glomerular filtration rate (GFR). Bxs from 36 FD patients (M/F=25 /11) age 23[4-63] years were studied by electron microscopy stereology to estimate PC GL-3 volume density [Vv (Inc/PC)]. Results were correlated with age and UPCR.
Results: GFR was 85±22 ml/min/1.73 m2 in the PCU cohort and 109±23 in the biopsy cohort. UPCR was 0.1[0.03-1.1] mg/gCr in the PCU cohort and 0.1[0-3.1] in the biopsy cohort. There were 670-62000 PCX+ cells/gCr in urine samples, 49-88% of them PCs. 24±12% of PCs had small nuclei. TUNEL confirmed apoptosis in majority of PCX+ cells with both small and normal size nuclei. Among the different cell types counted only PCX+/CL1- cells with small nuclei (PCX+/CL1-S), representing apoptotic PCs correlated with UACR (r=0.73, P= 0.007) and UPCR (r= 0.75, P=0.005). PCX+/CL1-S cell numbers also correlated with age(r=0.70, P=0.01). Although females (56±13 years) were older than males (26±13 years) in our cohort (p=0.002), by multiple regression analysis (MRA) only PCX+/CL1-S, and not gender or age, showed a trend to independently predict UPCR (R2=0.72, p=0.07). Bx Vv(Inc/PC) similarly correlated with UPCR (r=0.36, P=0.032). MRA showed that both age and Vv(Inc/PC) independently predicted UPCR (R2=0.52, p=0.0003).
Conclusions: Our studies suggest that urine apoptotic PCs progressively increase with age in FD patients, correlate with proteinuria, and thus, of pathogenetic significance and may become a useful non-invasive FDN biomarker. Our Bx study similarly showed a relationship between PC involvement in FD and proteinuria, confirming the above conclusion.
Category: Kidney (does not include tumors)

Monday, March 4, 2013 1:00 PM

Poster Session II # 250, Monday Afternoon


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