Podocyte effacement closely links to suPAR levels at time of posttransplantation focal segmental glomerulosclerosis occurrence and improves with therapy

Abstract

Background: Focal segmental glomerulosclerosis (FSGS) recurs after kidney transplantation in more than 30% of cases and can lead to allograft loss. Serum soluble urokinase-type plasminogen activator receptor (suPAR) is implicated in the pathogenesis of native and recurrent FSGS.

Methods: We conducted a retrospective study of 25 adults with posttransplantation FSGS. We investigated the relationship between suPAR levels and podocyte changes and the impact of therapy on podocyte structure. We assessed response to therapy by improvement in proteinuria, allograft function, and resolution of histologic changes.

Results: A median (interquartile range) of 15 (10-23) plasmapheresis sessions was administered; 13 of the subjects also received rituximab. Median pretreatment suPAR levels were higher among those with severe (≥75%) versus those with mild (≤25%) podocyte foot process effacement (13,030 vs. 4806 pg/mL; P=0.02). Overall, mean±SD of proteinuria improved from 5.1±3.8 to 2.1±2.8 mg/dL (P=0.003), mean podocyte effacement decreased from 57%±33% to 22%±22% (P=0.0001), estimated glomerular filtration rates increased from median (interquartile range) of 32.9 (20.6-44.2) to 39.3 (28.8-63.4; P<0.0001), and suPAR levels decreased from a median of 6.781 to 4.129 pg/mL (P=0.02) with therapy.

Conclusions: Podocyte effacement is the first pathologic manifestation of FSGS after transplantation. The degree of podocyte effacement correlates with suPAR levels at time of diagnosis. Response to therapy results in significant reduction of suPAR levels and complete or significant improvement of podocyte effacement.

Figure 1. Changes in clinical parameters with therapy

Panel a. Serum creatinine in mg/dL prior to treatment and upon completion of treatment. Panel b. Proteinuria in g/g prior to treatment, at peak level, upon completion of treatment, and last available level. Abbreviations: CR, complete remission; PR, partial remission; NR, no response. Panel c. Podocyte foot process effacement changes with therapy

Figure 2. Histopathologic changes before and after therapy

Biopsy taken 10 months after kidney transplantation from a patient with recurrent FSGS shows segmental glomerular sclerosis changes on light microscopy (arrow) before treatment (A) that did not change (arrow) after therapy (B). Electron microscopy (power of 3000) showed moderate (arrow) podocyte foot process effacement (C) that recovered (arrow) after therapy (D). Biopsy taken from another patient 3 months after transplantation; electron microscopy (scale of 5 µm) shows severe (arrow) podocyte foot process effacement (E) that recovered (arrow) after therapy (F); no light microscopic changes