Recurrent Primary Focal Segmental Glomerulosclerosis Managed With Intensified Plasma Exchange and Concomitant Monitoring of Soluble Urokinase-Type Plasminogen Activator Receptor–Mediated Podocyte β3-integrin Activation

Abstract

Background Primary focal segmental glomerulosclerosis (FSGS) often causes nephrotic proteinuria and frequently results in end-stage renal disease and recurrence after kidney transplantation. Recent studies describe soluble urokinase-type plasminogen activator receptor (suPAR) as a circulating factor implicated in FSGS. Methods This single-center study included 12 adult patients with histologically proven primary FSGS (n = 2) or recurrent FSGS after transplantation (n = 10). The effect of plasma exchange (PE) on clinical outcome, suPAR levels, and in vitro podocyte β3-integrin activation was investigated over a median of 11 (6–18) sessions of PE. Results The course of treatment was monitored in a total of 70 sessions of PE, which partly eliminated suPAR, with a mean reduction of 37 ± 12% of serum concentration per session. However, a substantial rebound was observed between sessions, with suPAR levels reaching 99 ± 22% of the pretreatment levels after a median of 4 days. Podocyte β3-integrin activation dropped significantly after PE but rebounded within 4 days concomitant with a rising suPAR level. In 11 of 12 patients, multimodal treatment (including extensive PE) reduced proteinuria significantly (from 5.3 [2.0–7.8] to 1.0 [0.4–1.6] g/d), indicating clinical efficacy of the therapy. One patient suffered allograft loss due to FSGS recurrence. A persisting response was independent of a lasting reduction in the level of total suPAR because there was no sustained significant change in suPAR levels before and after the course of intensified treatment (3814 ± 908 to 3595 ± 521 pg/mL; P = 0.496). Conclusions We conclude that multimodal therapy including extensive PE was associated with stabilization of recurrent FSGS and a temporary lowering of plasma suPAR as well as podocyte β3-integrin activation. Whether a sustained lowering of total suPAR results in further improved outcomes requires additional study.

Removal of focal segmental glomerulosclerosis (FSGS) factor suPAR using CytoSorb

“…Clearance of suPAR in the serum by TPE was shown to be effective with a 25.12% total reduction; however, because of the low number of repetitions, it is unclear whether these data can be generalized to a heterogeneous FSGS patient population. The suPAR lowering effect of a single TPE session was comparable to recently obtained data from kidney‐transplanted patients with recurrent FSGS in the transplanted organ showing a suPAR reduction limited to 38% . Changes in the efficacy might be associated with mean variation, but also the mean suPAR level before treatment was higher in the study by Staeck et al compared to our pre‐treatment measurements.…”

“…The suPAR lowering effect of a single TPE session was comparable to recently obtained data from kidney‐transplanted patients with recurrent FSGS in the transplanted organ showing a suPAR reduction limited to 38% . Changes in the efficacy might be associated with mean variation, but also the mean suPAR level before treatment was higher in the study by Staeck et al compared to our pre‐treatment measurements. The mean suPAR level in the study of Alachkar et al was also detected to be higher, treatment with TPE was associated with a suPAR reduction of approximately 39%.…”

Soluble urokinase receptor (suPAR) predicts microalbuminuria in patients at risk for type 2 diabetes mellitus

“…Most data available is from patients with FSGS. In these patients, an association of suPAR and urinary albumin excretion has been shown and extracorporeal elimination of suPAR by plasmapheresis resulted in reduced β 3 -integrin activity and reduction of proteinuria19. In animal models of diabetic nephropathy, blockade of β 3 -integrin using monoclonal antibodies inhibits progression of albuminuria20.…”

SuPAR, an emerging biomarker in kidney and inflammatory diseases

“…Consequently, lowering serum suPAR concentrations, through plasmapheresis, resulted in less podocyte β3-integrin activation and stabilisation of recurrent FSGS disease 17. Moreover, elevated pretransplant suPAR levels indicated an increased risk for recurrence of FSGS after transplantation 8.…”