#2519 THE EFFECT OF TRPC5 AND PALLADIN EXPRESSION ON TREATMENT RESPONSE AND RENAL OUTCOME IN FOCAL SEGMENTAL GLOMERULOSCLEROSIS
Authors: Ural Zeynep , Öğüt Betül , Gönül İpek , Guz Galip 
Published: June 2023

Abstract

Background and Aims
Focal segmental glomerulosclerosis (FSGS) is a disease that is among the primary glomerulopathies and often progresses to chronic renal failure. Despite advances in immunosuppressive therapy for the treatment of glomerular diseases, some FSGS patients are resistant to single or combination immunosuppressive regimens containing; glucocorticoids, cyclophosphamide, calcineurin inhibitors, mycophenolate mofetil (MMF), and/or rituximab. FSGS-related nephrotic syndrome, the degree of proteinuria and response to steroid therapy are the most important factors associated with long-term prognosis, independent of histological findings. Failure to respond to immunosuppressive therapy, including corticosteroids, has been evaluated as one of the most important markers of the risk of developing renal failure. Unfortunately, there is no reliable marker that can predict steroid response. One of the earliest manifestations of podocyte damage is cytoskeletal remodeling, known as deletion of foot ridges. It was recently shown that transient receptor potential channel 5 (TRPC5) plays an important role in initiating this process. However, the role of TRPC5 in disease progression is unknown. It is thought that calcium influx caused by sustained TRPC5 activation in the chronic disease setting may lead to calcium toxicity and podocyte death. It is known that the actin regulatory protein palladin, which is highly expressed here, is also highly related to podocyte function and podocytopathies, and plays an important role in the stability of the actin cytoskeleton. The aim of our study was to define the frequency of TRPC5 and palladin renal expressions in podocytes in focal segmental glomerulosclerosis (FSGS) and its relationship with prognosis and treatment response.

Method
A total of 182 patients were enrolled for baseline clinical and histopathological features and 103 patients with a clinical follow-up for more than 2 years were evaluated for outcomes. Immunohistochemical staining was performed with TRPC5 and palladin antibodies on kidney biopsies and glomerular staining was evaluated.

Results
Baseline characteristics, and health parameters were similar between TRPC5+/TRPC5− and palladin+/palladin− groups. TRPC5 expression was observed in 69% of the patient biopsies and palladin expression in 73%. We found that TRPC5 and palladin expression was a significant predictor of FSGS severity and poor treatment response (both p&lt;0.05). In addition, TRPC5 expression was significantly associated with the development of end-stage renal disease and ongoing proteinuria.

Conclusion
The development of proven treatments that delay the progression of FSGS is critical to patient survival. The development of new treatments is possible only by knowing the underlying pathophysiological mechanism of the disease. Podocyte loss is a critical step in the development of irreversible glomerulosclerosis, which causes chronic kidney disease. Therefore, blocking TRPC5 channel and palladin may be an effective treatment strategy, especially in treatment-resistant FSGS patients with positive staining on biopsy. Our study is the first in the literature to show these two antigens in kidney tissue in FSGS and to associate them with disease prognosis. TRPC5 and palladin expression may serve as a biomarker to facilitate diagnosis and choose new treatment regimens of proteinuric kidney diseases in the future.