Investigation of novel biomarkers and treatment strategies in steroid-resistant nephrotic syndrome

Abstract

Steroid-resistant nephrotic syndrome (SRNS) is a heterogeneous condition with significant numbers of patients progressing to end-stage renal failure (ESRF) requiring transplantation. After transplant, around half suffer disease recurrence, suggesting the existence of circulating pathogenic factors. The aim of this study was to investigate the interplay of phenotype, genetics and potential biomarkers with response to treatment and long-term outcome.

Detailed phenotyping of patients with SRNS, all of whom had had genetic testing, was used to examine for associations between baseline characteristics and outcomes. Novel biomarkers were sought in plasma by using mass spectrometry-based proteomics. The effects of putative circulating factors were investigated by treating podocytes in vitro with plasma samples followed by phosphoproteomic analysis of cell extracts.

This study found a genetic cause in 21.2% of patients with SRNS who underwent clinical genetic testing (n = 255) and in 27.8% who had whole exome sequencing (n = 187). Those with genetic disease were significantly more likely to progress to ESRF but none suffered post-transplant recurrence. Patients with secondary steroid resistance were highly unlikely to have a genetic cause and more frequently suffered recurrence. Only approximately 25% of patients had a complete response to the first intensified immunosuppressive (IIS) agent. Any response to first IIS was associated with a highly significantly lower risk of progression to ESRF compared with no response. Plasma proteomics identified uteroglobin as a potential biomarker, being raised at the time of relapse versus remission, although further validation is necessary. Phosphoproteomics suggested increased phosphorylation of palladin in podocytes after treatment with relapse plasma. Given the role of palladin in actin cytoskeleton remodelling, this protein is worthy of further investigation.

Stratification of patients with SRNS by genetics, pattern of steroid resistance and response to first IIS should be considered in future clinical trials and may help with targeting treatments.

Date of Award	7 May 2019
Original language	English
Awarding Institution	University of Bristol
Supervisor	Moin Saleem (Supervisor) & Gavin I Welsh (Supervisor)