Identifying biomarkers of response to treatment and long-term outcomes in lupus nephritis
File(s)
Author(s)
Wilson, Hannah
Type
Thesis
Abstract
Lupus nephritis (LN) is a common yet serious manifestation of systemic lupus erythematosus (SLE), carrying significant risk of morbidity and mortality. Treatments have, in real terms, progressed little in recent years and poor responses are associated with bad long-term outcomes. Clinically useful predictors of response to treatment and long-term outcomes are desperately needed for use both in clinic and in clinical trials as endpoints to aid the progression of new treatments.
Analysis of LN patients, staining and mass spectrometry (MS) were employed to examine the demographic, clinical, histopathological and proteomic profiles of LN patients.
470 patients and 803 biopsies were described in a database of LN patients treated over a 20-year period including the largest described cohort of patients treated with no oral glucocorticoids. Proteinuria level at biopsy, ‘full house’ pattern on immunohistochemistry and percentage of glomeruli with chronic damage predicted response to treatment. Proteinuria level and eGFR at one year predicted long-term outcome. Achieving both an eGFR >80mls/min/1.73m2 and proteinuria <90mg/mmol predicted a good outcome at 7 years with odds ratio 9.922 (95% CI 4.979-19.774) p<0.001. LN was demonstrated to be treated successfully without oral glucocorticoids or cyclophosphamide. The membrane attack complex was shown to be strongly associated with LN, however not a useful marker of on-going activation of complement C5. For the first time, the proteome of LN renal biopsy tissue was explored using SWATH-MS. The pathways of mitochondrial processes, oxidative phosphorylation and metabolism were found to be downregulated in LN and even more so in non-responders.
Together, this body of work identifies predictors of response to treatment, parameters to target with treatments and possible pathogenic targets of new treatments. It indicates that rapid diagnosis of LN and flares followed by targeting of excellent renal function with early initiation of treatments is key to preserving renal function long-term.
Analysis of LN patients, staining and mass spectrometry (MS) were employed to examine the demographic, clinical, histopathological and proteomic profiles of LN patients.
470 patients and 803 biopsies were described in a database of LN patients treated over a 20-year period including the largest described cohort of patients treated with no oral glucocorticoids. Proteinuria level at biopsy, ‘full house’ pattern on immunohistochemistry and percentage of glomeruli with chronic damage predicted response to treatment. Proteinuria level and eGFR at one year predicted long-term outcome. Achieving both an eGFR >80mls/min/1.73m2 and proteinuria <90mg/mmol predicted a good outcome at 7 years with odds ratio 9.922 (95% CI 4.979-19.774) p<0.001. LN was demonstrated to be treated successfully without oral glucocorticoids or cyclophosphamide. The membrane attack complex was shown to be strongly associated with LN, however not a useful marker of on-going activation of complement C5. For the first time, the proteome of LN renal biopsy tissue was explored using SWATH-MS. The pathways of mitochondrial processes, oxidative phosphorylation and metabolism were found to be downregulated in LN and even more so in non-responders.
Together, this body of work identifies predictors of response to treatment, parameters to target with treatments and possible pathogenic targets of new treatments. It indicates that rapid diagnosis of LN and flares followed by targeting of excellent renal function with early initiation of treatments is key to preserving renal function long-term.
Version
Open Access
Date Issued
2023-01-26
Date Awarded
01/10/2023
Advisor
Lightstone, Liz
Cook, Terence
Sponsor
Auchi Foundation
Lupus UK
Grant Number
WMIR_P57348
WMIR_P68867
Publisher Department
Department of Immunology and Inflammation
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)