Risk prediction and mitigation in adults with Immunoglobulin A nephropathy and chronic kidney disease

Abstract

Chronic kidney disease (CKD) affects over 10% of the global population and is projected to become the 5th leading cause of death by 2040. IgA nephropathy is the most common primary glomerular disorder, with high rates of kidney failure. Identifying high-risk individuals and preventing progression is critical. Corticosteroids have long been used in IgA nephropathy, yet their net effect remains uncertain. This thesis aims to 1) evaluate therapies including corticosteroids that reduce kidney failure risk in IgA nephropathy, 2) identify those at risk of corticosteroid-related side effects in IgA nephropathy, and 3) explore patient factors and novel methods to predict kidney failure risk in IgA nephropathy and CKD. Chapter 1 summarises the burden of CKD, IgA nephropathy and risk stratification tools. Chapter 2 reviews evidence on corticosteroid therapy in IgA nephropathy. The TESTING trial that corticosteroids improve kidney outcomes in IgA nephropathy compared to supportive care. Chapters 3–6 present TESTING secondary analyses: reduced-dose methylprednisolone improves kidney outcomes with fewer adverse events compared to full-dose; corticosteroid benefits persist across proteinuria and eGFR strata but may not outweigh risks in advanced disease; methylprednisolone induces haematuria remission; and sex does not modify kidney effects, though males face higher side effects and kidney failure risk. Chapter 7 is a meta-analysis of randomised trials showing nonimmunologic therapies, corticosteroids, B-cell modulators, and complement inhibitors improve kidney outcomes in IgA nephropathy. Chapter 8 outlines NIMBLE-CKD, a study developing MRI biomarkers for tubulointerstitial fibrosis to improve risk prediction in CKD. Chapter 9 synthesises findings, examines unanswered questions and explores future directions arising from this thesis. Collectively, this work informs personalised treatment and advances risk assessment to improve outcomes in IgA nephropathy and CKD.