Deep phenotyping and precision medicine approaches to understand and treat Autosomal Dominant Tubulointerstitial Kidney Disease due to UMOD mutations

Abstract

Autosomal Dominant Tubulointerstitial Kidney Disease due to UMOD variants (ADTKD-UMOD) is a rare monogenic kidney disorder, historically viewed as a Mendelian condition with uniform clinical expression. However, growing evidence reveals significant variability in disease severity, progression, and phenotype. This thesis presents the most comprehensive characterisation of ADTKD-UMOD undertaken in the UK, integrating clinical, genetic, and biomarker data across multiple cohorts to investigate the complex modifiers of disease expression and progression. Using data from the UK RaDaR registry, local cohorts, and UK Biobank, this work defines the national spectrum of UMOD variants and shows that the recurrent UMOD p.Val93_Gly97delinsAlaAlaSerCys variant likely represents a UK-specific founder variant. Despite this genetic homogeneity, significant intra-genotypic heterogeneity was observed in gout onset, salt-wasting symptoms, age of kidney failure, and kidney imaging. Genome-wide association studies (GWAS) and gene burden analyses identified genetic modifiers of disease progression, including loci involved in uric acid handling (e.g. ABCG2), mitochondrial function (e.g. COX6B2), and transcriptional regulation (e.g. KMT5C). Chromatin interaction mapping suggested a regulatory link between ABCG2 and PKD2, indicating shared pathways between cystic and tubulointerstitial kidney diseases. Polygenic risk scores for chronic kidney disease were independently associated with kidney survival, emphasising the contribution of background genetic architecture in a monogenic context. Biomarker analyses confirmed that serum and urinary uromodulin concentrations correlate with disease severity beyond the primary UMOD variant and kidney function and may serve as prognostic tools. Individuals with the UMOD p.Val93_Gly97delinsAlaAlaSerCys variant showed partial preservation of uromodulin secretion, suggesting variant-specific trafficking and a unique metabolic sub-phenotype with lower serum urate and absence of gout. Together, these findings reposition ADTKD-UMOD as a model of complex monogenic disease and lay the groundwork for genetically stratified trials and therapeutic targeting, with broader relevance to chronic kidney disease.