Primary hyperoxaluria type I Towards targeted treatment

Chapter 1 introduces Primary Hyperoxaluria type 1 (PH1) as a genetic metabolic disease, characterized by hepatic oxalate overproduction and causing kidney stones, nephrocalcinosis and kidney failure. The first part of this thesis (Chapter 2-5) describes the determinants, diagnosis and treatment of kidney failure in patients with PH1. In Chapter 2, determinants of kidney failure are investigated in PH1 patients included in the OxalEurope Registry. Genotype-phenotype correlations are described as well as clinical features and biochemical features. Chapter 3 addresses the question what concentrations of plasma oxalate and glycolate are found in patients with kidney failure, not related to PH1, in order to guide interpretation of these biomarkers in PH1 patients. Until recently, a liver-kidney transplantation was the recommended treatment for kidney failure in PH1. Chapter 4 and 5 describe long-term transplantation outcomes comparing several strategies. The second part of this thesis (Chapter 6-9) considers the place of recently developed RNA-interference therapeutics (lumasiran and nedosiran) in the treatment of PH1. In Chapter 6, we investigate the efficacy of lumasiran, making use of stable isotope assessments. In Chapter 7, we present five PH1 patients who underwent a kidney-alone transplantation under lumasiran treatment. In Chapter 8, we describe an exceptional case of a child with PH1 who received concomitant treatment with lumasiran and nedosiran. Chapter 9 includes the new European guidelines for clinical practice, a consensus statement containing 48 practical recommendations relating to the diagnosis and management of PH1. Finally, this thesis contains a general discussion including possible topics for further research.