Optimizing clinical outcomes of glomerular disease and kidney failure in children and adolescents

Abstract

Chronic kidney disease (CKD) and end-stage kidney disease (ESKD) is associated with excess mortality and impaired quality of life in children and adolescents. Paediatric glomerular disease, notably idiopathic nephrotic syndrome and lupus nephritis (LN), are important causes of CKD and ESKD in children and adolescents. Clinical epidemiology and disease outcomes of these renal disorders in children, however, varies considerably between ethnicities and regions, and local data pertaining to the long-term outcomes is especially lacking. Novel therapeutic strategies for these kidney diseases in children and adolescents also remain rather limited. Therefore, in this thesis, I investigated the long-term outcomes of children/adolescents with glomerular diseases and ESKD, and explored new management approaches for these renal disorders. Emerging therapeutic options offer new hope in children and adolescents with kidney diseases. Data from our international collaborative study showed that both rituximab dose and concurrent immunosuppression use had important impact on treatment efficacy in idiopathic nephrotic syndrome, and the low-dose regimen alone was associated with the shortest relapse-free period. Results from another international study supported the repeated use of rituximab in maintaining disease remission, with satisfactory efficacy and reasonable side effect profiles. Our results demonstrated that in the era of effective immunosuppressive treatments, long-term patient and renal survival in childhood-onset LN were favourable and yet 15% of patients showed no disease remission despite standard therapies. Preserving kidney function in childhood-onset LN is important, as the development of ESKD was associated with a 22-fold risk of death compared to the general paediatric population. Although the overall renal relapse rate in childhood-onset LN has become relatively low with our current standard induction/maintenance regimens, preventing relapse remains crucial as it is associated with worse kidney survival and treatment-related complications. In this thesis, I showed that early-onset LN, non-responsiveness to induction at 12-month and non-MMF maintenance are important risk factors for renal relapse. I also reported our experience in using rituximab as an add-on, rescue therapy in childhood-onset LN that were life-/organ-threatening and/or resistant to standard immunosuppressive therapy. Furthermore, findings from our 20-year territory-wide cohort indicated that glomerular disease was a leading cause of ESKD, especially among adolescents. Whereas the rates of morbidity and mortality were comparable to international cohorts, the hospitalization rates were relatively high. Of note, infants receiving maintenance dialysis have increased morbidity and mortality rates. Our studies on vaccination against COVID-19 and remote patient monitoring also substantiated these their effectiveness in protecting against COVID-19, improving fluid management and reducing unplanned hospitalisations in children with CKD and ESKD. While clinical outlook of children/adolescents with renal disorders has improved significantly over the past few decades, the presence of CKD and ESKD still confers significantly negative impacts on various patient outcomes. Novel management strategies such as the use of biologics, effective immunization policies and adoption of remote patient monitoring systems can help optimize outcomes in children and adolescents with kidney diseases.