Controversies and research agenda in nephropathic cystinosis: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference

Abstract

Nephropathic cystinosis is an autosomal recessive metabolic, lifelong disease characterized by lysosomal cystine accumulation throughout the body that commonly presents in infancy with a renal Fanconi syndrome and, if untreated, leads to end-stage kidney disease (ESKD) in the later childhood years. The molecular basis is due to mutations in CTNS, the gene encoding for the lysosomal cystine-proton cotransporter, cystinosin. During adolescence and adulthood, extrarenal manifestations of cystinosis develop and require multidisciplinary care. Despite substantial improvement in prognosis due to cystine-depleting therapy with cysteamine, no cure of the disease is currently available. Kidney Disease: Improving Global Outcomes (KDIGO) convened a Controversies Conference on cystinosis to review the state-of-the-art knowledge and to address areas of controversies in pathophysiology, diagnostics, monitoring, and treatment in different age groups. More importantly, promising areas of investigation that may lead to optimal outcomes for patients afflicted with this lifelong, systemic disease were discussed with a research agenda proposed for the future.

Worldwide view of nephropathic cystinosis: results from a survey from 30 countries

“…Although the treatment of nephropathic cystinosis is now well established in DeN, aiming at delaying ESRD and preventing late systemic complications mainly with the new ‘easier-to-take’ oral formulation and ocular cysteamine [28–31], cystinosis is still responsible for a high morbidity and mortality in children and young adults living in DiN [25]. …”

The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives

“…Impaired swallowing and chronic respiratory dysfunction favour the development of aspiration pneumonia, a major cause of death in affected patients 48,49 . Most of these complications, with the exception of established renal Fanconi syndrome, can be delayed or even prevented with cysteamine therapy 8,9 .…”

“…Moreover, adherence to conventional immediate-release cysteamine therapy is cumbersome. Pills must be taken every 6 h, day and night, and cause body odour, halitosis and severe gastrointestinal adverse effects 9,28 , which hinder treatment compliance. Using enteric-release technology, a delayed and prolonged release formulation of cysteamine 158–161 was approved by the FDA in 2013 (REF.…”

Orphan drug policies and use in pediatric nephrology

“…Extra-renal manifestations, typically occurring in late childhood or adulthood, may include endocrinological complications, myopathy, and swallowing disturbances as well as cardiac and neurological symptoms [28]. The current recommended therapy is cystine depletion using cysteamine, which converts lysosomal cystine to cysteine, however, this treatment is not a cure and patients do not achieve full life expectancy [29]. International consensus recommends the initiation of cysteamine treatment upon diagnosis and continuation of treatment throughout life [29].…”

“…The current recommended therapy is cystine depletion using cysteamine, which converts lysosomal cystine to cysteine, however, this treatment is not a cure and patients do not achieve full life expectancy [29]. International consensus recommends the initiation of cysteamine treatment upon diagnosis and continuation of treatment throughout life [29]. Cysteamine delays the onset of renal failure and extra-renal manifestations and improves life expectancy [28,30].…”