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

Abstract

Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. It is caused by a defect in the lysosomal cystine transporter, cystinosin, which results in an accumulation of cystine in all organs. Despite the ubiquitous expression of cystinosin, a renal Fanconi syndrome is often the first manifestation of cystinosis, usually presenting within the first year of life and characterized by the early and severe dysfunction of proximal tubule cells, highlighting the unique vulnerability of this cell type. The current therapy for cystinosis, cysteamine, facilitates lysosomal cystine clearance and greatly delays progression to kidney failure but is unable to correct the Fanconi syndrome. This Review summarizes decades of studies that have fostered a better understanding of the pathogenesis of the renal Fanconi syndrome associated with cystinosis. These studies have unraveled some of the early molecular changes that occur before the onset of tubular atrophy and identified a role for cystinosin beyond cystine transport, in endolysosomal trafficking and proteolysis, lysosomal clearance, autophagy and the regulation of energy balance. These studies have also led to the identification of new potential therapeutic targets and here, we outline the potential role of stem cell therapy for cystinosis and provide insights into the mechanism of haematopoietic stem cell-mediated kidney protection.

The tripartite interaction of phosphate, autophagy, and αKlotho in health maintenance

“…The decreased plasma Pi and increased urinary Pi excretion in mice after adminstration of TB-11, the active and functional peptide of beclin 1 futher proves the concept that high autophagy in the kidney promotes negative Pi balance. The restored body growth and reduced mortality in BK/BK;kl/kl mice was abolished by high-Pi diet further The role of autophagy in regulation of renal transport 66,67 including water, 68,69 glucose, 70 cysteine, 71 and other electrolytes 72 have been reported. The current manuscript provides new data linking autophagy with phosphate transport in the renal tubules.…”

Management of bone disease in cystinosis: Statement from an international conference

“…Later in life, individuals with cystinosis also suffer from mineral and bone disorders related to chronic kidney disease (CKD-MBD), including renal osteodystrophy, resulting in a complex bone phenotype termed cystinosis metabolic bone disease (CMBD). [3][4][5] The treatment of cystinosis involves replacement of renal losses, symptomatic management of nonrenal complications and, most critically, cystine-depleting therapy with oral cysteamine. 6,7 Both the early Fanconi syndrome and later CKD contribute to the bone changes of CMBD.…”

Oral alterations in patients with cystinosis

“…NC is characterized by a deficiency of cystinosin—a protein that transports cystine out of the lysosomes. Cystine is an amino acid present in several proteins and the deficiency of cystinosin causes accumulation of cystine within the lysosomes, forming crystals in various organs and causing cell death, oxidative stress, mitochondrial dysfunction, and inflammation …”

“…Accumulation of cystine within the kidneys results in loss of glomerular function and chronic renal failure (CRF) at around 10 years old, which may lead to kidney transplantation . Affected individuals may develop hypothyroidism, hypogonadism, diabetes, exocrine pancreatic insufficiency, liver failure, decreased pulmonary function, myopathies, and deterioration of the central nervous system . The incidence of NC ranges from 1:100 000 to 1:200 000 live births, being higher in some regions of northern Europe…”

“…The latter, which is diagnosed during adolescence, is manifested as milder forms of FRS or isolated proteinuria. Finally, the non‐nephropathic form (adult or ocular) involves deposition of cystine crystals in the cornea, conjunctiva, ciliary body, and retina, leading to photophobia …”