Nephropathic Cystinosis: A Distinct Form of CKD–Mineral and Bone Disorder that Provides Novel Insights into the Regulation of FGF23
Authors: Florenzano Pablo , Jimenez Macarena , Ferreira Carlos R. , Nesterova Galina , Roberts Mary Scott , Tella Sri Harsha , Fernandez de Castro Luis , Gafni Rachel I. , Wolf Myles , Jüppner Harald , Gales Barbara , Wesseling-Perry Katherine , Markovich Daniela , Gahl William A. , Salusky Isidro B. , Collins Michael T. 
Published: July 2020

Significance Statement
Most forms of CKD present with well recognized mineral and bone disorders. It is unknown whether a different biochemical pattern of mineral abnormalities is associated with causes of CKD that manifest with persistent tubular phosphate wasting, such as the lysosomal storage disease nephropathic cystinosis. The authors demonstrate that patients with CKD caused by nephropathic cystinosis have mineral abnormalities that are distinct from those in CKD arising from other causes, including significantly lower levels of fibroblast growth factor-23 (FGF23) and percent tubular reabsorption of phosphate. These findings support the notion that phosphate is a significant driver of increased FGF23 levels in CKD and that mineral abnormalities associated with CKD are likely to vary depending on the underlying renal disease.

Background
The rare lysosomal storage disease nephropathic cystinosis presents with renal Fanconi syndrome that evolves in time to CKD. Although biochemical abnormalities in common causes of CKD–mineral and bone disorder have been defined, it is unknown if persistent phosphate wasting in nephropathic cystinosis is associated with a biochemical mineral pattern distinct from that typically observed in CKD–mineral and bone disorder.

Methods
We assessed and compared determinants of mineral homeostasis in patients with nephropathic cystinosis across the predialysis CKD spectrum to these determinants in age- and CKD stage-matched patients, with causes of CKD other than nephropathic cystinosis.

Results
The study included 50 patients with nephropathic cystinosis-related CDK and 97 with CKD from other causes. All major aspects of mineral homeostasis were differentially effected in patients with CKD stemming from nephropathic cystinosis versus other causes. Patients with nephropathic cystinosis had significantly lower percent tubular reabsorption of phosphate and fibroblast growth factor-23 (FGF23) at all CKD stages, and lower blood phosphate in CKD stages 3–5. Linear regression analyses demonstrated lower FGF23 levels in nephropathic cystinosis participants at all CKD stages when corrected for eGFR and age, but not when adjusted for serum phosphate.

Conclusions
Nephropathic cystinosis CKD patients have mineral abnormalities that are distinct from those in CKD stemming from other causes. Persistently increased urinary phosphate excretion maintains serum phosphate levels within the normal range, thus protecting patients with nephropathic cystinosis from elevations of FGF23 during early CKD stages. These findings support the notion that phosphate is a significant driver of increased FGF23 levels in CKD and that mineral abnormalities associated with CKD are likely to vary depending on the underlying renal disease.