Pablo Florenzano1,2, Macarena Jimenez2, Carlos R Ferreira3, Galina Nesterova3, Mary Scott Roberts4, Sri Harsha Tella4, Luis Fernandez de Castro4, Rachel I Gafni4, Myles Wolf5, Harald Jüppner6, Barbara Gales7, Katherine Wesseling-Perry7, Daniela Markovich7, William A Gahl3, Isidro B Salusky7, Michael T Collins4. 1. Skeletal Disorders and Mineral Homeostasis Section, National Institutes of Dental and Craniofacial Research, Bethesda, Maryland pflorenz@uc.cl. 2. Endocrinology Department, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile. 3. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland. 4. Skeletal Disorders and Mineral Homeostasis Section, National Institutes of Dental and Craniofacial Research, Bethesda, Maryland. 5. Division of Nephrology, Department of Medicine, Duke University, Durham, North Carolina. 6. Endocrine Unit and Pediatric Nephrology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. 7. Division of Nephrology, Department of Pediatrics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.
Abstract
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.
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 cystinosisparticipants at all CKD stages when corrected for eGFR and age, but not when adjusted for serum phosphate. CONCLUSIONS:Nephropathic cystinosis CKDpatients 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.
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Authors: Ornatcha Sirimongkolchaiyakul; Katherine Wesseling-Perry; Barbara Gales; Daniela Markovic; David Elashoff; Georgina Ramos; Renata C Pereira; Mark R Hanudel; Isidro B Salusky Journal: JBMR Plus Date: 2022-04-08