Bone Disease in Nephropathic Cystinosis: Beyond Renal Osteodystrophy.

Irma Machuca-Gayet,Cécile Acquaviva-Bourdain,Aurélia Bertholet-Thomas,Débora Claramunt-Taberner,Thomas Quinaux,Justine Bacchetta,Ségolène Gaillard

doi:10.3390/ijms21093109

Abstract

Patients with chronic kidney disease (CKD) display significant mineral and bone disorders (CKD-MBD) that induce significant cardiovascular, growth and bone comorbidities. Nephropathic cystinosis is an inherited metabolic disorder caused by the lysosomal accumulation of cystine due to mutations in the CTNS gene encoding cystinosin, and leads to end-stage renal disease within the second decade. The cornerstone of management relies on cysteamine therapy to decrease lysosomal cystine accumulation in target organs. However, despite cysteamine therapy, patients display severe bone symptoms, and the concept of “cystinosis metabolic bone disease” is currently emerging. Even though its exact pathophysiology remains unclear, at least five distinct but complementary entities can explain bone impairment in addition to CKD-MBD: long-term consequences of renal Fanconi syndrome, malnutrition and copper deficiency, hormonal disturbances, myopathy, and intrinsic/iatrogenic bone defects. Direct effects of both CTNS mutation and cysteamine on osteoblasts and osteoclasts are described. Thus, the main objective of this manuscript is not only to provide a clinical update on bone disease in cystinosis, but also to summarize the current experimental evidence demonstrating a functional impairment of bone cells in this disease and to discuss new working hypotheses that deserve future research in the field.

Highlights

Pediatric patients with chronic kidney disease (CKD) display significant abnormalities in bone and mineral metabolism, known as CKD-MBD, for mineral and bone disorders associated with CKD
The bone and growth long-term consequences of CKD were highlighted in a cohort of 249 young Dutch adults with onset of end-stage renal failure before the age of 14 years: in this cohort, 61% of patients had severe growth retardation, 37% severe bone disease and 18% disabilities resulting from bone impairment [4]
In human osteoclasts differentiated from peripheral blood mononuclear cells (PBMCs), we showed that CTNS is required for proper osteoclastic differentiation and resorption activity, with a progressive increase of CTNS gene expression during osteoclastogenesis, with a peak observed at Day 6 on mature osteoclasts following the same pattern that cathepsin K transcripts a late marker of osteoclast differentiation which is essential for bone resorption [23]

Summary

Introduction

Pediatric patients with chronic kidney disease (CKD) display significant abnormalities in bone and mineral metabolism, known as CKD-MBD, for mineral and bone disorders associated with CKD. The pathophysiology of CKD-MBD is complex and multifactorial, multiple factors were identified such as abnormalities in calcium and phosphate metabolism, resistance to growth hormone (GH), modifications of the GH-insulin such as growth factor type 1 (IGF1) axis, hypogonadism, malnutrition, and drug toxicity (corticosteroids) [1]. Do these complications impact overall quality of life through their effects on both physical and mental well-being in children with CKD, but alterations in mineral metabolism and bone disease contribute to a significant decrease in life expectancy. The purpose of this review is to report the clinical update on bone pathology in nephropathic cystinosis and provide a summary of basic research findings on bone cell impairment that contribute to unbalanced bone remodeling in this orphan disease and to discuss new working hypotheses that deserve future research in the field

The Emerging Concept of Cystinosis Metabolic Bone Disease

Bone Impairment in Patients Nephropathic Cystinosis

Future Research Axes

Findings

Conclusions