Muscle and Bone Impairment in Infantile Nephropathic Cystinosis: New Concepts

Haffner, Dieter; Leifheit-Nestler, Maren; Alioli, Candide; Bacchetta, Justine

doi:10.3390/cells11010170

Cited by 7 publications

(2 citation statements)

References 57 publications

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“…Influences of this specific disease entity on the bones, e.g. the bones of the ribcage, include effects of the CTNS mutation on the functionality of osteoblasts and osteoclasts, as well as cysteamine toxicity [ 6 , 34 – 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…Infantile nephropathic cystinosis (INC) is a lysosomal storage disease causing multisystem intracellular cystine crystal accumulation and ensuing multisystem complications, often first affecting the kidney [ 1 – 3 ]. Symptoms due to generalized proximal tubule dysfunction (Fanconi syndrome), i.e., polyuria, failure to thrive and hypophosphatemic rickets, typically manifest within the first 18 months of life, followed by progressive chronic kidney disease (CKD) and a multitude of other complications including malnutrition, myopathy, and endocrine dysfunction [ 1 , 2 , 4 – 6 ]. Myopathy and associated respiratory dysfunction are frequent features in older patients with INC, with reported aberrations in chest shape in affected patients [ 7 – 9 ].…”

Section: Introductionmentioning

confidence: 99%

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Chest configuration in children and adolescents with infantile nephropathic cystinosis compared with other chronic kidney disease entities and its clinical determinants

Müller,

Kluck,

Jagodzinski

et al. 2023

Pediatr Nephrol

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Background Infantile nephropathic cystinosis (INC) is a systemic lysosomal storage disease causing intracellular cystine accumulation, resulting in renal Fanconi syndrome, progressive kidney disease (CKD), rickets, malnutrition, and myopathy. An INC-specific disproportionately diminished trunk length compared to leg length poses questions regarding the functionality of the trunk. Methods Thus, we prospectively investigated thoracic dimensions and proportions, as well as their clinical determinants in 44 pediatric patients with INC with CKD stages 1–5 and 97 age-matched patients with CKD of other etiology between the ages of 2–17 years. A total of 92 and 221 annual measurements of patients with INC and CKD, respectively, were performed, and associations between anthropometric and clinical parameters were assessed using linear mixed-effects models. Results Patients with INC exhibited altered chest dimensions that were distinct from CKD controls, characterized by markedly increased chest depth to height and chest depth to chest width ratio z-scores (> 1.0), while those of patients with CKD were only mildly affected (z-score within ± 1.0). Ratio z-scores differed significantly between both patient groups from 2–6 years of age onward. The degree of chest disproportion in INC patients was significantly associated with both the degree of CKD and tubular dysfunction (e.g., low serum phosphate and bicarbonate) across three different age groups (2–6, 7–12, and 13–17 years). Conclusion Our data show an INC-specific alteration in thoracic shape from early childhood onward, which is distinct from CKD of other etiologies, suggesting early childhood subclinical changes of the musculoskeletal unit of the thoracic cage, which are associated with kidney function. Graphical abstract

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chest configuration in children and adolescents with infantile nephropathic cystinosis compared with other chronic kidney disease entities and its clinical determinants

Müller,

Kluck,

Jagodzinski

et al. 2023

Pediatr Nephrol

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Leptin signalling altered in infantile nephropathic cystinosis‐related bone disorder

Cheung,

Zhou,

Zheng

et al. 2024

J cachexia sarcopenia muscle

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BackgroundThe CTNS gene mutation causes infantile nephropathic cystinosis (INC). Patients with INC develop Fanconi syndrome and chronic kidney disease (CKD) with significant bone deformations. C57BL/6 Ctns−/− mice are an animal model for studying INC. Hyperleptinaemia results from the kidney's inability to eliminate the hormone leptin in CKD. Ctns−/− mice have elevated serum leptin concentrations. Leptin regulates bone metabolism through its receptor that signals further via the hypothalamic melanocortin 4 receptor (MC4R). Leptin signalling may affect bone health in Ctns−/− mice.MethodsWe first defined the time course of bone abnormalities in Ctns−/− mice between 1 and 12 months of age. We used both genetic and pharmacological approaches to investigate leptin signalling in Ctns−/− mice. We generated Ctns−/−Mc4r−/− double knockout mice. Bone phenotype of Ctns−/−Mc4r−/− mice, Ctns−/− mice and wild type (WT) mice at 1, 4, and 9 months of age were compared. We then treated 12‐month‐old Ctns−/− mice and WT mice with a pegylated leptin receptor antagonist (PLA) (7 mg/kg/day, IP), a MC4R antagonist agouti‐related peptide (AgRP) (2 nmol, intracranial infusion on days 0, 3, 6, 9, 12, 15, 18, 21, 24, and 27), or vehicle (normal saline), respectively, for 28 days. Whole‐body (BMC/BMD, bone area) and femoral bone phenotype (BMC/BMD, bone area, length and failure load) of mice were measured by DXA and femoral shaft biochemical test. We also measured lean mass content by EchoMRI and muscle function (grip strength and rotarod activity) in mice. Femur protein content of JAK2 and STAT3 was measured by ELISA kits, respectively.ResultsBone defects are present in Ctns−/− mice throughout its first year of life. The deletion of the Mc4r gene attenuated bone disorder in Ctns−/− mice. Femoral BMD, bone area, length, and strength (failure load) were significantly increased in 9‐month‐old Ctns−/−Mc4r−/− mice than in age‐matched Ctns−/− mice. PLA and AgRP treatment significantly increased femoral bone density (BMC/BMD) and mechanical strength in 12‐month‐old Ctns−/− mice. We adopted the pair‐feeding approach for this study to show that the protective effects of PLA or AgRP on bone phenotype are independent of their potent orexigenic effect. Furthermore, an increase in lean mass and in vivo muscle function (grip strength and rotarod activity) are associated with improvements in bone phenotype (femoral BMC/BMD and mechanical strength) in Ctns−/− mice, suggesting a muscle‐bone interplay. Decreased femur protein content of JAK2 and STAT3 was evident in Ctns−/− mice. PLA or AgRP treatment attenuated femur STAT3 content in Ctns−/− mice.ConclusionsOur findings suggest a significant role for dysregulated leptin signalling in INC‐related bone disorder, either directly or potentially involving a muscle‐bone interplay. Leptin signalling blockade may represent a novel approach to treating bone disease as well as muscle wasting in INC.

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Addressing the psychosocial aspects of transition to adult care in patients with cystinosis

Stabouli,

Sommer,

Kraft

et al. 2024

Pediatr Nephrol

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Cystinosis is a rare autosomal-recessive lysosomal storage disease that progressively affects multiple organs beginning with the kidneys. Patients require lifelong multidisciplinary care for the management of kidney disease and progressive extra-renal manifestations, and thus, they are especially fragile and vulnerable during transition from pediatric to adult care. Previous documents have provided guidance to help the medical transition of these highly burdened patients. Patients and their families often experience great psychological distress and face significant social challenges; for these reasons, they often need help from psychologists, social workers, and other psychosocial professionals. Due to the rarity of the disease, most psychosocial professionals have no expertise in this disorder and require advice. To this end, a steering committee (SC) composed of six experts, including pediatric nephrologists, psychologists, and social workers with experience in the care for patients with cystinosis, have identified and addressed seven key questions related to psychosocial challenges of the disease and the burden of treatment. Ten additional international experts (the extended faculty, EF) were invited to answer these questions. Since robust evidence is lacking, as in many rare diseases, conclusions were based on collective agreement between members of the SC and the EF, and the consolidated answers were summarized into expert opinion statements. The present document contains information on the concerns and psychosocial burden of patients with cystinosis and of their caregivers, and provides practical advice for timely and appropriate support to facilitate the transition to adult care. Graphical abstract

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Muscle and Bone Impairment in Infantile Nephropathic Cystinosis: New Concepts

Cited by 7 publications

References 57 publications

Chest configuration in children and adolescents with infantile nephropathic cystinosis compared with other chronic kidney disease entities and its clinical determinants

Chest configuration in children and adolescents with infantile nephropathic cystinosis compared with other chronic kidney disease entities and its clinical determinants

Leptin signalling altered in infantile nephropathic cystinosis‐related bone disorder

Addressing the psychosocial aspects of transition to adult care in patients with cystinosis

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