An international cohort study spanning five decades assessed outcomes of nephropathic cystinosis

Emma, Francesco; Hoff, William van’t; Hohenfellner, Katharina; Topaloğlu, Rezan; Greco, Marcella; Ariceta, Gema; Bettini, Chiara; Böckenhauer, Detlef; Veys, Koenraad; Pape, Lars; Hulton, Sally‐Anne; Collin, Suzanne; Özaltın, Fatih; Servais, Aude; Deschênes, Georges; Novo, Robert; Bertholet‐Thomas, Aurélia; Oh, Jun; Cornelissen, Elisabeth A.M.; Janssen, Mirian C. H.; Haffner, Dieter; Ravà, Lucilla; Antignac, Corinne; Devuyst, Olivier; Niaudet, Patrick; Levtchenko, Elena

doi:10.1016/j.kint.2021.06.019

Cited by 45 publications

(66 citation statements)

References 40 publications

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“…Overall, measures of linear growth were significantly more impaired in INC patients, compared to CKD controls, despite more frequent use of rhGH which is in line with previous studies. 4,23,24 Though the youngest INC cohort showed less reduced eGFR than peer CKD controls, patients were considerably more impaired in growth. Since birth length did not differ between groups, the impaired growth in childhood (2-7 years) in the INC group seems to develop in the infantile period, during which patients are known to show the first signs of disease, that is, Fanconi syndrome.…”

Section: Discussionmentioning

confidence: 99%

Body growth, upper arm fat area, and clinical parameters in children with nephropathic cystinosis compared with other pediatric chronic kidney disease entities

Kluck

Müller

Jagodzinski

et al. 2022

J of Inher Metab Disea

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Children with infantile nephropathic cystinosis (INC), an inherited lysosomal storage disease resulting in cystine accumulation in all body cells, are prone to progressive chronic kidney disease (CKD), impaired growth and reduced weight gain; however, systematic anthropometric analyses are lacking. In this prospective multicenter study we investigated linear growth, body proportion, body mass index (BMI), upper arm fat area (UFA) and biochemical parameters in 43 pediatric INC patients with CKD stages 1 to 5 and 49 age‐matched CKD controls, with 193 annual measurements. INC patients showed more impaired height than CKD controls (−1.8 vs −0.7 z‐score; P < .001), despite adequate cysteamine therapy, treatment for Fanconi syndrome and more frequent use of growth hormone. Only the youngest INC patients shared the same body pattern with CKD controls characterized by preferential impairment of leg length and rather preserved trunk length. In late‐prepuberty, body pattern changed only in INC patients due to improved leg growth and more impaired trunk length. Mean UFA z‐score in INC patients was slightly reduced in early childhood and progressively decreased thereafter reaching −0.8 z‐score in adolescence, while CKD controls showed a steady increase in standardized BMI and UFA especially during adolescent age. Menarche in female INC patients was significantly delayed compared to CKD controls. Our data indicate that with age and progression of disease, pediatric INC patients undergo unique changes of body growth and fat stores that are distinct from those with CKD stemming from other causes, suggesting other factors apart from CKD to contribute to this development. Pediatric patients with infantile nephropathic cystinosis display more severe impaired linear growth than other peer CKD patients, despite of cysteamine treatment, supplementation for Fanconi syndrome, and more frequent use of growth hormone, with a distinct change of body proportions and overall lower body fat.

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Section: Discussionmentioning

confidence: 99%

Body growth, upper arm fat area, and clinical parameters in children with nephropathic cystinosis compared with other pediatric chronic kidney disease entities

Kluck

Müller

Jagodzinski

et al. 2022

J of Inher Metab Disea

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“…Although the studies reporting the use of indomethacin in cystinotic patients are scarce, several centers, particularly in Europe, widely use it in young cystinotic children to improve their renal Fanconi phenotype [ 78 ]. In a large multi-centre cohort of 453 cystinosis patients born between 1964 and 2016, the use of indomethacin was not associated with improved kidney function, and it cannot be excluded, though its direct anti-inflammatory effects were diluted in this large cohort, as the dose and the duration of treatment were not specified in this study [ 79 ]. In this regard, it is currently recommended to limit indomethacin to the first years of life, when renal water and salt losses are more severe, in order to avoid its potential long-term nephrotoxicity.…”

Section: Targeting Inflammation As a Potential Therapeutic Option In Cystinosismentioning

confidence: 99%

Nephropathic Cystinosis: Pathogenic Roles of Inflammation and Potential for New Therapies

Elmonem

Veys

Prencipe

2022

Cells

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The activation of several inflammatory pathways has recently been documented in patients and different cellular and animal models of nephropathic cystinosis. Upregulated inflammatory signals interact with many pathogenic aspects of the disease, such as enhanced oxidative stress, abnormal autophagy, inflammatory cell recruitment, enhanced cell death, and tissue fibrosis. Cysteamine, the only approved specific therapy for cystinosis, ameliorates many but not all pathogenic aspects of the disease. In the current review, we summarize the inflammatory mechanisms involved in cystinosis and their potential impact on the disease pathogenesis and progression. We further elaborate on the crosstalk between inflammation, autophagy, and apoptosis, and discuss the potential of experimental drugs for suppressing the inflammatory signals in cystinosis.

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“…Cysteamine significantly improves NC, but does not cure the disease. Despite adequate treatment, the majority of patients progress to end-stage kidney disease in the second or third decade of life [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Benefits and Toxicity of Disulfiram in Preclinical Models of Nephropathic Cystinosis

Taranta

Elmonem

Bellomo

et al. 2021

Cells

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Nephropathic cystinosis is a rare disease caused by mutations of the CTNS gene that encodes for cystinosin, a lysosomal cystine/H+ symporter. The disease is characterized by early-onset chronic kidney failure and progressive development of extra-renal complications related to cystine accumulation in all tissues. At the cellular level, several alterations have been demonstrated, including enhanced apoptosis, altered autophagy, defective intracellular trafficking, and cell oxidation, among others. Current therapy with cysteamine only partially reverts some of these changes, highlighting the need to develop additional treatments. Among compounds that were identified in a previous drug-repositioning study, disulfiram (DSF) was selected for in vivo studies. The cystine depleting and anti-apoptotic properties of DSF were confirmed by secondary in vitro assays and after treating Ctns-/- mice with 200 mg/kg/day of DSF for 3 months. However, at this dosage, growth impairment was observed. Long-term treatment with a lower dose (100 mg/kg/day) did not inhibit growth, but failed to reduce cystine accumulation, caused premature death, and did not prevent the development of renal lesions. In addition, DSF also caused adverse effects in cystinotic zebrafish larvae. DSF toxicity was significantly more pronounced in Ctns-/- mice and zebrafish compared to wild-type animals, suggesting higher cell toxicity of DSF in cystinotic cells.

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An international cohort study spanning five decades assessed outcomes of nephropathic cystinosis

Cited by 45 publications

References 40 publications

Body growth, upper arm fat area, and clinical parameters in children with nephropathic cystinosis compared with other pediatric chronic kidney disease entities

Body growth, upper arm fat area, and clinical parameters in children with nephropathic cystinosis compared with other pediatric chronic kidney disease entities

Nephropathic Cystinosis: Pathogenic Roles of Inflammation and Potential for New Therapies

Benefits and Toxicity of Disulfiram in Preclinical Models of Nephropathic Cystinosis

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