Clinical utility of chitotriosidase enzyme activity in nephropathic cystinosis

Orphanet Journal of Rare Diseases

Elena Levtchenko⁸  Neveen A Soliman⁷  Héloïse P Gaide Chevronnay³  Fayza A Hassan⁶  Fanny O Arcolino⁸  Marwa M Nabhan⁷  Leo AB Joosten¹  Dirk J Lefeber²  Elisabeth AM Cornelissen¹  Mirian C Janssen⁵  Xavier Bossuyt⁴  Safaa M Abdelrahman⁷  Hanan Abdelaziz⁷  Lambertus van den Heuvel¹  Samuel H Makar⁷  Mohamed A Elmonem⁶ 

[1] Department of Pediatric Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands;Department of Neurology, Laboratory for Genetic, Endocrine and Metabolic Diseases, Radboud University Medical Center, Nijmegen, The Netherlands;CELL Unit, Université Catholique de Louvain & de Duve Institute, Bruxelles, Belgium;University Hospitals Leuven & Department of Microbiology and Immunology, Laboratory Medicine, Catholic University of Leuven, Leuven, Belgium;Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands;Department of Clinical and Chemical Pathology, Inherited Metabolic Disorder Laboratory (IMDL), Cairo University, Cairo, Egypt;EGORD, Egyptian group of orphan renal diseases, Cairo, Egypt;Department of Pediatric Nephrology & Growth and Regeneration, University Hospital Leuven, Catholic University of Leuven, Leuven, Belgium

关键词: Therapeutic monitoring;    Cysteamine;    Clinical screening;    Chitotriosidase enzyme;    Macrophage activation;    Cystine crystals;    Nephropathic cystinosis;    Lysosomal storage disorders;   

Others  :  1149377
DOI  :  10.1186/s13023-014-0155-z

 received in 2014-07-29, accepted in 2014-09-30,  发布年份 2014

【 摘 要 】

Background

Nephropathic cystinosis is an inherited autosomal recessive lysosomal storage disorder characterized by the pathological accumulation and crystallization of cystine inside different cell types. WBC cystine determination forms the basis for the diagnosis and therapeutic monitoring with the cystine depleting drug (cysteamine). The chitotriosidase enzyme is a human chitinase, produced by activated macrophages. Its elevation is documented in several lysosomal storage disorders. Although, about 6% of Caucasians have enzyme deficiency due to homozygosity of 24-bp duplication mutation in the chitotriosidase gene, it is currently established as a screening marker and therapeutic monitor for Gaucher’s disease.

Methods

Plasma chitotriosidase activity was measured in 45 cystinotic patients, and compared with 87 healthy controls and 54 renal disease patients with different degrees of renal failure (CKD1-5). Chitotriosidase levels were also correlated with WBC cystine in 32 treated patients. Furthermore, we incubated control human macrophages in-vitro with different concentrations of cystine crystals and monitored the response of tumor necrosis factor-alpha (TNF-α) and chitotriosidase activity. We also compared plasma chitotriosidase activity in cystinotic knocked-out (n = 10) versus wild-type mice (n = 10).

Results

Plasma chitotriosidase activity in cystinotic patients (0–3880, median 163 nmol/ml/h) was significantly elevated compared to healthy controls (0–90, median 18 nmol/ml/h) and to CKD patients (0–321, median 52 nmol/ml/h), P < 0.001 for both groups. Controls with decreased renal function had mild to moderate chitotriosidase elevations; however, their levels were significantly lower than in cystinotic patients with comparable degree of renal insufficiency. Chitotriosidase activity positively correlated with WBC cystine content for patients on cysteamine therapy (r = 0.8), P < 0.001. In culture, human control macrophages engulfed cystine crystals and released TNF-α into culture supernatant in a crystal concentration dependent manner. Chitotriosidase activity was also significantly increased in macrophage supernatant and cell-lysate. Furthermore, chitotriosidase activity was significantly higher in cystinotic knocked-out than in the wild-type mice, P = 0.003.

Conclusions

This study indicates that cystine crystals are potent activators of human macrophages and that chitotriosidase activity is a useful marker for this activation and a promising clinical biomarker and therapeutic monitor for nephropathic cystinosis.

【 授权许可】

   
2014 Elmonem et al.; licensee BioMed Central Ltd.

【 图 表 】

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