Chitotriosidase as a Novel Biomarker for Therapeutic Monitoring of Nephropathic Cystinosis
Authors: Veys Koenraad R.P. , Elmonem Mohamed A. , Van Dyck Maria , Janssen Mirian C. , Cornelissen Elisabeth A.M. , Hohenfellner Katharina , Prencipe Giusi , van den Heuvel Lambertus P. , Levtchenko Elena 
Published: April 2020

Significance Statement
The rare, inheritable, lysosomal storage disorder nephropathic cystinosis is caused by mutations in the gene encoding cystinosin, a lysosomal cystine/proton cotransporter. Cystinosis is characterized by accumulation of cystine in all tissues and the development of CKD and multiple extrarenal complications, and is treated with cysteamine, a cystine-depleting agent. Treatment monitoring involves measuring white blood cell cystine levels, but this assay has important limitations and is not available in many countries. In a prospective study of 57 patients with nephropathic cystinosis, the authors demonstrated that chitotriosidase enzyme activity, a marker of macrophage activation, is a significant predictor for adherence to cysteamine therapy and for the presence of extrarenal complications. Their findings suggest that chitotriosidase holds promise as a novel biomarker for monitoring cysteamine treatment and highlight inflammation’s role in cystinosis pathophysiology.

Background
Nephropathic cystinosis, a hereditary lysosomal storage disorder caused by dysfunction of the lysosomal cotransporter cystinosin, leads to cystine accumulation and cellular damage in various organs, particularly in the kidney. Close therapeutic monitoring of cysteamine, the only available disease-modifying treatment, is recommended. White blood cell cystine concentration is the current gold standard for therapeutic monitoring, but the assay is technically demanding and is available only on a limited basis. Because macrophage-mediated inflammation plays an important role in the pathogenesis of cystinosis, biomarkers of macrophage activation could have potential for the therapeutic monitoring of cystinosis.

Methods
We conducted a 2-year prospective, longitudinal study in which 61 patients with cystinosis who were receiving cysteamine therapy were recruited from three European reference centers. Each regular care visit included measuring four biomarkers of macrophage activation: IL-1β, IL-6, IL-18, and chitotriosidase enzyme activity.

Results
A multivariate linear regression analysis of the longitudinal data for 57 analyzable patients found chitotriosidase enzyme activity and IL-6 to be significant independent predictors for white blood cell cystine levels in patients of all ages with cystinosis; a receiver operating characteristic analysis ranked chitotriosidase as superior to IL-6 in distinguishing good from poor therapeutic control (on the basis of white blood cell cystine levels of <2 nmol 1/2 cystine/mg protein or ≥2 nmol 1/2 cystine/mg protein, respectively). Moreover, in patients with at least one extrarenal complication, chitotriosidase significantly correlated with the number of extrarenal complications and was superior to white blood cell cystine levels in predicting the presence of multiple extrarenal complications.

Conclusions
Chitotriosidase enzyme activity holds promise as a biomarker for use in therapeutic monitoring of nephropathic cystinosis.