Neurocognitive functions and behavioral profiles in children with nephropathic cystinosis

Children with nephropathic cystinosis (NCTN) have evidence of defective intellec-tual functions and behavioral disorders. This prospective study was performed to detect the cognitive dysfunctions in patients with this rare hereditary lysosomal storage disease, define their behavioral phenotypes, and study the findings on magnetic resonance imaging (MRI) of the brain. Thirteen patients with confirmed diagnosis of cystinosis (mean age ± SD 5.9 ± 3.0, range 1.5 - 12 years) were subjected to the Stanford Binet test, Porteus Maze test, Child Behavior Checklist, and MRI brain. Thirteen age- and sex-matched children served as the control subjects (mean age ± SD 5.9 ± 2.9, range 1.7 - 12 years). The intelligence quotient (IQ) was significantly lower in patients with cystinosis (P <0.001), with a significant defect in verbal (language, memory, and compre-hension) and non-verbal abilities (visual perception and visiospatial and motor performance). A discrepancy between both abilities was detected - the non-verbal ability being lower; however, it did not reach statistical significance. Furthermore, analysis revealed the visiospatial ability to be significantly lower compared to the visual perception. In comparison to healthy controls, children with NCTN had evidence of increased incidence of behavioral problems, mainly social (P = 0.023). An MRI of the brain revealed varying degrees of atrophic changes in seven patients. Patients with NCTN need a wider scope of attention and care, encompassing not only the metabolic multisystem derangement, but also the neuropsychological impairment in the context of multidisciplinary management. This approach is crucial in formulating comprehensive plans for social and educational rehabilitation

Decreasing intra-dialytic morbid events and assessment of dry weight in children on chronic hemodialysis using non-invasive changes in hematocrit

Achieving dry weight after hemodialysis (HD) is critical as chronic fluid over-load can result in left ventricular hypertrophy, while small fluid shifts may result in intra-dialytic morbid events (IME). In the pediatric population, estimating dry weight can be difficult due to growth while on dialysis. Continuous non-invasive monitoring of the hematocrit (NIVM) has been proposed as a more accurate method of estimating dry weight. Fifteen pediatric patients on chronic HD (6 males and 9 females; mean age 11.4 ± 2.28 years) were included in an uncontrolled prospective study involving three phases. In phase 1, patients were observed for one month for their dry weight and frequency of IME. Phase 2 consisted of using NIVM-guided ultrafiltration algorithm for rate of blood volume (BV) reduction and post-dialysis refill, recommending an intra-dialytic reduction in BV of 8% in the first hour and 0.1). In phase 1, 40% of patients experienced no IME, 33% experienced one or two IME while 27% experienced more than two IME; during phase 3, 80% experienced no IME, 20% experienced one or two IME while no one experienced more than two IME. NIVM can serve as an objective method for determining dry weight as well as predicting and preventing IME in the pediatric population on maintenance HD

Chitotriosidase enzyme can be used as a screening marker and a therapeutic monitor for NephropathicCystinosis

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Clinical utility of chitotriosidase enzyme in nephropathic cystinosis

BackgroundNephropathic 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.MethodsPlasma 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-¿) and chitotriosidase activity. We also compared plasma chitotriosidase activity in cystinotic knocked-out (n¿=¿10) versus wild-type mice (n¿=¿10).ResultsPlasma 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-¿ 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.ConclusionsThis 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.status: publishe