Switching from immediate- to extended-release cysteamine in patients with nephropathic cystinosis: from clinical trials to clinical practice.

Background: The purpose of this study is to evaluate the effectiveness and safety of switching from immediate-release (IR) to extended-release (ER) cysteamine in patients with nephropathic cystinosis (NC) in Spain. Methods: We conducted an observational, retrospective, multicentre study in NC patients who received IR cysteamine for at least 12 months, switched to ER cysteamine, and received it for at least 6 months before inclusion. Results: Data were collected from nine patients (four children, five adults) 36 months before and after the switch. Despite the highly selected population, an improvement in growth, particularly in children and a significant reduction in hospitalization days was observed. A decrease in halitosis, body odour and gastrointestinal effects was reported in most of the patients who suffered before the switch, and the use of proton pump inhibitors (PPIs) decreased in some patients. The estimated glomerular filtration rate (eGFR) remained stable in patients with preserved kidney function. No significant changes in white blood cell (WBC) cystine levels were observed after the switch. There was no significant difference in the cysteamine dose received. However, some patients were receiving <50% of the recommended dose of cysteamine before and after the switch and showed elevated levels of WBC cystine. Conclusions: Switching from IR to ER cysteamine in clinical practice reduces hospital stays, improves nutritional status and growth in paediatric patients and could help to enhance treatment tolerability by reducing side effects. Furthermore, the dosing of ER cysteamine could promote therapeutic compliance and positively affect the quality of life of the NC population.

Cysteamine (Cystagon®) adherence in patients with cystinosis in Spain: successful in children and a challenge in adolescents and adults.

BACKGROUND: Cysteamine has improved survival and prognosis in cystinosis. Increasing numbers of patients reach adulthood and face new challenges such as compliance that wanes over time. The aim of this study was to evaluate adherence to cysteamine treatment in a group of cystinotic patients in Spain in an attempt to identify potential therapy pitfalls and improve the overall care of affected individuals. Despite the impact of cysteamine on prognosis, there is a paucity of data regarding adherence. METHOD: Thirty-four cystinotic patients (21 male) 38% ≥18 years were enrolled in a voluntary, anonymous survey. Replies were obtained from patients (15/34), mothers (11/34), fathers (4/34) and both parents (4/34). RESULTS: Patient age (median and interquartile range) at diagnosis was 1 year (0.57-1), and patient age at Cystagon® initiation was also 1 year (0.8-1.8). Sixteen (47%) were kidney transplant (KTx) recipients; six were retransplanted. Age at first KTx 10 years (8.7-13.7). Patient understanding of multiorgan involvement in cystinosis: 4.1 organs reported; eye 97% and kidney 91%. Cysteamine was given by mother (100%) and father (83%) in <11 year olds, or self-administered (94%) in ≥11 year olds. Four daily doses in 89% versus 56% in <11 year olds or ≥11 year olds, with fixed schedule in 94% versus 50% in <11 or ≥11 year olds and progressive loss of reminders over time. Furthermore, 44% complained of unpleasant smell. Motivation for treatment compliance was 100% versus 40% in <11 versus ≥11 year olds, respectively. Disease impact in patients <18 years is as follows: school (29%), social (14%), 'feeling different' (10%); in patients ≥18 years: 'feeling different' (62%), professional (39%) and job absenteeism (31%). Referring physician: paediatric nephrologist (94%) and nephrologist (63%) in <11 versus ≥11 year olds. Ophthalmological follow-up: 83% versus 38% in <11 versus ≥11 year olds. Patient opinion of physician expertise: paediatric nephrologist (94%) and nephrologist (44%). New treatment options (65%) and better information (42%) were demanded to improve adherence. CONCLUSION: Treatment with Cystagon is effective in young patients. However, adherence diminishes over time in adolescents and adults despite disease impact. Strategies such as better information on the disease, patient self-care promotion and facilitated transition to adult healthcare services are required to improve compliance and the clinical management of cystinosis.

Dent's disease: Identification of seven new pathogenic mutations in the CLCN5 gene.

Dent's disease is an X-linked proximal tubulopathy characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis and progressive renal failure. This disorder is frequently caused by mutations in the CLCN5 gene encoding the electrogenic chloride/proton exchanger ClC-5. Occasionally, Dent's disease has been associated to atypical cases of asymptomatic proteinuria with focal glomerulosclerosis. Twelve unrelated patients with Dent's disease, including two who presented with asymptomatic proteinuria and developed glomerulosclerosis, were studied. Mutational analysis of the CLCN5 gene was performed by DNA sequencing. We identified thirteen distinct CLCN5 mutations in the twelve patients. Seven of these mutations, p.P416fsX(*)17, p.[H107P, V108fs(*)27], p.G466D, p.G65R, p.G462S, p.Y164(*) and c.723+1G >T, were novel and possibly pathogenic. In one family, the patient's mother was not a carrier of the respective mutation. Our results increased the spectrum of CLCN5 disease causing defects with seven new pathogenic mutations and established a de novo origin in one of them. Remarkably, three new missense mutations, p.G466D, p.G65R and p.G462S, affect highly conserved glycine residues located in transmembrane α-helix GxxxG packing motifs. The two atypical cases further support that the diagnosis of Dent's disease should be considered in children with asymptomatic proteinuria and focal glomerulosclerosis and without evidence of primary glomerular disease.

Improvement in growth after 1 year of growth hormone therapy in well-nourished infants with growth retardation secondary to chronic renal failure: results of a multicenter, controlled, randomized, open clinical trial.

BACKGROUND AND OBJECTIVES: Our aim was to evaluate the growth-promoting effect of growth hormone (GH) treatment in infants with chronic renal failure (CRF) and persistent growth retardation despite adequate nutritional and metabolic management. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The study design included randomized, parallel groups in an open, multicenter trial comparing GH (0.33 mg/kg per wk) with nontreatment with GH during 12 months. Sixteen infants who had growth retardation, were aged 12+/-3 months, had CRF (GFR

Pathogenic mutations in the 5' untranslated region of BCS1L mRNA in mitochondrial complex III deficiency.

Mutations in the assembly chaperone BCS1L constitute a major cause of mitochondrial complex III deficiency. We studied the presence of BCS1L mutations in a complex III-deficient patient with metabolic acidosis, liver failure, and tubulopathy. A previously reported mutation, p.R56X, was identified in one BCS1L allele, and two novel heterozygous mutations, g.1181A>G and g.1164C>G, were detected in the second allele. The g.1181A>G mutation generated an alternative splicing site in the BCS1L transcript, causing a 19-nucleotides deletion in its 5'UTR region. Decreased BCS1L mRNA and protein levels, and a respiratory chain complex III assembly impairment, determine a pathogenic role for the novel BCS1L mutations.

Renal pathology in children with mitochondrial diseases.

We studied renal involvement in 42 children with mitochondrial diseases (MDs). The diagnosis of MD was established by morphological, biochemical, and molecular genetic criteria. Renal disease was considered when patients had renal failure, nephrotic syndrome, Fanconi's syndrome or any symptomatic renal alteration. Mild tubular disorder was established if they had abnormal laboratory findings with no apparent clinical symptom. Renal involvement was found in 21 children (50%), of whom 8 had an apparent clinical picture and 13 a mild tubular disorder. Five patients with renal disease showed Debré-Toni-Fanconi's syndrome, 2 of them with decreased glomerular filtration rate (GFR). One case had nephrotic syndrome, another one presented decreased GFR, and the last one had a neurogenic bladder and bilateral hydronephrosis. Patients with mild renal disease showed tubular dysfunction with normal GFR. Renal involvement is frequent and present in about half of the children with MD. Thus, studies for evaluating kidney function should be performed on children with MD. Conversely, patients with tubulopathy of unknown origin or progressive renal disease should be investigated for the existence of MD, especially if associated with involvement of other organs or tissues. Southern blot analysis to search for large-scale mitochondrial DNA (mtDNA) rearrangements should be performed for patients with MD and kidney involvement.