RESUMEN
OBJECTIVES: To assess whether copper deficiency plays a role in the recently described cysteamine toxicity in patients with cystinosis, and to examine whether polymorphisms in copper transporters, lysyl oxidase, and/or type I procollagen genes could be responsible for the occurrence of cysteamine toxicity in a small subset of patients with cystinosis. STUDY DESIGN: Thirty-six patients with cystinosis were included: 22 with Fanconi syndrome (including 7 with cysteamine toxicity), 12 after renal transplantation, 1 receiving hemodialysis, and 1 with ocular cystinosis. Serum copper and ceruloplasmin levels and urinary copper/creatinine ratio were measured. Genes ATP7A and CTR1 (encoding copper transporters), LOX (encoding lysyl oxidase), and COL1A1 and COL1A2 (encoding type I procollagen) were analyzed in patients with (n = 6) and without (n = 5) toxicity. Fibroblast (pro)collagen synthesis was compared in patients with (n = 3) and those without (n = 2) cysteamine toxicity. RESULTS: All 22 patients with Fanconi syndrome had increased urinary copper excretion. Serum copper and ceruloplasmin levels were decreased in 9 patients, including all 7 patients with cysteamine toxicity. No specific sequence variations were associated with toxicity. All fibroblasts exhibited normal (pro)collagen synthesis. CONCLUSION: Patients with cystinosis with cysteamine toxicity demonstrate copper deficiency. This can cause decreased activity of lysyl oxidase, the enzyme that generates the aldehydes required for collagen cross-linking. Thus, copper supplementation might prevent cysteamine toxicity.
Asunto(s)
Cobre/deficiencia , Cisteamina/efectos adversos , Cistinosis/complicaciones , Sustancias Protectoras/efectos adversos , Fármacos Renales/efectos adversos , Adenosina Trifosfatasas/genética , Adolescente , Adulto , Biomarcadores/metabolismo , Proteínas de Transporte de Catión/genética , Ceruloplasmina/metabolismo , Niño , Preescolar , Colágeno/metabolismo , Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I , Cobre/metabolismo , Transportador de Cobre 1 , ATPasas Transportadoras de Cobre , Cisteamina/uso terapéutico , Cistinosis/tratamiento farmacológico , Cistinosis/genética , Cistinosis/metabolismo , Síndrome de Fanconi/complicaciones , Síndrome de Fanconi/tratamiento farmacológico , Síndrome de Fanconi/genética , Síndrome de Fanconi/metabolismo , Femenino , Marcadores Genéticos , Humanos , Masculino , Polimorfismo Genético , Sustancias Protectoras/uso terapéutico , Proteína-Lisina 6-Oxidasa/genética , Fármacos Renales/uso terapéutico , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
OBJECTIVES: To evaluate intestinal mucosal cystine crystal (CC) load as a way to estimate tissue cystine content in children with cystinosis. STUDY DESIGN: Intestinal mucosal biopsies were obtained endoscopically from children (ages 2-18 years) with cystinosis. Using a special processing technique, CC within histiocytes were easily visible and enumerable in the mucosal tissue. Mean CC counts, calculated from stomach and duodenum combined (CC-GD), were correlated with duration of cysteamine treatment, estimated glomerular filtration rate (eGFR), and mean white blood cells (WBC) cystine levels. RESULTS: Seventeen subjects (6 male) were enrolled in 2 studies from 2001 and 2003. The CC-GD count (mean 12.5 ± 1.41 crystals/histiocyte) was lower than the colonic crystal count (mean 23.6 ± 3.38, P = .0031). Nine of 17 subjects underwent repeated endoscopy 2 years later and the trend for CC-GD was to decrease over time (P = .065). Biopsies, however, were never completely depleted of CC. In subjects who were diagnosed before age 18 months, the percent change from baseline of both eGFR and CC-GD were inversely correlated (P = .026). Mean WBC cystine levels were positively correlated with CC-GD (P = .023). CONCLUSIONS: CC are easily visible in the intestinal mucosa. CC-GD counts appear to correlate with eGFR and may help monitor response to treatment. Even when mean WBC cystine levels are low, the mucosal CC are not depleted suggesting that tissue cysteamine levels may not achieve therapeutic efficacy.
Asunto(s)
Cistina/metabolismo , Cistinosis/metabolismo , Síndrome de Fanconi/metabolismo , Mucosa Intestinal/metabolismo , Síndrome Nefrótico/metabolismo , Adolescente , Niño , Preescolar , Cristalización , Endoscopía Gastrointestinal , Femenino , Tasa de Filtración Glomerular , Histiocitos/metabolismo , Humanos , Inmunohistoquímica , Masculino , SigmoidoscopíaRESUMEN
The renal proximal tubule exhibits a very extensive apical endocytic apparatus that is involved in the reabsorption of molecules filtered in the glomeruli. Several key receptors appear to be involved in this function, which serves not only to conserve protein but also to reabsorb different vitamins in complex with their binding proteins. Recent research has established megalin as probably the most important receptor in this endocytosis process. Cubilin is another receptor identified in the proximal tubule endocytic apparatus. Because cubilin lacks transmembrane or cytoplasmic domains required for endocytosis, this receptor associates with megalin to recycle and internalize its ligands. Recent studies have shown that vitamin D-binding protein (DBP)/25-(OH)D3 complex is one of the megalin/cubilin ligands. Megalin knockout mice develop vitamin D deficiency and bone disease owing to an inability of the proximal tubules to capture the DBP/25-(OH)D3 complexes from the glomerular filtrate. In the same way, kidney-specific megalin knockout mice have severe plasma vitamin D deficiency, hypocalcaemia and serious bone disease, like the complete megalin knockout mice. Anti-cubilin antibodies inhibit cellular uptake of DBP/25-(OH)D3 by up to 70%. Anti-megalin antibodies produced a similar reduction in DBP/25-(OH)D3 endocytosis. When both antibodies were applied, impairment of DBP/25-(OH)D3 was only slightly more impaired (around 80%), suggesting that cubilin and megalin function through the same endocytic pathway. Specific forms of renal Fanconi syndrome are associated with endocytic pathway dysfunction with disruption of megalin-mediated uptake DBP/25-(OH)D3 complex, producing metabolic bone disease in affected individuals as a prominent clinical finding.
Asunto(s)
Calcifediol/metabolismo , Endocitosis/fisiología , Síndrome de Fanconi/metabolismo , Túbulos Renales Proximales/metabolismo , Proteína de Unión a Vitamina D/metabolismo , Animales , HumanosRESUMEN
This is a case of a 15-month-old child suffering from Fanconi-Bickel syndrome, characterized with Fanconi syndrome manifestations (glycosuria, amino aciduria and phosphaturia), and the build-up of glycogen in the liver in a similar manner as seen in cases of glycogenesis type Ia. Due to the presence of liver glycogenosis, the patient also has a tendency towards hypoglycemia, ketonuria, hypercholesterolemia and hypertriglyceridemia. The glycogenosis seen in the patients with the Fanconi-Bickel syndrome, does not depend on a defect in the activity of the glucose-6-phosphatase enzyme, but in fact is due to a defect in the transporter which mobilizes glucose and galactose in the liver and in the basolateral membrane of the proximal tubule of the kidney.
Asunto(s)
Síndrome de Fanconi/diagnóstico , Biopsia con Aguja , Síndrome de Fanconi/metabolismo , Síndrome de Fanconi/patología , Enfermedad del Almacenamiento de Glucógeno/diagnóstico , Enfermedad del Almacenamiento de Glucógeno/metabolismo , Enfermedad del Almacenamiento de Glucógeno/patología , Humanos , Lactante , Túbulos Renales Proximales/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Terminología como AsuntoRESUMEN
Two animal models for cystinuria have been examined: the Basenji dog with Fanconi syndrome and cystine stone-forming dogs of various breeds. Brush-border membranes were isolated from these animals and uptake of D-glucose and L-cystine was characterized. Experiments with isolated brush-border vesicles from Basenji dogs with cystinuria as a component of the Fanconi syndrome showed diminished sodium-dependent D-glucose uptake but no decrease in L-cystine uptake even though the cystine defect in vivo was as high as 94% (ie, 6% reabsorption). In contrast, brush-border vesicles isolated from the kidney of a cystine stone-forming dog (Welsh Corgi) with a cystine defect of only 16% (ie, 84% reabsorption) had decreased uptake of cystine compared to values found for Beagle and Basenji vesicles. Thus, cystinuria found in Basenji dogs with the Fanconi syndrome differs from that in classic stone-forming cystinuric dogs. The alteration responsible for the cystinuria of Basenji dogs with Fanconi syndrome does not appear to have a membrane locus and may reflect altered energetics for transport, which are not detected in isolated vesicles. The cystine defect in cystinuric stone-forming dogs does appear to be reflected in the isolated membrane.
Asunto(s)
Cistinuria/metabolismo , Síndrome de Fanconi/metabolismo , Aminoácidos/farmacología , Animales , Transporte Biológico , Cistina/metabolismo , Modelos Animales de Enfermedad , Perros , Femenino , Tasa de Filtración Glomerular , Glucosa/metabolismo , Riñón/metabolismo , Cinética , Masculino , Microvellosidades/metabolismo , Sodio/farmacologíaRESUMEN
Since the introduction of irradiated ergosterol into our food supply, nutritional vitamin D-deficiency rickets has become an uncommon disease. However, skeletal disorders due to abnormalities of vitamin D function still occur. These disorders can now be classified more exactly into two groups: those in which there is a deficiency of the active metabolite of vitamin D, 1,25-dihydroxyvitamin D, and those in which there is an abnormality of renal tubular function resulting in renal hypophosphatemia despite normal vitamin D metabolism. The various entities of these two groups are described and the theoretical basis of their treatment given.