The alpha-galactosidase A p.Arg118Cys variant does not cause a Fabry disease phenotype: data from individual patients and family studies.

Lysosomal α-galactosidase A (α-Gal) is the enzyme deficient in Fabry disease (FD), an X-linked glycosphingolipidosis caused by pathogenic mutations affecting the GLA gene. The early-onset, multi-systemic FD classical phenotype is associated with absent or severe enzyme deficiency, as measured by in vitro assays, but patients with higher levels of residual α-Gal activity may have later-onset, more organ-restricted clinical presentations. A change in the codon 118 of the wild-type α-Gal sequence, replacing basic arginine by a potentially sulfhydryl-binding cysteine residue - GLA p.(Arg118Cys) -, has been recurrently described in large FD screening studies of high-risk patients. Although the Cys118 allele is associated with high residual α-Gal activity in vitro, it has been classified as a pathogenic mutation, mainly on the basis of theoretical arguments about the chemistry of the cysteine residue. However its pathogenicity has never been convincingly demonstrated by pathology criteria. We reviewed the clinical, biochemical and histopathology data obtained from 22 individuals of Portuguese and Spanish ancestry carrying the Cys118 allele, including 3 homozygous females. Cases were identified either on the differential diagnosis of possible FD manifestations and on case-finding studies (n=11; 4 males), or on unbiased cascade screening of probands' close relatives (n=11; 3 males). Overall, those data strongly suggest that the GLA p.(Arg118Cys) variant does not segregate with FD clinical phenotypes in a Mendelian fashion, but might be a modulator of the multifactorial risk of cerebrovascular disease. The Cys118 allelic frequency in healthy Portuguese adults (n=696) has been estimated as 0.001, therefore not qualifying for "rare" condition.

Deferasirox-induced iron depletion promotes BclxL downregulation and death of proximal tubular cells.

Iron deficiency has been associated with kidney injury. Deferasirox is an oral iron chelator used to treat blood transfusion-related iron overload. Nephrotoxicity is the most serious and common adverse effect of deferasirox and may present as an acute or chronic kidney disease. However, scarce data are available on the molecular mechanisms of nephrotoxicity. We explored the therapeutic modulation of deferasirox-induced proximal tubular cell death in culture. Deferasirox induced dose-dependent tubular cell death and AnexxinV/7AAD staining showed features of apoptosis and necrosis. However, despite inhibiting caspase-3 activation, the pan-caspase inhibitor zVAD-fmk failed to prevent deferasirox-induced cell death. Moreover, zVAD increased deferasirox-induced cell death, a feature sometimes found in necroptosis. Electron microscopy identified mitochondrial injury and features of necrosis. However, neither necrostatin-1 nor RIP3 knockdown prevented deferasirox-induced cell death. Deferasirox caused BclxL depletion and BclxL overexpression was protective. Preventing iron depletion protected from BclxL downregulation and deferasirox cytotoxicity. In conclusion, deferasirox promoted iron depletion-dependent cell death characterized by BclxL downregulation. BclxL overexpression was protective, suggesting a role for BclxL downregulation in iron depletion-induced cell death. This information may be used to develop novel nephroprotective strategies. Furthermore, it supports the concept that monitoring kidney tissue iron depletion may decrease the risk of deferasirox nephrotoxicity.

Deferasirox nephrotoxicity-the knowns and unknowns.

In 2005, the oral iron chelator deferasirox was approved by the FDA for clinical use as a first-line therapy for blood-transfusion-related iron overload. Nephrotoxicity is the most serious and frequent adverse effect of deferasirox treatment. This nephrotoxicity can present as an acute or chronic decrease in glomerular filtration rate (GFR). Features of proximal tubular dysfunction might also be present. In clinical trials and observational studies, GFR is decreased in 30-100% of patients treated with deferasirox, depending on dose, method of assessment and population studied. Nephrotoxicity is usually nonprogressive and/or reversible and rapid iron depletion is one of several risk factors. Scarce data are available on the molecular mechanisms of nephrotoxicity and the reasons for the specific proximal tubular sensitivity to the drug. Although deferasirox promotes apoptosis of cultured proximal tubular cells, the trigger has not been well characterized. Observational studies are required to track current trends in deferasirox prescription, assess the epidemiology of deferasirox nephrotoxicity in routine clinical practice, explore the effect on outcomes of various monitoring and dose-adjustment protocols and elucidate the long-term consequences of the different features of nephrotoxicity. Deferasirox nephrotoxicity can be more common in the elderly; thus, specific efforts should be dedicated to investigate the effect of deferasirox use in this group of patients.

Use of radioactive iodine I-131 and monitoring of radioactivity in patients with chronic kidney disease on haemodialysis.

Thyroid carcinoma is a neoplasia with a higher incidence in patients with chronic kidney disease. In recent years advances have been made in diagnostic and therapeutic trials. Dialysis patients are a particular group, their cancer being detected indirectly in the study of secondary hyperparathyroidism and during the study prior to renal transplantation. Thyroidectomy is the definitive treatment, but in patients with risk of recurrence, ablative therapy is required using radioactive iodine I-131, which is predominantly eliminated by renal excretion, therefore its use in patients on dialysis poses a problem in terms of dosage. Two cases are presented of patients on haemodialysis undergoing radioablation with radioactive iodine I-131, which with multidisciplinary treatment had the expected results in the patients.

Parkinsonismo severo con insuficiencia respiratoria en paciente de diálisis peritoneal / Severe Parkinsonism with respiratory failure in peritoneal dialysis patient

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Uso de yodo radiactivo I-131 y monitorización de radiactividad en pacientes con enfermedad renal crónica en hemodiálisis / Use of radioactive iodine I-131 and monitoring of radioactivity in patients with chronic kidney disease on haemodialysis

El carcinoma tiroideo es una neoplasia que tiene una incidencia más alta en pacientes con enfermedad renal crónica. Durante los últimos años se ha avanzado en las pruebas diagnósticas y terapéuticas. Los pacientes de diálisis son un grupo particular, al ser detectado el cáncer de forma indirecta en el estudio del hiperparatiroidismo secundario y durante el estudio previo al trasplante renal. La tiroidectomía es el tratamiento definitivo, pero en pacientes con riesgo de recidiva es necesaria la terapia ablativa con yodo radioactivo I-131, que es predominantemente excretado por vía renal, por lo que su uso en pacientes en diálisis supone un problema de dosificación. Se presentan dos casos de pacientes en hemodiálisis sometidos a radioablación con yodo radiactivo I-131, que con un manejo multidisplinar produjo los resultados esperados en los pacientes (AU)

Thyroid carcinoma is a neoplasia with a higher incidence in patients with chronic kidney disease. In recent years advances have been made in diagnostic and therapeutic trials. Dialysis patients are a particular group, their cancer being detected indirectly in the study of secondary hyperparathyroidism and during the study prior to renal transplantation. Thyroidectomy is the definitive treatment, but in patients with risk of recurrence, ablative therapy is required using radioactive iodine I-131, which is predominantly eliminated by renal excretion, therefore its use in patients on dialysis poses a problem in terms of dosage. Two cases are presented of patients on haemodialysis undergoing radioablation with radioactive iodine I-131, which with multidisciplinary treatment had the expected results in the patients (AU)