Crystallization of Calcium Oxalate and Calcium Phosphate at Supersaturation Levels Corresponding to Those in Different Parts of the Nephron

The risk of crystallization in solutions, with a composition corresponding to that of urine in various parts of the nephron, was assessed by studying urine samples containing standardized increments of calcium and oxalate concentrations. The experiments were carried out in salt solutions with and without dialysed urine and the appearance of crystals was detected and measured with a Coulter counter. With increased concentrations of calcium, crystals of calcium phosphate were predominantly formed in solutions with a composition corresponding to that in the proximal and distal tubuli, whereas, calcium oxalate was the primary crystallization product in solutions with a composition corresponding to the collecting duct. These conclusions were based on calculations of ion-activity products of calcium oxalate, hydroxyapatite, and calcium hydrogen phosphate, at the first appearance of crystals; studies on crystal morphology with scanning electron microscopy, and precipitation of [14C]-oxalate following addition of calcium. The ion-activity products of calcium oxalate at the first appearance of crystals following addition of oxalate to solutions with a composition corresponding to the collecting duct were significantly lower in the presence of dialysed urine. This might reflect a promoting effect of some macromolecules on the nucleation of calcium oxalate. Dialysed urine in these samples also had a pronounced influence on the development of the crystals by markedly reducing the mean crystal volume during the first hour following the formation of 100 crystals with a diameter between 3.5 and 5 μm. Such an effect was not observed in those solutions in which calcium phosphate crystals had formed

The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management

Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment. We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment-auditory neuropathy (AN). All patients were clinically suspected of CAPOS and had hearing problems. In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony. Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here. Molecular modelling and in vitro electrophysiological studies of the specific CAPOS mutation were performed. Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site. Molecular dynamics simulations confirm that the structure of the C-terminal region is affected. In conclusion, we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons. This has implications for diagnosis and patient management. Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective in CAPOS patients