Clinical and genetic studies on patients with cystinuria
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Cystinuria is a genetic disorder with autosomal recessive inheritance. It is caused by a defective proximal tubular reabsorbtion of cystine and the dibasic amino acids. The low urinary solubility of cystine causes a life-long stone disease, contributing to about 1% of all urinary stones in adults. Treatment is based on high fluid intake and the use of sulfhydryl compounds such as tiopronin and D-penicillamine to decrease the urinary concentration of cystine, and alkalinization of the urine to increase the urinary solubility of cystine. Reduction of sodium intake is also a favoured regimen because of eo-transportation of sodium and cystine in the proximal tubules. Advancements in molecular genetics have led to the identification of two genes associated with cystinuria (SLC3A1 and SLC7A9). These genes cannot, however, explain all cases of cystinuria.
Investigation of SLC3A1 in 53 Swedish patients with cystinuria revealed 12 novel mutations, and the allelic frequency of the most common mutation (M467T) was shown to be 0.5% in a normal population. (Paper I). Studies of SLC7A9 revealed three novel and one previously known mutation. One patient had novel mutations in both alleles, one patient showed a novel mutation in one of the alleles and one patient showed a previously known mutation in SLC7A9 and two in SLC3A1, leaving 14 patients in whom cystinuria was not explained by genetic observations (Paper m. In order to relate these genetic findings to excretion of cystine in the urine, 33 patients treated with sulfhydryl compounds were studied (Paper III). Ten of these patients showed either mutation in one of the SLC3A1 alleles (8) or a complete lack of mutations in both genes (2). These 10 patients showed a significantly higher urinary excretion of total cystine compared to 23 patients in whom both SLC3A1 alleles were mutated (p < 0.01). The same was true for the 8 patients with only one SLC3A1 allele mutated (p < 0.05). These findings support the existence of yet unknown genes involved in the regulation of urinary cystine excretion, the basis of cystine stone formation. Treatment is primarily aimed at the prevention of such stones and should be guided by the urinary cystine concentration, trying to avoid supersaturation. In order to improve patient surveillance in terms of urinary supersaturation with cystine a procedure was introduced comprising one daytime and one night urine sample during the 24-hour period (Paper IV). Twenty-six patients were followed over a 3.5 year period using this strategy. It was found that 47% of cystine supersaturation episodes (> 1200 µmol/L) would have evaded detection by analysis carried out in 24-hour urine collections. Furthermore, a significant decrease in the frequency of renal stone episodes (p < 0.05) and active stone removals (p < 0.01) was found when compared to a previous, equivalent period during which 24-hour urine collections were used. The period guided by divided urine samples was also characterized by a significant decrease in free cystine concentrations (p < 0.01) and a significant increase in urinary volumes (p < 0.05). In the tiopronin-treated patients, there was a significant increase in the tiopronin dose and a subsequent decrease in urinary cystine excretion (p < 0.05). The use of cystine analysis in divided urine samples thus made a higher degree of individual treatment possible. The effects of sodium bicarbonate and potassium citrate were compared in 14 cystinuric patients (Paper V). Potassium citrate has been the favoured agent, as it does not contain sodium, but there have been no reports in which potassium citrate has been compared to sodium bicarbonate in the treatment of patients with cystinuria. Sodium bicarbonate was effective in alkalizing the urine, but caused a significantly increased urinary sodium excretion (p < 0.01). A significant correlation was found between urinary sodium and cystine excretion in tiopronin treated patients (p < 0.001). Potassium citrate was shown to produce a significant increase in urinary pH. Potassium citrate was associated with a significant increase in plasma potassium (p < 0.05), but no case of severe hyperkalemia was found. Potassium citrate could thus be recommended for urinary alkalinization in cystinuric patients without severe renal impairment.
Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2003. , 74 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 817
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-25643Local ID: 10018ISBN: 91-7373-507-8OAI: oai:DiVA.org:liu-25643DiVA: diva2:246191
2003-11-05, Viktoriasalen, Hälsouniversitet, Linköping, 13:00 (Swedish)
Ala-Opas, Martti, Docent
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