Clinical studies on cystinuria : With special reference to treatment with tiopronin

Sammanfattning: Cystinuria is an inherited disorder of the renal tubular transport of cystine and the dibasic amino acids across cell membranes. Defective renal tubular reabsorption causes a greatly increased urinary excretion of thepoorly soluble cystine, which in turn results in the formation of renal stones. Because of the life-long tendency for stone formation the patients are highly susceptible to complications of renal stone disease. Urinary supersaturation of cystine can be counteracted by reducing the urinary concentration (increased fluid intake, chemical modification with a sulfhydryl compound) or by increasing its solubility (urinary alkalinization).Long-tenn treatment with the sulfhydryl compound tiopronin (2-mercaptopropionylglycine) was evaluated in 31 patients with homozygous cystinuria (Papers I, II, IV). The patients were followed over an average of 7.8 years and the treatment was monitored by regular measurements of cystine in 24-hour urine samples by ionexch: mge chromatography, and by X-ray examinations. In 40 cystimnic patients total and split kidney function were investigated by gamma camera renography and measurement of glomerular filtration rate (GFR), mainly51CR-EDTA-clearance (Paper Ill). The diurnal variations in urinary cystine excretion was studied in 8 patients (Paper VI), and the effect of a low sodium intake in 13 (Paper V).A urinary free cystine concentration below the assumed level of saturation of 1200 J..Lmol/1 in 24h urine samples was achieved in 90% of patients treated with tiopronin. The required doses varied from 500 to 3000 mg!day which illustrates the necessity for individualization of treatment by regular measurements of the urinary cystine concentration. Increasing doses of tiopronin resulted in an unexpected decrease in the urinary excretion of the soluble tiopronin-cysteine mixed disulphide suggesting an influence on the general metabolism of cystine and cysteine.The rate of new stone· formation wa<> reduced by 60% and the need for active stone removal by 72%. Stone fonnation was eliminated in two thirds of the patients. In the remaining third there was some formation ofrenal stones in spite of acceptable concentrations of cystine in 24h samples. This shows that also the therapeutic level of urinary cystine has to be individually adjusted in some patients. Measurements of cystine in6h samples in patients without tiopronin treatment revealed considerable variations with peak concentration exceeding the corresponding 24h concentration by as mUch as 91%. Fractionated urine sampling may therefore be a tool for further adjustment of therapy. Treatment with tiopronin was well tolerated by the majority of patients, and the finding of clinically reversible membranous glomerulonephritis in 3 patients does not disqualify the drug from further use.Thirty per cent of 40 patients had light to moderate impainnent of renal function. Only 28% had an entirely normal renal function with both GFR and renography within nonnallimits, but there was no case with severe renal impairment. A renographic comparison between the pre-treatment and treatment periods suggested that the stone-preventing treatment based on monitoring of urinary cystine concentration resulted in preservation of renal function.Restriction of sodium intake resulted in a decrease in urinary cystine excretion in patients without tiopronin treatment, whereas the effect was significantly less in patients with tiopronin. In the patients without tiopronin the sodium delivery conveyed by sodium bicarbonate treatment neutralized the increased solubility of cystine obtained by its alkalinizing effect. The excretion of the disulphide between tiopronin and cysteine wasalso sodium dependent suggesting an active tubular reabsorption of this compound.