Inborn errors of Metabolism

Cystinuria

Cystinuria
is a hereditary defect in the kidney´s ability to reabsorb cystine and the amino acids Arginine, Lysine and Ornithine from the urine. Unfortunately, cystine is poorly soluble in the urine and tends to form stones in the urinary tract if the concentration is too high. Cystine stones represent about 1-2% of urinary stones in adults. Arginine, Lysine and Ornithine, do not form stones.

Symptoms
The symptoms of cystinuria are the same as from other stones in the urinary tract, regardless of origin. Thus, when a stone gets trapped in the kidney or the ureter the patient suffers from intense and recurrent pain. The urine may also contain visible blood.

Diagnosis
Cystinuria is diagnosed by measuring the concentration of cystine in the urine. This is usually done in young patients who suffers from kidney stones and in patients with kidney stones in the family.

The most usual form of cystinuria (type I, also called type A) is inherited in an autosomal recessive way. The gene involved is named SLC3A1. The cystine concentration in the urine is usually in the thousands (umol/L). If only one chromosome is affected the person has no increased concentration of cystine in the urine and no cystine stone formation.

In the less common form of cystinuria (non type I, or type B), only one chromosome needs to be affected to have an increase in cystine concentration i.e. autosomal dominant inheritance. The gene involved in this type of cystinuria is named SLC7A9. The urinary cystine concentration in the heterozygotes are usually in the high hundreds (umol/L) and may form stones. The homozygotes have the same very high urinary concentration as homozygote type I.

Treatment of cystinuria
The treatment of cystinuria is usually a triad:

Increased fluid intake to increase the urine volume and thus decrease the cystine concentration in the urine. This is the cornerstone and the basis for the other two strategies.
Increasing pH in the urine. This is because the solubility of cystine increases sharply above pH 7. Usually this is done using potassium citrate as this is to be preferred to sodium based preparations. The Urinary pH goal is usually 7-7.5, as with higher U-pH there is an increased risk for calcium-phosphate stone formation.

The reason non-sodium based preparations are preferred is a co-transportation of sodium and cystine from the urine in the renal tubuli, not affected by the disease. This means that if the patient has a lower sodium intake, more sodium will be reabsorbed from the urine and thus cystine as well.

However, if potassium citrate cannot be used (e.g. due to hyperkalaemia, dyspepsia etc), it is better to use sodium containing preparations (e.g. sodium bicarbonate) as compared to no alkalizing treatment.
Cystine binding drugs such as tiopronine and penicillamine (also called SH-substances). These drugs contain a sulfhydryl (SH-) group which binds to the disulphide bridge in cystine and forms a more soluble compound.

References:

Ala-Opas M, Sipilä I, Kivinen S, Lethonen T. Diagnostic problems associated with cystinuria. Scand J Nephrol 1990; 24: 133-135
Lee WS, Wells RG, Sabbag RV, Mohandas TK, Hediger MA. Cloning and chromosomal localisation of a human cDNA involved in cystine, dibasic and neutral amino acid transport. J Clin Invest 1993; 91: 1959-1963
Feliubadalo L, et al, International Cystinuria Consortium. Non-typ I cystinuria caused by mutations in SLC7A9, encoding a subunit (b0,+ AT) of rBAT. Nat Genet 1999; 23(1): 52-7
Rogers, A., et al. Management of cystinuria. Urol Clin North Am, 2007. 34: 347
Sakhaee K, Nicar M, Hill K, Pak CYC. Contrasting effect of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stone forming salt. Kidney Int 1983; 24: 60
Lindell Å, Denneberg T, Edholm E, Jeppsson J-O. The effect of sodium intake on cystinuria with and without tiopronin treatment. Nephron 1995; 71: 407-415
Fjellstedt, E, Denneberg T, Jeppsson J-O, Christensson A, Tiselius H-G. Cystine analyses of separate day and night urine as a basis for the management of patients with homozygous cystinuria. Urol Res, 2001. 29: 303