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Definition, Etiology, PathogenesisTop
Cystinuria is an autosomal recessive hereditary disorder of cystine and other dibasic amino acid (ornithine, arginine, lysine) transport system in the renal tubules and gastrointestinal tract. Excretion of excessive amounts of poorly soluble cystine in urine is the cause of cystine urolithiasis, which may develop as early as in infancy but usually occurs in patients >20 years of age.
Cystine is a homodimer of the amino acid cysteine (linked through a disulfide bond), which is freely filtered across the glomerulus and then subsequently absorbed in the proximal convoluted tubule via the cystine transporter. The absorption apparatus requires a carrier protein that assists with the expression of the protein transport channel. Mutations in the carrier protein and others in the channel are responsible for the disease phenotype. The precipitation of cystine leads to heavy stone burden, infections, and eventually to chronic kidney disease.
The same apparatus is responsible for transport of other dibasic amino acids, but their excretion does not result in stone formation because of higher urinary solubility.
Cystinuria should be suspected in patients who present with stones early in life and in those with a family history. Diagnosis can be made on the basis of results of urine microscopy revealing pathognomonic hexagonal cystine crystals, stone analysis, and a 24-hour urine collection for cystine. Under physiologic conditions, urinary excretion of cystine is <0.13 mmol/d (30 mg/d), whereas the majority of patients with cystinuria excrete >1.7 mmol/d (400 mg/d). Genetic testing is not recommended.
The goal of therapy is decreasing urinary concentration and increasing urinary solubility and excretion of cystine.
1. Reduction in urinary concentrations can be achieved by limiting salt and animal protein intake, which results in lower excretion of cysteine. The mechanisms explaining why reduced salt or sodium intake results in reduced cystine elimination are not understood.
2. Urinary solubility can be improved by increasing fluid intake and urinary alkalinization. Urine pH can be increased by potassium citrate supplementation; sodium citrate and acetazolamide are generally avoided due to their adverse effect profile. The dose of potassium citrate is weight dependent. Usually a dose of 3 to 4 mEq/kg is effective. Treatment can be started with 20 mEq orally tid and the dose subsequently increased to target a urine pH >7.0 (maximizing cystine solubility).
3. In patients refractory to the above therapy, thiol-containing drugs can be used, including D-penicillamine or tiopronin. Thiol breaks down the cystine disulfide bond, allowing for free cysteine formation and excretion. Adverse effects from both drugs can be minimized by starting with low doses (200 mg orally tid) and titrating up (usually a maximum of 400 mg orally tid). Captopril is an alternative agent that has been shown to induce similar changes as thiol compounds, forming captopril-cysteine bonds that have a significantly higher solubility than cystine alone. However, this is achieved only with high doses and may lead to significant antihypertensive effects. Evidence for clinical efficacy of captopril is very limited.Evidence 1 Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Goldfarb DS, Coe FL, Asplin JR. Urinary cystine excretion and capacity in patients with cystinuria. Kidney Int. 2006 Mar;69(6):1041-7. PubMed PMID: 16501494.
Progressive disease and lack of response to therapy can lead to heavier stone burden and may require urological intervention.