Cystinuria in childhood and adolescence: recommendations for diagnosis, treatment, and follow-up

Abstract

Cystinuria, an autosomal-recessive disorder of a renal tubular amino acid transporter, is the cause of about 10% of all kidney stones observed in children. Different genetic characteristics are not represented by different phenotypes. The stones are formed of cystine, which is relatively insoluble at the physiological pH of urine. Without any preventive measures, the patients will suffer from recurrent stone formation throughout their life. Even with medical management, long-term outcome is poor due to insufficient efficacy and low patient compliance. Many patients suffer from renal insufficiency as a result of recurrent stone formation and repeated interventions. However, regular follow-up and optimal pharmacotherapy significantly increase stone-free intervals. Medical management is mainly based on hyperhydration and urine alkalinization. Sulfhydryl agents such as tiopronin can be added. Recurrent stone formation necessitates repeated urological interventions. These mostly minimally invasive procedures carry the risk of impairment of renal function. In adults, extracorporeal shockwave lithotripsy (SWL) as well as intracorporeal lithotripsy is often unsuccessful. However, in children SWL shows excellent results for cystine stones. In cases with large stone burden, percutaneous nephrolithotripsy (PNL) or even open surgical nephrolithotomy are preferred. This review discusses the underlying pathogenetic mechanisms and provides guidance for the diagnosis, therapy, and management of cystinuria following the recommendations of the International Cystinuria Consortium and the European Association of Urology.

Slc7a9knockout mouse is a good cystinuria model for antilithiasic pharmacological studies

“…Dietary and pharmacological metaphylaxis may lower the frequency of recurrent stones but are often not practiced (28). In humans, pharmacological treatment with thiol drugs, although quite effective, is reserved for the most severe cases (when cystine excretion exceeds 3 mmol/day), due to the number and severity of their side effects in a significant number of patients (7,11,28), entailing that 69 and 31% of the patients do not tolerate the treatment with DP and MPG, respectively; this limits treatment success (32).…”

“…In fact, cystinuria is the cause of up to 10% of all urinary stones in children (6, 14 -16, 28). More than 80% of cystinuric patients develop their first cystine stone within the first two decades of life, 75% in both kidneys (28). Most patients suffer from recurrent stone formation throughout their life, with the need for repeated interventions (37,38).…”

“…However, regular follow-up and optimal pharmacotherapy significantly increase stone-free intervals (28). Human cystinuria is treated by preventing the urolithiasis through high fluid intake, a low-salt diet (Ͻ2 g NaCl/day), moderate reduction of protein intake (Ͻ0.8 g/day), and urine alkalinization to pH values of at least 7.5 (with potassium citrate, or sodium bicarbonate in severe renal insufficiency cases) to maximize cystine solubility, and if this fails, by the dissolution or breakage of calculi (25,28,34). Calculi are removed by surgical nephrolithotomy (large stones), percutaneous nephrolithotripsy, intracorporeal lithotripsy and, in the case of recently formed calculi, by extracorporeal shock wave lithotripsy.…”

“…Calculi are removed by surgical nephrolithotomy (large stones), percutaneous nephrolithotripsy, intracorporeal lithotripsy and, in the case of recently formed calculi, by extracorporeal shock wave lithotripsy. These procedures, mostly minimally invasive, carry the risk of progressive renal function impairment (28). The pharmacological approach is based on oral administration of sulfhydryl molecules able to displace the redox equilibrium between cystine (insoluble) and cysteine (soluble), by forming a soluble complex with cysteine.…”

“…DP is associated with a wide spectrum of adverse effects and toxicities, including copper and pyridoxine depletion, proteinuria, glomerulonephritis, and nephrotic syndrome (12,26,28). ␣-Mercaptopropionylglycine seems to have significantly fewer side effects than DP and is preferred by most physicians (32).…”