Early Recognition and Management of Rare Kidney Stone Disorders

Ross Goldstein, MD, MBA; David S. Goldfarb, MD


Urol Nurs. 2017;37(2):81-89. 

In This Article


Cystinuria is an autosomal recessive disorder in which the kidney, due to a genetic defect in the cystine transporter, is unable to reabsorb cystine in the proximal tubule, resulting in urinary hyperexcretion of amino acids cystine, ornithine, lysine, and arginine (COLA). Of these, only cystine is relatively insoluble at normal urinary pH, leading to stone formation when cystine concentration rises above the solubility limit (Biyani & Cartledge, 2006; Knoll, Zollner, Wendth-Nordahl, Michel, & Alken, 2005; Sumorok & Goldfarb, 2013).

Epidemiology of Cystinuria

Although cystinuria is a rare disorder, it is the most common of the rare stone disorders, accounting for 6% to 8% of stones in children and 1% of stones in adults (Biyani & Cartledge, 2006; Prot-Bertoye et al., 2015). The prevalence of cystinuria is estimated to be 1 in 7,000, globally (Claes & Jackson, 2012), but varies greatly by population. For example, the prevalence of cystinuria is as low as 1 in 100,000 in Sweden and as high as 3% to 4% of the population in Turkey, Oman, and Iran (Al-Marhoon et al., 2015; Celiksoy et al., 2015; Claes & Jackson, 2012; Mohammadjafari et al., 2014; Segal & Thier, 1995). In the United States, the estimated prevalence of cystinuria is about 1 in 10,000, equating to approximately 33,000 cases (NIH, 2014). Given that there are more than 15,000 practicing urology professionals (urologists, urology nurses, and urology physician assistants) in the U.S. (American Urological Association [AUA], 2015; Hilton, 2013; Quallich, 2011), it is likely that every urology practitioner will see at least one cystinuria patient in his or her current practice.

Clinical Presentation of Cystinuria

Acute Stage of Cystinuria. Although stones may present at any age, stone presentation in cystinuria most commonly occurs within the first two decades of life, with approximately 50% of cystinuric patients developing their first stone in the first decade of life and 25% to 40% during their teenage years (Biyani & Cartledge, 2006; Edvardsson et al., 2013). About 75% of these patients will present with bilateral stones (Biyani & Cartledge, 2006). Males are generally more severely affected than females, with a larger number of stones (Edvardsson et al., 2013). A small percentage of patients do not form stones. On average, untreated patients experience one new stone every year and undergo a surgical procedure to remove the stones every three years. By middle age, the average cystinuria patient will undergo seven surgical procedures (Barbey et al., 2000).

Chronic Kidney Disease From Kidney Stones. Up to 70% of patients with cystinuria may develop some form of chronic kidney disease (CKD), which may lead to end stage renal disease (ESRD) (Barbey et al., 2000). In a retrospective study that collected data from 442 patients with cystinuria, 27% of patients had an estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73m2, indicating some degree of CKD. Hypertension was also common in this study, with 28.6% of patients having high blood pressure (Prot-Bertoye et al., 2015). Bilateral stones may also increase the risk for acute kidney injury, particularly in children. Indeed, young children with acute renal failure due to ureteral stones should be tested for cystinuria (Nalcacioglu et al., 2013). Compared with calcium oxalate stone formers, patients with cystinuria are more likely to have abnormal serum creatinine levels and are at higher risk for nephrectomy (Assimos, Leslie, Ng, Streem, & Hart, 2002).

Diagnosis of Cystinuria

The diagnosis of cystinuria is easily made by stone analysis, microscopic examination of the urine, and 24-hour urine testing. Microscopic examination of urine will often show hexagonal crystals, which are pathognomonic of cystinuria (see Figure 1). Analysis of 24-hour urine will show elevated cystine concentrations of greater than 400 mg/L urine (Biyani & Cartledge, 2006).

Figure 1.

Hexagonal Crystals in the Urine Are Pathognomonic of Cystinuria
Source: reprinted with permission from Edvardsson et al., 2013.

Treatment of Cystinuria

The goal of treatment in cystinuria is to prevent recurrence of stones by decreasing urinary cystine concentrations to below the solubility limit (< 250 mg/L) or increasing the solubility of cystine. According to AUA guidelines for the management of kidney stones, the first approach to treatment of cystinuria is a conservative program that includes initiation of therapeutic lifestyle changes involving increased fluid intake and restriction of sodium and protein, as well as urinary alkalinization therapy (Pearle et al., 2014). If conservative therapy fails to reduce urinary cystine concentrations to less than 250 mg/L or stones recur despite therapy, cystine-binding thiol drugs are the next step in treatment (Pearle et al., 2014).

Therapeutic Lifestyle Changes and Urinary Alkalinization

Fluid intake should be increased to achieve a urine volume of at least 2.5 liters daily (Pearle et al., 2014). The general goal of fluid intake is to reduce the concentration of cystine to less than 250 mg/L at pH 7, and patients should be counseled on the importance of maintaining high fluid intake. For patients with cystinuria, achieving this goal may require much higher levels of fluid intake (up to 5 L/day) than for other types of stone formers (Pearle et al., 2014).

Clinicians should counsel patients with cystinuria to limit sodium intake with the goal of decreasing urine cystine excretion (Lindell, Denneberg, Edholm, & Jeppsson, 1995; Pearle et al., 2014; Rodriguez, Santos, Málaga, & Martínez, 1995). Ideally, sodium intake should be limited to 2,300 mg or less (Pearle et al., 2014).

A low-protein/vegetarian diet reduces cystine excretion because foods of animal origin are rich in cystine and methionine, which is metabolized to cystine (Pearle et al., 2014). Re ducing animal protein intake also helps with urinary alkalinization. In a study of seven patients with cystinuria, urinary cystine excretion decreased significantly when patients were maintained on a low-protein diet (9% protein) versus a higher-protein diet (27% protein) (Rodman et al., 1984).

At urine pH 7.5, the solubility of cystine increases to about 500 mg/L (Barbey et al., 2000), hence the importance of urine alkalinization therapy in patients with cystinuria. Urine alkalinization therapy with potassium citrate is recommended for patients with cystine stones to raise urinary pH to an optimal level (Pearle et al., 2014). This may require dosing throughout the day (Pearle et al., 2014). Potassium citrate is preferred over sodium bicarbonate because sodium bicarbonate increases sodium load and cystine excretion (Fjellstedt, Denneberg, Jeppsson, & Tiselius, 2001). How ever, potassium citrate should not be used in patients with severe renal impairment (Fjellstedt et al., 2001).

Following initiation of therapeutic lifestyle changes and urine alkalinization therapy, 24-hour urine should be collected again after three to six months and analyzed. If urinary cystine levels are still greater than 250 mg/L or there is stone recurrence, cystine-binding thiol drugs constitute the next line of therapy (Pearle et al., 2014). The failure rate of conservative therapy (therapeutic lifestyle changes and urinary alkalinization) may be as high as 55% (Barbey et al., 2000).

Cystine-binding Thiol Drugs

Cystine-binding thiol drugs include alpha-mercaptopropionylglycine, also known as tiopronin (Thiola®) and D-penicillamine. Tiopronin should be considered first if conservative therapy fails (Pearle et al., 2014) because tiopronin has been shown to be approximately 1.5 times as effective as D-penicillamine both in reducing urinary excretion of free cystine and increasing the amounts of soluble mixed disulfide in the urine (Harbar, Cusworth, Lawes, & Wrong, 1986). Dosing of tiopronin should be based on the amount required to reduce urinary cystine concentration to below its solubility limit (generally < 250 mg/L), which in turn is determined by urinary cystine level.

Thiol derivatives, such as tiopronin and D-penicillamine, cleave cystine into two cysteine moieties and combine with cysteine to form a highly soluble disulfide compound, decreasing the excretion of poorly soluble-free cystine and increasing its solubility. Although captopril has sometimes been promoted for the management of cystinuria, it is not approved by the United States Food and Drug Administration for the treatment of cystinuria, and it does not appear in the urine in sufficient amounts to be useful. The effect of these thiol drugs depends on urine pH, with less cystine dissolved at lower pH. Therefore, thiol drugs should be used in conjunction with alkalinization therapy (Asplin & Asplin 2013).

In a study by Barbey et al. (2000), addition of thiol drugs to standard hyperdiuresis/alkalinization therapy was shown to decrease cystine excretion by 32% versus baseline. A treatment regimen of hyperdiuresis, alkalinization, and thiol drugs with frequent follow up and monitoring prevents or markedly de creases cystine stone formation, and precludes the need for urologic procedures in the majority of patients (Barbey et al., 2000; Chow & Streem, 1996; Denneberg, Jeppsson, & Stenberg, 1983; Hautmann, 1983; Koide, Kinoshita, Takemoto, Yachiku, & Sonoda, 1982; Lindell, Denneberg, Hellgren, & Jeppsson, 1995; Strologo, Laurenzi, Legato, & Pastore, 2007).

Importance of Treatment Adherence

The importance of treatment adherence for patients with cystinuria cannot be overemphasized. In a retrospective study of 20 patients treated at a single urology center, compliance with a treatment regimen that included fluid intake, urinary alkalinization, and cystine-binding drugs was associated with a lower rate of stone formation and surgical interventions (Pareek, Steele, & Nakada, 2005). In this study, 73% of the 11 compliant patients were stone-free versus 33% of the 9 noncompliant patients. The compliant patients underwent significantly fewer surgical procedures per year versus the noncompliant patients (1.0/patient versus 4.0/patient, respectively; p < 0.05) (Pareek et al., 2005).