The story behind cystinuria: genetic, lifelong, and life-limiting3,4
Cystinuria is a rare condition characterized by lifelong, recurrent stones that are difficult to manage.3 Defective amino acid transporters in the proximal tubules of the kidney result in elevated urinary cystine concentration, and when these cystine levels rise above the limit of solubility (generally 250 mg/L), cystine stones form.2
Understand the mechanism behind the disease.
Proper management of cystinuria and subsequent reduction of stone burden in your patients relies on keeping cystine levels below the line of solubility (generally <250 mg/L).2,6
Cystinuria can pose unique and significant challenges that are distinct from those associated with the more common kidney stones.5 Below are some fast facts about cystinuria that make this disease particularly difficult to manage.
It has been reported that patients experience an average of 1 stone formation per year.7
Up to 70% of patients experience long-term kidney disease.3
Patients undergo an average of 1 surgical procedure every 3 years, with 7 surgical procedures by middle age.7,8
About 1 in 10,000 people in the United States live with cystinuria.9
More than 80% of people with cystinuria develop cystine kidney stones by age 20.10
Cystinuria is the cause of approximately 10% of all kidney stones in children.6
Elevated cystine should elevate your suspicion of cystinuria1,10
If your patients fit any of the following criteria, they may need extensive diagnostic evaluation.
- A history of recurrent nephrolithiasis3
- A history of stones during the first decades of life3
- Complicated imaging findings11
- Family history of disease3
- Recurrent crystalluria3
A positive diagnosis can be made if patients with cystine stones are shown to have elevated levels of cystine in the urine.1,10
In addition to using a 24-hour urine test, diagnostic-related guidelines recommend1:
- Obtaining a stone analysis at least once
- Obtaining or reviewing available imaging studies to quantify stone burden
- Performing additional metabolic testing in high-risk or interested patients with a first-time stone and those with recurrent stones
A 24-hour urine test is more than just an important diagnostic tool. Regular monitoring of cystine via urine collection can help prevent the next stone from forming by allowing you to optimize the treatment plan and THIOLA® (tiopronin) tablets dosage needed to keep your patient’s cystine level <250 mg/L.1,2,6
Cystine stone prevention relies on keeping cystine below the line of solubility2
Due to the chronic, genetic nature of cystinuria, cystine stones are constantly forming as a result of cystine buildup.2,3 Even if your patients are not experiencing a stone-related event, they are at risk. It is therefore critical to develop a treatment plan focused on managing cystine levels.2
Encourage your patients to ask you questions about these goals and provide them with access to educational resources.
Follow the methods of stone prevention
Emphasize the importance of following the treatment plan.
Patients should consume >3 L of fluid per day (10 glassfuls, 10 oz each) to achieve a minimum urine output of 2 L per day on a consistent basis.12
Patients should maintain a urine pH level between 6.5 and 7.0, often made possible by taking potassium alkali.12
Patients should eat a diet low in protein and sodium, and high in fruits and vegetables.1,6
Cystine-binding thiol drugs can be used in conjunction with therapeutic lifestyle changes if stones continue to form.1
Establish and maintain an optimal long-term management plan by performing the following ongoing measures:
Consistently monitor cystine levels with a 24-hour urine test to adjust treatment plans, if necessary.6
Evaluate and adjust your patient’s medication and dosing regimen.12
Maintain constant communication with your patients to create, evaluate, and optimize treatment plans.
The best way to prevent cystine stone formation in your patients is by encouraging adherence to their treatment plans and regularly monitoring their cystine levels to determine the best regimen to keep cystine concentration <250 mg/L.2,6
References: 1. Pearle MS, Goldfarb DS, Assimos DG, et al. Medical management of kidney stones: AUA guideline. J Urol. 2014;192(2):316-324. 2. Pareek G, Steele TH, Nakada SY. Urological intervention in patients with cystinuria is decreased with medical compliance. J Urol. 2005;174(6):2250-2252. 3. Biyani CS, Cartledge JJ. Cystinuria: diagnosis and management. EAU-EBU Update Series. 2006;4(5):175-183. doi:10.1016/j.eeus.2006.06.001. 4. Parr JM, Desai D, Winkle D. Natural history and quality of life in patients with cystine urolithiasis: a single centre study. BJU Int. 2015;116(suppl 3):31-35. doi:10.1111/bju.13169. 5. Modersitzki F, Pizzi L, Grasso M, Goldfarb DS. Health-related quality of life (HRQoL) in cystine compared with non-cystine stone formers. Urolithiasis. 2014;42(1):53-60. doi:10.1007/s00240-013-0621-4. 6. Knoll T, Zöllner A, Wendt-Nordahl G, Michel MS, Alken P. Cystinuria in childhood and adolescence: recommendations for diagnosis, treatment, and follow-up. Pediatr Nephrol. 2005;20(1):19-24. doi:10.1007/s00467-004-1663-1. 7. Barbey F, Joly D, Rieu P, Méjean A, Daudon M, Jungers P. Medical treatment of cystinuria: critical reappraisal of long-term results. J Urol. 2000;163(5):1419-1423. doi:10.1016/S0022-5347(05)67633-1. 8. Goodyer P. The molecular basis of cystinuria. Nephron Exp Nephrol. 2004;98(2):e45-e49. doi:10.1159/000080255. 9. Cystinuria. Genetics Home Reference website. https://ghr.nlm.gov/condition/cystinuria. Published December 13, 2016. Accessed December 15, 2016. 10. Eggermann T, Venghaus A, Zerres K. Cystinuria: an inborn cause of urolithiasis. Orphanet J Rare Dis. 2012;7:19. doi:10.1186/1750-1172-7-19. 11. Claes DJ, Jackson E. Cystinuria: mechanisms and management. Pediatr Nephrol. 2012;27(11):2031-2038. doi:10.1007/s00467-011-2092-6. 12. THIOLA [package insert]. San Antonio, TX: Mission Pharmacal Company.
INDICATIONS: THIOLA® (tiopronin) tablets are indicated for the prevention of cystine (kidney) stone formation in patients with severe homozygous cystinuria with urinary cystine >500 mg/day, who are resistant to treatment with conservative measures of high fluid intake, alkali and diet modification, or who have adverse reactions to d-penicillamine.
Important Safety Information
CONTRAINDICATIONS: THIOLA is contraindicated during pregnancy (except where the benefits clearly outweigh the risks), in nursing mothers, and in patients who have previously developed agranulocytosis, aplastic anemia or thrombocytopenia while on this medication.
WARNINGS AND PRECAUTIONS:
- While no deaths have been reported with THIOLA treatment, THIOLA can potentially cause all the serious adverse reactions reported for d-penicillamine, including death.
- Hematologic abnormalities requiring drug discontinuation may occur: inform patients to report promptly signs or symptoms of hematologic abnormalities.
- Proteinuria, sometimes severe enough to cause nephrotic syndrome: monitor affected patients closely.
- Discontinue THIOLA therapy if there are findings suggestive of Goodpasture’s syndrome, myasthenic syndrome, or myasthenia gravis. If pemphigus-type reactions occur, discontinue therapy and consider steroid treatment.
- Inform patients about potential complications; advise them to promptly report any treatment-emergent signs or symptoms.
- To reduce the risk of serious complications, the following tests should be conducted:
- Peripheral blood counts, direct platelet counts, hemoglobin, serum albumin, liver function tests, 24-hour urinary protein, routine urinalysis: 3-6 month intervals
- Urinary cystine analysis: frequently during dose optimization, and at 6 month intervals thereafter
- Abdominal roentgenogram: annually
- In animal studies, THIOLA has been shown to cause fetal harm. THIOLA should only be used during pregnancy if the potential benefit justifies potential risk to the fetus.
- THIOLA should not be used in nursing mothers.
- The safety and efficacy of THIOLA in children under 9 years of age have not been established.
Adverse reactions associated with THIOLA include the following:
- Drug fever during the first month
- Generalized rash with pruritus
- Lupus erythematous-like drug reaction (e.g., fever, arthralgia, lymphadenopathy, positive antinuclear antibody test)
- Vitamin B6 deficiency (uncommon)
- Wrinkling and friability of skin
- Jaundice and abnormal liver function tests (in non-cystinuric conditions)
THIOLA is associated with fewer or less severe reactions than d-penicillamine, however the following adverse reactions may occur:
- Gastrointestinal (nausea, emesis, diarrhea, anorexia, abdominal pain, bloating, flatus)
- Impairment in taste or smell
- Dermatologic (pharyngitis, oral ulcers, rash, ecchymosis, pruritus, urticaria, warts, skin wrinkling, pemphigus, elastosis perforans serpiginosa)
- Hypersensitivity reactions (laryngeal edema, dyspnea, respiratory distress, fever, chills, arthralgia, weakness, fatigue, myalgia, adenopathy)
- Hematologic (increased bleeding, anemia, leukopenia, thrombocytopenia, eosinophilia)
- Renal (proteinuria, nephrotic syndrome, hematuria)
- Pulmonary (bronchiolitis, hemoptysis, pulmonary infiltrates, dyspnea)
- Neurologic (myasthenic syndrome)
These reactions are more likely to occur during THIOLA therapy for patients who had previously shown toxicity to d-penicillamine.
Please see full Prescribing Information.