History

The presentation in patients with cystinuria is similar to that of patients with other types of renal calculi and includes the following:

Renal colic
Chronic urinary tract infections in a young person with a family history of kidney stones
Passage of stones or gravel
Hematuria
Dysuria

Infrequent association with retinitis pigmentosa, hemophilia, muscular dystrophy, Down syndrome, and hereditary pancreatitis has been reported.

Twenty-five percent of symptomatic patients report their first stone in the first decade of life. Another 30%-40% have their first experience as teenagers.

Homozygous cystinuria is characterized by lifelong, recurrent urolithiasis that is difficult to manage, either surgically or medically. In general, more than 50% of homozygotes develop kidney stones; 75% of these patients present with bilateral calculi.

Physical Examination

Examination findings of fever (with urinary tract infection) and costovertebral angle tenderness are identical to those of other types of calculi.

Differential Diagnoses

Leslie SW, Sajjad H, Nazzal L. Cystinuria. 2023 Jan. [QxMD MEDLINE Link]. [Full Text].
Kowalczyk NS, Zisman AL. Cystinuria: Review of a Life-long and Frustrating Disease. Yale J Biol Med. 2021 Dec. 94 (4):681-686. [QxMD MEDLINE Link]. [Full Text].
Barbey F, Joly D, Rieu P, et al. Medical treatment of cystinuria: critical reappraisal of long-term results. J Urol. 2000 May. 163(5):1419-23. [QxMD MEDLINE Link].
[Guideline] Eisner BH, Goldfarb DS, Baum MA, Langman CB, Curhan GC, Preminger GM, et al. Evaluation and Medical Management of Patients with Cystine Nephrolithiasis: A Consensus Statement. J Endourol. 2020 Nov. 34 (11):1103-1110. [QxMD MEDLINE Link]. [Full Text].
Wollaston WH. On cystic oxide. A new species of urinary calculus. Trans R Soc London. 1810. 100:223-30.
Berzellius J. Calculus urinaires. Traite Chem. 1833. 7:424.
Garrod AE. Inborn errors of metabolism. Lancet. 1908. 2:1, 73, 142, 214.
Yeh HL, Frankl W, Dunn MS. The urinary excretion of amino acids by cystinuric subjects. Am J Med Sci. 1974. 214:507-12.
Dent CC, Rose GA. Amino acid metabolism in cystinuria. Q J Med New Series. 1974. 214:507-12.
Harris H, Mittwoch U, Robson EB, Warren FL. Phenotypes and genotypes in cystinuria. Ann Hum Genet. 1955 Aug. 20(1):57-91. [QxMD MEDLINE Link].
Milne MD, Asatoor AM, Edwards KD, Loughridge LW. The intestinal absorption defect in cystinuria. Gut. 1961 Dec. 2(4):323-37. [QxMD MEDLINE Link].
Tabachnick M, Eisen HN, Levine B. A new mixed disulphide: penicillamine-cysteine. Nature. 1954 Oct 9. 174(4432):701-2. [QxMD MEDLINE Link].
Crawhall JC, Scowen EF, Watts RW. Effect of penicillamine on cystinuria. Br Med J. 1963 Mar 2. 5330:588-90. [QxMD MEDLINE Link].
Lee WS, Wells RG, Sabbag RV, et al. Cloning and chromosomal localization of a human kidney cDNA involved in cystine, dibasic, and neutral amino acid transport. J Clin Invest. 1993 May. 91(5):1959-63. [QxMD MEDLINE Link].
Bisceglia L, Calonge MJ, Totaro A, et al. Localization, by linkage analysis, of the cystinuria type III gene to chromosome 19q13.1. Am J Hum Genet. 1997 Mar. 60(3):611-6. [QxMD MEDLINE Link].
Markazi S, Kheirollahi M, Doosti A, Mohammadi M, Koulivand L. A Novel Mutation in SLC3A1 Gene in Patients With Cystinuria. Iran J Kidney Dis. 2016 Jan. 10 (1):44-7. [QxMD MEDLINE Link].
Chillarón J, Font-Llitjós M, Fort J, Zorzano A, Goldfarb DS, Nunes V, et al. Pathophysiology and treatment of cystinuria. Nat Rev Nephrol. 2010 Jul. 6(7):424-34. [QxMD MEDLINE Link].
Dent CE, Senior B. Studies on the treatment of cystinuria. Br J Urol. 1955 Dec. 27(4):317-32. [QxMD MEDLINE Link].
Pak CY, Fuller C, Sakhaee K, et al. Management of cystine nephrolithiasis with alpha- mercaptopropionylglycine. J Urol. 1986 Nov. 136(5):1003-8. [QxMD MEDLINE Link].
Pak CY, Fuller CJ. Assessment of cystine solubility in urine and of heterogeneous nucleation. J Urol. 1983 May. 129(5):1066-70. [QxMD MEDLINE Link].
Martins MC, Meyers AA, Whalley NA, Rodgers AL. Cystine: a promoter of the growth and aggregation of calcium oxalate crystals in normal undiluted human urine. J Urol. 2002 Jan. 167(1):317-21. [QxMD MEDLINE Link].
Gasparini P, Calonge MJ, Bisceglia L, et al. Molecular genetics of cystinuria: identification of four new mutations and seven polymorphisms, and evidence for genetic heterogeneity. Am J Hum Genet. 1995 Oct. 57(4):781-8. [QxMD MEDLINE Link].
Andreassen KH, Pedersen KV, Osther SS, Jung HU, Lildal SK, Osther PJ. How should patients with cystine stone disease be evaluated and treated in the twenty-first century?. Urolithiasis. 2016 Feb. 44 (1):65-76. [QxMD MEDLINE Link].
Pras E. Cystinuria at the turn of the millennium: clinical aspects and new molecular developments. Mol Urol. 2000 Winter. 4(4):409-14. [QxMD MEDLINE Link].
Dello Strologo L, Pras E, Pontesilli C, et al. Comparison between SLC3A1 and SLC7A9 cystinuria patients and carriers: a need for a new classification. J Am Soc Nephrol. 2002 Oct. 13(10):2547-53. [QxMD MEDLINE Link].
Martens K, Jaeken J, Matthijs G, Creemers JW. Multi-system disorder syndromes associated with cystinuria type I. Curr Mol Med. 2008 Sep. 8(6):544-50. [QxMD MEDLINE Link].
Rosenberg LE, Downing S, Durant JL, Segal S. Cystinuria: biochemical evidence for three genetically distinct diseases. J Clin Invest. 1966 Mar. 45(3):365-71. [QxMD MEDLINE Link].
Gaildrat P, Lebbah S, Tebani A, Sudrié-Arnaud B, Tostivint I, Bollee G, et al. Clinical and molecular characterization of cystinuria in a French cohort: relevance of assessing large-scale rearrangements and splicing variants. Mol Genet Genomic Med. 2017 Jul. 5 (4):373-389. [QxMD MEDLINE Link]. [Full Text].
Goldstein B, Goldfarb DS. Early Recognition and Management of Rare Kidney Stone Disorders. Urol Nurs. 2017 Mar-Apr. 37 (2):81-9, 102. [QxMD MEDLINE Link]. [Full Text].
Fazaeli S, Ashouri S, Kheirollahi M, Mohammadi M, Fazilati M. A Novel Mutation in SLC7A9 Gene in Cystinuria. Iran J Kidney Dis. 2017 Mar. 11 (2):138-141. [QxMD MEDLINE Link]. [Full Text].
Obaid A, Nashabat M, Al Fakeeh K, Al Qahtani AT, Alfadhel M. Delineation of cystinuria in Saudi Arabia: A case series. BMC Nephrol. 2017 Feb 6. 18 (1):50. [QxMD MEDLINE Link]. [Full Text].
Chow GK, Streem SB. Contemporary urological intervention for cystinuric patients: immediate and long-term impact and implications. J Urol. 1998 Aug. 160(2):341-4; discussion 344-5. [QxMD MEDLINE Link].
Lindell A, Denneberg T, Granerus G. Studies on renal function in patients with cystinuria. Nephron. 1997. 77(1):76-85. [QxMD MEDLINE Link].
Prot-Bertoye C, Lebbah S, Daudon M, et al. CKD and Its Risk Factors among Patients with Cystinuria. Clin J Am Soc Nephrol. 2015 May 7. 10 (5):842-51. [QxMD MEDLINE Link]. [Full Text].
Pareek G, Steele TH, Nakada SY. Urological intervention in patients with cystinuria is decreased with medical compliance. J Urol. 2005 Dec. 174(6):2250-2, discussion 2252. [QxMD MEDLINE Link].
Daudon M, Cohen-Solal F, Barbey F, et al. Cystine crystal volume determination: a useful tool in the management of cystinuric patients. Urol Res. 2003 Jul. 31(3):207-11. [QxMD MEDLINE Link].
Coe FL, Clark C, Parks JH, Asplin JR. Solid phase assay of urine cystine supersaturation in the presence of cystine binding drugs. J Urol. 2001 Aug. 166(2):688-93. [QxMD MEDLINE Link].
Dolin DJ, Asplin JR, Flagel L, et al. Effect of cystine-binding thiol drugs on urinary cystine capacity in patients with cystinuria. J Endourol. 2005 Apr. 19(3):429-32. [QxMD MEDLINE Link].
van Hoeve K, Vermeersch P, Regal L, Levtchenko E. Necessity of fractionated urine collection for monitoring patients with cystinuria. Clin Chem. 2011 May. 57(5):780-1. [QxMD MEDLINE Link].
Sakhaee K, Poindexter JR, Pak CY. The spectrum of metabolic abnormalities in patients with cystine nephrolithiasis. J Urol. 1989 Apr. 141(4):819-21. [QxMD MEDLINE Link].
Pontoni G, Rotondo F, Spagnuolo G, et al. Diagnosis and follow-up of cystinuria: use of proton magnetic resonance spectroscopy. Amino Acids. 2000. 19(2):469-76. [QxMD MEDLINE Link].
Goldfarb DS. Potential pharmacologic treatments for cystinuria and for calcium stones associated with hyperuricosuria. Clin J Am Soc Nephrol. 2011 Aug. 6(8):2093-7. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Servais A, et al; Metabolic Nephropathy Workgroup of the European Reference Network for Rare Kidney Diseases (ERKNet) and eUROGEN. Cystinuria: clinical practice recommendation. Kidney Int. 2021 Jan. 99 (1):48-58. [QxMD MEDLINE Link]. [Full Text].
Sahota A, Tischfield JA, Goldfarb DS, Ward MD, Hu L. Cystinuria: genetic aspects, mouse models, and a new approach to therapy. Urolithiasis. 2019 Feb. 47 (1):57-66. [QxMD MEDLINE Link]. [Full Text].
Azer SM, Goldfarb DS. A Summary of Current Guidelines and Future Directions for Medical Management and Monitoring of Patients with Cystinuria. Healthcare (Basel). 2023 Feb 24. 11 (5):[QxMD MEDLINE Link]. [Full Text].
[Guideline] Pearle MS, Goldfarb DS, Assimos DG, Curhan G, Denu-Ciocca CJ, Matlaga BR, et al. Medical management of kidney stones: AUA guideline. J Urol. 2014 Aug. 192 (2):316-24. [QxMD MEDLINE Link]. [Full Text].
Koide T, Yamaguchi S, Utsonomiya M. A new therapeutic agent for cystinuria. VII International Symposium on Urolithiasis. Cairns, Australia. New York, NY: Plenum; 1992. 168.
Kachel TA, Vijan SR, Dretler SP. Endourological experience with cystine calculi and a treatment algorithm. J Urol. 1991 Jan. 145(1):25-8. [QxMD MEDLINE Link].
Schmidt J, Madersbacher S, Hochreiter WW, et al. Simultaneous replacement of both ureters with small intestine in a woman with cystinuria. J Urol. 2001 Dec. 166(6):2315-6. [QxMD MEDLINE Link].
Bucillamine Phase 2 Trial in Patients With Cystinuria (NCT02942420). ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT02942420. May 18, 2017; Accessed: August 2, 2023.
Tiselius HG. New horizons in the management of patients with cystinuria. Curr Opin Urol. 2010 Mar. 20(2):169-73. [QxMD MEDLINE Link].
Miyagi K, Nakada F, Ohshiro S. Effect of glutamine on cystine excretion in a patient with cystinuria. N Engl J Med. 1979 Jul 26. 301(4):196-8. [QxMD MEDLINE Link].

Media Gallery

Cystine solubility in urine.
Electron microscopic picture showing cystine crystals.
Plain radiograph of the abdomen showing cystine staghorn stones.
Faintly opaque (ground-glass appearance) left lower ureteric stone.
Intravenous urogram showing left ureterohydronephrosis.
Renal sonogram demonstrating renal calculi in the lower pole.
Treatment algorithm for cystinuria.

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Table. Classification of Cystinuria

Table. Classification of Cystinuria

Rosenberg et al ^[27]	Type I	Type II	Type III
Molecular	Type I	Non–Type I
Responsible gene	SLC3A1	SLC7A9
Band	2p21	19q13.1
No. of mutations	>60	39
Most common mutation	M467	V170M
Population affected	Mediterranean Spanish persons, 40%	Libyan Jews
Deletion rate	54%	25%
Protein	rBAT	BAT1
Amino acid transport system
Localization in proximal converted tubule	S3	S1, S2
Transporter characteristic	High affinity, low capacity	Low affinity, high capacity
Clinical features
Homozygotes	Symptomatic	approximately 90% symptomatic
Heterozygotes	Asymptomatic	approximately 10%-13% symptomatic
Urinary cystine levels	Normal	Elevated +++++	Elevated +
Plasma cystine levels after an oral load test	Same	Same or slight rise	Increased
Intestinal transport	Absent (no transport of cystine, lysine, or arginine)	Absent	Reduced

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Author

Chandra Shekhar Biyani, MS, MBBS, DUrol, FRCS(Urol), FEBU Consulting Urologist, Department of Urology, Pinderfields General Hospital, The Mid-Yorkshire Hospitals NHS Trust, UK

Chandra Shekhar Biyani, MS, MBBS, DUrol, FRCS(Urol), FEBU is a member of the following medical societies: British Medical Association, International College of Surgeons, British Association of Urological Surgeons, European Association of Urology

Disclosure: Nothing to disclose.

Coauthor(s)

Jon Cartledge, MB, BCh, MD, FRCS Consulting Urologist, Pyrah Department of Urology, St James's University Hospital, Leeds, UK

Jon Cartledge, MB, BCh, MD, FRCS is a member of the following medical societies: British Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Eleanor Lederer, MD, FASN Professor of Medicine, Chief, Nephrology Division, Director, Nephrology Training Program, Director, Metabolic Stone Clinic, Kidney Disease Program, University of Louisville School of Medicine; Consulting Staff, Louisville Veterans Affairs Hospital

Eleanor Lederer, MD, FASN is a member of the following medical societies: American Association for the Advancement of Science, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Transplantation, International Society of Nephrology, Kentucky Medical Association, National Kidney Foundation

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Society of Nephrology<br/>Received income in an amount equal to or greater than $250 from: Healthcare Quality Strategies, Inc.

Chief Editor

Bradley Fields Schwartz, DO, FACS Professor of Urology, Director, Center for Laparoscopy and Endourology, Department of Surgery, Southern Illinois University School of Medicine

Bradley Fields Schwartz, DO, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Association of Military Osteopathic Physicians and Surgeons, Endourological Society, Society of Laparoscopic and Robotic Surgeons, Society of University Urologists

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Endourological Society Board of Directors; President Elect North Central Section of the American Urological Association<br/>Serve(d) as a speaker or a member of a speakers bureau for: Cook Medical.

Additional Contributors

Cystinuria Clinical Presentation

History

Physical Examination

References

Tables

Contributor Information and Disclosures

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