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Cystine Stones

  • Nikhil AgrawalEmail author
  • Kambiz Zandi-Nejad
Chapter
Part of the Nutrition and Health book series (NH)

Abstract

Cystine stones are an uncommon form of kidney stones but carry high morbidity. They occur in patients with cystinuria, a rare genetic defect in tubular reabsorption of cationic amino acids leading to high amounts of cystine amino acids in urine. Inheritance is autosomal and two major genetic types have been identified. Cystine nephrolithiasis and related kidney diseases are usually the only clinically pertinent manifestation of this disorder.

These patients, mostly presenting in their teens, frequently have a high stone burden and high recurrence rate of kidney stones. Compared with the other more common forms of kidney stones, these patients require a much higher number of invasive procedures and are at higher risk for chronic kidney disease.

Diagnosis is made by stone analysis and measurement of very high cystine levels in urine. Medical management of these stones is successful at reducing the rate of recurrence and the need for surgical procedures but requires high compliance with dietary and pharmacological interventions as well as close follow-up. Cystine capacity is a new urine assay, which is used as a measure of cystine saturation in urine and is helpful in guiding the ongoing management of cystine stones.

The goal of therapy is to modify the urinary milieu to increase solubility of cystine and may include drugs that bind cystine in urine. Dietary management is critical with focus on increasing the urine volume and pH. Pharmacological therapy with urine alkalizing agents and cystine-binding thiol drugs (CBTDs) is often utilized. The two CBTDs, D-penicillamine and tiopronin, are effective agents but require close monitoring due to the need for dose titration and high incidence of adverse reactions.

Ongoing research may help develop newer therapeutic options in the future for this disease with high medical and psychosocial morbidity.

Keywords

Cystine stone cystinuria 

References

  1. 1.
    Pereira DJ, Schoolwerth AC, Pais VM. Cystinuria: current concepts and future directions. Clin Nephrol. 2015;83(3):138–46.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Mattoo A, Goldfarb DS. Cystinuria. Semin Nephrol. 2008;28(2):181–91.PubMedCrossRefGoogle Scholar
  3. 3.
    Fotiadis D, Kanai Y, Palacin M. The SLC3 and SLC7 families of amino acid transporters. Mol Asp Med. 2013;34(2–3):139–58.CrossRefGoogle Scholar
  4. 4.
    Chillaron J, et al. Pathophysiology and treatment of cystinuria. Nat Rev Nephrol. 2010;6(7):424–34.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Fattah H, Hambaroush Y, Goldfarb DS. Cystine nephrolithiasis. Transl Androl Urol. 2014;3(3):228–33.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Lambert EH, et al. Analysis of 24-hour urine parameters as it relates to age of onset of cystine stone formation. J Endourol. 2010;24(7):1179–82.PubMedCrossRefGoogle Scholar
  7. 7.
    Dello Strologo L, et al. Comparison between SLC3A1 and SLC7A9 cystinuria patients and carriers: a need for a new classification. J Am Soc Nephrol. 2002;13(10):2547–53.CrossRefGoogle Scholar
  8. 8.
    Rhodes HL, et al. Clinical and genetic analysis of patients with cystinuria in the United Kingdom. Clin J Am Soc Nephrol. 2015;10(7):1235–45.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Cranidis AI, et al. Cystine stones: the efficacy of percutaneous and shock wave lithotripsy. Urol Int. 1996;56(3):180–3.PubMedCrossRefGoogle Scholar
  10. 10.
    Worcester EM, et al. Reduced renal function and benefits of treatment in cystinuria vs other forms of nephrolithiasis. BJU Int. 2006;97(6):1285–90.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Assimos DG, et al. The impact of cystinuria on renal function. J Urol. 2002;168(1):27–30.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Modersitzki F, et al. Health-Related Quality of Life (HRQoL) in cystine compared with non-cystine stone formers. Urolithiasis. 2014;42(1):53–60.PubMedCrossRefGoogle Scholar
  13. 13.
    Prot-Bertoye C, et al. CKD and its risk factors among patients with cystinuria. Clin J Am Soc Nephrol. 2015;10(5):842–51.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Scriver CR. Garrod’s Croonian lectures (1908) and the charter ‘inborn errors of metabolism’: albinism, alkaptonuria, cystinuria, and pentosuria at age 100 in 2008. J Inherit Metab Dis. 2008;31(5):580–98.PubMedCrossRefGoogle Scholar
  15. 15.
    Eggermann T, et al. Clinical utility gene card for: cystinuria. Eur J Hum Genet. 2012;20(2):1–2.Google Scholar
  16. 16.
    Knoll T, et al. Cystinuria in childhood and adolescence: recommendations for diagnosis, treatment, and follow-up. Pediatr Nephrol. 2005;20(1):19–24.PubMedCrossRefGoogle Scholar
  17. 17.
    Moses R, et al. Changes in stone composition over two decades: evaluation of over 10,000 stone analyses. Urolithiasis. 2015;43(2):135–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Stoller ML, et al. Acalculous cystinuria. J Endourol. 1997;11(4):233–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Cochat P, et al. Nephrolithiasis related to inborn metabolic diseases. Pediatr Nephrol. 2010;25(3):415–24.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Andreassen KH, et al. How should patients with cystine stone disease be evaluated and treated in the twenty-first century? Urolithiasis. 2016;44(1):65–76.PubMedCrossRefGoogle Scholar
  21. 21.
    Masotti A, et al. Gender-related effects on urine L-cystine metastability. Amino Acids. 2014;46(2):415–27.PubMedCrossRefGoogle Scholar
  22. 22.
    Finocchiaro R, et al. Usefulness of cyanide-nitroprusside test in detecting incomplete recessive heterozygotes for cystinuria: a standardized dilution procedure. Urol Res. 1998;26(6):401–5.PubMedCrossRefGoogle Scholar
  23. 23.
    Giugliani R, Ferrari I, Greene LJ. An evaluation of four methods for the detection of heterozygous cystinuria. Clin Chim Acta. 1987;164(2):227–33.PubMedCrossRefGoogle Scholar
  24. 24.
    Barbey F, et al. Medical treatment of cystinuria: critical reappraisal of long-term results. J Urol. 2000;163(5):1419–23.PubMedCrossRefGoogle Scholar
  25. 25.
    Goldfarb DS, Coe FL, Asplin JR. Urinary cystine excretion and capacity in patients with cystinuria. Kidney Int. 2006;69(6):1041–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Rogers A, et al. Management of cystinuria. Urol Clin North Am. 2007;34(3):347–62.PubMedCrossRefGoogle Scholar
  27. 27.
    Rodman JS, et al. The effect of dietary protein on cystine excretion in patients with cystinuria. Clin Nephrol. 1984;22(6):273–8.PubMedGoogle Scholar
  28. 28.
    Jaeger P, et al. Anticystinuric effects of glutamine and of dietary sodium restriction. N Engl J Med. 1986;315(18):1120–3.PubMedCrossRefGoogle Scholar
  29. 29.
    Meschi T, et al. The effect of fruits and vegetables on urinary stone risk factors. Kidney Int. 2004;66(6):2402–10.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Torres VE, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367(25):2407–18.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    de Boer H, Roelofsen A, Janssens PM. Antidiuretic hormone antagonist to reduce cystine stone formation. Ann Intern Med. 2012;157(6):459–60.PubMedCrossRefGoogle Scholar
  32. 32.
    Pak CY, et al. Management of cystine nephrolithiasis with alpha-mercaptopropionylglycine. J Urol. 1986;136(5):1003–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Moe OW, Pearle MS, Sakhaee K. Pharmacotherapy of urolithiasis: evidence from clinical trials. Kidney Int. 2011;79(4):385–92.PubMedCrossRefGoogle Scholar
  34. 34.
    Chow GK, Streem SB. Medical treatment of cystinuria: results of contemporary clinical practice. J Urol. 1996;156(5):1576–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Xu H, et al. Kidney stones: an update on current pharmacological management and future directions. Expert Opin Pharmacother. 2013;14(4):435–47.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Hall CL, et al. Natural course of penicillamine nephropathy: a long term study of 33 patients. Br Med J (Clin Res Ed). 1988;296(6629):1083–6.CrossRefGoogle Scholar
  37. 37.
    Habib GS, et al. Penicillamine and nephrotic syndrome. Eur J Intern Med. 2006;17(5):343–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Ntoso KA, et al. Penicillamine-induced rapidly progressive glomerulonephritis in patients with progressive systemic sclerosis: successful treatment of two patients and a review of the literature. Am J Kidney Dis. 1986;8(3):159–63.PubMedCrossRefGoogle Scholar
  39. 39.
    Tasic V, et al. Nephrotic syndrome occurring during tiopronin treatment for cystinuria. Eur J Pediatr. 2011;170(2):247–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Cohen TD, Streem SB, Hall P. Clinical effect of captopril on the formation and growth of cystine calculi. J Urol. 1995;154(1):164–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Michelakakis H, et al. Ineffectiveness of captopril in reducing cystine excretion in cystinuric children. J Inherit Metab Dis. 1993;16(6):1042–3.PubMedCrossRefGoogle Scholar
  42. 42.
    Asplin DM, Asplin JR. The interaction of thiol drugs and urine pH in the treatment of cystinuria. J Urol. 2013;189(6):2147–51.PubMedCrossRefGoogle Scholar
  43. 43.
    Sumorok N, Goldfarb DS. Update on cystinuria. Curr Opin Nephrol Hypertens. 2013;22(4):427–31.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Pietrow P, et al. Durability of the medical management of cystinuria. J Urol. 2003;169(1):68–70.PubMedCrossRefGoogle Scholar
  45. 45.
    Pareek G, Steele TH, Nakada SY. Urological intervention in patients with cystinuria is decreased with medical compliance. J Urol. 2005;174(6):2250–2, discussion 2252.PubMedCrossRefGoogle Scholar
  46. 46.
    Fjellstedt E, et al. Cystine analyses of separate day and night urine as a basis for the management of patients with homozygous cystinuria. Urol Res. 2001;29(5):303–10.PubMedCrossRefGoogle Scholar
  47. 47.
    Haritopoulos K, et al. Impact of a metabolic stone clinic on management of patients with cystinuria: 5 years follow-up. Clin Ter. 2010;161(4):341–4.PubMedGoogle Scholar
  48. 48.
    Tuso P, et al. Cystinuria and renal transplantation. Nephron. 1993;63(4):478.PubMedCrossRefGoogle Scholar
  49. 49.
    Sahota A, et al. Novel cystine ester mimics for the treatment of cystinuria-induced urolithiasis in a knockout mouse model. Urology. 2014;84(5):1249 e9–15.CrossRefGoogle Scholar
  50. 50.
    Lee MH, et al. Cystine growth inhibition through molecular mimicry: a new paradigm for the prevention of crystal diseases. Curr Rheumatol Rep. 2015;17(5):33.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Rimer JD, et al. Crystal growth inhibitors for the prevention of L-cystine kidney stones through molecular design. Science. 2010;330(6002):337–41.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division NephrologyBeth Israel Deaconess Medical Center, Harvard Medical SchoolBostonUSA

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