Nephropathic cystinosis

Nephropathic Cystinosis is a type of a rare kidney disease of the lysosomal storage disorder type. It is genetically inheritable in the autosomal recessive fashion via CTNS (gene).[1] It characterized by systemic accumulation of the amino acid cystine within lysosomes, proximal tubulopathy and by progressive chronic kidney disease. If untreated, it leads to progressive cellular dysfunction and multiorgan involvement. The disease most commonly presents in infancy with renal Fanconi syndrome and, without treatment, progresses to end-stage kidney disease (ESKD) in childhood. Extra-renal manifestations affecting the eyes, thyroid, muscle, pancreas, and central nervous system may develop later in life. Early diagnosis and lifelong cystine-depleting therapy improve growth, delay progression to ESKD, and reduce many systemic complications.[2][3] Nevertheless, despite treatment, the mean age at death for individuals born between 1985 and 1999 has been 29 years.[4]

Classification

The classification is as follows:

  • Infantile (classic) nephropathic cystinosis: the most common and severe form, presenting within the first year of life with Fanconi syndrome and rapid progression to renal failure.[5]
  • Juvenile (intermediate) cystinosis: later onset and slower progression.[6]
  • Ocular (non-nephropathic or adult) cystinosis: primarily limited to the eyes with minimal or no renal involvement.[7]

Presentation

Presentation in the first 6–12 months with poor growth, polyuria, polydipsia, dehydration, and rickets secondary to proximal renal tubular dysfunction (Fanconi syndrome) causing urinary wasting of glucose, amino acids, bicarbonate, phosphate, and electrolytes. Progressive glomerular damage leading to chronic kidney disease and eventually to kidney failure typically in the first decade, if untreated.[8]

Complications

These complications often develop despite renal replacement therapy:

Ocular: corneal cystine crystal deposition causes photophobia, eye irritation, and decreased corneal sensitivity; crystals are visible on slit-lamp examination.[9]

Endocrine: hypothyroidism is common; growth hormone deficiency and diabetes mellitus may occur later.[10][11]

Muscular: Myopathy and swallowing difficulties from progressive proximal muscle weakness and distal involvement in adults.[12]

Neurologic: speech delay, cognitive impairment, and ataxia may appear in older children and adults.[13]

Other: hepatomegaly, pancreatitis, and gonadal dysfunction have been reported.[14][15][16][17]

Pathophysiology

Nephropathic cystinosis is caused by pathogenic variants in the CTNS gene (encoding cystinosin), located in region p13 on chromosome 17, which encodes a lysosomal membrane protein required for cystine transport out of lysosomes.[18] Loss of cystinosin function leads to intralysosomal accumulation of cystine crystals in lysosomes, which cause cellular dysfunction and apoptosis through mechanisms, that include oxidative stress and impaired autophagy. The degree of residual cystinosin function correlates with disease severity, accounting for the spectrum from classic infantile to milder forms.[18]

Diagnosis

Clinical suspicion:[19]

Infants with Fanconi syndrome and failure to thrive; ophthalmologic findings (corneal crystals) support the diagnosis.

Measurement of leukocyte cystine levels: the diagnostic biochemical test is elevated cystine concentration in isolated white blood cells (leukocytes).

Genetic testing: molecular analysis of CTNS confirms the diagnosis and allows for carrier testing and prenatal diagnosis.[20]

Additional testing: renal function and tubular markers, slit-lamp eye exam,[21] thyroid function tests, and assessments for other systemic complications.

Management

Current management aims to deplete intracellular cystine, treat renal tubular losses, preserve kidney function, and address systemic complications.[22]

Cysteamine therapy: Cysteamine (cysteamine bitartrate) is the only specific disease-modifying therapy. It enters lysosomes and reacts with cystine to form cysteine–cysteamine mixed disulfides that can exit the lysosome via alternative transporters, thereby lowering intralysosomal cystine. Oral cysteamine, started early and given lifelong, markedly reduces leukocyte cystine levels, delays progression to ESKD, and decreases some systemic complications. Both immediate-release and delayed-release formulations are used; adherence and dose optimization are critical.[3] Oral cysteamine therapy has extended the time to kidney failure by approximately 7 years (to a mean of 16 years) and mitigates or prevents late complications of the disease. In addition, cysteamine eyedrops can dissolve corneal cystine crystals within months.[4]

Supportive renal care: replacement of bicarbonate, phosphate, potassium, vitamin D and other supplements to manage Fanconi syndrome; growth monitoring and, when indicated, growth hormone therapy.[23][24][25]

Kidney transplantation: ESKD is managed with renal transplantation when necessary; however, transplantation does not correct systemic cystine accumulation, so cysteamine therapy should be continued after transplant.[26]

Ocular treatment: topical cysteamine eye drops reduce corneal crystal burden and symptoms.[27][9]

Multidisciplinary follow-up: regular monitoring by nephrology, ophthalmology, endocrinology, neurology, nutrition, and other specialties is recommended to manage complications and optimize quality of life.[28][14]

Prognosis

Before the invention of cysteamine treatment in the 1970's,[29] most children with classic nephropathic cystinosis reached end-stage chronic kidney disease (ESKD) by 10–12 years of age.[30] With early and continuous cysteamine therapy and modern supportive care, renal survival has improved substantially and many patients survive into adulthood, although they remain at risk for extra-renal complications that affect morbidity.[31]

Nevertheless, since cysteamine does not cure, but only slows down the disease progression, in many cases, the first kidney transplant in childhood/adolescence has to be followed by a second kidney transplant only 5–15 years later.[32]

Epidemiology

Cystinosis is rare, with estimated incidence of approximately 1 in 100,000–200,000 live births, although prevalence varies by population and may be higher in certain communities due to the founder effect.[33][34]

In the UK the prevalence of nephropathic cystinosis in children under the age of 16 years was 55 per million (pmp) and the incidence 7.92 pmp. The incidence and prevalence for South Asian were 3 times that of the White and Black populations.[35]

History

Cystinosis was first described in the early 20th century by cystine crystal identification in tissues.[36] The CTNS gene was identified in the late 1990s, enabling genetic diagnosis and improved understanding of pathogenesis.[37]

Research

Current research focuses on better formulations of cysteamine with improved tolerability and dosing schedules,[38] gene therapy approaches to restore CTNS function,[39][40][41][42] and therapies targeting downstream pathways (oxidative stress, autophagy) to prevent tissue damage.[43][44][45][46]

References

  1. ↑ Levtchenko, Elena; Emma, Francesco (2022), "Cystinosis", in Blau, Nenad; Dionisi Vici, Carlo; Ferreira, Carlos R.; Vianey-Saban, Christine (eds.), Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, Cham: Springer International Publishing, pp. 1287–1294, doi:10.1007/978-3-030-67727-5_65, ISBN 978-3-030-67726-8, retrieved 2025-12-21
  2. ↑ MedlinePlus Genetics. Cystinosis. U.S. National Library of Medicine. Available from: https://medlineplus.gov/genetics/condition/cystinosis/
  3. 1 2 National Organization for Rare Disorders (NORD). Cystinosis. Available from: https://rarediseases.org/rare-diseases/cystinosis/
  4. 1 2 Chang, Hayley E.; Hossain, Mahin S.; Song, Chris; Surampudi, Narayana; Nesterova, Galina; Gahl, William A. (2025-05-14). "Long-term outcomes in nephropathic cystinosis: a review". Pediatric Nephrology. 41 (2): 277–296. doi:10.1007/s00467-025-06790-6. ISSN 0931-041X. PMC 12727779. PMID 40369127.
  5. ↑ Haffner, Dieter; Leifheit-Nestler, Maren; Alioli, Candide; Bacchetta, Justine (2022-01-05). "Muscle and Bone Impairment in Infantile Nephropathic Cystinosis: New Concepts". Cells. 11 (1): 170. doi:10.3390/cells11010170. ISSN 2073-4409. PMC 8749987. PMID 35011732.
  6. ↑ Bäumner, Sören; Weber, Lutz T. (2018-03-14). "Nephropathic Cystinosis: Symptoms, Treatment, and Perspectives of a Systemic Disease". Frontiers in Pediatrics. 6 58. doi:10.3389/fped.2018.00058. ISSN 2296-2360. PMC 5861330. PMID 29594088.
  7. ↑ Biswas, Susmito; Gaviria, Martha; Malheiro, Luísa; Marques, João Pedro; Giordano, Vincenzo; Liang, Hong (December 2018). "Latest Clinical Approaches in the Ocular Management of Cystinosis: A Review of Current Practice and Opinion from the Ophthalmology Cystinosis Forum". Ophthalmology and Therapy. 7 (2): 307–322. doi:10.1007/s40123-018-0146-6. ISSN 2193-8245. PMC 6258572. PMID 30242621.
  8. ↑ "Nephropathic Cystinosis: Evaluation and Management | National Kidney Foundation". www.kidney.org. Retrieved 2026-01-04.
  9. 1 2 Dhiman, Shweta; Mahapatra, Santosh K; Parhi, Anjalika; Shree, Pallavi; Jain, Parul (April 2024). "Ocular cystinosis – Clinical presentation and review of the literature". Indian Journal of Ophthalmology: Case Reports. 4 (2): 444–448. doi:10.4103/IJO.IJO_1944_23. ISSN 2772-3070.
  10. ↑ Lucky, Anne W.; Howley, Peter M.; Megyesi, Klara; Spielberg, Stephen P.; Schulman, Joseph D. (August 1977). "Endocrine studies in cystinosis: Compensated primary hypothyroidism". The Journal of Pediatrics. 91 (2): 204–210. doi:10.1016/S0022-3476(77)80813-5. PMID 406375.
  11. ↑ Fivush, Barbara (1987-10-01). "Pancreatic Endocrine Insufficiency in Posttransplant Cystinosis". Archives of Pediatrics & Adolescent Medicine. 141 (10): 1087–1089. doi:10.1001/archpedi.1987.04460100065027. ISSN 1072-4710. PMID 3307383.
  12. ↑ Sadjadi, Reza; Ghossein, Cybele; Elenberg, Ewa (2025-07-07). "Clinical perspectives on myopathic complications in nephropathic cystinosis". Journal of Rare Diseases. 4 (1) 37. doi:10.1007/s44162-025-00092-z. ISSN 2731-085X.
  13. ↑ Trauner, Doris A (2010-04-29), "Neurological and Cognitive Consequences of Nephropathic Cystinosis", in Nass, MD, Ruth; Frank, MD, Yitzchak (eds.), Cognitive and Behavioral Abnormalities of Pediatric Diseases, Oxford University PressNew York, pp. 333–341, doi:10.1093/oso/9780195342680.003.0039, ISBN 978-0-19-534268-0, retrieved 2025-12-22
  14. 1 2 Nesterova, Galina; Gahl, William (June 2008). "Nephropathic cystinosis: late complications of a multisystemic disease". Pediatric Nephrology. 23 (6): 863–878. doi:10.1007/s00467-007-0650-8. ISSN 0931-041X. PMID 18008091.
  15. ↑ Gahl, William A.; Nesterova, Galina (2016), "Cystinosis and Its Renal Complications in Children", in Avner, Ellis D.; Harmon, William E.; Niaudet, Patrick; Yoshikawa, Norishige (eds.), Pediatric Nephrology, Berlin, Heidelberg: Springer Berlin Heidelberg, pp. 1329–1353, doi:10.1007/978-3-662-43596-0_37, ISBN 978-3-662-43595-3, retrieved 2025-12-22
  16. ↑ Treikauskas, U.; Zerell, K.; Harms, E.; Aghayan–Ugurluoglu, R.; Brangenberg, R.; Herzig, N.; Hintner, H.; Knerr, C.; Köppl, C.; Landthaler, I.; Marquardt, T.; Passow, M.; Rausch, A.; Römer, U.; Steidle, G. (2016-11-01). "Nephropathische Cystinose: Spätkomplikationen einer Multisystemerkrankung – Langzeitergebnisse der interdisziplinären Cystinose-Sprechstunde in Traunstein". Nieren- und Hochdruckkrankheiten. 45 (11): 432–438. doi:10.5414/NHX01812. ISSN 0300-5224.
  17. ↑ Kasimer, Rachel Nora; Langman, Craig B (February 2021). "Adult complications of nephropathic cystinosis: a systematic review". Pediatric Nephrology. 36 (2): 223–236. doi:10.1007/s00467-020-04487-6. ISSN 0931-041X. PMID 32016627.
  18. 1 2 NCBI Bookshelf. GeneReviews: Cystinosis. GeneReviews® [Internet]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1409/
  19. ↑ "Pädiatrische Nephrologie". Monatsschrift Kinderheilkunde (in German). 155 (3): 293–303. March 2007. doi:10.1007/s00112-007-1486-9. ISSN 0026-9298.
  20. ↑ Savostyanov, K. V.; Pushkov, A. A.; Shchagina, O. A.; Maltseva, V. V.; Suleymanov, E. A.; Zhanin, I. S.; Mazanova, N. N.; Fisenko, A. P.; Mishakova, P. S.; Polyakov, A. V.; Balanovska, E. V.; Zinchenko, R. A.; Tsygin, A. N. (2022-04-28). "Genetic Landscape of Nephropathic Cystinosis in Russian Children". Frontiers in Genetics. 13 863157. doi:10.3389/fgene.2022.863157. ISSN 1664-8021. PMC 9096100. PMID 35571017.
  21. ↑ Waghamare, Shalaka Ramesh; Kumari, Deepa; Samanta, Ramanuj; Agrawal, Ajai (2025-08-28). "Ocular manifestations and multimodal imaging in infantile nephropathic cystinosis". QJM: An International Journal of Medicine. 119 (1) hcaf198. doi:10.1093/qjmed/hcaf198. ISSN 1460-2725. PMID 40875547.
  22. ↑ Lu, D. L.; Teo, S. S. L.; Yap, H. K. (2021). "Management of Nephropathic Cystinosis". Pediatric Nephrology: On-The-Go (4th ed.). World Scientific. pp. 292–302.
  23. ↑ Todisco, Tommaso; Ubertini, Grazia Maria; Bizzarri, Carla; Loche, Sandro; Cappa, Marco (2024-07-01). "Chronic Kidney Disease and Growth Failure in Children". Children. 11 (7): 808. doi:10.3390/children11070808. ISSN 2227-9067. PMC 11274908. PMID 39062256.
  24. ↑ Guzzetti, Chiara; Ibba, Anastasia; Incandela, Valeria; Loche, Sandro (2024-12-24). "GH Therapy in Non–Growth Hormone-Deficient Children". Children. 12 (1): 3. doi:10.3390/children12010003. ISSN 2227-9067. PMC 11764098. PMID 39857834.
  25. ↑ Harms, Erik (2006), "Cystinosis", in Blau, Nenad; Leonard, James; Hoffmann, Georg F.; Clarke, Joe T. R. (eds.), Physician's Guide to the Treatment and Follow-Up of Metabolic Diseases, Berlin/Heidelberg: Springer-Verlag, pp. 221–229, doi:10.1007/3-540-28962-3_23, ISBN 978-3-540-22954-4, retrieved 2025-12-21
  26. ↑ Killeen, Trevor F.; Elfering, Sarah L.; Riad, Samy M.; Linden, Michael A.; Leng, Ethan Y.; Kandaswamy, Raja; Kizilbash, Sarah J.; Chavers, Blanche M.; Harmon, James V. (September 2022). "Nephropathic cystinosis in a kidney transplant recipient: A mesenteric lymph node demonstrates positive birefringent crystals". Human Pathology Reports. 29 300661. doi:10.1016/j.hpr.2022.300661.
  27. ↑ Liang, Hong; Baudouin, Christophe; Giordano, Vincenzo (April 2025). "Evaluation of a new classification system for measuring the progression of ocular cystinosis: an analysis of 64 patients". British Journal of Ophthalmology. 109 (4): 442–449. doi:10.1136/bjo-2023-325093. ISSN 0007-1161. PMC 12013570. PMID 39357989.
  28. ↑ Levtchenko, Elena; Servais, Aude; Hulton, Sally A; Ariceta, Gema; Emma, Francesco; Game, David S; Lange, Karin; Lapatto, Risto; Liang, Hong; Sberro-Soussan, Rebecca; Topaloglu, Rezan; Das, Anibh M; Webb, Nicholas J A; Wanner, Christoph (2022-08-22). "Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients". Clinical Kidney Journal. 15 (9): 1675–1684. doi:10.1093/ckj/sfac099. ISSN 2048-8505. PMC 9394719. PMID 36003666.
  29. ↑ Thoene, Jess G. (2010-08-23), "Cysteamine treatment of nephropathic cystinosis", Small Molecule Therapy for Genetic Disease, Cambridge University Press, pp. 101–113, doi:10.1017/cbo9780511777905.009, ISBN 978-0-521-51781-2, retrieved 2025-12-21
  30. ↑ Broyer, M. (2000). "[Cystinosis from childhood to adulthood]". Nephrologie. 21 (1): 13–18. ISSN 0250-4960. PMID 10730275.
  31. ↑ Helmy, Rasha; Atia, Fatma M.; Soliman, Neveen A. (2025-04-07). "Native kidney and graft survival in a cohort of Egyptian children with nephropathic cystinosis: national referral center experience". Italian Journal of Pediatrics. 51 (1) 110. doi:10.1186/s13052-025-01943-7. ISSN 1824-7288. PMC 11977944. PMID 40197488.
  32. ↑ Carter, Jade (2018-03-02). "Waiting for my second kidney transplant in 7 years". Journal of Kidney Care. 3 (2): 120–121. doi:10.12968/jokc.2018.3.2.120. ISSN 2397-9534.
  33. ↑ Wu, Chen-Han Wilfred; Tomaszewski, Alicja; Stark, Louisa A.; Scaglia, Fernando; Elenberg, Ewa; Schumacher, Fredrick R. (2023-05-05). "Uncovering the Prevalence of Cystinosis through Genetic Analysis". medRxiv 10.1101/2023.05.04.23289520.
  34. ↑ Levy, Micheline; Feingold, Josué (September 2000). "Estimating prevalence in single-gene kidney diseases progressing to renal failure". Kidney International. 58 (3): 925–943. doi:10.1046/j.1523-1755.2000.00250.x. PMID 10972657.
  35. ↑ Lewis, Malcolm A; Shaw, Joanne; Sinha, Manish; Adalat, Shazia; Hussain, Farida; Inward, Carol (2009). "UK Renal Registry 11th Annual Report (December 2008): Chapter 13 Demography of the UK paediatric Renal Replacement Therapy population". Nephron Clinical Practice. 111 (1): c257–c267. doi:10.1159/000210002. ISSN 1660-2110. PMID 19542701.
  36. ↑ Kroll, Wolfgang; Lichte, Karl-Henning (November 1973). "Cystinosis: A review of the different forms and of recent advances". Humangenetik. 20 (2): 75–87. doi:10.1007/BF00284842. ISSN 0340-6717. PMID 4594235.
  37. ↑ Attard, M.; Jean, G.; Forestier, L.; Cherqui, S.; van't Hoff, W.; Broyer, M.; Antignac, C.; Town, M. (1999-12-01). "Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin". Human Molecular Genetics. 8 (13): 2507–2514. doi:10.1093/hmg/8.13.2507. ISSN 0964-6906. PMID 10556299.
  38. ↑ Ariceta, Gema; Santos, Fernando; López Muñiz, Andrés; Hermida, Alvaro; Matoses, Maria Luisa; Ventura, Ana; Martin-Moreno, Paloma Leticia; González, Esther; Acuña, Laura; Giner, Elisa; Vara, Julia (2024-04-01). "Switching from immediate- to extended-release cysteamine in patients with nephropathic cystinosis: from clinical trials to clinical practice". Clinical Kidney Journal. 17 (4) sfae049. doi:10.1093/ckj/sfae049. ISSN 2048-8505. PMC 11022652. PMID 38633840.
  39. ↑ Dong, Fei; Amlal, Hassane; Venkatakrishnan, Jhuwala; Zhang, Jianhua; Fry, Matthew; Yuan, Yong; Cheng, Yu Chia; Hu, Yueh-Chiang; Kao, Winston W-Y (July 2023). "The gene therapy for corneal pathology with novel nonsense cystinosis mouse lines created by CRISPR Gene Editing". The Ocular Surface. 29: 432–443. doi:10.1016/j.jtos.2023.06.002. PMC 10725217. PMID 37355021.
  40. ↑ Cherqui, Stéphanie (March 2023). "Cystinose: De la découverte du gène aux premiers essais de thérapie génique". Médecine/Sciences. 39 (3): 253–261. doi:10.1051/medsci/2023025. ISSN 0767-0974. PMC 10629270. PMID 36943122.
  41. ↑ Khare, Veenita; Cherqui, Stephanie (December 2024). "Targeted gene therapy for rare genetic kidney diseases". Kidney International. 106 (6): 1051–1061. doi:10.1016/j.kint.2024.07.034. PMID 39222842.
  42. ↑ Leventoğlu, Emre (2025). "Gene Therapies: Any Merit in Nephrology?". Giornale Italiano di Nefrologia. 42 (5): 1. doi:10.69097/42-05-2025-06. ISSN 1724-5990. PMID 41184189.
  43. ↑ Elmonem, Mohamed A.; Veys, Koenraad R. P.; Prencipe, Giusi (2022-01-06). "Nephropathic Cystinosis: Pathogenic Roles of Inflammation and Potential for New Therapies". Cells. 11 (2): 190. doi:10.3390/cells11020190. ISSN 2073-4409. PMC 8773784. PMID 35053306.
  44. ↑ Chang, Hayley E.; Hossain, Mahin S.; Song, Chris; Surampudi, Narayana; Nesterova, Galina; Gahl, William A. (February 2026). "Long-term outcomes in nephropathic cystinosis: a review". Pediatric Nephrology. 41 (2): 277–296. doi:10.1007/s00467-025-06790-6. ISSN 0931-041X. PMC 12727779. PMID 40369127.
  45. ↑ Devitt, Lauren (2024-06-10). "Cystinosis — a review of disease pathogenesis, management, and future treatment options". Journal of Rare Diseases. 3 (1) 17. doi:10.1007/s44162-024-00041-2. ISSN 2731-085X.
  46. ↑ Goodyer, Paul; Torban, Elena (2025-05-21). "Emerging therapeutic strategies for cystinosis". Frontiers in Pediatrics. 13 1601409. doi:10.3389/fped.2025.1601409. ISSN 2296-2360. PMC 12135878. PMID 40469087.
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