Designed to offer practical advice to improve clinical outcomes for adolescents and adults living with the multi-organ effects of cystinosis.

The recommendations were made by a group of international clinicians with expertise in managing cystinosis. They aim to support specialist and non-specialist healthcare professionals in their daily clinical practice when treating young adults and adult patients with cystinosis;1 for simplicity the term “adult” is used to encompass both age groups.

In addition to the specific recommendations made here, all healthcare professionals caring for adults with cystinosis should consider each individual case on its own merits. We would encourage a thoughtful transition of adolescent patients to adult services in a timely manner.2

We have identified recommendations supported by evidence-based clinical guidance and additional published data. However, where such evidence is lacking we offer guidance based on collective expert opinion.

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Clinical guidance & resources around Cystinosis
General considerations
Multi-Organ Involvement
Patient Well-being

Clinical guidance & resources around Cystinosis

The KDIGO guidance1 is followed both internationally and in the majority of European countries. However, we advise that other international recommendations, national guidance and other sources should also be consulted including:

  • Nephropathic cystinosis: an international consensus document2
  • Specific guidelines for adult and adolescent patients3
  • Specific recommendations for the management of bone disease4

Supporting References:

  1. Langman, C. B. et al. Controversies and research agenda in nephropathic cystinosis: conclusions from a ‘Kidney Disease: Improving Global Outcomes’ (KDIGO) Controversies Conference. Kidney Int 89, 1192–1203 (2016).
  2. Emma, F. et al. Nephropathic cystinosis: an international consensus document. Nephrol Dial Transplant 29 Suppl 4, iv87-94 (2014).
  3. Ariceta, G. et al. Cystinosis in adult and adolescent patients: Recommendations for the comprehensive care of cystinosis. Nefrologia 35, 304–321 (2015).
  4. Hohenfellner, K. et al. Management of bone disease in cystinosis: Statement from an international conference. J Inherit Metab Dis 42, 1019–1029 (2019).

 

 

General considerations when treating a patient with cystinosis

Cystinosis is a rare multi-system disorder with overall incidence rates reported in France, Denmark, Sweden, Germany and Australia of between 1:115,000 and 1:260,000 live births.1,2 Because of its rarity, there can be a lack of awareness of the short- and long-term consequences and multi-organ impact of the disease, even among adult nephrologists.

In our opinion, an adult nephrologist or a metabolic physician with specific experience of cystinosis should take the lead and be the key clinician coordinator in the care of these patients, ideally in a centre of excellence, where a multidisciplinary healthcare team experienced in managing these patients is available.3 This will ensure that practical management strategies such as optimal dosing regimens, which includes monitoring of WBC cystine levels, improved adherence to therapy, as well as awareness of the long-term consequences and treatment of the disease in the different organ systems, is adequately monitored.2,4 Other healthcare specialties may also be involved, for example to provide education and support post-transplant or to optimise patient adherence for the long-term. We note that the multidisciplinary team structure, however, will vary case-by-case, hospital-to-hospital and country-to-country.

It is important to ensure that young adults with cystinosis are transitioned from paediatric to adult care through a formal paediatric to adult transition service, to ensure optimal long-term outcomes.5

Supporting References:

  1. Ariceta, G., Giordano, V. & Santos, F. Effects of long-term cysteamine treatment in patients with cystinosis. Pediatr Nephrol 34, 571–578 (2019).
  2. Elmonem, M. A. et al. Cystinosis: a review. Orphanet J Rare Dis 11, 47 (2016).
  3. Levtchenko, E. et al. Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients. Clinical Kidney Journal, 2022, vol. 15, no. 9, 1675–1684. https:/doi.org/10.1093/ckj/sfac099.
  4. Ariceta, G. et al. Cystinosis in adult and adolescent patients: Recommendations for the comprehensive care of cystinosis. Nefrologia 35, 304–321 (2015).
  5. Ariceta, G. et al. A coordinated transition model for patients with cystinosis: from pediatrics to adult care. Nefrologia 36, 616–630 (2016).

 

Multidisciplinary approach

We recommend a leader to co-ordinate the care of the complex issues experienced by patients with cystinosis.1 This may be a nephrologist or a metabolic specialist. Several other specialists from the multidisciplinary team are required to be involved in the care of adults cystinosis patients:1,2

 

Nephrologist

We recommend that a nephrologist is integral in the care of this condition. The frequency for review will vary according to patient need and range from 2 times/year to more if required.1

Metabolic specialist

A metabolic specialist may lead the care of an adult cystinosis patient in combination with a nephrologist,3 with special attention to endocrine functions, with review required at least annually or more frequently as required. It is the opinion of some of the experts that patients should be followed by a metabolic specialist or an endocrinologist for thyroid functions and diabetes;4 typically, annually or twice a year depending on individual centres and healthcare systems.1

Ophthalmologist

We recommend that a cystinosis patient be reviewed by an ophthalmologist annually or more frequently if required.1

Specialist renal nurse

Some experts work closely with a specialist renal nurse and recommend that they should always be present to help coordinate and assist with patient queries and offer support.5 However, we recognise that this function is not offered by all centres and healthcare systems.

Cardiology input

Cardiology input should be as appropriate for patients with chronic renal disease.1

Neurologist

We advise an annual visit for clinical evaluation in adult patients, with additional clinical examinations as required.1

Patient/parent/carer

The patient themselves are central to any discussions and family/friends/caregivers should also be considered as part of the team, to be involved in discussions and decisions regarding their care with the consent of the patient.6

Other

We advise that a patient should also receive dietetic support to assess nutritional status (especially if the patient experiences weight loss, has diabetes mellitus and/or renal failure).1 As approximately 30% of adult patients will have respiratory issues, support from a pulmonologist may be required.1 We would also advise psychology, neurology, and speech and language, occupational therapy follow-up, and input to social services.1

 

Finally, good communication and networking between the local hospital and the specialist centre is crucial as patients may have to travel long distances to attend the specialist centre.

 

Supporting References:

  1. Levtchenko, E. et al. Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients. Clinical Kidney Journal, 2022, vol. 15, no. 9, 1675–1684. https:/doi.org/10.1093/ckj/sfac099.
  2. Ariceta, G. et al. Cystinosis in adult and adolescent patients: Recommendations for the comprehensive care of cystinosis. Nefrologia 35, 304–321 (2015).
  3. Hohenfellner, K. et al. Management of bone disease in cystinosis: Statement from an international conference. J Inherit Metab Dis 42, 1019–1029 (2019).
  4. Vantyghem, M.-C. et al. Endocrine manifestations related to inherited metabolic diseases in adults. Orphanet J Rare Dis 7, 11 (2012).
  5. Ariceta, G. et al. A coordinated transition model for patients with cystinosis: from pediatrics to adult care. Nefrologia 36, 616–630 (2016).
  6. Doyle, M. & Werner-Lin, A. Family Strategies for Living with Rare Disease: The Experience of Cystinosis. Journal of the Society for Social Work and Research 7, 547–567 (2016).

 

Fertility impact & family-planning
Renal considerations
Nervous System & neurocognitive aspects
Muscle involvement
Ophtalmology
Cardio-Respiratory
Endocrine aspects
GI and hepatological involvement
Dermatology
Dental care

For female and male patients

For female patients

Female patients should be advised that the likelihood of becoming pregnant, including potential for a successful pregnancy outcome, is dependent upon their renal health.1 Female patients with cystinosis should still expect to be fertile. The patient should be made aware that they will need to stop cystine-depletion therapy on confirmation of pregnancy to prevent foetal exposure to cystine-depleting therapy.1 There is a lack of data around cystine-depleting therapy and breast-feeding and therefore cystine-depletion therapy should be avoided during breastfeeding.1 Finally, the advice and discussion should be tailored according to the individual female patient’s renal function; as per conventional chronic kidney disease (CKD) and post-transplant advice.

For male patients

Male patients should be advised that though previously thought to be infertile, in vitro fertilization techniques with intracytoplasmic sperm injection, may be an option if they wish to father children with their own sperm.2,3

Additionally, potential preservation in a sperm bank could be a possibility for a few individuals.4 We advise that this option is considered early in selected patients wishing to have children.5 Sperm can be collected using testis or epididymis biopsy, or from ejaculate in a small selection of patients not having complete azoospermia.2

We would also advise involving colleagues from other specialities, such as endocrinology or obstetrics and gynaecology, for further support and advice.5

Supporting References:

  1. Blakey, H., Proudfoot-Jones, J., Knox, E. & Lipkin, G. Pregnancy in women with cystinosis. Clinical kidney journal 12, 855–858 (2019).
  2. Besouw, M. T. P., Kremer, J. A. M., Janssen, M. C. H. & Levtchenko, E. N. Fertility status in male cystinosis patients treated with cysteamine. Fertil Steril 93, 1880–1883 (2010).
  3. Veys, K. R. et al. First Successful Conception Induced by a Male Cystinosis Patient. JIMD Rep 38, 1–6 (2018).
  4. Rohayem, J. et al. Testicular function in males with infantile nephropathic cystinosis. Hum Reprod 36, 1191–1204 (2021).
  5. Levtchenko, E. et al. Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients. Clinical Kidney Journal, 2022, vol. 15, no. 9, 1675–1684. https:/doi.org/10.1093/ckj/sfac099.

 

 

Based on the current guidance and available evidence we recommend monitoring renal function and disease progression according to the individual patient’s circumstance.1–4 As well as monitoring cystine levels in WBCs, we advise specific monitoring requirements for different patient scenarios based on our clinical experience, as follows:

1. For patients with Fanconi syndrome

We recommend the use of appropriate electrolyte supplementation for countering acidosis, chronic hypokalaemia, hypophosphatemia and carnitine, if needed. We do not advise using indomethacin in adults.1,2  

 

2. For patients on dialysis

Both dialysis modes are suitable depending on the medical and social situation of the patient.
For patients on haemodialysis, we recommend tailoring the ultrafiltration and dialysate electrolytes according to individual patient need.1
Tailoring the ultrafiltration and monitoring of potassium and phosphate levels by adapting supplementation accordingly is advised. We recommend that these patients are informed that transplantation is the optimal treatment option, if feasible.1,3

3. For patients before renal transplantation

We advise following current KDIGO pre-transplant recommendations5 for monitoring renal function in these patients.
For patients with CKD before transplantation: we suggest close monitoring of serum creatinine for calculation of eGRF values to monitor renal function. Serum creatinine may not correctly reflect kidney function in those patients with muscle wasting. For those patients with end stage renal disease (ESRD), we suggest carefully monitoring of potassium and phosphate levels and adapting supplementation to control acidosis and parathyroid hormone (PTH).1

4. For patients after renal transplantation

We advise following current KDIGO post-transplant recommendations5 for monitoring renal function with the addition of monitoring cystine levels in WBCs in these patients. Close attention should be paid to polyuria immediately post transplantation.
We recommend starting Cystine-depletion therapy (CDT) treatment as soon as possible once the patient can take oral medication. Additional electrolyte supplementation may be required.
We also strongly recommend educating transplant patients on the long-term benefits of adhering to both their Cystine-depletion therapy (CDT) and immunosuppressive therapeutic regimens.1

Supporting References:

  1. Levtchenko, E. et al. Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients. Clinical Kidney Journal, 2022, vol. 15, no. 9, 1675–1684. https:/doi.org/10.1093/ckj/sfac099.
  2. Langman, C. B. et al. Controversies and research agenda in nephropathic cystinosis: conclusions from a ‘Kidney Disease: Improving Global Outcomes’ (KDIGO) Controversies Conference. Kidney Int 89, 1192–1203 (2016).
  3. Emma, F. et al. Nephropathic cystinosis: an international consensus document. Nephrol Dial Transplant 29 Suppl 4, iv87-94 (2014).
  4. Ariceta, G. et al. Cystinosis in adult and adolescent patients: Recommendations for the comprehensive care of cystinosis. Nefrologia 35, 304–321 (2015).
  5. Chadban, S. J. et al. KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation. Transplantation 104, S11–S103 (2020).

Based on our clinical experience we recommend that routine assessment of distal muscle strength, motor-function ability and memory testing is performed at every patient visit together with directed discussion around possible neurological signs and symptoms.1

Specifically for the central nervous system: we recommend a clinical examination is undertaken and any history of headache investigated as intracranial hypertension may be observed. Regular ophthalmological examinations are also needed to exclude pseudotumor cerebri.2 Presence of pyramidal or cerebellar syndrome, bradykinesia, and other focal features suggestive of stroke should be investigated. The MMSE should be used to evaluate potential cognitive defect. A brain MRI can be performed to look for brain atrophy, white matter signal anomalies, or ischemic lesions; calcifications may be observed by tomodensitometry.1-3

In the peripheral nervous system: we recommend use of a rating scale to evaluate and monitor signs and symptoms in chronic muscular disorders.

To assess the impact on neurocognition: we recommend the MMSE is used for neurocognitive evaluation, particularly if there is some relevant patient complaint, for example, underperforming in school, visuo-spatial or behaviour issues. Such an evaluation needs to at least include an assessment of visual-spatial abilities, visual-motor coordination, and short-term memory evaluation.1,4

Regular consultation with the neurology team is recommended in order to highlight and recommend where further neurological evaluation is required and follow up is maintained. Further assessments may include the following:

  • Swallowing test5
  • MMSE6
  • MFM7
  • 6 Minute-Walking-Test8
  • cranial MRI9
  • ENMG10

However, we acknowledge that the frequency of the neurology assessment will vary from centre-to-centre and from country-to-country. 

 

Supporting References:

 

  1. Levtchenko, E. et al. Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients. Clinical Kidney Journal, 2022, vol. 15, no. 9, 1675–1684. https:/doi.org/10.1093/ckj/sfac099.
  2. Behdad, B., Bagheri, A., Tavakoli, M. & Pakravan, M. Association of Nephropathic Cystinosis and Pseudotumor Cerebri with Bilateral Duane Syndrome Type I. Neuroophthalmology 38, 74–77 (2014).
  3. Ariceta, G. et al. Cystinosis in adult and adolescent patients: Recommendations for the comprehensive care of cystinosis. Nefrologia 35, 304–321 (2015).
  4. Besouw, M. T. P. et al. Neurocognitive functioning in school-aged cystinosis patients. J Inherit Metab Dis 33, 787–793 (2010).
  5. Huckabee, M.-L. et al. The Test of Masticating and Swallowing Solids (TOMASS): reliability, validity and international normative data. International Journal of Language & Communication Disorders 53, 144–156 (2018).
  6. Myrberg, K., Hydén, L.-C. & Samuelsson, C. The mini-mental state examination (MMSE) from a language perspective: an analysis of test interaction. Clin Linguist Phon 34, 652–670 (2020).
  7. de Lattre, C. et al. Motor function measure: validation of a short form for young children with neuromuscular diseases. Arch Phys Med Rehabil 94, 2218–2226 (2013).
  8. Enright, P. L. The six-minute walk test. Respir Care 48, 783–785 (2003).
  9. Trauner, D. A. et al. Neurological impairment in nephropathic cystinosis: motor coordination deficits. Pediatr Nephrol 25, 2061–2066 (2010).
  10. Mansukhani, K. A. & Doshi, B. H. Interpretation of electroneuromyographic studies in diseases of neuromuscular junction and myopathies. Neurol India 56, 339–347 (2008).

 

 

 

 

 

In addition, and based on our clinical experience, we advise that healthcare professionals follow recommendations from neurology and speech and language colleagues when requesting neurological tests such as ENMG and video-fluoroscopy for swallowing, and to determine the frequency of assessment.1–3 

 

  • ENMG may be performed:
    o At baseline when signs of muscle weakness and wasting appear1
    o As part of a neurological examination1
    o Not as part of routine follow-up, but to differentiate muscle or peripheral nerve involvement1,3

 

  • Swallowing: 
    • Swallowing problems may be best assessed by a swallowing test and video fluoroscopy2
    • The Test of Masticating and Swallowing Solids (TOMASS) may be used4
      • Drink 100 mL of water; measure duration of drinking (choking present?)
      • A cracker (standardised; 5 cm2) is offered, with the request: ‘Please eat this as soon as you can’
      • After eating, the subject is asked to say their own name (assessment of voice)
      • Analysis and scoring: video recording, number of bites, chewing movements, swallowing movements, total duration of eating
    • Video fluoroscopy provides a moving image of swallowing in real time

For clinical muscle testing, rating scales (e.g. the Medical Research Council [MRC] Muscle Scale) can be used to detect distal muscular weakness and wasting.2 Alternatively, the Motor Function Measure (MFM) rating scale, or the 6 Minute-Walking-Test can be used to precisely monitor the severity and progression of motor function in neuromuscular disease.5,6

ENMG can also be performed to monitor the myogenic syndrome. We do not recommend routine serum creatine kinase assessment and muscle biopsies as part of regular neuromuscular follow-up. Muscle biopsy should not be performed in all patients as it is invasive and should be performed only in rare cases for specific indications.1

Typically, the signs/symptoms of the onset of muscle involvement in cystinosis are distal muscle weakness and wasting in the upper and lower limbs. Swallowing difficulties and oral dysfunction tend to appear later.7 Patient follow-up for muscle involvement is exclusively clinical.

As the nature of histological lesions are already well known in cystinosis (due to vacuolar myopathy), there is limited value in obtaining such histological information from the patient. We do not recommend performing muscle biopsy during routine patient follow-up.1

We recommend conducting ENMG at baseline. The patient should have regular clinical follow-up on an annual basis.1

During history-taking with each patient, we recommend assessing patient-reported difficulties with chewing, aspiration, dysphagia, excess of saliva, weight loss, mealtimes of long duration, and respiratory symptoms including infection.1

Based on the reported history, we suggest specific tests such as: ideally video-fluoroscopy of swallowing (if available) or fibre-optic endoscopic evaluation of swallowing.1

Supporting References:

  1. Levtchenko, E. et al. Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients. Clinical Kidney Journal, 2022, vol. 15, no. 9, 1675–1684. https:/doi.org/10.1093/ckj/sfac099.
  2. Ariceta, G. et al. Cystinosis in adult and adolescent patients: Recommendations for the comprehensive care of cystinosis. Nefrologia 35, 304–321 (2015).
  3. Mansukhani, K. A. & Doshi, B. H. Interpretation of electroneuromyographic studies in diseases of neuromuscular junction and myopathies. Neurol India 56, 339–347 (2008).
  4. Huckabee, M.-L. et al. The Test of Masticating and Swallowing Solids (TOMASS): reliability, validity and international normative data. International Journal of Language & Communication Disorders 53, 144–156 (2018).
  5. de Lattre, C. et al. Motor function measure: validation of a short form for young children with neuromuscular diseases. Arch Phys Med Rehabil 94, 2218–2226 (2013).
  6. Enright, P. L. The six-minute walk test. Respir Care 48, 783–785 (2003).
  7. Elmonem, M. A. et al. Cystinosis: a review. Orphanet J Rare Dis 11, 47 (2016).

                      

 

 

For the Anterior segment:

Assessment should include photophobia, visual acuity test, slit lamp examination for corneal depositions/neovascularization/keratopathy, and intraocular pressure (IOP).1

For the Posterior segment:

Despite the photophobia symptoms, the dilated fundoscopy is advised to investigate the crystals particularly on the surface of the retina, depigmentation, pigment epithelial alterations, affected vasculature.
We note that although in-vivo confocal microscopy are superior imaging techniques, it is not widely available outside of specialist centres.2 However, many ophthalmological centres are equipped with anterior-segment OCT to assess the extent of cornea crystal infiltration.
Finally, we advise that changes in cornea cystinosis score (Gahl’s score) and photophobia score can be useful to monitor a patient’s adherence with the cysteamine eye drops regimen.3,4
Complaints related to dry eyes are frequent and can be improved by using hydrating eye drops.

Supporting References:

  1. Pinxten, A.-M. et al. Clinical Practice: A Proposed Standardized Ophthalmological Assessment for Patients with Cystinosis. Ophthalmol Ther 6, 93–104 (2017).
  2. Levtchenko, E. et al. Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients. Clinical Kidney Journal, 2022, vol. 15, no. 9, 1675–1684. https:/doi.org/10.1093/ckj/sfac099.
  3. Liang, H., Baudouin, C., Tahiri Joutei Hassani, R., Brignole-Baudouin, F. & Labbe, A. Photophobia and corneal crystal density in nephropathic cystinosis: an in vivo confocal microscopy and anterior-segment optical coherence tomography study. Invest Ophthalmol Vis Sci 56, 3218–3225 (2015).
  4. Gahl, W. A., Kuehl, E. M., Iwata, F., Lindblad, A. & Kaiser-Kupfer, M. I. Corneal Crystals in Nephropathic Cystinosis: Natural History and Treatment with Cysteamine Eyedrops. Molecular Genetics and Metabolism 71, 100–120 (2000).
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We advise monitoring and managing endocrine disorders as follows:

 

Hypothyroidism1,2

  • Common in adults
  • Check every 6 months from an early age using total thyroxine (FT3, T4) and thyroid-stimulating hormone (TSH) thyroid function tests
  • Thyroid supplementation may be required

 

Diabetes mellitus1,2

  • Common in adults, especially after transplantation
  • Blood sugar should be checked at every visit, ideally 3–6 monthly; it may be necessary to alter immunosuppressive calcineurin inhibitor (CNI) regimens in transplant patients or to initiate insulin therapy

Hypogonadism1,2

  • Hypogonadism is an important problem particularly in adolescent males, and patients should be given appropriate fertility counselling
  • Testosterone replacement therapy may be used to restore secondary sexual characteristics in adolescent male patients, and for a limited time in some individuals to improve growth and final height (following expert guidance)
  • It is important to test regularly in boys in case testosterone replacement therapy is required such as when puberty is delayed. If appropriate, discussions on banking sperm may be considered 

Supporting References:

  1. Levtchenko, E. et al. Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients. Clinical Kidney Journal, 2022, vol. 15, no. 9, 1675–1684. https:/doi.org/10.1093/ckj/sfac099.
  2. Ariceta, G. et al. Cystinosis in adult and adolescent patients: Recommendations for the comprehensive care of cystinosis. Nefrologia 35, 304–321 (2015).
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Quality of life & psychological aspects
Diet & lifestyle
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The clinical recommendations were developed via a quasi-Delphi consensus methodology1 as follows: A Steering Committee (SC) of 6 international experts who treat patients with rare tubulopathies including cystinosis, met together with Chiesi Farmaceutici and agreed that there was a need for review of the existing guidance to offer practical advice to improve clinical outcomes for adolescents and adults living with the multi-organ effects of cystinosis.2

The SC identified a list of 15 key questions relating to practical strategies to advance the management of patients with this rare disease.

An additional group of 8 international experts (Faculty) were invited to participate in the process by answering the questions developed via an online digital platform. Each participant was able to review all comments and upload supporting published evidence where available. The consolidated answers generated were summarised into recommendations and reviewed by the SC. The Faculty were then invited to agree/disagree with the draft clinical recommendations and to vote on the final wording of the clinical recommendation. (Please see the algorithm below for the step-by-step approach taken.)2

Where there was disagreement with the draft wording the SC members reviewed the comments and made any necessary changes to the statement to the member’s satisfaction and agreement.

 

Step-by-step process:2

Step-by-step process

Supporting References:

  1. Hasson, F., Keeney, S. & Mckenna, H. Research guidelines for the Delphi Survey Technique. Journal of advanced nursing 32, 1008–15 (2000).
  2. Levtchenko, E. et al. Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients. Clinical Kidney Journal, 2022, vol. 15, no. 9, 1675–1684. https:/doi.org/10.1093/ckj/sfac099.

Supporting References:

  1. Levtchenko, E. et al. Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients. Clinical Kidney Journal, 2022, vol. 15, no. 9, 1675–1684. https:/doi.org/10.1093/ckj/sfac099.
  2. Ariceta, G. et al. A coordinated transition model for patients with cystinosis: from pediatrics to adult care. Nefrologia 36, 616–630 (2016).