Medical advances have transformed cystinosis from a historically fatal childhood disease1,2 into a chronic adult disease3 with longer life expectancy.4 Nevertheless, the transfer of young patients to adult units has led to interruptions in their medical care,5 inadequate patient follow-up and worsening of the disease.6 The acknowledgment of several factors underlying this situation illustrates the need to implement specific programs for the transition of adolescent cystinosis patients to adult care.7,8

Cystinosis is a rare (RD),1 severe systemic disease caused by mutations in the CTNS gene (17p13) that alter cystinosin synthesis, resulting in the accumulation of lysosomal cystine crystals in all body cells.2,9,10 With an incidence of 1/100,000–200,000 newborns,1 cystinosis is characterized by early renal involvement that evolves to kidney failure with corneal crystal deposits and other progressive extra-renal manifestations.11 Control of this disease requires a strict and complex therapeutic regimen1,5,6 together with rigorous periodic monitoring of cystine concentrations in granulocytes throughout the patient's life.9,11,12

Cystinosis use to be an exclusively pediatric disease and patients would die prematurely from kidney failure before the end of the first decade of life.1,4 The availability of specific treatment with cysteamine2,13 and the success of pediatric kidney transplant (KTx) programs14,15 now prolong patient survival to over 50 years.4 Consequently, a growing number of adolescents and young adults with cystinosis are being admitted to adult units where the number of experts in this rare disease is extremely low.16 Furthermore, since unexpected clinical worsening has been observed in many cases after these transfers, it is a matter of concern that the clinical progress achieved in pediatric patients tends to decline in adulthood. Numerous risk factors converge to explain this situation such as: (a) the inherent difficulty in caring for an adolescent/young adult with a chronic disease who has usually received a kidney transplant5,6 and thus has a high risk of graft loss7; (b) the lack of experience and familiarity of adult patient especialists with this RD4; (c) extra-renal involvement progression16; (d) non-compliance with treatment, which is common in this specific patient population,5,17 and (e) the lack of experts close to the patient's place of residence.8 Thus, various healthcare strategies for RD have been proposed including referrals to centers of expertise, among others.18,19

Cystinosis represents the paradigm of RD that requires a guided transition to adult medical care. Owing to the specific characteristics of the disease3–5 patients face unique challenges during the transfer process to adult units,6,7,20 which usually follows a generalized pattern.21 In Spain, there are currently around 60 patients with cystinosis, 30% of whom are children, 17% adolescents and the rest are adults who, in some cases, continue to receive treatment in pediatric units. Thus, it is imperative to implement healthcare strategies to educate patients about their disease, promote self-care and organization, and support their transition to adult care.17 This proposal is intended as a useful tool for healthcare professionals to facilitate the planning of a coordinated transition for cystinosis patients in our healthcare setting.

This work is the result of different methodologic strategies implemented by the T-CiS.bcn group: (1) a literature search on PubMed using the following key words: “cystinosis”, “transition”, “adolescent”, “renal transplant” and “adherence”; (2) a survey carried out on members of the T-CiS.bcn group themselves to identify the needs and challenges of transition in the healthcare setting and favor the implementation of improvement strategies; and (3) anonymous feedback from cystinosis patients and their relatives of the Spanish Cystinosis Group (www.grupocistinosis.org), represented by the Spanish Association for Information and Research on Genetic Renal Disease (AIRG-E; www.airg-e.org).

The European Union defines a disease as rare when it affects no more than 5 in 10,000 individuals. There are approximately 8000 different RD, affecting up to 8% of the population. The majority suffer from ultra-rare diseases, i.e. those with a frequency of ≤1 in 100,000, which render these patients particularly vulnerable and isolated.21 The European Commission has defined and adopted several preventive, diagnostic and treatment strategies for RD, aimed at improving healthcare access and equity among affected patients and ultimately improving their quality of life. The healthcare policies of each EU member state are based on the following Council Recommendations22:

• (1)

  Produce and adopt RD action plans and strategies based on the healthcare systems and social services of each country.

• (2)

  Define, encode and produce RD registers.

• (3)

  Foster research on RD.

• (4)

  Identify centers of expertise (CE), create European RD reference networks based on multidisciplinary healthcare, and to divulgue knowledge.

• (5)

  Centralize RD experience: good clinical practise guidelines and training programs on the diagnosis and treatment of RD; facilitate access to orphan drugs and clinico-therapeutic assessment reports.

• (6)

  Promote the empowerment of patient associations (PA) through their involvement in developing healthcare policies and providing access to up-to-date information on RD.

• (7)

  Ensure sustainability i.e. the long-term maintenance of information, research and healthcare structures.

In order to comply with recommendation N°4, the European Union Committee of Experts on Rare Diseases (EUCERD) defined the following criteria for the designation of a CE21:

• (1)

  Volume of relevant healthcare activity and capacity to offer quality services.

• (2)

  Capacity to provide expert advice and clinical diagnoses, and produce and implement clinical protocols and quality control.

• (3)

  Multi-disciplinary healthcare.

• (4)

  High level of expertise and experience documented through publications, grants and training courses.

• (5)

  Concerted contribution to research.

• (6)

  Involvement in epidemiologic surveillance: patient registries.

• (7)

  Close links and collaboration with other centers of excellence. Involvement in research networks.

• (8)

  Capacity to interact with Patient Associations (PA).

• (9)

  Advisory service.

• (10)

  Proven capacity for clinical patient follow-up.

Spain approved the Rare Diseases Strategy of the National Health System in June 2009.23 Likewise, the Spanish Federation for Rare Diseases (FEDER; www.enfermedades-raras.org) acts on behalf of the 3 million individuals with rare diseases in Spain.

Transition is a planned, anticipated and coordinated process that aims to prepare and transfer the pediatric patient from guardian-care to an adult unit where they will become responsible for their own self-care.24 The transition phase will be gradual, progressive and adapted to the patient's individual maturity, which often fails to match the approved age at transfer. This process must ensure that the patient receives adequate and continued care during the changeover.7,25

Identifying barriers is a fundamental step in recognising the patient's strengths and environment, and in improving the coordination and commitment of all parties involved. Child patients are seen by the pediatric nephrologist who focuses his/her attention on systemic involvement.5,6,18 This coordinated guardian care in pediatrics changes completely when the patient is transferred to adult care, where they are often seen by separate professionals primarily focused on their own speciality.19 The result is “fragmented care”, with negative repercussions on healthcare quality and continuity. This is seen by patients as a step backwards in terms of the care they are receiving and generates a loss of confidence in the medical team and resistance to change.18 This scenario is further exacerbated by the lack of resources set aside for RD. The result of this situation is reflected in Fig. 1, which presents the barriers to transition in cystinosis, some of which are also observed in many other RD.

Fig. 1.

Barriers to transition in cystinosis.

(0.3MB).

Through surveys conducted on patients and family members, information has been obtained on the impact of the disease along with attitudes towards transition.17,33–36

• (a)

  Physical impact: patients feel different, above all because of their short stature and the effects of the disease and treatment.

• (b)

  Psychologic impact: on personal relationships and in terms of their autonomy and social life. They are dependent on their family for care and the disease hinders their personal development. Conflicting feelings of overprotection and gratitude to those around them. Fear of rejection. Frequent discrimination at school and in the workplace. More depression and anxiety than in other chronic diseases.37

• (c)

  Development of positive strategies and attitudes: adapting to the disease, fostering a healthy lifestyle, desire for personal growth and an appreciation of life.

Fig. 2 summarizes the attitudes and perceptions of cystinosis patients and the T-CiS.bcn group with regard to transition.

Fig. 2.

Attitudes and perceptions in transition.

(0.51MB).

The treatment of cystinosis patients is closely linked to highly specialised hospital care. There is no single transition model and pediatric patients may be transferred from a variety of settings:

• 1.

  A children's hospital within a general hospital where the patient is not usually required to change site, thus favoring the continuum of care.

• 2.

  A children's hospital that must transfer its patients to another adult center. However, this center is usually within close proximity, with established collaboration, thereby facilitating interactions between the healthcare teams.

• 3.

  A children's hospital which, regardless of its nature, transfers patients to another referral center in a geographical area far from the patient's place of residence. This context poses the greatest difficulties, thereby reinforcing the need for a set transition plan.

The interests of the patient and their family and other personal factors will be assessed in all cases and at all times

• (a)

  Circuit:

  • (1)

    Advise the patient who is reaching transition age and implement the protocol on an individual basis (follow-up visits with the case manager to reinforce the healthcare instruction).

  • (2)

    Apply selection criteria for the center of reference based on: the patient's place of residence, the patient's decision and the existence of a CE or nearby center of reference.

  • (3)

    Identify the most suitable adult nephrologist to receive the cystinosis patient according to the organization of the department and available resources.

  • (4)

    Establish communication between the case manager of the children's hospital and that of the receiving adult department.

  • (5)

    Draw up a specific transition plan from pediatric to adult nephrology. This should be specifically designed for the patient and hospital in question, and will include:

    • -

      Briefing (face-to-face, by telephone or via email) of the pediatric nephrologists, case manager and adult nephrologist to establish contact between the teams and consolidate a lasting relationship.

    • -

      Whenever possible, try to hold a joint meeting of both teams (final or penultimate visit prior to the transfer) to remove any barriers and facilitate the transition to external adult nephrology appointments. Should geographic barriers exist, foster a network approach.

  • (6)

    Ensure that the pharmacy circuit adapts to the new circumstances and that the patient has enough of the specific medication required until admission to the receiving center.

  • (7)

    The actual transfer of the patient.

  • (8)

    Follow-up and monitoring of the transition to guarantee the continuum of care and detect any deviations from the protocol or unforeseen difficulties. The duration of this period will be agreed upon by both teams; it is recommended to last for the first year, which is the most critical period, or until a follow-up routine has been established at the adult center.

  • (9)

    Quality control of the transition model, including a registry of transferred patients and periodic updates of the transition protocol.

• (b)

  Essential documentation: medical report from the pediatric nephrologist and any other specialists involved in the patient's care. This record must include the following information:

  • -

    Clinical diagnosis (age at diagnosis, clinical characteristics, genetic diagnosis).

  • -

    Relevant personal history (including allergies and intolerances, vaccination schedule).

  • -

    Patient's childhood clinical history (on-going problems, resolved problems, serious renal and extra-renal complications).

  • -

    Pharmacologic treatment: up-to-date treatment plan, drug levels, specific therapeutic monitoring (intragranulocyte cystine levels) and report on treatment adherence.

  • -

    Final visit summary and a copy of the latest tests performed.

  • -

    Recommendations for clinical follow-up per speciality19:

    • -

      Up-to-date speciality-based appointment schedule.

    • -

      Appointment letter with comprehensive information for the patient and family (date and time of appointment, physician, contact details).

    • -

      Identification of the receiving specialist.

    • -

      Request for complementary tests for the next visit.

The T-CiS.bcn working group has proposed with the following transition recommendations for adolescents and young adults with cystinosis to complement those of the multidisciplinary follow-up recommendations for these patients in adult medicine, as indicated in the first part of the consensus document on comprehensive cystinosis care.19

Specific plans are provided herein for the most prevalent diseases in the transition phase: nephrologic, ophthalmologic, endocrinologic and neurologic (Tables 2–5), along with recommendations for improving treatment compliance (Table 6) and promoting patient self-care (Table 7).

Granulocyte cystine levels ≤1nmol hemicystine/mg protein indicate good adherence to oral cysteamine, resulting in therapeutic efficacy. The issue of non-adherence emerges during adolescence and is generally more pronounced during the transition to adult units, affecting both treatment and clinical adherence (missed clinic appointments and complementary tests). Non-adherence to cysteamine is associated with worse prognosis and greater renal and extra-renal disease progression.4,19,43 Nevertheless, suboptimal treatment compliance is not restricted to cystinosis and has been observed in KTx and other chronic diseases.17,44

Numerous converging risk factors that affect treatment adherence in cystinosis patients include a strict dosing regimen, tolerance problems, potential side effects and a complex multi-drug treatment plan. Furthermore, other equally important considerations not exclusive to cystinosis are: limited knowledge of the disease, lack of motivation, inadequate transition to adult care and impact of the disease on quality of life.8,45 A further factor is that cystinosis patients often present neuropsychologic involvement and disabilities which, when accompanied by neurocognitive immaturity, may further affect the patient's ability to manage the chronic disease.41

Assessing treatment adherence is essential in the patient's clinical follow-up, compliance should be routinely included in their medical notes, with an open and positive attitude that permits the correction of any prescription deviations.46,47 Thus, it is recommended that the different professionals involved assess the patient's degree of adherence and actively intervene with measures for improvement40,44–49 (Table 6).

The authors declare that they have no conflicts of interests.