Drug holiday: a challenging child–adult interface in kidney transplantation

Pierre Cochat,1, Sabina De Geest2 and Eberhard Ritz3

1 Département de Pédiatrie, Hôpital Edouard Herriot and Université Claude Bernard, Lyon, France, 2 Centre for Health Services and Nursing Research, Catholic University of Leuven, Leuven, Belgium, and 3 Sektion Nephrologie, Klinikum der Universität Heidelberg, Heidelberg, Germany

Introduction

Non-compliance is a major problem in any chronic medical condition and continues to be a challenge to the physicians. Increasing evidence shows its impact on graft function. Yet its assessment remains disheartening. The psychological motives underlying non-compliance are presumably more ‘forgetting’; as a result of weariness of treatment rather than pernicious self-destructive behaviour. Given its deleterious effect on graft outcome, non-compliance has increasingly become the focus of clinical research. Two scientific meetings have been devoted to this problem, which is both old and new (Arlington, USA, April 1998; Hof bei Salzburg, Austria, February 1999).

Psychological motives underlying non-compliance

Whether a patient accepts his chronic disease and the idea that he is responsible for his own health depends on many factors such as family history, religious and cultural backgrounds, emotional profile, age at onset and type of primary disease, presence of comorbid factors, and life events.

Some of the problems concern the patient. To a large extent non-compliance is related to side-effects of immunosuppressive drugs, especially in the paediatric transplant recipents: 10–50% of the patients experience cosmetic problems (i.e. hypertrichosis, increased body mass index, striae, warts, gum hyperplasia, acne) or other distressing physical symptoms (i.e. trembling hands, muscle weakness, bone disease, cataracts). These distressing side-effects can trigger non-compliance. Moreover, empirical evidence has shown that higher levels of symptom distress are associated with higher levels of depressive symptomatology, which in turn is a factor known to predispose to non-compliance. Yet, the prevalence of depression is often underestimated in chronic patient populations such as solid-organ transplant recipients. More banal reasons include simple forgetting, carelessness, medical or familial opposition. An important motive in the adolescent is the impulse to be free.

Some of the problems reside also with the parents. In infants and children, the occurrence of growth retardation in addition to aesthetic problems may be perceived as socially unacceptable. Both factors may cause parental depression and further parent-induced non-compliance. Depending on the cultural background, abnormalities such as growth delay, deformity, or disability are tolerated or not. In the worst cases, one may see plucking, shaving or even child abuse; it has been emphasized that Münchhausen syndrome by proxy may occur.

Non-compliance in adolescent patients can be triggered by developmental issues, such as conflicts over autonomy, control and body integrity, and related issues. The adolescent progressively discovers his power to decide whether he is going to take the drugs. Unfortunately, he also often unconsciously underestimates the potentially deleterious consequences of non-compliance on graft function. As part of the rebellion of the adolescent against the elder, he will often argue with the transplant physician when he proposes to modify drug dosage and will insist on making the decision himself. Moreover, the wish to be ‘normal’, defined in particular by the absence of the need to take medications, has been recognized as an important factor in paediatric non-compliance.

Assessment of drug compliance

Non-compliance is a multi-causal complex phenomenon rooted in psychological, behavioural and physiological dynamics. The reported frequency varies between 5 and 57% of renal-transplant recipients, depending on the methods of measurement (Table 1Go) and the operational definitions used [1,2]. The prevalence of non-compliance in the paediatric transplant population is even higher [6]. Non-compliance can be assessed from a clinical as well as from a subclinical perspective. Subclinical non-compliance refers to assessing non-compliance in a sample of initially clinically stable patients, thus allowing the detection of all actual non-compliers. Clinical non-compliance refers to assessing non-compliance in relation to the occurrence of a clinical event such as an acute rejection episode, allowing one to detect only the tip of the proverbial iceberg of non-compliers. Subclinical non-compliance is most valuable when trying to understand the long-term clinical effects of non-compliance with immunosuppressive regimen and is estimated to be 15–22% in adult transplant patients [1,5].


View this table:
[in this window]
[in a new window]
 
Table 1. Assessment methods of non-compliance with immunosuppressive regimen in transplantation [1,36]

 
The validity of non-compliance assessment is enhanced if patients are questioned in a non-threatening, non-accusatory, information-intensive manner during a private conversation rather than in the presence of medical staff or a family member. Such a ‘contract’ between patient and care-giver is a necessary basis for reciprocal confidence.

Clinical spectrum of non-compliance

Non-compliance can be suspected in the presence of: (i) unusual findings such as low drug concentration despite adequate dosage, failure to develop signs of steroid toxicity despite high-dose prednisone treatment, persistent arterial hypertension despite adequate hypertensive medication; (ii) presence of risk factors of non-compliance (see below); (iii) unexplained late graft dysfunction, and (iv) poor clinic attendance record [6]. We therefore wish to warn that the presentation of non-compliance is protean and a high index of suspicion is required. It is also difficult to know whether missing consecutive doses of immunosuppressive drugs for extended periods is as bad as occasional intermittent medication. A large multicentre survey revealed three profiles of non-compliers based on clustering of specific risk factors of non-compliance: accidental non-compliers, invulnerables, and decisive non-compliers [1]. One could also argue about the role of ‘physician-related’ non-compliance.

Risk factors

Non-compliance following renal transplantation has been related to risk factors such as age below 20 (adolescence), non-Caucasian race, unemployment, poverty, male gender, poor health insurance coverage, not living in a stable relationship with a partner, psychiatric history (i.e. depression, history of suicide attempts), substance abuse, inadequate health beliefs (i.e. concerning either the efficacy of immunosuppression or persistence of symptoms post-transplantation), previous non-compliance (i.e. dialysis or diet non-compliance), and antisocial behaviour [13]. In addition, some factors of non-compliance may be related to the treatment itself, such as the number of prescribed medications, alternate-day steroid therapy, drug packaging, and transfer from the paediatric to the adult transplant unit.

On the other hand, one has to identify conditions that fail to affect or even improve compliance: pre-emptive transplantation improves the quality of life without altering drug compliance [7], and enrolment of patients in clinical trials has been shown to improve compliance significantly. Diabetic patients used to adhering to treatment schedules tend to be more compliant.

The fate of non-compliance

Non-compliance poses problems to the individual patient, i.e. allograft rejection, graft loss, patient death, and to the community, i.e. raising health care expenditure and organ shortage [2,8]. Late acute rejection episodes are a typical consequence of subclinical non-compliance [5]. It remains unclear, however, to what extent non-compliance contributes to chronic rejection and ultimately to graft loss. Yet, given that acute rejections have been recognized as an aetiological factor in the occurrence of chronic rejection, it is likely that its influence on graft outcome is substantial. One should consider that even perfect compliance cannot guarantee that grafts are not lost, and on the other hand non-compliance is occasionally compatible with good long-term graft function. There is no doubt, however, that non-compliance is a frequent cause of the need for retransplantation. It is therefore sensible to carefully assess whether risk factors for non-compliance are present before transplantation is considered. This analysis should include the patient, the medical staff, and the relatives. It is interesting that if patients have lost the first graft from non-compliance, compliance is better once they have received a second graft [2, and personal communication], so that non-compliance should not be considered a contraindication against regrafting.

As well as causing medical problems, non-compliance significantly increases the financial cost of transplantation. Swanson et al. [8] found that readmission rates and subsequent mean costs were 2.4-fold higher in non-compliant than in compliant patients.

Can one improve drug compliance?

Because non-compliance is a risk factor for adverse renal transplant outcome, it is important to develop intervention strategies in order to enhance compliance. Risk factors for non-compliance, identified in exploratory studies, may be helpful in this context [5]. We emphasize that usually non-compliance is unintentional and is thus susceptible to improvement.

We have discussed above that non-compliance is deeply rooted in personality traits. This explains that an empathic approach by the physician works better than a coercive attitude. Once a basis of confidence between care-giver and patient has been established, patients are usually much more at ease to discuss the problem with ‘their’ doctor (or ‘their’ preferred nurse) rather than within the family circle. Exploration must be followed by procedures to prevent non-compliance. It helps to simplify treatment, to reduce the number of unessential drugs, to educate the patient (i.e. individual confrontation, comments about drug monitoring, selection of a representative), and to draw the patient's attention to the consequences of non-compliance which the community has to bear (financial cost, organ shortage). Most patients are very open-minded and interested in books and video training programmes aiming to explain the mode of action of drugs, their potential adverse effects and their expected benefits. It is sometimes useful to involve not only the patient, but also the close relatives, in this programme.

The transfer from the paediatric to the adult transplant unit is at the origin of specific crises. Such patients have usually been spoon-fed by paediatricians, but with the nephrologists for the adult they are more left to themselves [3]. Several preventive compliance interventions should be considered, more specifically: (i) transfer the patient at the time of majority, independent of growth or mental delay; (ii) clinic visits without parents from age of 15–16 years onward; (iii) starting psychological training during the last year in the paediatric unit together with occasional visits to the adult department; (iv) personal introduction by the paediatrician of the adolescent to the adult transplant physician and assistance at a couple of visits; (v) complete information from the paediatrician to the adult physician and vice-versa after transfer in order to improve patient's confidence in the quality of the medical transfer; (vi) increased frequency of monitoring after the transfer; and (vii) selection of a physician in the adult team who will be specially devoted to such transfer.

Several rules are useful. When low blood drug levels are found during regular monitoring, this should be discussed with and explained to the patient, instead of using it like an espionage procedure or a coercive measure. Most renal transplant patients are on a regime of steroids (vs no-steroids), an antimetabolite (azathioprine vs mycophenolic acid), and a calcineurin inhibitor (cyclosporin vs tacrolimus). Ideally (i) in view of cosmetic side-effects one should make an attempt to withdraw steroids and to substitute tacrolimus for cyclosporin; (ii) concerning the number of drug administrations per day, cyclosporin and tacrolimus are comparable (twice daily regimen) but azathioprine is superior in this respect to mycophenolate (once vs twice daily regime); and (iii) with respect to the need of drug monitoring, again cyclosporin and tacrolimus are comparable, but azathioprine might be superior to mycophenolate. Consequently, the most appropriate theoretical immunosuppressive regime to reduce the risk of non-compliance would be a combination of azathioprine, tacrolimus, and no-steroids, which, however, may not always produce the best graft survival.

What can one do when overt non-compliance of a patient is discovered? It is useful to increase the frequency of clinic visits and to use electronic devices (electronic event-monitoring), which report dates and times of opening of the pill-bottle with a microprocessor in the cap [4,6]. When non-compliance is a manifestation of depression, supportive therapy and antidepressant agents are required.

Physicians need the help of drug companies to minimize non-compliance as a result of poor taste and inconvenient packaging of immunosuppressive drugs. Long-acting drugs, limiting the number of administrations per day, are certainly helpful and may enhance the possibility of self-assessment for non-compliance.

Conclusions

Non-compliance comes in many forms. It may be total, partial, or erratic. It should be regarded as an essential aspect of transplant patient management. Its prevention requires exhaustive information prior to transplantation, and education throughout the long-term course of follow-up. Taking account of the behavioural dimension of the transplant process by targeting non-compliance may improve both graft survival and quality of life since non-compliance has been identified as a major cause of late graft loss.

Notes

Correspondence and offprint requests to: Pierre Cochat MD, Département de Pédiatrie, Hôpital Edouard Herriot, F-69437 Lyon cedex 03, France. Back

References

  1. Greenstein S, Siegal B. Compliance and noncompliance in patients with a functioning renal transplant: a multicenter study. Transplantation1998; 66: 1718–1726[ISI][Medline]
  2. Dunn J, Golden D, van Buren CT, Lewis RM, Lawen J, Kahan BD. Causes of graft loss beyond two years in the cyclosporine era. Transplantation1990; 49: 349–353[ISI][Medline]
  3. Cochat P, Vial M. Les transplantations d'organes. In: Alvin P, ed. Médecine de l'adolescence. Masson, Paris 1999; 142–149
  4. Cramer JA, Mattson RH, Prevey ML, Scheyer RD, Ouellette VL. How often is medication taken as prescribed? A novel assessment technique. JAMA1989; 261: 3273–3277[Abstract]
  5. De Geest S, Borgermans L, Gemoets H et al. Incidence, determinants, and consequences of subclinical noncompliance with immunosuppressive therapy in renal transplant recipients. Transplantation1995; 59: 340–347[ISI][Medline]
  6. Blowey DL, Hebert D, Arbus GS, Pool R, Korus M, Koren G. Compliance with cyclosporine in adolescent renal transplant recipients. Pediatr Nephrol1997; 11: 547–551[ISI][Medline]
  7. Mahmoud A, Saïd MH, Dawahra M et al. Outcome of preemptive renal transplantation and pretransplantation dialysis in children. Pediatr Nephrol1997; 11: 537–541[ISI][Medline]
  8. Swanson M, Hull D, Bartus S, Schweitzer R. Economic impact of noncompliance in kidney transplant recipients. Transplant Proc1992; 24: 2722–2725[ISI][Medline]