Adherence to Immunosuppressive Medication

The development of emphasis on long-term care following kidney

transplantation is connected with the development of powerful IM. Following kidney transplantation, renal transplant recipients, like all recipients of solid organs, must take IM on a regular basis to prevent rejection of the

transplanted organ (Achille et al. 2006). After pre- or intra-operative induction therapy, the medication regimen in Germany typically consists of a triple therapy of two types of IM, a calcineurin inhibitor and an anti-proliferative agent, along with cortisone. This regimen must be taken accurately at specific times at least once, but more commonly twice, daily (Krämer et al. 2012). Also, IM must be monitored very closely, as the dosing is delicate and must be carefully balanced between overdose and under-dose. Often, this medication is accompanied by other drugs that treat underlying diseases or co-morbidities, as well as side effects of the IM. It is therefore common that a renal transplant recipient takes more tablets than before transplantation. Although patients are informed about this prior to surgery, my impression is that freshly-transplanted persons are frequently overwhelmed by the amount of medication they need to take.

The need for regular medication to prevent complications or aggravations of a disease is not exclusive to solid organ transplant recipients, but rather a feature shared with many other chronically ill patient groups. In most chronic conditions relying on medication-taking, from mental illnesses to HIV

infections, regular intake of medication is a difficult issue for many patients (Sabaté 2003; Haynes et al. 2008). The consequences of non-adherence are severe, in terms of both medical and financial concerns.

Medical consequences of non-adherence may include sub-optimal clinical benefits, re-hospitalisations, deterioration of the disease, medical or psychosocial complications, and reductions in the patient's QoL (Sabaté 2003; Sokol et al. 2005). In renal transplant recipients, poor adherence can induce rejection, which may lead eventually to loss of the transplant (Nevins & Matas 2004; Chisholm et al. 2007; Gordon et al. 2009). Non-adherent renal transplant recipients face a seven- to eight-fold risk of graft loss compared to their adherent peers (Chisholm et al. 2007; Takemoto et al. 2007).

In financial terms, the consequences of not taking medication as prescribed place an estimated annual financial burden of €13 billion on the German healthcare system (Laschet 2013), a sum exceeding the total cost of the treatment of coronary heart disease (Gorenoi et al. 2007). The German

Federal Statistical Office (2014) has recently estimated that a minimum of 3% of the total healthcare spending in Germany goes to the consequences of medication non-adherence, and with growing numbers of chronically ill patients, this number is likely to rise. No data could be found regarding the financial consequences of medication non-adherence following renal

transplantation in Germany. However, older data from 2004 suggests that in the USA alone, between 14 and 16 million US$ were spent to treat non- adherence-related episodes of rejection (Hansen et al. 2007).

Intake of IM may be challenging. Most IM is associated with severe side effects (Table 5) (Kley & Sasse 2003; Fiebiger et al. 2004; International Transplant Nurses Society 2007a; International Transplant Nurses Society 2007b; Rote Liste® _{Service GmbH 2014). In a review, Kugler et al. (2009)}

showed that many recipients of solid organ transplants experience a variety of distressing symptoms related to IM.

Steroids Calcineurin Inhibitors (CsA, Tacrolimus) Anti-Proliferative Agents (Azathioprine, MMF) mTOR-Inhibitors (Sirolimus, Everolimus)  Infections  Diabetes  Hypertension  Hyperlipidaemia  Osteoporosis  Delayed wound healing  Stomach irritation/ulcers  Oedema  Candidosis  Cataracts  Glaucoma  Increased appetite  Weight gain  Alopecia  Acne  Mood changes  Cushingoid appearance  Infections  Renal failure  Diabetes  Arterial hypertension  Malignancies  Hand tremors  Gingival hypertrophia  Thrombotic thrombocytopenic purpura/ haemolytic uraemic syndrome  Nausea  Diarrhoea  Cephalalgia  Insomnia  Numbness  Tingling of hands and feet  Hirsutism  Acne  Alopecia  Depression  Infections  Diarrhoea  Bone marrow suppression  Stomach irritation  Mouth sores  Nausea, emesis  Fatigue  Thrombotic thrombocytopenic purpura/ haemolytic uraemic syndrome  Cephalalgia  Alopecia  Arthritis  Muscle cramps  Infections  Hyperlipidaemia  Pancreatitis  Delayed wound healing  Thrombotic thrombocytopenic purpura/ haemolytic uraemic syndrome  Acne  Alveolitis

Table 5: Side effects of IM.

Abbreviations: CsA = Cyclosporine A, MMF = Mycophenolat Mofetil, mToR = mechanistic Target of Rapamycin

Due to the immune system suppression, patients taking IM are at higher risk of acquiring infections than the general population. Patients thus need to consider food safety, general hygiene, and contact with others (International Transplant Nurses Society 2007b). Moreover, many IMs are nephrotoxic agents (Table 5), meaning that regular intake of the medications may slowly destroy the transplanted kidney.

Research has shown that non-adherence is a major international problem among renal transplant recipients. About one-third of recipients display some extent of non-adherence at some time (Denhaerynck et al. 2005; Dew et al. 2007); exact numbers for German kidney transplant recipients are not known. Around one-third of kidney graft losses are caused by medication non-

adherence (Butler et al. 2004c; Morrissey et al. 2005; Chisholm et al. 2007). In renal transplant recipients, non-adherence may occur in different forms. These include timing adherence, or taking medication correctly at specific times of day, and dosing adherence, or taking the correct dose (Osterberg & Blaschke 2005). In renal transplant recipients, both forms of adherence deserve attention, as IMs are narrow therapeutic index (NTI) drugs; that is, the patient's blood levels must be monitored closely in order to avoid reduced immunosuppression and its associated risk of rejection, as well as possible toxicity and severe side effects (Johnston 2013).

Two features of non-adherence in renal transplant recipients warrant closer attention. First, kidney transplant recipients are significantly less adherent than recipients of other solid organs. In a meta-analysis, Dew et al. (2007) showed that 35.6% of renal transplant recipients displayed some extent of medication non-adherence, compared to only 6.7% of liver recipients and 14.5% of heart recipients. Similar results were found by Hansen et al. (2007). Reasons for this are largely unknown, but causes of non-adherence in renal transplant recipients will be discussed in detail in Chapter Three. The second feature unique to renal transplant recipients’ adherence is that non-

adherence occurs relatively early after transplantation (Sabaté 2003; Nevins & Matas 2004; Osterberg & Blaschke 2005; Hansen et al. 2007), although no satisfactory explanations for this have been advanced to date.

It is thus unsurprising that graft rejection is a leading admission diagnosis in renal transplant recipients to my area of practice, the Department of

Nephrology and General Medicine at a major German university hospital. Although graft rejection may have diverse aetiologies (Howard et al. 2002; Sellarés et al. 2012), a likely explanation is non-adherence, given its

prevalence among renal transplant recipients. Therefore, this issue must be actively addressed when caring for these patients, as the appropriate

international guideline (KDIGO 2009) recommends.

However, in my area of practice, this crucial issue is rarely addressed. This lack of communication applies to all parties involved in treatment, in this case nurses, physicians, and patients. The issue of medication-taking is rarely addressed by nurses in my area of practice. The reasons for this are diverse. Many nurses lack knowledge of IM, as this is regarded as the physician’s domain. Moreover, renal transplant recipients often face the ‘problem’ of being relatively independent in terms of nursing care. In my area of practice, the normal patient-to-nurse ratio during day shifts is about ten-to-one.

However, in hospitals not affiliated with Schools of Medicine, a nurse has to care for about 13 patients (Aiken et al. 2012). This is the highest patient- nurse ratio in Europe, burdening nurses in German hospitals with extremely high workloads. Additionally, patients with low self-care capability are

common in my area, and nurses tend to prioritise and dedicate their scarce working time to patients requiring more direct care. This, however, neglects the fact that a high extent of self-care does not necessarily imply a low illness burden.

In my experience, physicians do not discuss the issue of adherence, despite claiming to follow the relevant guideline (KDIGO 2009). This applies during any contact the patient may have with the university hospital, either on the ward or in the outpatient clinic. This gap in medical care was detected in an internal quality review several years ago (Steffl 2009), but, from my

perspective, not much has changed since. This may be due to a lack of awareness that patients may experience adherence as problematic, or, as a consultant responsible for the care of renal transplant recipients once put it, “we don’t have an issue with adherence here.” Another reason for this gap may be the system of physician education, which involves bi-annual rotations of young physicians between different departments in the hospital. These frequent changes of medical contact persons may impede the familiarity necessary for an appropriate discussion of such a sensitive issue.

The issue of adherence is also rarely addressed by patients. Patients may be reluctant to address possible issues for fear of being blamed as ‘incompliant,’ as non-adherence is referred to in Germany. Indeed, they may be correct in this, as any actual or potential episodes of non-adherence are reported in the patient charts and are likely to remain there forever. Moreover, as physicians and nurses are reluctant to address adherence (Steffl 2009), the patient may assume that perfect adherence is simply expected by carers and that any problems will evoke negative responses. However, research clearly indicates that addressing adherence and connected issues in a non-judgemental way is one of the most important facilitators of adherence (Sabaté 2003).