Prospective Study on Late Consequences of Subclinical
In this prospective study we compared the incidence of late acute rejections (LAR) and changes in serum-creatinine over time between compliers and noncompliers with immunosuppressive therapy more than 1 year post transplantation and explored the relative contribution of non-compliance and other risk factors in the occurrence of LAR.

One hundred and forty-six adult renal transplant recipients were followed during a 5-year period. Patients were interviewed at the beginning of the study and categorized as non-compliers if they admitted to have skipped immunosuppressive medication on a regular basis during the previous 12 months. The occurrence of LAR during the follow-up period was recorded.

We identified 22.6% non-compliers of which 21.2% experienced a late acute rejection compared with 8% in the group of compliers at 5 years postinclusion (p < 0.05). Kaplan-Meier survival analysis showed a decreased rejection free time in non-compliers compared with compliers (p = 0.03). Non-compliant patients had a 3.2 higher risk of LAR (Cox regression analysis, p = 0.005). Non-compliers experienced a higher increase in serum-creatinine over time (Linear Mixed Models, p < 0.001).

Non-compliance in renal transplant patients more than 1-year post transplantation is associated with an increased risk for LAR and a higher increase in serum-creatinine during the following 5 years.

Short- and medium-term graft survival following renal transplantation has improved considerably over the past years as result of the use of new immunosuppressive agents. One-year graft survival after cadaver kidney transplantation is now greater than 90%. However, long-term graft loss has improved to a lesser extent. Death of patients with a functioning kidney allograft accounts for greater than 50% of late graft losses. In surviving patients, chronic rejection or chronic allograft nephropathy is the most common cause of graft failure (50-80%). The etiology of chronic allograft nephropathy is not fully understood; however, acute rejection is an important risk factor. Especially late acute rejection episodes have been identified to have a strong correlation with late graft loss.

Little is known about the factors that cause late graft loss (5 years or more post transplant). Risk factors associated with long-term renal allograft survival reported in literature are race, donor age > 50 years, gender mismatch (female donors in male recipients), older recipient age, older donor age, HLA mismatching, delayed graft function, >1 acute rejection and high serum creatinine at 1 year post transplant.

Increasing evidence shows that also non-compliance has a negative impact on graft function, late acute-rejection episodes, organ loss and in some transplant populations death. Successful outcome in renal transplantation depends on the continued use of immunosuppressive medication. Life-long use of immunosuppressive drugs is necessary for good organ function and long-term graft survival. Despite advances in immunosuppressive therapy a major weakness in the therapeutic chain remains the patient's behavior. Non-compliance, also referred to as non-adherence, is a major problem in chronic health care and is a challenge for the health team.

Depending on the method and the operational definition used, the incidence of medication non-compliance in the adult renal transplant recipients ranges from 4.7% clinical non-compliance (or non-compliance assessed in relation to graft loss) to 53% subclinical non-compliance (or non-compliance assessed in the absence of a rejection episode or graft loss). Several methods are described to assess non-compliance in transplant patients but no gold standard exists. Interviews and patient self-reports do not reveal patterns of compliance behavior and are found to underestimate the incidence of non-compliance. However for the assessment of large study populations they are a good method, easy to use in daily practice and very cost-effective.

Several studies on all types of organ transplantation show that compliance declines with time. Patients are more compliant in the early post transplant period and less compliant as times goes by. However, most studies only focus on the non-compliance behavior in the first year post-transplant. A retrospective study on the incidence, determinants and consequences of subclinical non-compliance with immunosuppressive medication in renal transplant patients published by our group in 1995 suggested a correlation between non-compliance and the occurrence of late acute rejection. In that study we found that non-compliance is a risk factor for late acute rejection and results in lower graft survival. The aim of the present prospective study was to compare the incidence of late acute rejections (acute rejection more than 1 year post transplantation) as well as the changes in serum creatinine over time between compliers and non-compliers with immunosuppressive medication, and to explore the relative contribution of non-compliance and other known risk factors in the occurrence of these late acute-rejection episodes after renal transplantation. We also wanted to investigate if it was possible to identify potential non-compliers in daily clinical practice using self-report at an arbitrary time point after transplantation. Hypotheses are that by using self-report it is possible to identify non-compliers and find differences in time to the occurrence of late acute rejection and changes in serum creatinine over time.