In general, adherence increased between years 3 and 5 compared to between years 1 and 3 (paired t test). For example, overall adherence increased from 82.9% to 89.4% (P < 0.0001) (n = 428), adherence to prednisone increased from 87.6% to 92.6%, P < 0.0001 (n = 394) and adherence to tac/CSA increased from 93.1% to 95.3%, (P < 0.0001) (n = 424). Adherence to MMF/AZA and sirolimus remained stable between years 1 to 3 and 3 to 5 (93.2% to 92.6% (P = 0.24) (n = 427); 94.0% to 94.2% (P = 0.86) (n = 4), respectively). The distribution of adherence continuously over time is depicted in Figure 2.
Three hundred eighty-two (69.2%) patients had a renal allograft biopsy 5 years posttransplant. Prevalence of fibrosis and inflammation was 8.1% (n = 31) and prevalence of transplant glomerulopathy was 8.9% (n = 34). Both of these histologic changes have been previously associated with shortened allograft survival.19 Fibrosis and inflammation on 5-year biopsy was associated with 3- to 5-year overall nonadherence, whereas transplant glomerulopathy was not (see Table 3 and Figure 3). The relationship between fibrosis and inflammation and 3- to 5-year overall nonadherence was independent of other variables, including induction immunosuppression, maintenance immunosuppression and history of acute rejection (see Table 4). After adjusting for nonadherence to tac/CSA and prednisone therapy, only 3- to 5-year nonadherence to AZA/MMF remained significantly associated with fibrosis and inflammation (odds ratio, 10.6; 95% confidence interval, 1.5-76.1; P = 0.02). In patients with fibrosis and inflammation on 5-year biopsy (n = 31), mean eGFR at 5 years posttransplant was 13.3 mL/min per 1.73 m2 less than mean eGFR at 1 year posttransplant (39.3 mL/min per 1.73 m2 vs 52.7 mL/min per 1.73 m2, respectively; P < 0.0001 [paired t test]).
Our study is the first to examine: 1) whether nonadherence changes 3 years after kidney transplant when Medicare coverage of immunosuppression ends and 2) the relationship between nonadherence during years 3 to 5 and allograft histology. Among patients who used the Mayo Clinic Specialty Pharmacy for the first 5 years posttransplant, we found that overall adherence increased during years 3 to 5 compared with years 1 to 3 after kidney transplant. In addition, we found that overall nonadherence during posttransplant years 3 to 5 was associated with fibrosis and inflammation on 5-year allograft biopsy, but not with transplant glomerulopathy. After adjusting for nonadherence to other immunosuppressive therapy, only 3- to 5-year nonadherence to AZA/MMF remained significantly associated with fibrosis and inflammation.
Our study had several surprising findings. The first is that adherence increased between posttransplant years 1 to 3 and 3 to 5, despite loss of Medicare coverage at year 3 in patients younger than 65 years. The few studies that have examined long-term adherence after kidney transplant suggest that adherence declines over time.20,21 The increasing adherence over time seen in our cohort may reflect the benefits of using a specialty pharmacy for immunosuppression. Transplant specialty pharmacies have been associated with higher rates of adherence after kidney transplant.22 In addition, patients at our center receive education about the loss of Medicare coverage 3 years after transplant and may proactively take steps to find alternative sources of coverage before the transition. A second intriguing finding in our study was that nonadherence to particular immunosuppressive medications during posttransplant years 3-5 appeared to be associated with graft fibrosis and inflammation on 5-year surveillance biopsies. After adjusting for nonadherence to calcineurin inhibitor and prednisone therapy, only 3-5 year nonadherence to antimetabolite therapy remained significantly associated with fibrosis and inflammation. Mycophenolate has proven to be a powerful deterrent to rejection after kidney transplant and dose reduction has been associated with allograft failure.23-25 Our findings suggest that patients with fibrosis and inflammation on allograft biopsy should be questioned regarding nonadherence, especially nonadherence with antimetabolite therapy.
A third surprising finding of our study is that nonadherence to immunosuppressive medications during posttransplant years 3 to 5 was not associated with transplant glomerulopathy on 5-year surveillance biopsies. Nonadherence is a well-documented risk factor for the development of de novo DSA which in turn contributes to chronic antibody mediated injury.26 However, it is possible we did not see a relationship between nonadherence and transplant glomerulopathy because the prevalence of transplant glomerulopathy may peak later than 5 years posttransplant and longer follow-up time is needed.27
Strengths of our study include the relatively large cohort of patients with refill records available during the first 5 years posttransplant, in addition to 5-year surveillance biopsies. Limitations include the single-center design, the retrospective nature of the study, the lack of insurance information and the fact that only a subset of our patients used the Mayo Clinic Specialty Pharmacy for the first 5 years posttransplant. For example, our finding that patients taking sirolimus-based immunosuppression were more likely to be nonadherent may be confounded by the fact that only 18 patients were on sirolimus-based therapy. Another limitation of our analyses is the use of medication refill records to estimate adherence. Refill records are an imperfect estimate of adherence and may be erroneously affected by medication dose adjustment, the use of multiple pharmacies, and patient hospitalizations which contribute to fewer refills. Unfortunately, we lacked information about all of these variables in this study. However, measuring long-term adherence is a challenging issue and using refill records in a closed pharmacy system is a promising solution which is often more feasible and less expensive than direct monitoring of medication use or patient self-report. When using medication refills to estimate adherence, calculating the PDC is often the preferred method because it does not overestimate adherence, unlike another commonly used calculation called the medication possession ratio.28-31 Lastly, we would ideally have had data on the incidence of de novo DSA, but before 2006, we did not routinely monitor for de novo DSA. In light of these limitations, results of our study should be interpreted with caution. The findings of our study may not generalize to other patient populations and need to be confirmed in future, multicenter studies. However, they pave the way for future studies of the important and understudied topic of long-term adherence to immunosuppressive therapy.
In conclusion, we found that adherence to immunosuppression does not decline after loss of Medicare coverage 3 years posttransplant, but rather increases in patients who use a specialty pharmacy. Nonadherence to immunosuppression during posttransplant years 3 to 5 appears to be associated with fibrosis and inflammation but not with transplant glomerulopathy on 5-year surveillance biopsies. Efforts to improve late medication nonadherence, especially with antimetabolite therapy, may improve long-term allograft histology and survival, but additional studies are need to replicate our findings.
The authors would like to thank the Mayo Clinic transplant coordinators for their dedication to patient follow-up. These studies were supported in part by grants from the Mayo Clinic Division of Nephrology and Hypertension.
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