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A Retrospective Analysis of Immunosuppression Compliance, Dose Reduction and Discontinuation in Kidney Transplant Recipients
Open accessAbstract
We describe factors associated with poor compliance and dose reductions and examine the relative impact of compliance, dose reduction and discontinuation on graft outcome. Medicare claims for MMF in 7062 deceased donor renal recipients with at least 1 year of graft function were used to calculate compliance and dose reductions. Compliance was modeled using medication possession ratio to define quartiles for poor, low, medium and high compliance. The relative impact of compliance, dose reduction and discontinuation on graft outcome was assessed with Cox proportional hazards. Pediatric (Age 0-18, Odds ratio = 1.71, 95% CI 1.11-2.63, p = 0.014) and adolescent recipients (19-24, 1.57, 1.23-2.00, p < 0.001) were more likely poorly compliant compared to adults age 25-44. Poor compliance was also associated with physical limitations, hypertension, delayed graft function, rejection, infection and GI conditions. Poor (1.43, 1.11-1.84, p = 0.005) and low (1.46, 1.13-1.88, p = 0.004) compliance was associated with an increased hazard of graft loss as was >50% dose reduction (1.69, 1.15-2.50, p = 0.008) and discontinuation (8.34, 6.85-10.2, p < 0.001). Medication possession ratios lower than the 3-year mean were associated with an increased risk of graft loss. These results may indicate that interventions to improve compliance among kidney transplant recipients should strive for high rather than discourage low compliance.
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“Other groups used the discrepancy between immunosuppressant dosages and prescription refills or data from health insurances for the assessment of adherence[35,36].”
From Adherence is associated with a favorable outcome after lung transplantation (2019) · cites this paper as [36]
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“MMF has been shown to be an effective adjunct to calcineurin inhibitor (CNI) regimens for preventing acute (27) and chronic rejection (28,29) of renal allografts, and has become the standard adjunct immunosuppressant at most transplant centers in the United States (30).”
BackgroundA Checklist for Medication Compliance and Persistence Studies Using Retrospective Databases
Peterson, A. M., Nau, D. P., Cramer, J. A., Benner, J., Gwadry-Sridhar, F. H., & Nichol, M. B. (2006) · Value in Health · doi:10.1111/j.1524-4733.2006.00139.x · Cited by 638 · cited 3×
“MPR has been used to assess compliance to anti-hyperglycemic, lipid-lowering and anti-hypertensive therapies (13).”
BackgroundMethodInfluentialButler, J. A., Roderick, P., Mullee, M., Mason, J. C., & Peveler, R. (2004) · Transplantation · doi:10.1097/01.tp.0000110408.83054.88 · Cited by 545
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“Most other studies have either used rejection as an endpoint or estimated the percentage of graft losses attributable to poor compliance (2,11).”
BackgroundMethodInfluentialWoodward, R. S., Schnitzler, M. A., Baty, J., Lowell, J. A., Lopez-Rocafort, L., Haider, S., WOODWORTH, T. G., & Brennane, D. C. (2003) · American Journal of Transplantation · doi:10.1034/j.1600-6143.2003.00082.x · Cited by 400 · cited 3×
“Diabetic (15) and GI complications (16,17) were defined as”
BackgroundSelf-citationMYCOPHENOLATE MOFETIL REDUCES LATE RENAL ALLOGRAFT LOSS INDEPENDENT OF ACUTE REJECTION
OJO, A. O., Meier‐Kriesche, H., Hanson, J. A., Leichtman, A. B., Cibrik, D. M., Magee, J. C., Wolfe, R. A., Agodoa, L. Y. C., & Kaplan, B. E. (2000) · Transplantation · doi:10.1097/00007890-200006150-00033 · Cited by 399 · cited 1×
“MMF has been shown to be an effective adjunct to calcineurin inhibitor (CNI) regimens for preventing acute (27) and chronic rejection (28,29) of renal allografts, and has become the standard adjunct immunosuppressant at most transplant centers in the United States (30).”
BackgroundThe barrier function of CYP3A4 and P-glycoprotein in the small bowel
Watkins, P. B. (1997) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(97)00041-0 · Cited by 390 · cited 1×
“Calcineurin inhibitors have a narrow therapeutic window, and therefore warrant frequent drug monitoring and adjustment (21).”
BackgroundDavies, S. (2002) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/17.6.1085 · Cited by 387 · cited 2×
“For instance, if diabetes was the cause of end-stage renal disease (ESRD) or if it was indicated that the patient suffered from diabetes on the recipient registration survey, we considered that patient to be a diabetic.”
BackgroundIncidence and Predictors of Myocardial Infarction after Kidney Transplantation
Lentine, K. L., Brennan, D. C., & Schnitzler, M. A. (2004) · Journal of the American Society of Nephrology · doi:10.1681/asn.2004070580 · Cited by 353 · cited 2×
“These diagnosis codes have been used to show that posttransplant complications including diabetes (14,15), gastrointestinal (GI) conditions (16,17), myocardial infarction (18) and congestive heart failure (19) are associated with poor graft outcome.”
BackgroundSelf-citationAdverse Gastrointestinal Effects of Mycophenolate Mofetil
Behrend, M. (2001) · Drug Safety · doi:10.2165/00002018-200124090-00002 · Cited by 325 · cited 1×
“Despite its efficacy, use of MMF is associated with a high incidence of GI, hematologic and metabolic complications (6,27,31).”
BackgroundVLAMINCK, H., Maes, B., Evers, G. C. M., Verbeke, G. N., Lerut, E., Damme, B. V., & Vanrenterghem, Y. F. C. (2004) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2004.00537.x · Cited by 229 · cited 1×
“The impact of poor compliance on graft outcome may be even greater in later periods after transplantation (37).”
BackgroundDenhaerynck, K., Steiger, J., Bock, A., Schäfer-Keller, P., Köfer, S., Thannberger, N., & De Geest, S. (2007) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2006.01611.x · Cited by 184 · cited 3×
“Unfortunately, this methodology may overestimate compliance rates because most patients are hesitant to reveal their pill taking behavior (2,11).”
BackgroundMethodHardinger, K. L., Brennan, D. C., Lowell, J. A., & Schnitzler, M. A. (2004) · Transplant International · doi:10.1111/j.1432-2277.2004.tb00394.x · Cited by 163
Self-citationBunnapradist, S., Lentine, K. L., Burroughs, T. E., Pinsky, B. W., Hardinger, K. L., Brennan, D. C., & Schnitzler, M. A. (2006) · Transplantation · doi:10.1097/01.tp.0000225760.09969.1f · Cited by 159 · cited 4×
“We previously reported an increased risk of graft failure for kidney transplant recipients with GI complications whose MMF dose was reduced or discontinued (16,17).”
BackgroundMethodInfluentialSelf-citationButler, J. A., Peveler, R., Roderick, P. J., Smith, P. W. F., Horne, R., & Mason, J. C. (2004) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfh505 · Cited by 158
Baseline Comorbidity in Kidney Transplant Recipients: A Comparison of Comorbidity Indices
Jassal, S. V., Schaubel, D. E., & Fenton, S. S. A. (2005) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2005.03.006 · Cited by 153 · cited 1×
“A recent report compared the Charlson Comorbidity Index to three other indices and found that it was the best at predicting death among kidney transplant recipients reported to the Canadian Organ Replacement Registry (38).”
MethodThe natural history of azathioprine compliance after renal transplantation
Nevins, T. E., Kruse, L., Skeans, M. A., & Thomas, W. J. (2001) · Kidney International · doi:10.1046/j.1523-1755.2001.00961.x · Cited by 149 · cited 1×
“That estimate was based on a 35% 1-year graft loss rate in 13 patients noncompliant to azathioprine compared to 5% in 107 compliant patients (7).”
BackgroundRENAL TRANSPLANT PATIENT COMPLIANCE WITH FREE IMMUNOSUPPRESSIVE MEDICATIONS1
Chisholm, M. A., Vollenweider, L. J., Mulloy, L. L., Jagadeesan, M., Wynn, J. J., Rogers, H. E., Wade, W. E., & DiPiro, J. T. (2000) · Transplantation · doi:10.1097/00007890-200010270-00020 · Cited by 139
Lentine, K. L., Schnitzler, M. A., Abbott, K. C., Li, L., Burroughs, T. E., Irish, W. D., & Brennan, D. C. (2005) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2005.06.019 · Cited by 136 · cited 2×
“These diagnosis codes have been used to show that posttransplant complications including diabetes (14,15), gastrointestinal (GI) conditions (16,17), myocardial infarction (18) and congestive heart failure (19) are associated with poor graft outcome.”
BackgroundSelf-citationGeest, S. D., Schäfer‐Keller, P., Denhaerynck, K., Thannberger, N., Köfer, S., Bock, A. H., Surber, C., & Steiger, J. U. (2006) · Clinical Transplantation · doi:10.1111/j.1399-0012.2006.00493.x · Cited by 125
Improved cadaveric renal transplant outcome in children
Ettenger, R. B., Rosenthal, J. T., Marik, J. L., Malekzadeh, M., Forsythe, S., Kamil, E. S., Salusky, I. B., & Fine, R. Ν. (1991) · Pediatric Nephrology · doi:10.1007/bf00852871 · Cited by 123
Payment for Immunosuppression After Organ Transplantation
Kasiske, B. L. (2000) · JAMA · doi:10.1001/jama.283.18.2445 · Cited by 105
Jarzembowski, T. M., John, E. G., Panaro, F., Heiliczer, J. D., Kraft, K., Bogetti, D., Testa, G., SANKARY, H. N., & Benedetti, E. (2004) · Pediatric Transplantation · doi:10.1111/j.1399-3046.2004.00158.x · Cited by 104
Alloway, R. R., Isaacs, R. B., Lake, K. D., Hoyer, P. F., First, R. M., Helderman, H., Bunnapradist, S., Leichtman, A. B., Bennett, M. W., Tejani, A. H., et al. (2003) · American Journal of Transplantation · doi:10.1046/j.1600-6143.2003.00212.x · Cited by 104 · cited 1×
“The importance of strict compliance to treatment regimens for optimizing graft outcome has been well documented (1,2,20).”
BackgroundSelf-citationNon‐adherence in pediatric transplantation: A review of the existing literature
Griffin, K. J., & Elkin, T. D. (2001) · Pediatric Transplantation · doi:10.1034/j.1399-3046.2001.005004246.x · Cited by 101 · cited 1×
“On the other hand, factors associated with poor compliance were consistent with other literature (5).”
BackgroundIssues of Adherence to Immunosuppressant Therapy After Solid-Organ Transplantation
Chisholm, M. A. (2002) · Drugs · doi:10.2165/00003495-200262040-00002 · Cited by 95
HLA matching for kidney transplantation
Takemoto, S. K., Port, F. K., Claas, F. H. J., & Duquesnoy, R. J. (2004) · Human Immunology · doi:10.1016/j.humimm.2004.06.008 · Cited by 80 · cited 1×
“The increased hazards after censoring at death with a functioning graft may indicate that poor compliance affects immune regulation rather than the general health of the recipient since a similar effect is seen with patients receiving HLA-matched transplants (32).”
Self-citationChisholm, M. A., Lance, C. E., & Mulloy, L. L. (2005) · American Journal of Health-System Pharmacy · doi:10.2146/ajhp040541 · Cited by 73 · cited 1×
“The majority of studies have used surveys to obtain a patient self-report of compliance (1,2,10).”
BackgroundArns, W., Cibrik, D. M., Walker, R. G., Mourad, G., Budde, K., Mueller, E. A., & Vincenti, F. G. (2006) · Transplantation · doi:10.1097/01.tp.0000232697.38021.9a · Cited by 73 · cited 1×
“In contrast, mycophenolate mofetil (MMF) is usually given at fixed doses since therapeutic drug monitoring was deemed unnecessary due to its favorable safety profile (22).”
BackgroundThe Economic Implications of Non-Adherence after Renal Transplantation
Cleemput, I., Kesteloot, K., Vanrenterghem, Y. F. C., & Geest, S. D. (2004) · PharmacoEconomics · doi:10.2165/00019053-200422180-00006 · Cited by 72
The Economic Implications of HLA Matching in Cadaveric Renal Transplantation
Schnitzler, M. A., Hollenbeak, C. S., Cohen, D. S., Woodward, R. S., Lowell, J. A., Singer, G. G., Tesi, R. J., Howard, T. K., Mohanakumar, T., & Brennan, D. C. (1999) · New England Journal of Medicine · doi:10.1056/nejm199911043411906 · Cited by 58 · cited 1×
“Other data available from administrative claims include costs associated with medical care (40) and posttransplant complications not collected on the OPTN survey forms (15,16,18,19).”
BackgroundSelf-citationHealth insurance considerations for adolescent transplant recipients as they transition to adulthood
Willoughby, L. M., Fukami, S., Bunnapradist, S., Gavard, J. A., Lentine, K. L., Hardinger, K. L., Burroughs, T. E., Takemoto, S. K., & Schnitzler, M. A. (2006) · Pediatric Transplantation · doi:10.1111/j.1399-3046.2006.00639.x · Cited by 46
Self-citationStirnemann, P. M., Takemoto, S. K., Schnitzler, M. A., Brennan, D. C., Abbott, K. C., Salvalaggio, P. R. D. O., Burroughs, T. E., Gavard, J. A., Willoughby, L. M., & Lentine, K. L. (2006) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006030258 · Cited by 24 · cited 8×
“Rejection was defined based on the OPTN discharge, 6-month or first-year follow-up responses indicating a rejection episode, steroid or antibody rejection therapy.”
ResultInfluentialSelf-citationMachnicki, G., Pinsky, B. W., Takemoto, S. K., Lentine, K. L., Willoughby, L. M., Bunnapradist, S., Burroughs, T., & Schnitzler, M. A. (2005) · PubMed · Cited by 1
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Cited by
Sorted by citations
Transplant Outcomes and Economic Costs Associated with Patient Noncompliance to Immunosuppression
Pinsky, B. W., Takemoto, S., Lentine, K. L., Burroughs, T. E., Schnitzler, M. A., & Salvalaggio, P. R. D. O. (2009) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2009.02798.x · Cited by 331
“Using this methodology, we recently found that poor compliance with MMF was associated with 43–46% increased risk of graft failure (14).”
MethodSelf-citationDobbels, F., Ruppar, T. M., Geest, S. D., Decorte, A., Damme‐Lombaerts, R. V., & Fine, R. Ν. (2009) · Pediatric Transplantation · doi:10.1111/j.1399-3046.2010.01299.x · Cited by 306
“2007 (19) USA N = 40 (adolescents out of larger study) Retrospective analysis Prescription refill Medication possession ratio (MPR) over a 1–3-year time period (divided in quartiles using time dependent analysis): high adherence >98% MPR; medium between 81 and 98%, low between 69 and 81%; and poor: <69% 44% Adherence…”
BackgroundNonadherence Consensus Conference Summary Report
Fine, R. Ν., Becker, Y. T., Geest, S. D., Eisen, H. J., Ettenger, R. B., Evans, R., Rudow, D. L., McKay, D. B., Neu, A. M., Nevins, T. E., et al. (2008) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2008.02495.x · Cited by 297
“<95% adherence to the immunosuppressive regimen) are sufficient to result in poor outcomes (10,14).”
BackgroundInterventions to improve medication-adherence after transplantation: a systematic review
Bleser, L. D., Matteson, M., Dobbels, F., Russell, C. L., & Geest, S. D. (2009) · Transplant International · doi:10.1111/j.1432-2277.2009.00881.x · Cited by 248
“2 Counseling/behavioral interventions targeted, shaped, and/or reinforced behavior, empowered patients to participate in their care, positively changed a patient’s skill level or normal routine [3,7,8].”
BackgroundMethodResultInfluentialImproved Adherence to Tacrolimus Once-Daily Formulation in Renal Recipients
Kuypers, D. R. J., Peeters, P. C., Sennesael, J. J., Kianda, M. N., Vrijens, B., Kristanto, P., Dobbels, F., Vanrenterghem, Y. F. C., & Kanaan, N. (2012) · Transplantation · doi:10.1097/tp.0b013e3182725532 · Cited by 228
Metadata
- Authors
- Takemoto, S. K., Pinsky, B. W., Schnitzler, M. A., Lentine, K. L., Willoughby, L. M., Burroughs, T. E., & Bunnapradist, S.
- Affiliations
- Saint Louis University (US)
- University of California, Los Angeles (US)
- Corresponding author
- Takemoto, S.K.
- Venue
- American Journal of Transplantation
- Publisher
- Elsevier BV
- Published
- 2007-12
- Volume
- 7
- Issue
- 12
- Pages
- 2704-2711
- ISSN
- 1600-6135 (ISSN-L)
- OpenAlex
- W2020224358
- Cited by
- 202
- References
- 40
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 7 · 2022: 7 · 2021: 12 · 2020: 7 · 2019: 14 · 2018: 8 · 2017: 6 · 2016: 7 · 2015: 9 · 2014: 20 · 2013: 15 · 2012: 23
- FWCI
- 9.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal of Transplantation (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK073036)
- Topics
- Health Sciences › Medicine › Transplantation › Renal Transplantation Outcomes and Treatments
- Health Sciences › Medicine › Family Practice › Medication Adherence and Compliance
- Health Sciences › Medicine › Nephrology › Dialysis and Renal Disease Management
- Keywords
- kidney transplantation, medication possession ratio, mycophenolate mofetil, dose reduction, drug discontinuation, graft loss, graft rejection, delayed graft function, hypertension, gastrointestinal diseases
- MeSH terms
- Adolescent, Adult, Child, Child, Preschool, Dose-Response Relationship, Drug, Gastrointestinal Diseases, Graft Rejection, Medicare, Humans, Immunosuppressive Agents, Infant, Infant, Newborn, Insurance Claim Review, Middle Aged, Mycophenolic Acid, Patient Compliance, Retrospective Studies, Risk Factors, United States, Logistic Models, Proportional Hazards Models, Kidney Transplantation, Treatment Outcome
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