Predicting acute rejection in children, adolescents, and young adults with a kidney transplant by assessing barriers to taking medication

Pediatric Nephrology (2021)Cite this article

Abstract

Background

Nonadherence to immunosuppression is common among pediatric, adolescent, and young adult kidney transplant recipients and a leading cause of graft loss. Assessing barriers to medication adherence in clinical practice may identify patients at risk for rejection and provide therapeutic targets.

Methods

Kidney transplant patients and/or their caregivers were assessed for 14 barriers to medication adherence using the barriers assessment tool. We compared rejection rates between patients with at least one reported adherence barrier to those without reported adherence barriers using a Kaplan-Meier estimator and Cox proportional hazard models to adjust for other mediators of acute rejection at 2 years following barriers assessment.

Results

Ninety-eight patients were assessed for barriers to adherence. Over the 2-year observation period, 22 patients developed biopsy-proven acute rejection (BPAR). Kaplan-Meier estimates show that patients with an identified barrier to adherence were more likely to have BPAR (p = 0.02) than patients without an identified barrier in the 24 months following barriers assessment. The median time to rejection for patients who experienced acute rejection was 175.5 days (IQR 63–276 days) from the time of barriers assessment. An identified barrier to adherence remained the only statistically significant predictor of BPAR with Cox modeling (HR 2.6, p = 0.04), after accounting for age, sex, and race.

Conclusions

Pediatric and adolescent kidney transplant recipients with identified adherence barriers are at increased risk for acute rejection. Barriers to adherence provide a potentially modifiable therapeutic target that can be assessed in clinic to guide targeted interventions.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

US$ 39.95

Tax calculation will be finalised during checkout.

Fig. 1

Abbreviations

AMR:

Antibody-mediated rejection

BAT:

Barriers assessment tool

BPAR:

Biopsy-proven acute rejection

CAKUT:

Congenital anomaly of the kidney and urinary tract

DSA:

Donor-specific antibody

CKD 5:

Stage 5 chronic kidney disease

TCMR:

T cell–mediated rejection

References

  1. 1.

    Tejani A, Ho PL, Emmett L, Stablein DM, North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) (2002) Reduction in acute rejections decreases chronic rejection graft failure in children: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Am J Transplant 2:142–147

    Article  Google Scholar 

  2. 2.

    Dobbels F, Ruppar T, De Geest S, Decorte A, Van Damme-Lombaerts R, Fine RN (2010) Adherence to the immunosuppressive regimen in pediatric kidney transplant recipients: a systematic review. Pediatr Transplant 14:603–613

    CAS  Article  Google Scholar 

  3. 3.

    2016 USRDS annual data report: Epidemiology of kidney disease in the United States, in USRDS Annual Data Report, N.I.D.D.K. National Institutes of Health, Editor. 2016, United States Renal Data System: Bethesda, MD.

  4. 4.

    Goldstein SL, Rosburg NM, Warady BA, Seikaly M, McDonald R, Limbers C, Varni JW (2009) Pediatric end stage renal disease health-related quality of life differs by modality: a PedsQL ESRD analysis. Pediatr Nephrol 24:1553–1560

    Article  Google Scholar 

  5. 5.

    Nevins TE, Nickerson PW, Dew MA (2017) Understanding medication nonadherence after kidney transplant. J Am Soc Nephrol 28:2290–2301

    Article  Google Scholar 

  6. 6.

    Osterberg L, Blaschke T (2005) Adherence to medication. N Engl J Med 353:487–497

    CAS  Article  Google Scholar 

  7. 7.

    Mehta P, Steinberg EA, Kelly SL, Buchanan C, Rawlinson AR (2017) Medication adherence among adolescent solid-organ transplant recipients: a survey of healthcare providers. Pediatr Transplant 21(7). https://doi.org/10.1111/petr.13018

  8. 8.

    Skeens MA, Gerhardt CA, Bajwa R, Akard TF (2020) Toward a better understanding: an exploration of provider perceptions in pediatric hematopoietic stem cell transplant adherence. Pediatr Transplant 24:e13786

    Article  Google Scholar 

  9. 9.

    Smith AW, Mara CA, Modi AC (2018) Adherence to antiepileptic drugs in adolescents with epilepsy. Epilepsy Behav 80:307–311

    Article  Google Scholar 

  10. 10.

    Gutierrez-Colina AM, Smith AW, Mara CA, Modi AC (2018) Adherence barriers in pediatric epilepsy: From toddlers to young adults. Epilepsy Behav 80:229–234

    Article  Google Scholar 

  11. 11.

    Smith AW, Mara C, Ollier S, Combs A, Modi AC (2017) Rebellious behaviors in adolescents with epilepsy. J Pediatr Psychol 43:52–60

    Article  Google Scholar 

  12. 12.

    Varnell CD Jr, Rich KL, Nichols M, Dahale D, Goebel JW, Pai ALH, Hooper DK, Modi AC (2017) Assessing barriers to adherence in routine clinical care for pediatric kidney transplant patients. Pediatr Transplant 21. https://doi.org/10.1111/petr.13027

  13. 13.

    Foster BJ, Pai ALH, Zelikovsky N, Amaral S, Bell L, Dharnidharka VR, Hebert D, Holly C, Knauper B, Matsell D, Phan V, Rogers R, Smith JM, Zhao H, Furth SL (2018) A randomized trial of a multicomponent intervention to promote medication adherence: the Teen Adherence in Kidney Transplant Effectiveness of Intervention Trial (TAKE-IT). Am J Kidney Dis 72:30–41

    Article  Google Scholar 

  14. 14.

    Gray WN, Denson LA, Baldassano RN, Hommel KA (2012) Treatment adherence in adolescents with inflammatory bowel disease: the collective impact of barriers to adherence and anxiety/depressive symptoms. J Pediatr Psychol 37:282–291

    Article  Google Scholar 

  15. 15.

    Modi AC, Quittner AL (2006) Barriers to treatment adherence for children with cystic fibrosis and asthma: what gets in the way? J Pediatr Psychol 31:846–858

    Article  Google Scholar 

  16. 16.

    Simons LE, McCormick ML, Devine K, Blount RL (2010) Medication barriers predict adolescent transplant recipients’ adherence and clinical outcomes at 18-month follow-up. J Pediatr Psychol 35:1038–1048

    Article  Google Scholar 

  17. 17.

    Simons LE, Blount RL (2007) Identifying barriers to medication adherence in adolescent transplant recipients. J Pediatr Psychol 32:831–844

    Article  Google Scholar 

  18. 18.

    Modi AC, Monahan S, Daniels D, Glauser TA (2010) Development and validation of the Pediatric Epilepsy Medication Self-Management Questionnaire. Epilepsy Behav 18:94–99

    Article  Google Scholar 

  19. 19.

    Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, Halloran PF, Baldwin W, Banfi G, Collins AB, Cosio F, David DS, Drachenberg C, Einecke G, Fogo AB, Gibson IW, Glotz D, Iskandar SS, Kraus E, Lerut E, Mannon RB, Mihatsch M, Nankivell BJ, Nickeleit V, Papadimitriou JC, Randhawa P, Regele H, Renaudin K, Roberts I, Seron D, Smith RN, Valente M (2008) Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant 8:753–760

    CAS  Article  Google Scholar 

  20. 20.

    Haas M, Sis B, Racusen LC, Solez K, Glotz D, Colvin RB, Castro MC, David DS, David-Neto E, Bagnasco SM, Cendales LC, Cornell LD, Demetris AJ, Drachenberg CB, Farver CF, Farris AB 3rd, Gibson IW, Kraus E, Liapis H, Loupy A, Nickeleit V, Randhawa P, Rodriguez ER, Rush D, Smith RN, Tan CD, Wallace WD, Mengel M, Banff meeting report writing committee (2014) Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions. Am J Transplant 14:272–283

    CAS  Article  Google Scholar 

  21. 21.

    Foster BJ, Dahhou M, Zhang X, Platt RW, Samuel SM, Hanley JA (2011) Association between age and graft failure rates in young kidney transplant recipients. Transplantation 92:1237–1243

    Article  Google Scholar 

  22. 22.

    Nascimento E, Fabreti de Oliveira RA, Maciel MD, Pereira AB, das Mercêz de Lucas F Jr, Salomão-Filho A, Pereira WA, Moreira JB, Vilaça SS, de Castro Gontijo R, Lasmar MF, Vianna HR, Magalhâes A, Calazans CA, Simão-Filho C, Vilela B (2014) Kidney transplantation: evaluation and clinical outcome of 237 recipients at low, medium, high, or strong immunological risk of rejection. Transplant Proc 46:101-107

  23. 23.

    Omoloja A, Mitsnefes M, Talley L, Benfield M, Neu A (2007) Racial differences in graft survival: a report from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS). Clin J Am Soc Nephrol 2:524–528

    Article  Google Scholar 

  24. 24.

    Patzer RE, Mohan S, Kutner N, McClellan WM, Amaral S (2015) Racial and ethnic disparities in pediatric renal allograft survival in the United States. Kidney Int 87:584–592

    Article  Google Scholar 

  25. 25.

    Dunn TB, Noreen H, Gillingham K, Maurer D, Ozturk OG, Pruett TL, Bray RA, Gebel HM, Matas AJ (2011) Revisiting traditional risk factors for rejection and graft loss after kidney transplantation. Am J Transplant 11:2132–2143

    CAS  Article  Google Scholar 

  26. 26.

    Gonzales MM, Bentall A, Kremers WK, Stegall MD, Borrows R (2016) Predicting individual renal allograft outcomes using risk models with 1-year surveillance biopsy and alloantibody data. J Am Soc Nephrol 27:3165–3174

    Article  Google Scholar 

  27. 27.

    Eid L, Tuchman S, Moudgil A (2014) Late acute rejection: incidence, risk factors, and effect on graft survival and function. Pediatr Transplant 18:155–162

    Article  Google Scholar 

  28. 28.

    Favier LA, Taylor J, Loiselle Rich K, Jones KB, Vora SS, Harris JG, Gottlieb BS, Robbins L, Lai JT, Lee T, Kohlheim M, Gill J, Bouslaugh L, Young A, Griffin N, Morgan EM, Modi AC (2018) Barriers to adherence in juvenile idiopathic arthritis: a multicenter collaborative experience and preliminary results. J Rheumatol 45:690–696

    Article  Google Scholar 

  29. 29.

    Pascoe JE, Sawnani H, Hater B, Sketch M, Modi AC (2019) Understanding adherence to noninvasive ventilation in youth with Duchenne muscular dystrophy. Pediatr Pulmonol 54:2035–2043

    Article  Google Scholar 

  30. 30.

    Badawy SM, Thompson AA, Penedo FJ, Lai JS, Rychlik K, Liem RI (2017) Barriers to hydroxyurea adherence and health-related quality of life in adolescents and young adults with sickle cell disease. Eur J Haematol 98:608–614

    CAS  Article  Google Scholar 

  31. 31.

    Pollock-Barziv SM, Finkelstein Y, Manlhiot C, Dipchand AI, Hebert D, Ng VL, Solomon M, McCrindle BW, Grant D (2010) Variability in tacrolimus blood levels increases the risk of late rejection and graft loss after solid organ transplantation in older children. Pediatr Transplant 14:968–975

    Article  Google Scholar 

  32. 32.

    Goodall DL, Willicombe M, McLean AG, Taube D (2017) High intrapatient variability of tacrolimus levels and outpatient clinic nonattendance are associated with inferior outcomes in renal transplant patients. Transplant Direct 3:e192

    CAS  Article  Google Scholar 

  33. 33.

    Whitehouse W, Morris B (1997) Paediatric out-patient antiepileptic drug doses recorded in the medical charts are not reliable: implications for the notion of noncompliance. Seizure 6:41–42

    CAS  Article  Google Scholar 

  34. 34.

    Danziger-Isakov L, Frazier TW, Worley S, Williams N, Shellmer D, Dharnidharka VR, Gupta NA, Ikle D, Sweet SC, CTOTC-05 Consortium (2016) Perceived barriers to medication adherence in pediatric and adolescent solid organ transplantation. Pediatr Transplant 20:307–315

    Article  Google Scholar 

  35. 35.

    Danziger-Isakov L, Frazier TW, Worley S, Williams N, Shellmer D, Dharnidharka VR, Gupta NA, Ikle D, Shemesh E, Sweet SC, CTOTC-05 Consortium (2019) Perceived barriers to medication adherence remain stable following solid organ transplantation. Pediatr Transplant 23:e13361

    Article  Google Scholar 

  36. 36.

    Tadros HJ, Rawlinson AR, Martin E, Pietra BA, Fricker FJ, Gupta D (2020) Family functioning in pediatric heart transplantation: variables associated with poor outcomes. Pediatr Transplant 24:e13883

    Article  Google Scholar 

  37. 37.

    Viswanathan M, Golin CE, Jones CD, Ashok M, Blalock S, Wines RC, Coker-Schwimmer EJ, Grodensky CA, Rosen DL, Yuen A, Sista P, Lohr KN (2012) Closing the quality gap: revisiting the state of the science (vol. 4: medication adherence interventions: comparative effectiveness). Evid Rep Technol Assess (Full Rep). (208.4):1–685

  38. 38.

    Wu YP, Pai ALH (2014) Health care provider-delivered adherence promotion interventions: a meta-analysis. Pediatrics 133:e1698–e1707

    Article  Google Scholar 

  39. 39.

    Kelly B, Squires JE, Feingold B, Hooper DK, Mazariegos GV (2019) Quality initiatives in pediatric transplantation. Curr Opin Organ Transplant 24:64–72

    Article  Google Scholar 

Download references

Funding

CDV received funding from the National Center for Advancing Translational Sciences of the National Institutes of Health, under Award Number 2KL2TR001426-05A1.

Author information

Affiliations

  1. Division of Nephrology & Hypertension, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, MLC 7022, Cincinnati, OH, 45229, USA

    Charles D. Varnell Jr & David K. Hooper

  2. James M. Anderson Center for Health Systems Excellence, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Charles D. Varnell Jr, Adam C. Carle & David K. Hooper

  3. Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA

    Charles D. Varnell Jr, Kristin L. Rich, Bin Zhang, Ahna L. H. Pai, Avani C. Modi & David K. Hooper

  4. Division of Behavioral and Clinical Psychology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Kristin L. Rich, Ahna L. H. Pai & Avani C. Modi

  5. Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Bin Zhang

  6. Department of Psychology, College of Arts and Sciences, University of Cincinnati, Cincinnati, OH, USA

    Adam C. Carle

Authors
  1. Charles D. Varnell Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kristin L. Rich
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Adam C. Carle
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ahna L. H. Pai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Avani C. Modi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. David K. Hooper
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Participated in research design: CDV, KLR, ALHP, ACM, DKH

Participated in writing of the paper: CDV, KLR, ACM, DKH

Participated in performance of the research: CDV, KLR, ALHP, ACM, DKH

Participated in data analysis: CDV, BZ, ACC, ACM, DKH

Corresponding author

Correspondence to Charles D. Varnell Jr.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Disclaimer

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Varnell, C.D., Rich, K.L., Zhang, B. et al. Predicting acute rejection in children, adolescents, and young adults with a kidney transplant by assessing barriers to taking medication. Pediatr Nephrol (2021). https://doi.org/10.1007/s00467-021-04946-8

Download citation

Keywords

  • Medication adherence
  • Immunosuppression adherence
  • Pediatric transplantation
  • Acute rejection
  • Pediatric nephrology