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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2019  |  Volume : 30  |  Issue : 3  |  Page : 686-693
A study of prevalence and correlates of nonadherence to immunosuppressive medications in renal transplant recipients of South Indian population and their impact on long-term graft function

Institute of Nephrology, Madras Medical College, Chennai, Tamil Nadu, India

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Date of Submission12-Jun-2018
Date of Decision16-Sep-2018
Date of Acceptance19-Sep-2018
Date of Web Publication26-Jun-2019


Nonadherence to immunosuppressant medications leading onto poor graft outcome is frequent among renal transplant recipients. In this study, we sought to assess the prevalence and correlates of nonadherence to immunosuppressants and its impact on graft function. A singlecenter, retrospective cum cross-sectional study of renal transplant recipients of age >18 years and who had completed at least six months after transplantation was performed. Nonadherence was assessed based on the Immunosuppressant Therapy Adherence Scale questionnaire. Factors attributed to nonadherence were assessed based on the Immunosuppressant Therapy Barriers Scale (ITBS) questionnaire. Social, economic, demographic data, and all transplant related information were recorded. Two hundred and seventy-nine patients were included in the study, of whom 78% were male. Median follow-up period was 46 months (interquartile range – 24 months to 82 months). Seventy-four patients (26.5%) admitted nonadherence to immunosuppressants. The nonadherence was significantly related to the male gender, late acute rejection episodes, rise in serum creatinine from > 0.5 mg/dL from nadir level, lower blood levels of calcineurin inhibitor, and higher ITBS scores. Refill rates and use of alarm reminders were not significantly associated with better adherence.

How to cite this article:
Saravanakumar K, Prakash A, Thopalan B, Dhanapriya J, Thanigachalam D, Ramanathan S, Gopalakrishnan N. A study of prevalence and correlates of nonadherence to immunosuppressive medications in renal transplant recipients of South Indian population and their impact on long-term graft function. Saudi J Kidney Dis Transpl 2019;30:686-93

How to cite this URL:
Saravanakumar K, Prakash A, Thopalan B, Dhanapriya J, Thanigachalam D, Ramanathan S, Gopalakrishnan N. A study of prevalence and correlates of nonadherence to immunosuppressive medications in renal transplant recipients of South Indian population and their impact on long-term graft function. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2020 Sep 25];30:686-93. Available from: http://www.sjkdt.org/text.asp?2019/30/3/686/261345

   Introduction Top

Renal transplant remains the most satisfying treatment modality providing a better quality of life. The long-term survival depends on adherence to immunosuppressive medications.[1]

Adherence plays an essential role for graft maintenance in solid organ transplant in spite of this significant proportion of patients continue to be nonadherent to immunosuppressive medications.[2]

A meta-analysis performed of 147 studies, including patients of various organ transplant recipients, revealed the highest rates of non-adherence in renal transplant recipients.[3] The nonadherence which occurs commonly in renal transplant recipients predisposes them to allograft loss frequently.[4]

Tielen et al’s study on renal transplant recipients have shown that nonadherence to be related with allograft rejection, graft loss, and mortality.[5] Various published studies have revealed an estimated prevalence of nonadherence in 20%–50% of renal transplant recipients.[6] A study from Alabama, the USA has reported nonadherence to be the most common cause of preventable rejection episodes.[7]

Chisholm et al reported that one in 10 deaths that occur in renal transplant recipients are due to medication nonadherence.[8] Life expectancy also reported to be four years less from the study done in Belgium.[9]

Nonadherence to immunosuppressants cannot only cause acute rejection but also can lead to progressive graft dysfunction. In many non-adherent patients, graft histopathology has revealed significant interstitial fibrosis and tubular atrophy without any clinical features of acute rejection.[10] Availability of immuno-suppressants that are highly efficacious to decrease the rejection episodes, has rendered the adherence to medications an essential role in the long-term outcome of transplant reci-pients.[11]

Various methods used to assess the non-adherence:

  1. Electronic medication monitoring - gold standard for adherence measurement[12]
  2. Prescription “refill rate” and self-reporting of patients may underestimate nonadhe-rence, but they are simple and commonly used assessment method[10],[13]
  3. Drug level monitoring has variable correlation with compliance and tends to overestimate nonadherence.[14]

Self-reporting of patients to assess adherence is preferable since it is inexpensive and does not need invasive procedure and used to relate Immunosuppressive therapy (IST) adherence to patient-specific factors.[15] The Immunosup-pressive Therapy Adherence Scale (ITAS) among solid organ transplants was found to have reliability, validity, and convergence.[16] There are several factors contributing to non-adherence of which majority of them are patient related.[17] IST adherence barriers scale (ITBS) is a reliable instrument which is useful in identifying these contributory factors and in formulating intervention strategies to improve the adherence rate among transplant recipients.[18],[19]

   Objectives of the study Top

In this study, we sought to assess the prevalence of nonadherence, to identify demographic and social correlates of nonadherence, to analyze the barriers to nonadherence, to study the impact of nonadherence on acute rejection episodes and chronic graft dysfunction, and to study the relation of nonadherence to immuno-suppressant blood levels and medication refill records.

   Methods Top

A retrospective cum cross-sectional study was performed in the outpatient transplant clinic of the Institute of Nephrology, Madras Medical College (MMC). A unique feature is that immunosuppressants are provided free of cost lifelong in all government institutions of Tamil Nadu including our center. The study was approved by the Institutional Ethics committee of MMC. Informed consent was obtained from all the study patients.

Eligibility criteria

Renal transplant recipients who have completed at least six months after transplant and those whose aged are >18 years were included in the study.

Exclusion criteria

1. Renal transplant recipient who have become dialysis dependent

Demographic, laboratory, and medication data were collected. Demographic information included – age, gender, education level, marital status, and occupation. Transplant-related data included transplant date and number, donor type, immunosuppressants, comor-bidities, biopsy-proven rejection episodes after four months of transplant and medication refill records for the past three months. Laboratory information included serum creatinine, calci-neurin inhibitor (CNI) trough levels in the previous three months. The method used if any to get reminded about drug intake was also documented.

The following two questionnaires in vernacular language were given and were explained as how to fill it.

  1. Immunosuppressant therapy adherence scale,
  2. Immunosuppressant therapy barrier scale. Those people who were not literate enough to complete the questionnaire were instructed to get help from the relatives accompanying them.

Immunosuppressive Therapy Adherence Scale

It is a well-validated questionnaire to assess nonadherence, its frequency and gross reasons for nonadherence.[20] It consists of four items, namely (1) whether forget to take immuno-suppressants, (2) omitted immunosuppressants due to carelessness, (3) omitted immunosup-pressants due to perceived side effects, and (4) omitted immunosuppressants due to any other reason. Each item was scored from 0 to 3, total score of <12 was considered to be non-adherent.

Adherence was assessed for the period of preceding three months. Three months is often considered adequate for recognizing patterns of long-term medication adherence.[21] Ability to recall decreases beyond that three months which may impair the reliability of responses.

Immunosuppressant Therapy Barriers Scale

This 13-point questionnaire with 5-point Likert responses to assess the barriers and causes for nonadherence were also recorded

Published studies revealed that three months refill rates of 90% or greater has significant correlation with other IST adherence mar-kers;[22] hence, it was used as cutoff point for adherence based on immunosuppressant refill records. Medication refill rate was assessed by the observation of the patients’ follow-up records. In our center, patients are provided immunosuppressants for 14 days during each visit. Hence, they are instructed to visit outpatient department every fortnight. Regarding CNI trough levels, cyclosporine <75 ng/mL, and tacrolimus <3 ng/mL were used as cutoff for assessing adherence. Lower concentration was used as a conservative approach to allow for the varying time after transplant.

ITBS has been validated by various studies.[16] The IST adherence barriers were compared between adherent and nonadherent patients.

   Statistical Analysis Top

Among the independent variables, categorical variables were listed as proportions between the groups and were compared using the Chi-square test. The continuous variables were listed as means with standard deviations and analyzed using Student’s t-test of independent variables. Binary logistic regression model was used to assess the association between variables found to be significant by Chi-square or Student’s t-test and nonadherence reported by the patient. Values of P < 0.05 were considered statistically significant. Statistical Package for Social Sciences (SPSS) version 18.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis.

   Results Top

We enrolled 279 renal allograft recipients who were willing to participate in the study. The mean age was 36 years ± 9 years, mean duration posttransplant was 4 years 8 months ± 3 years 3 months. Male-to-female ratio was 3.5:1, living donor transplants contributed to 70% of the total transplants. The mean serum creatinine was 1.41 ± 0.72 mg/dL.

Among the participants 74 (26.52%) had self-reported nonadherence with ITAS score of <12. The various ITAS scores are depicted in [Figure 1].
Figure 1: ITAS score. The figures in the bracket indicate the response in last three months of the percentage of times they have been non adherent.
ITAS: Immunosuppressive Therapy Adherence Scale.

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By statistical analysis using the Chi-square test and Student’s t-test, the following factors were found to be significantly associated with nonadherence, namely male gender, rise in serum creatinine of >0.5 mg/dL from nadir value, late acute rejection episodes (>4 months after transplant), lower immunosuppressant blood levels (tacrolimus <3 ng/mL, cyclosporine porine <75 ng/mL), and higher number of barriers reported on ITBS score. One hundred and five patients reported the use of alarms set in their mobile phone as reminder to take immunosuppressants.

Drug refill rate and reminder using mobile alarm were not associated with better adherence. The salient features of the study population and the relation to self-reported non-adherence are documented in [Table 1] and [Table 2].
Table 1: Comparison of demographic factors.

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Table 2: Comparison of treatment-related factors.

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Various barriers to intake of immuno-suppression were reported by 129 (46%) of the patients. The percentage of the overall sample reporting difficulties in each barrier along with comparison to nonadherent cohorts is shown in [Figure 2].
Figure 2: Percentage of patients reporting barriers to adherence.

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Among the overall sample which included both adherent and nonadherent patients, the most common barriers were too many dosages per day and too many medications at once.

Nonadherent patients had reported a higher number of barriers when compared to the adherent patients (P = 0.002), which was statistically significant. The following barriers were found to be significantly associated with nonadherence depicted in [Table 3].
Table 3: Significant barriers to adherence.

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The factors found to be statistically significant by initial analysis were further evaluated by binary logistic regression analysis. Non-adherence was significantly associated with higher ITBS scores. When late acute rejection episodes were evaluated as outcome they were significantly associated with nonadherent individuals who had 4-fold increased risk of having rejection episodes.

   Discussion Top

Nonadherence to immunosuppressants is perceived as an important cause for poor graft outcome. The real magnitude of nonadherence is unknown. The study on adult renal transplant recipients revealed significant number of patients (one in four) had reported nonadhe-rence to immunosuppression medications. The nonadherence was statistically associated with risk factors such as male gender, lower immunosuppressant concentration, and higher barriers to nonadherence. Nonadherence was also associated with outcomes such as late acute rejection episodes and late graft dysfunction.

The patient’s drug refill rate was not associated with nonadherence and also reminders for drug intake such as alarm mobile was also not significantly useful in increasing the adherence. Published studies from India regarding medication nonadherence are very limited. Sharma et al from Jaipur published a retrospective study of 152 patients, of which 21.7% of patients were nonadherent.[23] Another study from Adhikari et al showed the extent of nonadherence was 35%.[24]

This study has the largest number (279) of patients with relatively longer time of follow-up when compared to other studies in evaluating nonadherence to immunosup-pressants in renal transplant recipients. The study showed that despite medications being issued free for lifelong by the government, financial constraints were reported to be a significant barrier by nonadherent patients which may be because they are unemployed and also they had to travel long distance once in two weeks to get the immunosuppressants.

Vlaminck et al reported late acute rejection episodes are increased three-fold[25] and graft failure increased seven-fold in nonadherent individuals.[26] This study had similar results showing four-fold increased risk of late acute rejection episodes.

The interventions which could be planned based on the results are reemphasize the patients during discharge and subsequent visits regarding medication adherence, routine evaluation whether the medications are being taken at an appropriate time without any confusion. Patients also should be advised to avoid unnecessary travel away from home, which also tends to increase the nonadherence.

Limitations of the study were it was singlecenter transplant study, whereas various factors may influence the occurrence of adherence in other centers, the study did not include patients who did not have functioning graft whose graft loss could have been due to nonadherence, moreover the study was cross section study analyzing nonadherence only during the past three months. Hence, it could have underestimated nonadherence.

There is urgent need for devising strategies to minimize nonadherence. Vigorous counseling before transplantation and periodically after transplantation on the potential risks of nonadherence has to be done.

   Conclusions Top

Nonadherence to immunosuppressants was prevalent in a significant number (26.5%) of he study population. Nonadherence was significantly associated with late rejection episodes nd long-term graft function and lower immu-nosuppressant levels. Innovative measures have to be applied to overcome the barriers ontributing to nonadherence.

Conflict of interest: None declared.

   References Top

Shabany Hamedan M, Mohamad Aliha J. Relationship between immunosuppressive medications adherence and quality of life and some patient factors in renal transplant patients in Iran. Glob J Health Sci 2014;6:205-12.  Back to cited text no. 1
Hilbrands LB, Hoitsma AJ, Koene RA. Medication compliance after renal transplan-tation. Transplantation 1995;60:914-20.  Back to cited text no. 2
Dew MA, DiMartini AF, De Vito Dabbs A, et al. Rates and risk factors for nonadherence to the medical regimen after adult solid organ transplantation. Transplantation 2007;83:858-73.  Back to cited text no. 3
Sellarés J, de Freitas DG, Mengel M, et al. Understanding the causes of kidney transplant failure: The dominant role of antibody-mediated rejection and nonadherence. Am J Transplant 2012;12:388-99.  Back to cited text no. 4
Tielen M, van Exel J, Laging M, et al. Attitudes to medication after kidney transplantation and their association with medication adherence and graft survival: A 2-year follow-up study. J Transplant 2014; 2014:675301.  Back to cited text no. 5
Denhaerynck K, Dobbels F, Cleemput I, et al. Prevalence, consequences, and determinants of nonadherence in adult renal transplant patients: A literature review. Transpl Int 2005;18:1121-33.  Back to cited text no. 6
Gaston RS, Hudson SL, Ward M, Jones P, Macon R. Late renal allograft loss: Noncompliance masquerading as chronic rejection. Transplant Proc 1999;31:21S-23S.  Back to cited text no. 7
Chisholm MA, Lance CE, Mulloy LL. Patient factors associated with adherence to immuno-suppressant therapy in renal transplant recipients. Am J Health Syst Pharm 2005; 62:1775-81.  Back to cited text no. 8
Cleemput I, Kesteloot K, Vanrenterghem Y, De Geest S. The economic implications of non-adherence after renal transplantation. Pharmacoeconomics 2004;22:1217-34.  Back to cited text no. 9
Lerut E, Kuypers DR, Verbeken E, Cleutjens J, Vlaminck H, Vanrenterghem Y. Acute rejection in non-compliant renal allograft recipients: A distinct morphology. Clin Transplant 2007; 21:344-51.  Back to cited text no. 10
Nevins TE, Matas AJ. Medication noncom-pliance: Another iceberg’s tip. Transplantation 2004;77:776-8.  Back to cited text no. 11
Denhaerynck K, Steiger J, Bock A, et al. Prevalence and risk factors of non-adherence with immunosuppressive medication in kidney transplant patients. Am J Transplant 2007;7: 108-16.  Back to cited text no. 12
Denhaerynck K, Schäfer-Keller P, Young J, Steiger J, Bock A, De Geest S. Examining assumptions regarding valid electronic monitoring of medication therapy: Development of a validation framework and its application on a European sample of kidney transplant patients. BMC Med Res Methodol 2008;8:5.  Back to cited text no. 13
Schäfer-Keller P, Steiger J, Bock A, Denhaerynck K, De Geest S. Diagnostic accuracy of measurement methods to assess non-adherence to immunosuppressive drugs in kidney transplant recipients. Am J Transplant 2008;8:616-26.  Back to cited text no. 14
Frazier PA, Davis-Ali SH, Dahl KE. Correlates of noncompliance among renal transplant recipients. Clin Transplant 1994 8:550-7.  Back to cited text no. 15
Chisholm MA, Lance CE, Williamson GM, Mulloy LL. Development and validation of an immunosuppressant therapy adherence barrier instrument. Nephrol Dial Transplant 2005;20: 181-8.  Back to cited text no. 16
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Chisholm MA, Mulloy LL, Jagadeesan M, DiPiro JT. Impact of clinical pharmacy services on renal transplant patients’ compliance with immunosuppressive medications. Clin Transplant 2001;15:330-6.  Back to cited text no. 18
Chapman JR. Compliance: The patient, the doctor, and the medication? Transplantation 2004;77:782-6.  Back to cited text no. 19
Chisholm MA, Lance CE, Williamson GM, Mulloy LL. Development and validation of the immunosuppressant therapy adherence instrument (ITAS). Patient Educ Couns 2005;59:13-20.  Back to cited text no. 20
Stewart RB, Caranasos GJ. Medication compliance in the elderly. Med Clin North Am 1989;73:1551-63.  Back to cited text no. 21
Chisholm MA, Vollenweider LJ, Mulloy LL, et al. Renal transplant patient compliance with free immunosuppressive medications. Transplantation 2000;70:1240-4.  Back to cited text no. 22
Sharma AK, Gupta R, Tolani SL, Gupta H, Singh AK, Rathi GL. Non compliance in renal transplantation. Indian J Nephrol 1999;9:13-5.  Back to cited text no. 23
Adhikari UR, Taraphder A, Hazra A, Das T. Medication adherence in kidney transplant recipients in an urban Indian setting. Indian J Nephrol 2017;27:294-300.  Back to cited text no. 24
[PUBMED]  [Full text]  
Vlaminck H, Maes B, Evers G, et al. Prospective study on late consequences of subclinical non-compliance with immunosu-ppressive therapy in renal transplant patients. Am J Transplant 2004;4:1509-13.  Back to cited text no. 25
Butler JA, Peveler RC, Roderick P, Horne R, Mason JC. Measuring compliance with drug regimens after renal transplantation: Comparison of self-report and clinician rating with electronic monitoring. Transplantation 2004; 77:786-9.  Back to cited text no. 26

Correspondence Address:
Avinash Prakash
Institute of Nephrology, Madras Medical College, Chennai, Tamil Nadu
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DOI: 10.4103/1319-2442.261345

PMID: 31249234

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  [Table 1], [Table 2], [Table 3]


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