Objectives: To evaluate the pattern of immuno­suppressive drug adverse reactions in adult kidney transplant recipients in Iran

Materials and Methods: Adult kidney transplant outpatients under immunosuppressive therapy were recruited into the study. All adverse drug reactions to immunosuppressants and their relevant clinical and paraclinical characteristics were recorded. Causality assessment was performed by the Naranjo algorithm. The seriousness of adverse drug reactions was determined by the World Health Organization definition. The Schumock and Thornton questionnaire was used to assess the preventability of adverse drug reactions. Statistical analyses were performed.

Results: A total of 1100 adverse drug reactions were detected from 120 kidney transplant recipients. Increased appetite (9.09%) was the adverse reaction reported most frequently. Causality assessment revealed that 1019 adverse drug reactions (92.64%) were possible. Forty adverse drug reactions (3.64%) were identified as serious. Six hundred seventy-one adverse drug reactions (61%) were preventable. Posttransplant duration was significantly correlated with the number of adverse drug reactions (R=0.19; P = .035).

Conclusions: All renal allograft recipients experienced at least 1 immunosuppressant-related adverse reaction. Prolongation of immuno­suppressive treatment resulted in an increase in adverse drug reactions.

Key words : Immunosuppressants, Adverse drug reactions, Renal allograft, Engraftment, Iran

End-stage renal disease (ESRD) is the stage 5 chronic kidney disease in which the glomerular filtration rate drops below 15 mL/min.¹ The prevalence of ESRD in the United States and the European Union has been reported to be 1500 and 800 per million population, respectively.² The number of patients with ESRD in the Middle East is estimated to be 100 000.³ According to the Aghighi and associates study, the prevalence and incidence of ESRD in Iran have increased from 238 and 49.9 per million population in 2000 to 357 and 63.8 per million population in 2006.⁴

Patients with ESRD require renal replacement therapy (dialysis or transplant) to remove uremic toxins and to maintain hemodynamic stability. Transplant is the preferred long-term therapeutic option for most of these patients. The suppression of the recipient’s immune system by immuno­suppressive agents has had the most notable effect on patient and graft survival.⁵ However, immuno­suppressants are well known for their various and serious adverse reactions.⁶ Numerous factors such as calcineurin nephrotoxicity, immunosuppressant-induced hypertension or hyperlipidemia, and noncompliance to immunosuppressive therapy, which might be partially caused by adverse drug reactions (ADRs), participate significantly in chronic allograft nephropathy.⁷ Furthermore, the results of several studies have demonstrated the significant association between immunosuppressive ADRs and quality of life in kidney transplant recipients.^8-10

Owing to undeniable effects on graft survival and quality of life, different aspects of immuno­suppressive ADRs in kidney transplant have been the subject of numerous studies. However, all immunosuppressive-related adverse reactions in patients who underwent renal transplant were not considered simultaneously in most-relevant drug safety investigations. The purpose of the current survey was to evaluate the pattern of immunosuppressive ADRs in Iranian adult kidney transplant recipients.

Materials and Methods

During a 6-month period in 2007, a cross-sectional study was conducted on adult kidney transplant patients (≥ 18 years) under maintenance immuno­suppressive therapy attending the office of a nephrologist (M.M.S.). No specific inclusion-exclusion criteria regarding time from transplant, number of transplants (first, second, or more), type of dialysis before transplant (hemodialysis vs peritoneal dialysis), type of graft donor (deceased vs living-related or unrelated), and immunosuppressive regimen were used for patient selection. The maintenance immunosuppressive regimen of the study population mainly included a glucocorticoid (prednisolone), a calcineurin inhibitor (cyclosporine), and an antiproliferative agent (mycophenolate mofetil or azathioprine). The study was approved by the Institutional Review Board and the Medical Ethics Committee of Shiraz University of Medical Sciences. It was in accordance with the ethical guidelines of the 1975 Helsinki Declaration. Written, informed consent was obtained from all patients.

All adverse reactions that occurred after starting immunosuppressive treatment were recorded by a clinical pharmacist. Detection of ADRs was based on face-to-face interviews with patients at regular follow-up office visits and reviewing their brief office charts containing physical examinations and laboratory data. Required information about patients’ age, sex, time from transplant, and cause of ESRD; immuno­suppressive regimen and coadministered medications (name, dosage, frequency, indication, and route of administration); and detected ADRs (clinical manifestation, related laboratory findings, the causative immuno­suppressant[s], and outcomes) were registered in ADR yellow cards by the clinical pharmacist.

The World Health Organization (WHO) definition of ADR was used in the present study.¹¹ System-organ categorization of the reported ADRs was performed according to WHO Adverse Reaction Terminology (WHO-ART).¹² The Naranjo probability scale was used to assess the causality relation between reported ADRs and suspected medication(s).¹³ The seriousness of ADRs was determined by WHO definition; any ADR that resulted in death, a life-threatening situation, persistent or substantial disability/ incapacity, hospital admission, or prolonged hospital stay was considered as serious.¹⁴ The Schumock and Thornton questionnaire was used to evaluate the preventability of reported ADRs.¹⁵

Statistical Analyses
Categoric data were expressed as percentage. Continuous variables were reported as mean ± standard deviation (SD) or standard error (SE). The frequency of each ADR was calculated by the number of each ADR divided by the total number of detected ADRs. The possible relation between age, total number of drugs (including immuno­suppressive and nonimmunosuppressive drugs), as well as posttransplant duration and the number of detected ADRs was examined with the Pearson product moment correlation analysis. The independent t test was used to examine for any association between number of ADRs and sex, concomitant diseases, and immunosuppressive regimen (with mycophenolate mofetil versus mycophenolate mofetil-free). P values < .05 were considered statistically significant. Statistical analyses were performed with SPSS software for Windows (SSPS: An IBM Company, version 11.5, IBM Corporation, Armonk, New York, USA).

Results

During 6 months, 120 adult kidney transplant recipients under maintenance immunosuppressive therapy were recruited for the study. All patients except 1 had their first engraftments. Demographic characteristics of the study population are shown in Table 1. Of the total patients, 72.5% were men. Only 2 patients (1.67%) were ≥ 65 years of age. Hypertension (29.86%) was the most-common cause of ESRD, followed by nephrolithiasis (13.89%), and glomerulonephritis (11.11%).

Immunosuppressive treatment characteristics of kidney transplant recipients are summarized in Table 2. The combination of prednisolone/cyclosporine/ mycophenolate mofetil (69.17%) was the predominant immunosuppressive regimen. All (100%) and nearly all patients (97.5%) received prednisolone and cyclosporine as part of their immunosuppressive treatment, while only 25% were azathioprine-treated.

Of the entire study population, 1100 ADRs were recorded. All patients experienced at least 1 immunosuppressant-related adverse reaction. The mean ± SD number of ADRs per patient was 9.24 ± 3.26. Nearly half of the patients (47.5%) developed 10 or more ADRs. Table 3 lists the 5 most-frequent ADRs and their causative immuno­suppressants. Increased appetite (9.09%) was the most frequently reported ADR, followed by hirsutism (8.18%), and acne (6.73%). Of the patients who received prednisolone, cyclosporine, or mycophenolate mofetil, more than 80% developed increased appetite and more than 50% noted increased weight. Posttransplant hyperlipidemia, hypertension, and diabetes mellitus were detected in 49 (40.83%), 33 (27.5%), and 11 (9.17%) patients. Among patients who developed posttransplant hyperlipidemia, hypertension, or diabetes mellitus, 28 (57.14%), 32 (96.97%), and 9 (81.82%) received pharmacotherapy for managing these ADRs. One of 4 reported thrombocytopenia was associated with severe gingival bleeding and epistaxis. Of 35 infectious episodes reported in 32 subjects, urinary tract (37.14%) was the most-common site of infection, followed by respiratory tract (28.57%), and skin (17.14%). Overt pulmonary tuberculosis was documented in 2 patients. Gingival hyperplasia as a cosmetic adverse reaction of immunosuppressive drugs was detected in 18 patients (15%).

System-organs involved with adverse reactions of immunosuppressants are shown in Table 4. The 3 most commonly involved systems were endocrine and metabolic system (23.27%), skin and appendages system (22%), and central and peripheral nervous system (21.18%).

According to the Naranjo causality assessment, 1019 ADRs (92.64%) were considered possible and the remaining 81 probable (7.36%). Of the entire immunosuppressant-related adverse reactions, only 40 (3.64%) from 25 patients (20.83%) were identified as serious. The mean ± SD age of patients who developed serious ADRs was 43.16 ± 10.32 years. The most-common serious ADR was osteoporosis, detected in 10 patients, followed by bacterial, viral, or fungal infection reported in 7 patients. The diagnosis of osteoporosis was based on the results of bone mineral density measured by dual x-ray absorptiometry. According to WHO categorization, T scores less than -2.5 SD are defined as osteoporosis.¹⁶

Six hundred seventy-one ADRs (61%) were recognized as preventable. Among 7 preventability criteria of Schumock and Thornton’s questionnaire, drug-drug interactions (78%) and poor patient compliance (65%) accounted for most of the preventable ADRs. Among detected ADRs, only 128 (11.64%) recovered and the remaining 972 (88.36%) existed at the time of interview.

According to the results of the Pearson product moment correlation analysis, no statistically significant correlations were identified between the number of ADRs and age (R=-0.17; P = .065), as well as total number of administered medications (R=0.037; P = .69). In contrast, time interval from transplant (posttransplant duration) was significantly correlated with the number of immunosuppressant-related adverse reactions (R=0.19; P = .035). The results of independent t test indicated no statistically significant associations between the number of detected ADRs and sex
(P = .064), concomitant disease (P = .445), and immunosuppressive regimen regarding the presence of mycophenolate mofetil (P = .629).

Discussion

Kidney transplant has been advocated as the treatment of choice for most of patients with ESRD.⁵ According to Iran's Minister of Health announcement at the Eastern Mediterranean Region Organization preparatory meeting in 2007, Iran ranks fourth in kidney transplants in the world. By the end of 2007, around 23 600 renal transplants had been performed in Iran.¹⁷ From December 1988 to December 2003, 1200 kidney transplant operations were performed in the Shiraz Organ Transplant Center.¹⁸ Progress in surgical techniques, better postoperative care, and effective immuno­suppressive regimens all have contributed to prevent graft rejection and improve short-term (especially) and long-term survival rates. Despite this, immunosuppressive therapy is associated with several long-term complications, such as hypertension, hyperlipidemia, osteoporosis, and diabetes mellitus. Furthermore, immunosuppressive therapy can cause graft loss through direct nephrotoxicity, infection, malignancy, and nonadherence to treatment.⁷ Therefore, having a comprehensive knowledge about the profile of immunosuppressive ADRs in kidney transplant recipients has been recommended emphatically.

Infection after a kidney transplant is associated with substantial morbidity and mortality. It has been considered as the main cause of death in the early period after engraftment.^19-21 The prevalence of infectious episodes in kidney transplant recipients in the current survey was 32/120 (26.67%). This rate is much lower than that observed in the Pourmand and associates study. They reported that 77 of 142 patients (54.23%) developed infections.²² The variation in the prevalence of infections could be explained partially by the difference in the methodology of these 2 studies. Our study was cross-sectional, and as the office files of patients were brief and sometimes incomplete, detection of ADRs was mainly dependent to face-to-face interview and patients’ own memories. In contrast, in the Pourmand and associates study, patients were assessed prospectively and routine laboratory evaluations were performed for the diagnosis of infections. Therefore, the prevalence of infectious episodes in our study might be underestimated. Similar to the scientific literature,^23-26 the urinary tract was the most-common site of infection in our patients. The prevalence of posttransplant tuberculosis in the present study (1.67%) was within the range reported from other investigations in Iran (1% to 1.4%)^{27, 28} and Europe (1% to 4%).²⁹

Posttransplant diabetes mellitus (PTDM) is a common and serious complication of kidney transplant.³⁰ According to the results of a systematic review of solid organ transplant recipients, the prevalence of PTDM varies from 2% to 50%.³¹ This broad range is mainly due to various definitions of PTDM used in different studies.³² The prevalence of PTDM in the current survey (9.17%) was congruent with values reported from other studies. The diagnosis of PTDM in the present study was based on American Diabetes Association’s (ADA) 2007 criteria.³³ Posttransplant diabetes mellitus is associated with chronic allograft nephropathy and could adversely affect patient and graft survival.^{34, 35} The cross-sectional design of our study did not allow us to assess the effect of PTDM on graft function and patient survival. Among many proposed factors, immunosuppressive drugs (the total dosage of steroids) have been shown to be major risk factors for PTDM development.³⁶ Compared to cyclosporine, tacrolimus is generally associated with higher risk of developing PTDM.³⁷ As none of our study population received tacrolimus, comparing the effects of these 2 calcineurin inhibitors on PTDM development was impossible. The therapeutic approach for patients with PTDM is generally the same as that recommended by ADA for type 2 diabetes mellitus.³⁸ More than 80% of our patients with PTDM received insulin, oral hypoglycemic agents, or a combination of insulin-oral hypoglycemic agents for controlling their diabetes.

Immunosuppression-related physical changes (eg, hair loss, hirsutism, facial coarsening, gingival hyperplasia, and acne) are common among kidney transplant recipients and could adversely affect patients’ mental health, overall well-being, quality of life, and adherence to immunosuppressive treatment.^{39, 40} The results of the Rosenberger and associates study implicated that the cosmetic effects of immunosuppressive medications were strong stressors for kidney transplant patients, especially women and children.⁶ Hirsutism and acne were the second and the third most-common immuno­suppressive-related adverse reactions in our study, respectively. Gingival hyperplasia was detected in 15% of the study population. The frequency of gingival hyperplasia in Iranian renal allograft recipients from 2 other studies (Ghafari and associates⁴¹ and Kafaie and associates⁴²) was reported to be 35% and 43.3%. Similar studies from other countries have reported rates from 21% to 88%.^43-46 The discrepancy in the rate of gingival hyperplasia could be justified by different sample sizes, immunosuppressive regimens, possible presence of pharmacodynamic drug interactions (eg, cyclosporine with calcium channel blocking agents), sociocultural beliefs regarding oral hygiene, and variable sources of detecting gingival hyperplasia. Concerning the last issue, the diagnosis of gingival hyperplasia in Kafaie and associates and our study was made by nephrologists, whereas in Ghafari and associates survey, dental examinations were implemented by an experienced dentist. Steroid-sparing regimens, protocols with early withdrawal of steroids, and conversion from cyclosporine to tacrolimus all have been shown to decrease physical changes related to immunosuppressive treatment and improve patients’ well-being and compliance.^47-49

Posttransplant osteoporosis is a complex and multifactorial issue.⁵⁰ Early studies indicated that the bone mineral density of renal allograft recipients decreases 3% to 7% in the first 6 to 12 months after transplant.^51-53 According to the results of a prospective study in Hong Kong of 31 deceased renal allograft recipients, 2 (6.5%), 1 (3.2%), and 1 (3.2%) developed in the lumbar spine, femoral neck, and total hip osteoporosis at 1 year posttransplant.⁵⁴ Nouri-Majalan and associates detected lumbar vertebrae osteoporosis in 21.13% and femoral neck osteoporosis in 9.8% of Iranian kidney transplant recipients.⁵⁵ The most-common serious immuno­suppressive drug adverse reaction in the current study was osteoporosis, with the prevalence rate of 10%, which approximates the results of the Hong Kong survey.⁵⁴ Owing to incomplete patients’ office files, the sites of osteoporosis in our patients was unknown. Among many factors, steroids play a pivotal role in posttransplant osteoporosis.^{56, 57} The probable effects of cyclosporine on human bone mass have remained unclear.⁵⁴

Treatment duration could be considered as a drug-related risk factor for ADR development.⁵⁸ The incidence and severity of steroid-induced adverse reactions depends on both dosage and duration of treatment. Long-term steroid therapy is associated with several ADRs, such as acne, hirsutism, glucose intolerance, hyperlipidemia, hypertension, osteoporosis, and mental disturbances.⁵⁹ In line with this, we observed a statistically significant direct but weak correlation between posttransplant duration and the number of ADRs (R=0.19; P = .035). In other words, prolongation of immunosuppressive treatment resulted in an increase in detected ADRs.

Azathioprine, the first immunosuppressive drug in the prophylaxis regimen of acute allograft rejection,⁶⁰ has been replaced completely with mycophenolate mofetil by most transplant centers worldwide.^{61, 62} Concerning the safety profile, the results of a systematic review demonstrated that in comparison to azathioprine, the use of mycophenolate mofetil in kidney transplant was associated with a slight increase in some gastrointestinal (diarrhea, vomiting, and abdominal pain) and hematologic (leucopenia and anemia) adverse reactions, as well as cytomegalovirus infection. The rate of nausea and overall occurrence of malignancies was similar for both medications. Nevertheless, the incidence of thrombocytopenia with azathioprine was higher than that of mycophenolate mofetil.⁶³ Hakemia and associates did not observe nephrotoxicity, neurotoxicity, and substantial hepatotoxicity among Iranian renal allograft recipients receiving mycophenolate mofetil. In addition, the incidence of leucopenia was substantially higher in patients with azathioprine than with mycophenolate mofetil.⁶⁴ We found no statistically significant association between the number of detected ADRs and immunosuppressive regimens with or without mycophenolate mofetil (P = .629). Inasmuch as the number of patients who developed nausea and vomiting, diarrhea, nephrotoxicity, hepatotoxicity, or thrombocytopenia was limited in the current survey (9, 8, 6, 5, and 4 subjects), comparing the effect of different immunosuppressive regimens on the prevalence of these ADRs was not statistically feasible.

The major limitation of the current study is that the detection of ADRs was based predominantly on patients’ own memory rather than their office charts. This could result in the underestimation of the total number of immunosuppressive ADRs, as well as the absence of most details of detected ADRs, such as onset, duration, and pattern of severity changes in response to alterations (escalation/de-escalation) in immunosuppressive drug dosage. This also limited the usefulness of using the Naranjo probability scale. Regarding this, 92.64% of ADRs were considered as possible, as many scoring items would not have been assessed or were scored as “do not know.” A well-designed prospective study in a large cohort is warranted to determine the exact pattern of immunosuppressive ADRs in kidney transplant patients.

In conclusion, we demonstrated that all renal allograft recipients experienced at least 1 immunosuppressant-related adverse reaction. Endocrine and metabolic disorders were identified as both the most frequently involved organ system and as the most common serious ADRs (osteoporosis). Posttransplant duration significantly correlated with the number of ADRs. Strategies such as continuous follow-up of patients, regular monitoring of cyclosporine level and adjusting its doses with respect to monitoring findings, avoiding clinically significant interactions of immuno­suppressants with other drugs, adopting much safer immunosuppressive regimens (eg, cyclosporine conversion to tacrolimus or steroid-sparing protocol), and educating patients could substantially decrease the rate of preventable immunosuppressive ADRs among kidney transplant recipients.

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