Prescription pattern and safety of immunosuppressive drugs in patients of renal transplant in IGIMS Patna-An observational study

Objective: Survival of post renal transplant patients has been improved by the suppression of the recipient’s immune system by immunosuppressive agents. However, various adverse drug reactions are also associated with immunosuppressive agents. Keeping this in mind, present study was planned to study the prescriptions pattern of immunosuppressant drugs and to study adverse drug reactions associated with immunosuppressant drugs. Materials and Methods: It was an observational and cross-sectional study. We have collected reported ADRs, prescriptions, IPD files and laboratory reports of 40 patients who had already undergone renal transplant prior to start of this study and 10 patients who undergone renal transplant after start of this study. Result: Most patients were prescribed prednisolone + tacrolimus + MMF as immunosuppressive regimen (70%) followed by prednisolone + cyclosporine + MMF (22%). Prednisolone was prescribed to all patients. Tacrolimus was prescribed to 72% of patients. Total 78 ADRs were reported from 50 patients in our study (incidence rate 68%). Drug MMF was mostly associated with ADRs (35.90%) followed by tacrolimus (29.49%), prednisolone (19.23%) and cyclosporine (15.38%). Most of the ADRs was mild (65.38%) while only one ADR was severe. Conclusion: Corticosteroid continues to be mainstay of therapy in post renal transplant patients. Calcineurin inhibitors were exclusively associated with nephrotoxicity. MMF was associated with most ADRs followed by tacrolimus. Most of the ADRs were mild and treated symptomatically. © This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Introduction
Kidney transplant is essential in case of ESRD (End Stage Renal Diseases) to improve survival and quality of life and reduce health care cost. But it also challenges nephrologist in preventing rejection of the graft and to use immunosuppressant judiciously to avoid their adverse effect and to also avoid infection common in immunocompromised host. Chronic kidney disease is also associated with altered intestinal transport mechanisms and this can affect the oral bioavailability of immunosuppressive drugs. 1 So there is more risk of adverse reactions. 2 Survival of post renal transplant patients has been improved by the suppression of the recipient's immune system by immunosuppressive agents. 3 However, various adverse drug reactions are also associated with immunosuppressive agents. 4 Chronic allograft nephropathy is significantly affected by various factors such as Calcineurin nephrotoxicity, drug induced hypertension and non-compliance to immunosuppressive therapy. 5 Furthermore, it has been demonstrated from results of various studies that quality of life in renal transplant patient is significantly associated with immunosuppressive ADRs. [6][7][8] ADRs are one of the important issue which needs attention while treating the patients with drugs. They are having great effect on life of patients. Mechanism of action of immunosuppressant i.e. suppression of the immune system is the leading factor for various adverse drug reaction. And the ongoing crisis that the patient suffers by End Stage Renal Disease (ESRD) adds to the problem. Calcineurin inhibitors are associated with a number of potentially serious adverse effects, including nephrotoxicity, diabetes, hypertension, and neurotoxicity which contributes to morbidity and mortality after transplantation. [9][10][11][12][13] Cyclosporine has become less relevant in the modern era of organ transplantation. So 92% of kidney transplant recipients are now being prescribed tacrolimus as the first-line calcineurin inhibitor. 14 Combined therapy with tacrolimus and mycophenolic acid may be associated with high risk of BK virus infection, 15 which can lead to failure of the transplanted kidney. Everolimus have beneficial effect on renal function and may reduce the occurrence of malignancy 16,17 but it can cause impaired wound healing, mouth ulcers, stomatitis, arthralgia, hyperlipidaemia, and anemia. [18][19][20][21] In spite of the numerous side effects, most transplant patients are maintained on long-term low-dose steroids. 22

Study site/place
Renal Transplant Unit of IGIMS, Patna.

Study duration
Months from December 2019 to May 2020

Materials
Prescriptions of patients who have undergone Renal transplant.

Study design
It was an observational and cross-sectional study. We have collected reported ADRs, prescriptions, IPD files and laboratory reports of 40 patients who had already undergone renal transplant prior to start of this study and 10 patients who undergone renal transplant after start of this study. ADRs reports were collected from ADR monitoring centre (AMC), Department of Pharmacology, IGIMS, Patna. Study was started after approval from Institutional Ethics Committee of IGIMS, Patna.
According to WHO, any ADR that resulted in death, a life-threatening situation, persistent or substantial disability/ incapacity, hospital admission, or prolonged hospital stay is considered as serious. 23

Inclusion criteria
Patients who have undergone renal transplant and were on maintenance immuno-suppressive therapy.

Exclusion criteria
Patients already having immunodeficiency disease.

Statistical analysis
Results obtained from this study were presented in tabular form and data were interpreted by using Microsoft Excel 2007 software.

Discussion
In our study, more male patients (62%) have undergone renal transplant than females (38%). Most of patients were >45 years old (62%). Most common cause of End Stage Renal Disease (ESRD) was Diabetes mellitus (38%) followed by hypertension (26%). Namazi et al. found in their study that 72.5% of total patients were men. They found only 2 patients (1.67%) were ≥ 65 years of age. Most common cause of ESRD in their study was hypertension (29.86%) followed by nephrolithiasis (13.89%), and glomerulonephritis (11.11%). 24 Love et al. found in their study that 69.2% of total patients were male and 52.52% of total patients were between 46 to 75 years of age. Most common cause of ESRD in their study was Diabetes Mellitus followed by hypertension. 25 Most patients were prescribed prednisolone + tacrolimus + MMF as immunosuppressive regimen (70%) followed by prednisolone + cyclosporine + MMF (22%). Prednisolone was prescribed to all patients. Tacrolimus was prescribed to 72% of patients. Namazi et al. found in their study that combination therapy of prednisolone/cyclosporine/ mycophenolate mofetil (69.17%) was most prescribed immunosuppressive regimen. In their study, all patients were prescribed prednisolone and nearly all patients (97.5%) received cyclosporine as part of their immunosuppressive treatment and 25% were treated with azathioprine. 24 Total 78 ADRs were reported from 50 patients in our study. These ADRs were reported from 34 patients. So, incidence rate of patients affected due to ADR was calculated to be 68%. Incidence rate = (Total number of patients reported ADRs/ Total number of patients) x 100.
Love et al. 25 found in their study that the incidence rate of ADR was 75.78%. When we compared our findings with other ADRs monitoring studies, we found our incidence rate to be quite high. Benkirane et al 26 and Nicholas moore 27 found in their study that incidence rate of ADR was only 15.5% and 9.42% only. The reason for these differences could be many pathological change that develop       15 (19.23) in patients due to End Stage Renal Disease (ESRD). Calcineurin inhibitors are well known for nephrotoxicity as their common adverse effect and this was also found in our study as all reports of nephrotoxicity was found in patients receiving cyclosporine or tacrolimus. Similar results were found in studies of Robert F. English et al 28 and Busauschina A. el al. 29 In renal transplant patients, infection is one of the leading cause of morbidity and mortality. It is also considered as the main cause of death in the early period after renal transplant. [30][31][32] In our study, 7 cases of oral candidiasis, 7 cases of UTI and 8 cases of wound healing complications were found. In a study done by Namazi et al. 24  Most of the ADRs were found in age-group 46-60. Patients of old age were mostly affected by ADRs and poor prognosis. Oral Candidiasis, Urinary Tract Infection, Wound healing complication were most common ADRs. Most of the ADRs were mild (65.38%) while only one ADR was severe. 50% of ADRs were treated symptomatically. Responsible drug was withdrawn in only 3 cases. Similar results were found in other studies. 25

Conclusions
Most common immunosuppressive regimen prescribed was prednisolone + tacrolimus + MMF. Among these corticosteroids were mainstay of therapy. Mycophenolate Mofetil (MMF) was associated with most ADRs followed by tacrolimus. Most of the ADRs were mild and treated symptomatically. To decrease the rate of ADRs that are preventable, we can adopt various strategies such as regular follow-up of patients, periodic monitoring of cyclosporine level and it's dose adjustment according to monitoring findings, taking care of clinically significant drug interactions, prescribing much safer immunosuppressive regimens (eg. cyclosporine conversion to tacrolimus or sirolimus, preferring steroid-sparing protocol) and educating patients.

Source of Funding
No financial support was received for the work within this manuscript.

Conflict of Interest
The authors declare they have no conflict of interest.