|Year : 2022 | Volume
| Issue : 3 | Page : 282-287
Deceased donor renal transplant outcome in a south Indian tertiary care hospital with zonal allocation model - An observational study
Kandasamy Sadayandi1, Devdas Madhavan2, Prabu Murugesan1, Balamurugan Mathavan1, Kuppurajan Narayanasamy2, Pollachi Balasundaraj Baranikumar2, Anandan Murugesan2, Sengoda G Balasundaram3, Vengetesh Kilvani Sengottayan4, R Vasanthan5, S Jeevithan6
1 Department of Nephrology, Kovai Medical Centre and Hospital, Coimbatore, Tamil Nadu, India
2 Department of Urology, Kovai Medical Centre and Hospital, Coimbatore, Tamil Nadu, India
3 Department of Vascular Surgery, Kovai Medical Centre and Hospital, Coimbatore, Tamil Nadu, India
4 Department of Urology, GKNM Hospital, Coimbatore, Tamil Nadu, India
5 Department of Surgery, Kovai Medical Centre and Hospital, Coimbatore, Tamil Nadu, India
6 Department of Community Medicine, KMCH Medical College Hospital, Coimbatore, Tamil Nadu, India
|Date of Submission||02-Nov-2021|
|Date of Acceptance||14-May-2022|
|Date of Web Publication||30-Sep-2022|
Dr. Kandasamy Sadayandi
Department of Nephrology, Kovai Medical Centre and Hospital, Avinashi Road, Coimbatore - 641 014, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: With the rising incidence of diabetes and hypertension, the prevalence of end-stage renal disease has increased greatly so as the need for renal replacement therapy. Availability of suitable living-related donors is a major problem which increases the demand for deceased donor renal transplantation (DDRT), making it a lifeline for the patients on dialysis without any living donors. Methodology: This is a retrospective analysis of 118 DDRT done between 2012 and 2020, in a private quaternary care hospital in a south Indian state. All patients received basiliximab induction, with maintenance immunosuppression using steroids, mycophenolate mofetil (MMF) or mycophenolate sodium, and tacrolimus. Results: In our study, we report unadjusted graft survival of 93.2% and 81.3%, patient survival of 94.9% and 83.1% at the end of 1 and 5 years, respectively. The recipients with age < 60 years had 5 years graft survival of 87%. The study group consisted of 15.25% of the patients with panel reactive antibody (PRA) positive and 10.16% of them with donor-specific antibody (DSA) during renal transplantation, and there was only one allograft loss in this subset of the patients. Conclusion: This study confirms that human leukocyte antigen matching is not very important with the current immunosuppressive protocol using tacrolimus and MMF. Early initiations of tacrolimus do not increase the incidence of delayed graft function. We report 91.6% graft survival in the DSA-positive group, with basiliximab induction and desensitization protocol.
Keywords: Basiliximab, deceased donor renal transplant, donor-specific antibody, mycophenolate mofetil, tacrolimus
|How to cite this article:|
Sadayandi K, Madhavan D, Murugesan P, Mathavan B, Narayanasamy K, Baranikumar PB, Murugesan A, Balasundaram SG, Sengottayan VK, Vasanthan R, Jeevithan S. Deceased donor renal transplant outcome in a south Indian tertiary care hospital with zonal allocation model - An observational study. Indian J Transplant 2022;16:282-7
|How to cite this URL:|
Sadayandi K, Madhavan D, Murugesan P, Mathavan B, Narayanasamy K, Baranikumar PB, Murugesan A, Balasundaram SG, Sengottayan VK, Vasanthan R, Jeevithan S. Deceased donor renal transplant outcome in a south Indian tertiary care hospital with zonal allocation model - An observational study. Indian J Transplant [serial online] 2022 [cited 2022 Dec 4];16:282-7. Available from: https://www.ijtonline.in/text.asp?2022/16/3/282/357601
| Introduction|| |
In India, approximately 175,000 patients are added each year to the pool of end-stage renal disease; however, only 10% of them receive renal replacement therapy and 2.4% of patients receive renal transplant (RT). We detail our experience over 99 months in deceased donor renal transplantation (DDRT), with patients who did not have prospective living-related donors. The objective of this study is to estimate the efficacy of basiliximab induction with the current immunosuppresive protocol of low dose steroids, tacrolimus, and mycophenolate mofetil (MMF) in terms of graft and patient survival, and rejection episodes.
| Methodology|| |
Our study period is from March 2012 to June 2020. About 118 DDRT recipients who have received basiliximab induction and triple immunosuppressive drugs (tacrolimus, MMF and steroid) were included in the study. Only one patient received antithymocyte globulin (ATG) induction during this period and was excluded from the study.
The Transplant Authority Government of Tamil Nadu (TRANSTAN), does not give any priority of organ allocation for sensitized or panel-reactive antibody (PRA)-positive patients. PRA is defined as positive in our study if quantitative PRA is more than 25%, or moderate positivity by PRA screening for either Class I or Class II antigens or both. Both were done using Luminex xMap technology with Immucor lifecodes commercial kits. PRA positive groups, months earlier to the transplant as they come top in the priority list, have received some form of immunosuppression except one patient. There was no uniformity of the immunosuppressive regimen in these patients. It includes bortezomib 2 mg (4–8 doses) and or rituximab 200 mg ± MMF which was given for few weeks to 3 months.
The PRA-positive group as they reach the “Be ready list,” single antigen bead (SAB) assay for human leukocyte antigen (HLA) Class1 and Class 2 antibodies are done. Moreover, as the patient is allocated with a deceased donor kidney, HLA typing for donor is done by specific sequence probe along with crossmatch. If crossmatch is negative then the remote serum SAB results are compared with the HLA of the donor for the presence of donor-specific antibodies (DSAs). If there are DSAs then the transplant is done with desensitization.
Organ allocation model
In Tamil Nadu's deceased donor transplant model, the state is divided into three zones North, South, and West. Organ allocation is not HLA based, so these transplants are generally considered to be HLA-mismatched transplants. According to the TRANSTAN policy, recipients with an age above 60 years are allocated with organs from donor aged above 60 years and the adult recipient with an age <60 are eligible to get kidney from donor of any age above 12 years. Dual kidney allocation for the marginal donors by TRANSTAN is possible only if there are no takers for the second kidney from all three zones of Tamil Nadu. Deceased donor kidneys of the age 12 years or less are given preference to young recipients of age <12 years. As a unit policy, the kidneys from donors aged above 60 years are not considered for recipients younger than 60 years. However, when there were no takers for a younger donor kidney then it was permitted for the elderly recipient. Transplant surgery is done as per the standard techniques, only after the negative donor T-cell crossmatch test.
Induction was done with basiliximab 20 mg, first dose 2–3 h before restoration of perfusion and second dose on the 4th postoperative day, in all the deceased donor recipients including PRA- and DSA-positive patients. Methylprednisolone 500 mg will be given intraoperatively, followed by tablet prednisolone 40 mg on the first postoperative day and was gradually reduced 5 mg every 5 days and maintained a dose of 2.5–5.0 mg by 45 days.
Tacrolimus was initiated at 0.1–0.15 mg/kg in two divided doses, first dose before the surgery itself and continued postoperatively even if there is delayed graft function (DGF). Tacrolimus trough level of 8–12 ng/ml for the first 3 months, 6–8 ng/ml between 3 and 12 months, and 5–7 ng/ml thereafter was maintained.
MMF was given as 2 g/day for the first 15 days, 1.5 g/day for the second 15 days, and 1 g/day after a month. Some patients are given equivalent dose of mycophenolate sodium.
Immediate graft function was defined as nonrequirement of dialysis after transplantation. DGF was defined as a need for dialytic support within a week of transplant. Primary nonfunction (PNF) when there was permanent lack of function from the time of transplantation.
The data was analysed using IBM SPSS Statistics for Windows, Version 27.0, Armonk, NY: IBM Corp. The descriptive data was expressed as frequency/percentages for categorical variables and mean ± standard deviation (SD) for continuous variables. Patient's overall survival and graft survival were done using Kaplan Meier survival analysis. P value < 0.05 was considered as significant.
Declaration of patient consent
The authors certify that patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that their names and initials would not be published, and all standard protocols will be followed to conceal their identity.
The study was done after getting approval from the institutional human ethical committee (IHEC-KMCH) with the waiver of consent from patients and the study was conducted in accordance with the Declaration of Helsinki. (IHEC No.:EC/AP/912/05/2021). The study was performed according to the guidelines in Declaration of Helsinki.
| Results|| |
Among 118 patients, 86 (72.9%) were male and 32 (27.1%) were female. About 97 recipients (82.2%) fall under the age of 60 years and 21 patients (17.8%) were above 60 years [Table 1].
Thirty-three people (27.9%) were diabetic. Eight patients had coronary revascularization before RT which included five patients with coronary artery bypass graft and three recipients with left anterior descending artery stenting. Four patients were hepatitis C positive at the time of RT and two patients were positive for both hepatitis B and hepatitis C. Two patients had combined liver and kidney transplantation. The mean donor age was 37.6 years, the youngest donor was 9 years old and oldest was 84 years. Seventeen were of extended criteria donors (age more than 60 years or 50–59-year-old and fullfilling two out three criteria consisting of the preexisting hypertensive, cerebrovascular accident as the cause of brain stem death, and terminal serum creatinine more than 1.5 mg/dl).
In our study group, the patient survival was around 94.9% for the 1st year, 89.8% for the 2rd year, and 83.1% for the 5th year. Death with functioning graft was seen in 5 (4.2%), 9 (7.6%) and 12 (10.16%) patients at the end of 1st, 3rd, and 5th year respectively.
The death-censored graft survival was 97.5% for the 1st and 3rd year, and 91.5% at the end of 5th year. The unadjusted graft survival was 93.22% for the 1st year, 89.8% for the 3rd year, and 81.3% for the 5th year.
In the age group <60 years, the unadjusted graft survival was 96.9% at the end of 1 year. At the end of 3rd and 5th years, the graft survival was 96.5% and 87%, respectively.
Eight patients had DGF with an incidence of 6.8%, and one patient had PNF. Ten patients (8.5%) required re-exploration (seven cases for hematoma, two for lymphocele, and one for abscess around the allograft). The overall rejection rate including early and late rejections was 11.1%. About 21 patients (17.8%) were above 60 years of age. Only 11 (52.4%) patients of age above 60 years are alive with good graft function and 8 (38.1%) have died with functioning grafts during the study period. Two (9.5%) patients have died after the graft loss. In total, 12 (10.16%) patients in the study group died with the functioning allograft. Three recipients (2.5%) had recurrent native kidney disease, two patients with focal segmental glomerulosclerosis (FSGS) and one with immunoglobulin A (IgA) nephropathy.
| Discussion|| |
The Kidney Disease: Improving Global Outcomes (KDIGO) recommendations (2009) on induction were based on randomized controlled studies that compared interleukin-2 receptor antagonist (IL2RA) or ATG with placebo. Biopsy-proven rejection was 30% lower in IL2RA versus placebo. ATG was no better than IL2RA in preventing rejection and the safety profile favored IL2RA.
In our study, basiliximab induction with tacrolimus, MMF, and steroid maintenance protocol was followed and the results were summarized. We preferred basiliximab over ATG, as it has lower infection potential.
A meta-analysis by Ali et al. revealed no significant difference in patient and graft survival between IL-2RA and rabbit ATG with the tacrolimus-based maintenance immunosuppression.
A study by Brennan et al., on RT showed that the ATG group, as compared with the basiliximab group, had lower incidences of acute rejection (15.6% vs. 25.5%, P = 0.02) and of acute rejection that required treatment with antibody (1.4% vs. 8.0%, P = 0.005). The ATG group and the basiliximab group were similar in the incidences of graft loss (9.2% and 10.2%), DGF (40.4% and 44.5%), and death (4.3% and 4.4%), respectively.
Wang et al., in their meta-analysis of eight RCT included 1153 patients and among them, 547 (47%) had received basiliximab, and 606 (53%) had received ATG. The pooled results revealed that the basiliximab group had a lower rate of neoplasm in comparison with ATG (odds ratio 0.26; 95% confidence interval 0.08–0.78; P = 0.02). There were no significant differences between the two drugs on the outcome observed as 1-year acute rejection rate (P = 0.13), 1-year graft survival rate (P = 0.20), 1-year patient survival rate (P = 0.06), and 1-year infection rate (P = 0.73).
In all our patients, tacrolimus was started before the surgery and continued during the immediate posttransplant period immaterial of allograft function. According to the KDIGO clinical practice guideline, it is recommended to start with a combination of immunosuppressive medications before or at the time of transplant (Class 1A recommendation), and also recommends the addition of IL2RA. The guideline also mentions that there are no proper studies using tacrolimus for early versus late initiation in RT recipients. However, it is suggested that the risk of early calcineurin inhibitor nephrotoxicity could be minimized and optimal prevention of acute rejection can be achieved with the regimen including induction and reduced dose tacrolimus. Since the patients with DGF without ATG, has a greater potential for rejection, we did not stop tacrolimus.
Delayed graft function and primary nonfunction
In our study, only eight patients had DGF with the incidence of 6.8%, and one patient had PNF. Out of 8 patients with DGF, 3 were due to antibody mediated rejection. The lowest DGF in our study possibly is the result of the zonal distribution of organs and short ischemic time. Except one patient who had combined liver-kidney transplant, none of them had cold ischemic time (CIT) more than 12 h. In a study by Lauronen et al., donor age was an important risk factor for DGF, and among patients with young donors with short CIT <12 h, the frequency of DGF was reported to be 6%. In another study by Gopalakrishnan et al., the incidence of DGF was 48.5%. Surendran et al. reports 15.24% incidence of DGF.
In our study group of 118 patients, 10 (8.5%) required re-exploration (seven cases for hematoma, two for lymphocele, and one for abscess around the allograft) which apparently looks higher. Four out of seven patients with hematoma were DSA-positive group and had a preoperative plasmapheresis. They had bleeding despite fresh frozen plasma replacement. In a study by Jain et al., among 350 cases of live and cadaveric RT, immediate re-exploration was needed in 13 patients either for hematoma around the allograft or for the thrombus in vessels of the graft.
PRA positivity in our study
In our study group, 18 (15.2%) were found PRA positive during the waiting period and two of them were awaiting the third transplant and six were on the waitlist for second transplant. In the remaining ten patients, the sensitizing events were either transfusion or pregnancy.
One patient had transplant without desensitization after excluding the presence of DSA in the remote serum. Three more patients who had negative crossmatch with their respective donor had negative DSA by lysate method and had transplant without desensitization. Thus, totally four patients in PRA-positive group had transplant without desensitization. The remaining 14 patients had the presence of DSA in remote serum and they were taken for transplant with perioperative concurrent desensitization along with the standard protocol. A sample is drawn for SAB assay for HLA Class 1 and 2 antibodies before desensitization. The SAB results taken at the time of transplant was negative for DSA in two of them even though they had DSA in the remote serum. One patient belonged to retransplant group and the other patient was for the first transplant and so they were unnecessarily subjected to desensitization. Although the major drawback in the PRA testing is the available commercial kit may not truly represent the local population, we confirmed the presence of DSA by SAB assay in these patients.
Donor-specific antibody-positive patients
A total of 12 (10.16%) recipients had DSA at the time of transplant and seven (5.9%) were retransplant group and the remaining five (4.2%) were for the first transplant and all these patients had received perioperative concurrent desensitization. Perioperative desensitization included one to three-volume plasmapheresis, intravenous immunoglobulin 1–2 g/kg, and low dose rituximab 100–200 mg ± bortezomib.
All the five DSA positive for first transplant were female and the sensitization event was pregnancy. Four out of these five patients in the first transplant group had active antibody-mediated rejection (ABMR). Three allografts were salvaged and one developed acute cortical necrosis and subjected to graft nephrectomy. Moreover, none of the retransplant recipient with DSA had rejection either early or late and all have normal allograft function. It appears that sensitization due to pregnancy is more significant than sensitization due to previous transplant. However, the number is too small to draw any conclusions.
Eleven (9.3%) patients had retransplant and three among them were PRA negative during wait-list. They had their transplant without desensitization and one had ABMR, but fortunately, the allograft was salvaged and now 6 years posttransplant with serum creatinine 1.7 mg/dl. The remaining eight PRA-positive retransplant patients, as already mentioned had desensitization and none of them had any rejection and have normal renal function during the study period.
In our study group, early rejection was observed in six (5.6%) patients, one related to withdrawing the immunosuppression for life-threatening multilobar pneumonia resulting in graft loss. Five were active ABMR resulting in one allograft failure. Other four ABMR were reversed with treatment.
Late rejection occurred in seven (5.9%) patients and four were related to drug noncompliance, resulting in graft loss. One had late chronic active ABMR, resulting in graft loss. Another two had T-cell-mediated rejection related to tacrolimus variability and one had complete remission and the other patient had partial remission with treatment. Hence, in our study, the overall rejection rate including early and late rejections was 11.1%.
In a study by Kute et al., 20.7% had biopsy-proven acute rejection over median follow-up of 3.93 years.
Graft and patient survival
The mean serum creatinine during discharge from the hospital after the surgery was 1.94 mg/dl, 1.18 mg/dl at the end of 5 years, and 1.12 mg/dl at 99 months. The factors influencing the graft and patient survival are summarized in [Table 2] and [Table 3].
Surendran et al. recorded 75% of the patient survival and 89.58% graft survival at the end of 1 year. One year patient survival in our study was 94.9% which is better than the reports from Shroff et al., Surendran et al., and Gumber et al. showing 1 year patient survival of 86%, 75%, and 75.8%, respectively. Moreover, 5 years patient survival in our study was 83.1%. Kute et al., in their study on 294 DDRT, showed a patient and graft survival rates of 81.7% and 92.6%, respectively, with a median serum creatinine of 1.5 mg/dL over a median follow-up of 3.93 years.
The 3 years unadjusted graft failure in our study is 10.2%, better compared to the UNOS registry data, where the 3 years graft failure of 14.9%, and 16.7% among the lower and high quartile centers were reported. The unadjusted graft survival in the 1st year was 93.2% in our study whereas it is 93.4%, 96%, 90.7%, and 94.9% in the US primary, Australia & New Zealand primary, Europe primary, and Canada primary outcome data, respectively. 5 years graft survival was 81.3% in our study as against 72.4%, 81%, 77.8%, and 81.4% graft survival in US primary, ANZ primary, and EUR-primary. In our study, the strongest predictors of patient survival were episodes of rejection with a hazard ratio of 5.87 (2.33–14.80) and age above 60 years with a hazard ratio of 12.19 (3.2–46.3) with a significant P < 0.001. The Kaplan Meier graph for the graft survival in patients below 60 years has been added in [Figure 1].
Outcome in the age group above 60 years
RT in elderly people above 60 years of age is considered to be of high risk. In our study group, 21 patients (17.8%) were above 60 years. None of them received dual kidney transplant. Only 11 (52.4%) patients are alive with good graft function and 8 (38.1%) have died with functioning graft during the study period. Two (9.5%) patients have died after the graft loss. These elderly recipients have also received the old donor's kidney. The older kidneys, compared to younger kidneys have an increased incidence of acute rejection and if it happens, the ability to mount tissue repair is impaired. None of the elderly recipient had rejection in the early posttransplant period. However, the outcome of elderly recipients in our study is dismal and dominated by infection, malignancy, and cardiovascular mortality.
Death with functioning allograft
A Total of 12 (10.16%) patients in the study group died with the functioning allograft. Six were related to infection, three related to malignancy, one was brought dead to the hospital, and two patients had acute coronary syndrome and cardiac arrest.
Recurrent kidney disease
Two patients had FSGS and the first patient had the recurrence immediately posttransplant, with anasarca and remitted with plasmapheresis. Now he has completed 8 years, has normal allograft function. The second patient in the 5th year had a rapid decline in renal function back to dialysis. One patient had crescentic IgA nephropathy requiring pulse cyclophosphamide and steroid in the 3rd year and now in the 5th year with normal allograft function.
Larger, multi-zonal studies from different parts of country would help in validating findings of the study.
| Conclusion|| |
Our study confirms the fact that HLA matching is not very important with the current immunosuppression protocol with tacrolimus and MMF. Early initiation of tacrolimus did not increase the incidence of DGF. The lowest incidence of DGF of 6.8% is possible by the TRANSTAN zonal organ allocation model. There was no early T-cell-mediated rejection in our study. We report 91.6% graft survival in the DSA-positive patients with desensitization protocol and basiliximab induction. Our study predicts a graft survival of 84% at 99 months in the age group below 60 years with the zonal allocation of the organ with basiliximab induction and tacrolimus-based triple immunosuppression in DDRT.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]