|Year : 2021 | Volume
| Issue : 4 | Page : 313-319
Low-dose induction immunosuppression in deceased donor kidney transplantation during coronavirus disease pandemic - A multicentric prospective observational study
Jacob George1, Noble Gracious1, Anjana Gopal1, Satish Balan1, Praveen Murlidharan2, Sreedas Gopalakrishnan3, Vasudevsan Potty4, Satheesh Kurup4
1 Department of Nephrology, Government Medical College, Kollam, Kerala, India
2 KIMS Hospital, Kollam, Kerala, India
3 Department of Nephrology at Travancore Medicity Hospital, Kollam, Kerala, India
4 Department of Urology, Government Medical College, Thiruvananthapuram, Kerala, India
|Date of Submission||01-Sep-2020|
|Date of Decision||02-Dec-2020|
|Date of Acceptance||08-Dec-2020|
|Date of Web Publication||30-Dec-2021|
Dr. Jacob George
Department of Nephrology, Government Medical College, Thiruvananthapuram - 695 011, Kerala
Source of Support: None, Conflict of Interest: None
Context: There are concerns regarding the use of induction immunosuppression during deceased donor renal transplantation in the coronavirus disease 2019 (COVID-19) pandemic and whether lower doses may suffice. Aims: We aimed to compare different induction immunosuppression regimens in deceased donor renal transplantation during the COVID-19 pandemic. Settings and Design: A multicenter, prospective observational study of patients undergoing deceased donor renal transplantation during the COVID-19 pandemic in Southern Kerala from April to June 2020 with differing induction immunosuppression and follow-up for at least 6 months. Subjects and Methods: Patients were from Government (Group A) and Private hospitals (Group B). Induction immunosuppression included low dose rituximab and/or low dose anti-thymocyte globulin in group A and higher dose induction with anti-thymocyte globulin or basiliximab in Group B. Graft function at 1 and 6 months, infectious complications, and cost of induction immunosuppression were compared. Statistical Analysis Used: Mood's median, Chi-square, Fisher Exact, and Mann–Whitney U test. Results: Of eleven deceased donor kidney transplantations, six were from Group A and 5 from Group B. Three in Group A and two in Group B had reversible antibody-mediated rejections. Median serum creatinine (interquartile range) in both groups at 1 month was 1.35 (1.1, 3) and 1.5 (1.1, 3.5) mg/dl, respectively, and by 6 months 1.5 (1.05, 2.33) mg/dl and 1.7 (1.15, 2.6) mg/dl, respectively. Two patients in Group A died, one due to Gram-negative septicemia at the 2nd month and the second by the 3rd month following a cardiovascular event. Mean cost of induction immunosuppression in both groups was INR 40,500 ± 22,827 and 107,200 ± 57,595 (P = 0.01). There was no difference in infection episodes in both groups. Rituximab in a dose of 100 mg was used as induction in 4 patients with comparable graft functions and cost-benefit with a mean cost of INR 33,750 ± 26,196 and Rs. 92,000 ± 53,715 in the rituximab and nonrituximab groups, respectively (P = 0.056). Conclusions: Low-dose induction immunosuppression in the COVID pandemic was cheaper with comparable graft functions at 1 and 6 months.
Keywords: Acute antibody-mediated rejection, acute cellular rejection, coronavirus disease 2019 pandemic, deceased donor kidney transplantation, low-dose induction immunosuppression, rituximab
|How to cite this article:|
George J, Gracious N, Gopal A, Balan S, Murlidharan P, Gopalakrishnan S, Potty V, Kurup S. Low-dose induction immunosuppression in deceased donor kidney transplantation during coronavirus disease pandemic - A multicentric prospective observational study. Indian J Transplant 2021;15:313-9
|How to cite this URL:|
George J, Gracious N, Gopal A, Balan S, Murlidharan P, Gopalakrishnan S, Potty V, Kurup S. Low-dose induction immunosuppression in deceased donor kidney transplantation during coronavirus disease pandemic - A multicentric prospective observational study. Indian J Transplant [serial online] 2021 [cited 2022 Jan 26];15:313-9. Available from: https://www.ijtonline.in/text.asp?2021/15/4/313/334295
| Introduction|| |
Following reports of a novel coronavirus-producing pneumonia, declaring it a pandemic and lockdown ordered in various parts of the world, renal transplantation has drastically come down globally., The virus was subsequently named severe acute respiratory syndrome coronavirus type 2 and the disease named coronavirus disease 2019 (COVID-19). Other concerns were the use of immunosuppressive drugs being associated with higher morbidity and mortality with COVID-19 as reported for related viruses, and risk of transmitting infection from the donor. In this context, need for modifying immunosuppressive drugs in renal transplantation has been suggested. However, there are no studies yet regarding the relative risks of rejection episodes as well as COVID 19 infection with different types of immunosuppressant drugs. The economic recession following the COVID-19 pandemic is another barrier in low economy countries. As induction immunosuppression accounts for the main initial cost of transplantation, lowering the dose of induction immunosuppression could have an added advantage. In this background, we report our experience with performing 11 deceased donor renal transplantations in Sothern Kerala, India, during the COVID 19 pandemic with differing degrees of induction immunosuppression. We designed this study to compare early rejection rate, early infection rate, and graft functions, and cost after 4 weeks and 6 months in deceased donor kidney transplant recipients where low-dose induction regime was used with patients who received higher-dose induction immunosuppression. We also aimed for subgroup analysis to assess the role of low-dose rituximab (100 mg) as a part of induction immunosuppression.
| Subjects and Methods|| |
This was a multicenter, prospective, observational study. Inclusion criteria-Subjects consisted of patients who underwent deceased donor renal transplantations from the Kerala network of organ sharing (KNOS) waitlist in South India during the COVID-19 pandemic from April to June 2020 and were followed up for at least 6 months. Donors and recipients were evaluated for symptoms or signs of COVID 19 infection and were checked with real-time polymerase chain reaction (RT-PCR, Seegene kit) for coronavirus from nasal swabs and bronchial secretions of donors and nasal and throat swabs of recipients 24 h before surgery along with total and differential leukocyte count, Exclusion criteria-Those who were unwilling to give informed consent were excluded. C reactive protein, Serum Ferritin, procalcitonin, Chest X rays, microbiological cultures, biochemical tests, and cell-dependent lymphocytic (complement-dependent cytotoxicity [CDC]) cross match. Kidney donor profile index was calculated based on age, height, weight, ethnicity, history of diabetes and hypertension, serum creatinine, cause of death, and Hepatitis C status. The risk of COVID 19 infection following transplantation and immunosuppression was explained to the recipients and induction immunosuppression and surgery were proceeded after obtaining their consent. The study was approved by the institutional research and ethics committee of the institution (A2/SBMR/256/2020/GMCT) and was conducted in accordance with the declaration of Helsinki.
As per KNOS guidelines, both kidneys from a donor were transplanted in two different hospitals, one being s state-run hospital and the other being private hospital. Recipients in state-run hospital (Group A) received a lower dose of induction immunosuppression than private hospitals (Group B). Details of recipients, induction immunosuppression, cold ischemia time, the incidence of delayed graft function (DGF), rejection episodes if any, and renal functions at the end of 1 week, 1 month, and 6 months in both groups were compared. All donor's kidneys were perfused in situ with 5 liters and 1 liter for bench perfusion with the University of Wisconsin solution (Belzer).
All recipients (Group A and B) received 3 daily doses of 500 mg Methyl prednisolone started just prior to surgery. Induction agents used alone or in combination included rabbit anti thymocyte globulin (r ATG/Thymoglobulin, Sanofi-Aventis) obtained after immunization with human thymocytes or T-lymphoblast Jurkat cell line (ATG-F, Neovii, previously ATG-Fresenius marketed in India as Graflon, Zydus), Basiliximab (Novartis) and Rituximab (Maball, HETRO Oncology, a bio similar of rituximab approved by Central Drugs Standards Control Organization, India). Maintenance immunosuppression in both groups included prednisolone, mycophenolate mofetil (MMF) in doses between 1 and 2 g daily, and tacrolimus titrated to achieve a target trough level of 7 and 10 ng/mL. Tacrolimus was delayed or dose reduced in those with DGF.
Low dose induction immunosuppression in group A was defined as a single dose of r ATG mg ≤50 mg or r ATG-F ≤100 mg with or without Rituximab 100 mg. Further doses of ATG in group A were given only if the absolute lymphocyte count exceeded 750/μL or in cases of DGF. All patients in Group B received two or more doses of ATG or 2 doses of Basiliximab. CD3 counts were not monitored due to the lack of facility in the participating centers. Acute cellular rejection was managed in both groups with 3 doses of pulse methylprednisolone and if not responding further doses of ATG. Antibody-mediated rejections in both groups were managed with plasmapheresis, intravenous immunoglobulin, and bortezomib.
DGF was defined as the need for hemodialysis during the 1st-week posttransplant due to inadequate allograft function. The high immunological risk was defined as the history of previous transplantation, multiple blood transplantations, and borderline CDC crossmatch results. Graft kidney biopsies using light microscopy and immunofluorescence with C4d staining were described as suggested by Banff 2017. Valganciclovir in a daily dose of 450 mg was given to all who received more than one dose of lymphocyte-depleting induction agent. The cost of immunosuppression in both groups was based on the subsidized cost available at Government pharmacy outlets.
Continuous data are presented as median and interquartile range (IQR) and categorical variables as number (%). Medians of two groups of continuous variables with normal distribution were compared by Mood's median test. Significance of study parameters on categorical scale between two was assessed using Chi-square and Fisher Exact test. Means of two groups were compared by independent sample t-test and those with nonnormal distribution by Mann–Whitney U test. Significance was assessed at 5% level of significance. Statistical software SPSSspss software version 16( SPSS Inc, Chicago, IL, USA) was used for analyzing data.
The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names and initials would not be published, and all standard protocols will be followed to conceal their identity.
This study was approved by the Institutional Research Committee, Government Medical College, Thiruvananthapuram with IRB Number A2/SBMR/256/2020/GMCT. The procedure was carried out in accordance with the Declaration of Helsinki and International Council for Harmonization-Good Clinical Practice (ICH-GCP).
| Results|| |
Eleven kidneys were retrieved from six deceased donors during the study period. One kidney was discarded due to anatomical complexity. Six kidney recipients were from state-run hospital and five from private hospitals. None of the donors or recipients were positive for COVID-19 RT PCR and all had CDC crossmatch <10%. Details of donors are shown in [Table 1]. Baseline characteristics and 6-month outcome of all the recipients are shown in [Table 2]. One patient with primary oxalosis underwent simultaneous kidney and liver transplantation. Details of dialysis vintage, cold ischemia time, induction treatment given, complications encountered, and renal biopsy findings are shown in [Table 3]. Second dose anti-thymoglobulin was needed in 4 patients in Group A due to DGF and subsequent decreasing or withholding tacrolimus, whereas all patients in Group B received preplanned two or more additional doses of induction agent. Five had DGF, of which three had acute tubular necrosis in biopsy and others antibody-mediated rejection. DGF did not appear to affect the short-term graft function by 1 month and all could be taken off dialysis after a median period of 14 days (IQR 5, 16). Renal histology revealed antibody-mediated rejection in two and combined cellular and antibody-mediated rejection in three but all recovered renal functions following treatment.
|Table 2: Base line characteristics of recipients and one and six-month outcome|
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By 1 month, infections were seen in three patients, one of them had urinary tract infection which responded to treatment. Bloodstream infections were seen in the other two which responded to treatment.
All were discharged after a mean period of 27 + 6 days with a mean creatinine of 2 ± 1.3 mg/dL (eGFR 51 ± 29 ml/min/1.73 m2). All patients in Group B and 4 patients in Group A received valganciclovir prophylaxis in a dose of 450 mg daily.
The median duration of follow-up was 7 months (IQR 6.5, 7.25).Two patients in Group A died, one due to gram-negative septicemia at 2 months posttransplant and the second in the 3rd month posttransplant due to a cardiovascular event. At the time of death, the serum creatinine of these patients was 2.1 mg/dl and 2.5 mg/dl, respectively, and were excluded for further analysis at the 6th month. Details of the outcome at 1 and 6 months are shown in [Table 2] and [Table 4].
|Table 4: Comparison of outcome between patients who received and did not receive low dose rituximab|
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The cost of induction immunosuppression in Group A and B was INR 40500 ± 22827 (USD 540 ± 304) and INR 107200 ± 57595 (USD 1429 ± 767), respectively. Reduction in frequency of induction agents in Group A helped in reducing the median cost from USD 1200 in Group B to 720 (P = 0.08) with comparable graft functions and without increased risk of rejection. The cost of induction when rituximab was given was INR 33750 ± 26196 (USD 450 ± 349) and for the nonrituximab group INR 92000 ± 53715 (USD 1226 ± 716). The addition of low dose rituximab appeared to help in limiting additional doses of ATG with economic benefits with comparable graft functions [Table 4].
| Discussion|| |
Though immunosuppression following renal transplantation increases the risk of COVID 19 infection, there is a justification for performing deceased donor transplantations due to the shortage of live donors and to avoid wastage of organs. This however may need precautions and reducing overall immunosuppression without unduly increasing the risk of graft rejection. It is also possible that the donor, as well as recipient, could be harboring an asymptomatic or even active infection in which case transplantation could be hazardous. A detailed clinical and laboratory evaluation of both recipients and donors was done to minimize the possibility of even subclinical infection. Though it has been reported that combining RT PCR with a CT of the chest may be preferable to diagnose early pneumonia, we did not do CT of the chest in the recipients due to low clinical suspicion though Chest X rays were taken. None of the recipients or donors came from areas of the high prevalence of COVID19.
Though all recipients were tissue crossmatch negative they were considered to be having increased immunologic risk due to presumed poor HLA match with their donors. Induction immunosuppression with preference for ATG has been recommended by KDIGO for renal transplantation with high immunologic risk. However, the use of lymphocyte-depleting agents in this pandemic may need caution considering the propensity of lymphopenia predisposing to viral infections., COVID 19 patients who have lymphopenia have a more severe course. This would suggest avoiding or at least reducing the dose of lymphocyte-depleting agents in this pandemic. The dose recommended for rATG is 1–1.5 mg/kg for up to 5–7 doses with a cumulative dose of as high as 2 to13.5 mg/kg being suggested in the manufacturers prescribing information. For ATG-F the initial dose recommended is 9 mg/kg. However, there are reports of lesser frequency of ATG-F of 1.5 mg/kg daily for 4 days being used without increased risk of rejection., Due to these apprehensions along with economic problems faced by patients attending Government hospitals, they were given an initial dose of ATG and subsequent doses were avoided if the absolute lymphocyte count was low. We noted that low dose and lesser frequency of ATG had similar clinical efficacy to higher doses given to economically better patients from private hospitals without increase in early rejection rates and comparable renal functions at the time of discharge. It has also been suggested that targeting the CD3 counts could prevent unnecessary higher doses. Though monitoring CD3 counts and targeting further doses of ATG could probably be considered in the COVID era to reduce the cumulative dose of ATG, we could not target CD3 based dosage due to delay in obtaining the results as it had to be outsourced due to lack of facility in Southern Kerala institutions. Other centers have also reported benefits with a single dose of ATG. ATG-F is said to have less suppression of the lymphocytes than r-ATG. Three of our patients received ATG-F with similar efficacy. Whether targeting the need for further doses of ATG and thereby avoiding prolonged lymphopenia can decrease the risk of COVID infection and its effect on long-term graft function needs further studies.
Basiliximab as an induction agent is considered to be less potent than ATG and may not be ideal in high immunological risk recipients., T-cell depleting agents have been shown to predispose to viral infections like cytomegalovirus (CMV). This could suggest increased risk for COVID 19 as well. However, as Basiliximab is a nonlymphocyte depleting induction agent, it may have theoretical advantage over ATG with regard to the risk of COVID infection. Only one patient in our study received Basiliximab precluding comparison.
Rituximab is a monoclonal antibody targeting B-cells. Concerns have been raised whether B-cell depleting agents should be avoided in the COVID pandemic. However, considering that other viral infections like CMV are reported with T-cell depleting agents and not B-cell depleting agents this may suggest lesser risk of COVID infection with a B-cell depleting agent compared to a T-cell depleting agent and could suggest advantages of rituximab over ATG as an induction agent in the COVID-19 pandemic. This as well as theoretical advantage in preventing antibody-mediated rejection could make it an attractive induction agent in this pandemic. It can be given as an induction agent either alone or in combination with ATG with reduced risk of antibody mediated rejection. It has also been successfully used in ABO-incompatible transplants. Low dose of 100 mg was shown to suppress the CD19B cells for up to a year in renal allograft recipients who had received ATG induction. Targeting the initial dose and deciding on the need for further doses depending on the CD 19 count has also been found to be effective and may have advantages by limiting the state of immunosuppression., It has also been shown to have cost advantages. We have used rituximab in 4 patients with similar efficacy to other induction with cost benefits.
MMF is preferred over Azathioprine as an anti-proliferative agent with regard to preventing rejections. Being a leucocyte-depleting agent, caution has been advised due to the increased risk of COVID infection with MMF and recommendations of reducing the dose when used in glomerular diseases. We have used a lesser dose of MMF when combined with ATG considering the risk of COVID. Monitoring blood levels of MMF and deciding on the effective dose has been suggested, with an area under the curve of 30–60 mg/h/l at 0–12 h being recommended to prevent renal allograft rejection. This method of titrating the dose of MMF based on these levels can help to maintaining effective immunosuppression while avoiding overdosing, decreasing the risk of leucopenia and could have advantages in the COVID era.
Although early rejection episodes were noted in 5 of our patients, all responded. As late rejection episodes are thought to affect long-term graft functions more than early reversible rejection episodes, this may not suggest the disadvantage of lower doses of induction in the COVID pandemic. We did not give valganciclovir prophylaxis in those who had received no or <2 doses of ATG and may help to reduce the cost of further immunosuppression and could have advantages in resource-limited countries.
Limitations of the study
Our study has major limitations of low numbers and short follow-up. More patients with longer follow up are needed to clarify the role of dosing of induction agents in reducing risk or severity of COVID-19 infection as well as long-term graft functions.
We thank the Staff of KNOS, Anaesthesiologists, Nursing Staff, Tissue cross-match technicians for their assistance
| Conclusion:|| |
Reducing the dose of induction immunosuppression in deceased donor renal transplantation could be considered during the Covid pandemic
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]