Objectives: Gujarat, Tamil Nadu, Telangana, Maharashtra, Kerala, Chandigarh, and Karnataka are states in India with active programs for deceased donor kidney transplant. We report our experience of 2 decades of deceased donor kidney transplant at the Institute of Kidney Diseases and Research Center, Dr. H. L. Trivedi Institute of Transplantation Sciences, Ahmedabad, Gujarat, India.
Materials and Methods: This single-center retrospective study comprised data from 831 deceased donor kidney transplant recipients between January 1, 1997 and December 31, 2018. Mean recipient age was 38 ± 14 years; 564 were male, and 267 were female. Mean donor age was 45.3 ± 17.13 years; 565 were men, and 266 were women.
Results: Between January 1, 1997 and March 15, 2020, 5838 kidney transplants were completed, including 4895 living donor kidney transplants, 943 deceased donor kidney transplants, and 440 kidney paired donation transplants. Over the mean follow-up time of 8 ± 5.4 years, patient survival rate was 70% (n = 581) and death-censored graft survival rate was 84% (n = 698). Delayed graft function was shown in 210 patients (25%) and biopsy-proven acute rejection rate in 180 patients (21%). Our experience of favorable outcomes with deceased donor kidney transplants has expanded the donor pool in many ways, including transplant from expanded criteria donors to younger recipients; transplant from older donors to older recipients; donation after cardiac death; successful intercity organ procurement; dual-kidney transplant; en bloc transplant from a pediatric deceased donor; and transplant from brain death deceased donors who died from neurotoxic snakebite, recurrent primary brain tumor, bacterial meningitis, or head injury, or with disseminated intravascular coagulation and deranged renal functions. The pathway to increase organ donation was investigated.
Conclusions: Deceased donor kidney transplant can achieve acceptable graft function with patient/graft survival, which may encourage the use of this approach to increase the number of available organs.
Key words : Deceased donor kidney transplant, Deceased donor liver transplant, Graft survival, Living donor kidney transplant, Patient survival
Kidney transplant is the best cost-effective renal replacement therapy option for patients with end-stage kidney disease and has shown better long-term survival rates compared with dialysis. Most kidney transplants in India are from living donors (80% to 90%); and few are from deceased donors (10% to 20%).1,2 Gujarat, Tamil Nadu, Telangana, Maharashtra, Kerala, Chandigarh, and Karnataka are states in India with active deceased donor organ transplant (DDOT) programs in the past decade. We report our experience of 2 decades of deceased donor kidney transplant (DDKT) at the Institute of Kidney Diseases and Research Center, Dr. H. L. Trivedi Institute of Transplantation Sciences (IKDRC-ITS), Ahmedabad, Gujarat, which is the largest public sector transplant hospital in India.
Materials and Methods
This single-center retrospective study comprised data from 831 DDKT recipients who received transplants between January 1, 1997 and December 31, 2018. The clinical study was reviewed by the ethics committee according to international standards of Good Clinical Practice and local laws and regulations (Transplantation of Human Organs Act, India). We abided by the principles of the Declaration of Helsinki and the Declaration of Istanbul. Written informed consent was obtained from all recipients. We evaluated demographics, patient survival, graft survival, graft function with serum creatinine, rejection episodes, delayed graft function, and immunosuppression regimen.
Each kidney was allotted appropriately, with regard to the DDKT wait list. An old-for-old and young-for-young strategy was used for allocation, similar to the standards of the Eurotransplant Kidney Allocation System. There was no upper or lower age limit to accept the deceased donor kidney. Kidneys were allocated to dual or single allograft according to pretransplant biopsy for expanded criteria donors. Immunological compatibility was documented by negative complement-dependent cytotoxicity assay for lymphocyte crossmatch in all recipients; we also performed additional flow crossmatch with and without panel-reactive antibody and Luminex donor-specific antibody (2007 onwards) in retransplant and sensitized recipients.
Induction immunosuppressive therapy consisted of methylprednisolone (500 mg/d for 3-5 days) and an intraoperative single dose of rabbit thymoglobulin (1-2 mg/kg; Genzyme). We used 20 mg basiliximab (Simulect, Novartis Pharma) both during kidney transplant surgery and on day 4 after surgery, in case of contraindication to thymoglobulin such as uncontrolled diabetes, low platelet/white cell count, or recent tuberculosis or other infections (hepatitis C virus). The lower dose of rabbit thymoglobulin was used in an attempt to mitigate the known risk factor for death with functioning kidney allograft, which is a common cause of recipient loss in developing countries such as India, where the population is susceptible to endemic infections.
The maintenance immunosuppressive regimen consisted of prednisolone (20 mg/d, tapered to 10 mg/d at 3 months posttransplant, then 5-10 mg/d continued thereafter), a calcineurin inhibitor (cyclosporine [3-5 mg/kg/d] or tacrolimus [0.06-0.08 mg/kg/d]), and mycophenolate mofetil (1.5-2 g/d) or azathioprine (1-2 mg/kg/d). The doses of azathioprine and mycophenolate were adjusted according to complete blood counts. The calcineurin inhibitor doses were adjusted according to the serum trough levels (C0), measured by fluorescence polarization immunoassay technology during the first 3 months; thereafter, adjustments were made only in cases of increased creatinine or changes in drug dosage. Regular routine monitoring could not be performed because of financial constraints. Cyclosporine was used until 2005. Thereafter, tacrolimus was used in the majority of patients, and dosing was adjusted to achieve the target C0 concentration of 10 to 12 ng/mL during the first 3 months posttransplant, 8 to 10 ng/mL at 3 to 12 months posttransplant, and 4 to 8 ng/mL thereafter. All patients received prophylaxis against cytomegalovirus (valganciclovir, 450 mg/d), fungal infection (fluconazole, 100 mg/d for 3 months), and Pneumocystis jirovecii pneumonia (sulfamethoxazole and trimethoprim, 960 mg/d for 1 year). Graft biopsy was performed in cases of acute graft dysfunction to evaluate possible rejection and other causes.
Cost of transplant
We are a public sector transplant hospital. Transplantation and follow-up treatment are free to all children in the Gujarat Government School Health program and also free to all patients with income below the poverty line, patients from scheduled casts and tribes, and farmers. For all other patients, subsidized treatment is provided free, as required. The cost of kidney transplant is USD 5000, and liver transplant is USD 10 000 to 15 000. The generic maintenance immunosuppressive drugs for public sector hospital are around 50% cheaper than for private sector transplant hospitals in India.
Figure 1 shows total numbers of actual deceased organ donors in India from 2010 to 2018.1 Figures 2 and 3 show data for DDKT and LDKT reported by the IKDRC-ITS, Ahmedabad, India, from January 1, 1997 to March 15, 2020. Table 1 shows IKDRC-ITS transplant data from January 1, 1997 to March 15, 2020. Table 2 shows DDKT outcome data reported by the IKDRC-ITS, Ahmedabad, India from January 1, 1997 to December 31, 2018.
Dr. H. L. Trivedi, founder-director of our institute, performed the first successful living donor kidney transplant (LDKT) in 1984 and the first successful DDKT from donation after cardiac death (DCD) on October 4, 1987. Between January 1, 1997 and March 15, 2020, a total of 5838 kidney transplants were completed, including 4895 LDKT, 943 DDKT, and 440 living donor kidney paired donation transplants. From January 1, 2008 to March 15, 2020, Dr. Pranjal Modi, head of transplant surgery, performed 361 deceased donor liver transplants (DDLT) at our transplant institute. Mean recipient age was 38 ± 14 years (range, 7-76 years); 564 were male, and 267 were female. Mean donor age was 45.3 ± 17.13 years (range, 1-89 years); 565 recipients were male, and 266 were female. A majority of the donors were those with brain death due to cerebrovascular accidents, comorbid conditions such as hypertension and/or diabetes, and road traffic accidents. The most common diseases that may lead to end-stage kidney disease in recipients were chronic glomerulonephritis (24%), diabetes (16%), hypertension (16%), end-stage kidney disease of unknown etiology (12%), autosomal-dependent polycystic kidney disease (5.9%), glomerular diseases (5%), obstructive uropathy (5%), single unit kidney (4%), retransplant (4%), and other causes. There were 120 deceased donor recipients from states other than Gujarat. With a mean follow-up time of 8 ± 5.4 years, patient survival was 70% (n = 581), and death-censored graft survival rate was 84% (n = 698). There was delayed graft function in 25% of patients (n = 210) and biopsy-proven acute rejection in 21% of patients (n = 180). Other biopsy findings indicated acute calcineurin inhibitor toxicity in 6% of patients and acute tubular necrosis in 20% of patients (n = 170). In 2014, Dr. Jamal Rizvi performed the first successful simultaneous combined pancreas-kidney transplant in a patient with end-stage kidney disease due to type 1 diabetes, and Dr. Rizvi has completed a total of 8 simultaneous combined pancreas-kidney transplants to date.
We have expanded our donor pool through our experience with favorable DDKT outcomes, including expanded criteria donation to younger recipients, older donor transplant to older recipients, controlled DCD, intercity organ retrieval, dual-kidney transplant, en bloc transplant of pediatric deceased donor, and brain death deceased donors who died from neurotoxic snakebite, recurrent primary brain tumor, bacterial meningitis, or head injury, or disseminated intravascular coagulation and deranged renal functions.
Deceased donor kidney transplant outcome data from the Institute of Kidney
Diseases and Research Center, Dr. H. L. Trivedi Institute of Transplantation
We have previously reported our DDKT outcome data.3-23 We report DDKT outcomes in 294 patients (age, 36.5 ± 14.1 years; male:female ratio, 200:94) between 2005 and 2012. With a mean follow-up time of 3.93 years, patient and graft survival rates were 81.7% and 92.6%, respectively, with a median serum creatinine of 1.5 mg/dL and a biopsy-proven acute rejection rate of 20.7%.3 We reported DDKT outcomes of DCD donors ≥ 70 years old (group 1; n = 14; mean age, 75.7 ± 5.81 years) versus DCD donors < 70 years old (group 2; n = 19; mean age, 51.7 ± 10.1 years) between January 1999 and January 2012. With a mean follow-up time of 3.21 ± 3.46 years, the 1-, 5-, and 10-year patient survival rates were 77%, 67.4%, and 67.4%, respectively; death-censored graft survival rates were 85.7% each for 1, 5, and 10 years. Rates for patient survival (P = .27), graft survival (P = .20), delayed graft function (P = .51), and biopsy-proven acute rejection (P = .74) were similar in 2 groups.4 Twenty DDKT were performed at our center using grafts from older deceased donors ≥ 70 years old between June 2004 and September 2011. Kidneys were allocated to dual or single allograft according to the results from pretransplant biopsy.5 Mean age of recipients was 47.60 years, 13 of whom were male. Mean age was 76.4 years for donors, 10 of whom were male. With a mean follow-up time of 2.8 ± 1.7 years, patient and graft survival rates were 75% (n = 15) and 80% (n = 16), respectively, with a mean serum creatinine of 1.78 ± 0.56 mg/dL and a rate of biopsy-proven acute rejection episodes of 20%. Deceased donor kidney transplants from older donors achieved acceptable rates of patient/graft survival, provided that organs were allocated to dual or single allograft in accordance with the results of the pretransplant biopsy. Forty-three expanded criteria donor transplants among 158 total DDKT procedures were performed between January 2006 and December 2009.12 Deceased donor kidney transplant of expanded criteria donor organs for younger recipients is a feasible option with acceptable outcomes.6,12 In our experience, we have had favorable DDKT outcomes from various cases, including a brain death deceased donor who died from neurotoxic snakebite,7 a donor with recurrent primary brain tumor,8 a deceased donor who died of bacterial meningitis,9 a brain death deceased donor with head injury and disseminated intravascular coagulation and deranged renal functions,10 en bloc transplant of a pediatric deceased donor,11 and expanded criteria donors for younger recipients.12 Older donor transplants to older recipients and controlled DCD kidney transplants may expand the donor pool. Intercity organ retrieval is a viable option by which to increase the donor pool.13 Long-distance transport of procured organs may increase cold ischemia times, but good recipient outcomes are possible if appropriate protocols for procurement and preservation are applied with rigor. At our center, we have observed acceptable long-term survival of patients and grafts after DDKT in patients with diabetic nephropathy14 or autosomal dominant polycystic kidney disease,15 in patients with Alport syndrome, and in pediatric recipients; therefore, we believe DDKT should be encouraged. Laparoscopic DDKT that is performed via vaginal insertion (n = 4) is technically feasible and safe in a selected group of patients.16 Long-term outcomes should be evaluated in a larger study. Dual-kidney transplant from expanded criteria brain death donors has shown better graft and patient survival than from DCD donors.20 Organs were successfully transplanted from posttransplant patients who developed brain death with functioning kidney allograft.21 There is a paucity of information and awareness regarding organ donation among patients with chronic kidney disease and the general population. Mass media and religious and political leaders may be a key factor in future attempts to raise the level of social awareness with regard to organ donation.22,23 Overall, our DDKT outcome is similar to that of other centers in India.24-31
Transplantation of Human Organs Act, India, and deceased donor organ
Human organ and tissue transplantation was started in India in 1962. Initially, organ transplantation was unregulated, and organ trafficking was rampant. The Transplantation of Human Organs Act, India (THOA) was passed in 1994 to regulate the removal, storage, and transplant of human organs for therapeutic purposes and to prevent commercial dealing in human organs.32,33 Public health is a state level responsibility in India, and the THOA of 1994 was adopted by Gujarat to enable a DDOT program at IKDRC-ITS in Ahmedabad in July 1997. The 1994 version of THOA was subsequently amended in 2011, and these new rules became effective in 2014.
Form No. 7 of the THOA is related to organ or tissue pledging for members of the general population in their lifetimes. If the donor has pledged organs before death, then there is an additional requirement of consent from a close relative or person in lawful possession of the body. Form No. 8 is a declaration and consent form to be certified by a close relative (or other person in lawful possession of the dead body); this form must be accompanied by an address for correspondence and signatures of 2 witnesses. Form No. 10 is for certification of brainstem death, which requires signatures from a group of 4 doctors comprising (1) a registered medical practitioner(s) who is in charge of the hospital in which the death occurred, (2) a registered medical practitioner(s) nominated from a panel of names sent by the hospitals and approved by the appropriate authority, (3) a neurologist /neurosurgeon, and (4) a registered medical practitioner(s) who had treated the aforementioned person before death. In the recent 2014 rules, apart from a neurologist or neurosurgeon, there is a provision to allow the patient’s anesthetists, critical care specialists, intensivists, physicians, or surgeons as eligible participants in the approval process, to better facilitate the rapid completion of the brain death declaration.
Challenges and solution for deceased donor organ transplant in Gujarat
Our challenges for DDOT in the initial period (1997-2006) included lack of public education with regard to deceased donation and transplant; limited knowledge by the medical community with regard to the concept of brain death and the legality of organ donation; lack of potential deceased donor management skills, family communication, and grief counselling; lack of dedicated transplant teams and organ procurement organizations; delayed declaration of brain death and subsequent loss of patients; lack of medical training with regard to proper methods to maintain viability of organs in a brain death patient; lack of surgical training with regard to organ procurement, preservation, transport, and transplant; difficulties in the process for transfer of a brain death organ donor from one facility to a certified transplant center; most donors were expanded criteria brain death deceased donors in unstable condition; Ringer lactate was the only perfusion fluid available; delays in procurement of organs and related complications; limited availability of induction agents; and high risk for sepsis-related perioperative morbidity and mortality. We initiated mass education (conferences, workshops, and seminars) for the general population in Gujarat, we trained transplant teams on the process of organ donation, and we encouraged involvement of religious persons, public recognition of donor families, and involvement of the government, bolstered by positive media support. We successfully established local programs for procurement of deceased donor organs in local hospitals, as well as training procurement teams to facilitate successful transfer of potential deceased donors, if the opportunity arises, to our transplant centers in a manner suitable to local conditions. The government provided financial support for histidine-tryptophan-ketoglutarate (Custodiol) solution and transplants for patients in need of financial assistance. We used the green corridor method with our intercity DDOT program to facilitate rapid transport (including airlifts, if possible) of organs or potential deceased donors to our transplant centers to reduce cold ischemia times. Donate Life, a nonprofit, nongovernment organization in Surat, supported our DDOT program along with other nongovernment organizations from Rajkot and Bhavnagar, which served to raise awareness in the general population and among intensive care unit doctors. As a result of the support of these dedicated nongovernment organizations, we have received the majority of our organ donations from Surat, a city 400 km from our transplant center.
Our transplant team was trained by Dr. Carl Groth and Dr. Bo Goran Ericzon at Karolinska Institute, Sweden, in 2006 for establishment of a liver transplant program throughout Gujarat to improve success rates of organ donation after brain death. Our liver transplant center was inaugurated by Dr. Carl Groth on December 1, 2007. Dr. Pranjal Modi performed the first successful DDLT in Gujarat in 2008. The cost of DDLT in our transplant hospital is USD 10 000 to 15 000, much less than the cost of USD 30 000 to 50 000 in private sector facilities in India. The first successful combined deceased donor kidney-pancreas transplant for patient with type 1 diabetes and end-stage kidney disease was performed in 2014 by Dr. Jamal Rizvi, who was trained at Oxford University.
We acknowledge and promote international mentorship. Dr. H. L. Trivedi, founder and director of our institution, has established a yearly transplantation congress at IKDRC-ITS, Ahmedabad. We receive ongoing guidance for the future of our transplant program from Dr. Carl Groth, Rolf Martin Zinkernagel, Sir Roy Calne, Dr. Paul Terasaki, Dr. Kathryn Wood, Dr. Manikkam Suthanthiran, Dr. Alvin Roth, Dr. Marcelo Cantarovich, Dr. Michael Rees and other members of the international leadership.
Establishment of Gujarat University of Transplantation Sciences
The IKDRC-ITS, Ahmedabad, is the only public sector transplant hospital in Gujarat and the largest in India, with 400 beds for care of patients with kidney failure. Established in 2015 under the State University Act, the Gujarat University of Transplantation Sciences is the first University for Transplantation and Allied Sciences in the world. The Gujarat University of Transplantation Sciences received enthusiastic support from the Honorable Chief Minister of Gujarat, Smt. Anandiben Patel, and the H. E. Governor of Gujarat, Shri O. P. Kohliji. The Gujarat government has pledged support for a new 600-bed transplant facility, for 2020, to expand our transplant services. We also received the status of State Organ and Tissue Transplant Organization (SOTTO) in Gujarat in January 2019, to expand our DDOT program.
Gujarat State Organ and Tissue Transplant Organization plan of action to expand
deceased donor organ transplant programs
We planned to post grief counsellors in intensive care unit and emergency areas, along with mandatory grief counselling, as well as reporting to the Gujarat SOTTO of potential deceased donors with Glasgow Coma scale/score ≤ 5. This plan passed government order for mandatory declaration of brain death in all patients and not just for cases of organ donation. We are focused on providing integrated support for organ donation from the specialties of neurosurgery, critical care, and anesthesia; our plan includes frequent and regular workshops with regard to brain death certification, to educate stakeholders, transplant coordinators, and intensive care unit doctors, with a special focus on the proper methods for maintenance of deceased donors for multi-organ procurement (how to do it right the first time and every time), which is the guiding principle of organ allocation and organ-sharing networks. We have planned a professional education family donation conversation program to increase organ donation rates; this program includes introductory donation awareness training, as well as core, practical, and E-learning family donation conversation workshops. We established a process for felicitation ceremonies for organ donor families, hosted by Government authorities and religious leaders, such as a ceremony to plant a tree in memory of a deceased donor, which is an environmentally friendly initiative. Expert committees and standard operating protocols have been initiated for use of expanded criteria donors and DCD programs, as well as international collaboration for exchange of knowledge and ideas. We have planned hospital-to-government and local-to-global policies to further expand DDOT programs in Gujarat.
There is potential for a DCD organ transplant program expansion at IKDRC-ITS. Further research and work is required to improve the present DDOT program, including establishment of best practices for the use of machine perfusion to facilitate improved viability of marginal organs. A program for abdominal organ transplantation from deceased donors is in progress at IKDRC-ITS. The Gujarat SOTTO is the first state organization in India to establish a living and deceased donor list exchange program.19
The first DDKT from a brain death deceased donor occurred in 1997 at our transplant hospital. After merely a decade of kidney transplantation, liver and pancreas transplantation became a reality in 2008. Establishment of the Gujarat University of Transplantation Sciences has fostered new opportunities for development of transplantation sciences. The patient and graft survival rates for DDOT are acceptable in our transplant hospital, which should encourage the growth of the existing DDOT program.
Volume : 18
Issue : 5
Pages : 549 - 556
DOI : 10.6002/ect.2020.0318
From the 1Department of Nephrology and Clinical Transplantation, Institute of
Kidney Diseases and Research Center, Dr. H. L. Trivedi Institute of
Transplantation Sciences, Ahmedabad, India; the 2Department of Urology and
Transplantation, Institute of Kidney Diseases and Research Center, Dr. H. L.
Trivedi Institute of Transplantation Sciences, Ahmedabad, India; the 3Department
of Anesthesia, Institute of Kidney Diseases and Research Center, Dr. H. L.
Trivedi Institute of Transplantation Sciences, Ahmedabad, India; the 4Department
of Radiology, Institute of Kidney Diseases and Research Center, Dr. H. L.
Trivedi Institute of Transplantation Sciences, Ahmedabad, India; and the
5Institute of Kidney Diseases and Research Center, Dr. H. L. Trivedi Institute
of Transplantation Sciences, Ahmedabad, India
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential interest.
Corresponding author: Vivek B. Kute, Department of Nephrology and Transplantation, Institute of Kidney Diseases and Research Center, Dr. H. L. Trivedi Institute of Transplantation Sciences, Ahmedabad, India
Phone: +91 90 9992 7543
Figure 1. Total Numbers of Actual Deceased Organ Donors in India: 2010-2018
Figure 2. Institute of Kidney Diseases and Research Center, Dr. H. L. Trivedi Institute of Transplantation Sciences, Ahmedabad, India: Deceased Donor Kidney Transplants From January 1, 1997 to March 15, 2020
Figure 3. Institute of Kidney Diseases and Research Center, Dr. H. L. Trivedi Institute of Transplantation Sciences, Ahmedabad, India: Living Donor Kidney Transplants From January 1, 1997 to March 15, 2020
Table 1. Institute of Kidney Diseases and Research Center, Dr. H. L. Trivedi Institute of Transplantation Sciences, Ahmedabad, India: Transplant Data From January 1, 1997 to March 15, 2020
Table 2. Institute of Kidney Diseases and Research Center, Dr. H. L. Trivedi Institute of Transplantation Sciences, Ahmedabad, India: Deceased Donor Kidney Transplant Outcomes From January 1, 1997 to December 31, 2018