EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: This study reports our experience of the first 4-way kidney exchange transplant combined with desensitization in India, which allows increased access to living-donor kidney transplant for sensitized patients.

Materials and Methods: Four-way kidney exchange transplant procedures were approved by the ethics committee of our institution and the Organ Transplantation Authorization Committee of state governments of India (as per the Transplantation of Human Organs Act of India). The protocols conformed to Declaration of Istanbul principles and the ethical guidelines of the 1975 Helsinki Declaration. Written informed consent was obtained from patients, donors, and their guardians.

Results: In April 2016, our transplant team completed simultaneous 4-way kidney exchange transplant pro-cedures without any medical (rejection and infections) or surgical complications. Reasons for being included for kidney exchange transplant were ABO incom-patible (2 recipients) and sensitization (2 recipients). All 4 recipients had stable graft function with no proteinuria and donor-specific antibody at 11-month follow-up on standard triple immunosup-pression. Patient and graft survival rates were both 100%.

Conclusions: To the best of our knowledge, this is the first single-center report of 4-way kidney exchange transplant combined with desensitization from India. This procedure has the potential to expand living-donor kidney transplant in disadvantaged groups (eg, sensitized patients). Recipients who are hard to match due to high panel reactive antibody and difficult to desensitize due to strong donor-specific antibodies can receive a transplant with a combination of kidney exchange and desensitization. Our study suggests that 4-way kidney exchange transplant can be performed in developing countries (India) similar to that shown in programs in developed countries with team work, kidney exchange registry, and counseling.

Key words : ABO incompatible, Blood group incompatibility, Kidney transplantation, Living donor, Paired exchange, Sensitized patients

Kidney exchange (KE) is well established in the developed world but is now being slowly expanded in developing countries such as India.^1-7 Traditional 2-way KE, which is the most commonly performed KE (> 80%) in Indian KE transplant programs, has inherent limitations for quality and quantity of matching, mainly in disadvantaged groups like sensitized and O blood group patients. Kidney transplant options for sensitized patients include the use of a compatible donor recipient pair (DRP) or longer KE donor chains, acceptable mismatch KE, international KE, KE combined with desensitization or ABO-incompatible transplant (ABOiKT), living-to deceased-donor exchange, and deceased-donor kidney transplant (DDKT). The optimal donor chain length for KE programs is 3 in the developed world8; however, this is not clear for developing countries like India. Longer KE donor chains with their inherent logistic and regulatory burdens do not lead to significantly more transplant procedures.

Here, we report our experience of the first 4-way KE transplant combined with desensitization in India. The simultaneous surgeries involving 4 living donors and 4 recipients were made possible by a nationally recognized single-center KE program (Institute of Kidney Diseases and Research Center and Dr. H. L. Trivedi Institute of Transplantation Sciences [IKDRC-ITS], Ahmedabad, India).

Materials and Methods

The 4-way KE transplant was approved by the ethics committee of our institution and by the organ transplantation authorization committee of the state governments of India as per the Transplantation of Human Organs Act, India. The protocols conformed to Declaration of Istanbul principles and the ethical guidelines of the 1975 Helsinki Declaration. Written informed consent was obtained from patients, donors, and their guardians before study enrollment. The study was reviewed and approved by the Science and Research Office of IKDRC-ITS (Ahmedabad, India).

Kidney exchange allocation
Donor recipient pairs were counseled on available transplant options (KE vs desensitization vs ABOiKT vs DDKT vs combined modality) by the dedicated transplant team. Explanations on advantages and disadvantages of the available transplant options were provided. Patients were also informed that unequal outcomes after KE transplant can occur due to patient-related factors (eg, infections or comorbid conditions, heart disease), and we attempted to prevent unequal outcomes from donor-related factors. Once the incompatible pairs gave written informed consent for KE, they were registered in the KE database with no additional fees or admin-istrative charges.^1-5

All 4 DRPs underwent uniform pretransplant evaluation and posttransplant medical care with the help of standardized HLA and pathology laboratory and a dedicated transplant team. The medical fitness of the 4 DRPs was assessed by the transplant team, which consisted of experts from nephrology, urology, anesthesia, gynecology, and psychiatry departments. This complete work-up of pairs before allocation avoided chain collapse. Immunologic compatibility was documented by negative donor-specific antibody (DSA) using single antigen beads, flow crossmatch (FCM), and lymphocyte crossmatch. The 4 DRP candidates were allowed to meet each other before and after living-donor kidney transplant (LDKT). They were also told that the team attempted to exchange kidneys of similar quality and that transplant surgeries would be done simultaneously to avoid risk of donor reneging. Manual allocation was performed by a nephrologist under supervision of the organ transplant authorization committee of the institute, ensuring equitable allocation. The monthly income of the 4 DRP candidates was < 200 US dollars, and the economic status of recipient 1 was below the poverty line, resulting in free medical treatment from the Gujarat government. The other 3 DRP candidates received 50% of the cost of transplant paid by the Indian government, with the remaining 50% paid by the patient. All donors were near family members, and there was no direct or indirect economic compensation for kidney donation. Figure 1 shows the variables considered in the 4-way KE.

Recipient 1
Recipient 1 was a highly sensitized patient, and his mother was his kidney donor due to blood trans-fusions on hemodialysis. Lymphocyte crossmatch, dithiothreitol, and anti-human globulin-enhanced, complement-dependent cytotoxicity crossmatches with mother as donor was 80%/80%/90% (normal range ≤ 20%) and T- and B-cell FCM were 110 and 108 median channel shift (MCS) (normal range < 100). Class 1 and 2 panel reactive antibody (PRA) test was 80%. Donor-specific antibodies were A2 = 10971, Bw6 = 7000, and DQ2 = 2100 mean fluorescence intensity (MFI). He was also enrolled in the DDKT wait list due to high PRA. His immunologic profile was persistently positive and remained unacceptable for kidney transplant even after administration of desensitization therapy (2 mg intravenous borte-zomib + 125 mg intravenous methyl prednisolone on days 1, 4, 8, and 11 along with daily 0.05 mg/kg tacrolimus + 1 g mycophenolate mofetil and 4 sessions of therapeutic plasma exchange) with his mother, 5 deceased donors, and more than 20 KE donors. His lymphocyte crossmatch and FCM were negative and acceptable with the KE donor (donor 4), and DSA results were positive (B35 = 9000 and B58 = 2000). Therefore, we decided to go ahead with a combination of KE and desensitization therapy with KE donor (Figure 1). Lymphocyte crossmatch and FCM were negative, and DSA was acceptable at < 2000 MFI with the KE donor after the above-described desensitization therapy.

Recipient 2
Recipient 2 was sensitized with his mother as a kidney donor due to blood transfusions on hemodialysis. Lymphocyte crossmatch, dithiothreitol, and anti-human globulin-enhanced, complement-dependent cytotoxicity crossmatches with mother as donor was 15%/15%/20%; T- and B-cell FCM were 150 and 258 MCS. Result of class 1 and 2 PRA test was 40%. Donor-specific antibody results were DQ2 = 12 000 and DR53 = 11 000 MFI. His immunologic profile was persistently positive and remained unacceptable (positive FCM > 300 MCS and class 2 DSA > 10 000 MFI) for kidney transplant even after administration of desensitization therapy (2 mg intravenous bortezomib + 125 mg intravenous methylpred-nisolone on days 1, 4, 8, and 11 along with daily 0.05 mg/kg tacrolimus + 1 g mycophenolate mofetil, and therapeutic plasma exchange) with his mother and more than 10 KE donors. He was detected to be positive for hepatitis B virus (HBV) and hepatitis C virus (HCV) by an enzyme-linked immunosorbent assay. Therefore, further desensitization therapy was avoided. His HBV DNA and HCV RNA viral loads by polymerase chain reaction were negative after oral antiviral therapy and before KE. His lymphocyte crossmatch, FCM, and DSA were negative and acceptable with the KE donor (number 1).

Recipients 3 and 4
Recipients 3 and 4 were ABO incompatible and had high ABO titers with their family donors. In our transplant unit, ABOiKT is avoided when the ABO titer is > 256. After various transplant options were discussed with these patients, ABOiKT was avoided due to economic reasons and pretransplant history of tuberculosis and bacterial pneumonias in recipients 3 and 4, respectively.

From January 2000 to July 2016, a total of 3616 kidney transplants were performed at our institution including 300 KE and 561 DDKT. Of the KE procedures, 248 patients had 2-way (n = 124), 42 had 3-way (n = 14), 4 had 4-way (n = 1), and 6 patients had 6-way exchanges (n = 1). This was the first 4-way KE + desensitization performed in our transplant center and in India. Table 1 shows patient demog-raphics, and Table 2 shows HLA data in the 4 DRP candidates.

Mean age of the 4 recipients (3 male and 1 female patient) and 4 female donors was 31 and 51 years, respectively. The group included 3 sets of mother-child pairs and a married couple. All donors were of similar ages and exchanged kidneys of similar quality (creatinine, glomerular filtration rate by diethylenetriaminepentaacetic acid renal scan, and single renal vessel in the donor kidney). Two of the DRP candidates were ABO incompatible and 2 were sensitized. The 2 sensitized recipients failed to respond to the desensitization protocol. We required 2 months to obtain legal permission from 3 state governments as the 4 DRP candidates were from different states. The transplant team and family members actively supported the 4 DRPs to complete the legal permission process from the 3 states, as required by the Transplant of Human Organs Act.

In April 2016, 4 transplant surgeons and 4 assistant transplant surgeons at our hospital com-pleted the 4-way KE transplant involving 4 DRPs from 3 Indian states without any medical (rejection and infections) or surgical complications (Figure 1). The surgeries were done simultaneously over a 10-hour period. All 4 recipients had stable graft function with no proteinuria and DSA at 11-month follow-up on standard triple immunosuppression (tacrolimus + mycophenolate mofetil + prednisolone). Patient and graft survival rates were both 100%. Table 1shows the surgical details and outcomes. Donor-specific antibodies were monitored weekly for 4 weeks and monthly for 3 months. Cytomegalovirus DNA and BK polyomavirus DNA were monitored monthly for 6 months after LDKT in both of the sensitized recipients. Cytomegalovirus DNA, BK polyomavirus DNA, and DSA were found to be negative on routine monitoring after LDKT.

Our team also performed the first nonsimul-taneous 4-way KE transplant procedure (3 ABO incompatible and 1 sensitized DRP) on 2 days in April 2017 after consent of the 4 DRPs and the organ transplant authorization committee of the institute.

The transplant team at IKDRC-ITS (Ahmedabad, India) is being hailed for setting yet another milestone by performing the first 4-way KE transplant in combination with desensitization protocol in India.¹This 4-way KE shows the team work and high level of cooperation of people from 3 different states involved in performing such an extensive procedure and how KE can benefit the 4 lives involved in the procedure. Four lives were saved as a result of this 4-way KE. The dedicated transplant team who made this simultaneous 4-way KE transplant possible included transplant physicians, surgeons, anesthetics, pathologist, HLA laboratory experts/technicians, transplant coordinators, operating room staff, medical and paramedical staff, critical care specialists, social workers, psychologists, and pharmacists, as well as government support for legal permission and economic support and administrative support personnel. All of the recipients and donors had healthy and positive outcomes.

A 4-way KE shortens the wait time for LDKT and reduces wait times for other patients on DDKT wait lists. In our patient group, a compatible LDKT was not possible for the highly sensitized recipient 1 other than combination of KE and desensitization. We have previously reported 2-way and 3-way KE combined with desensitization protocols to increase access to LDKT for sensitized recipients.^9,10

Recipient 1 was highly sensitized and unlikely to undergo LDKT with KE alone. He was able to undergo LDKT with a combination of KE and desensitization therapy. Thymoglobulin-based induction and triple immunosuppression therapy (tacrolimus + mycophenolate + steroid) were able to control acute immune injury. Better HLA matching could improve long-term graft survival. Recipient 1 had full class 2 HLA matching with the donor, which would contribute to protection from chronic immune injury. Recipient 2 was HBV and HCV positive; therefore, aggressive desensitization therapy could lead to reactivation of virus after transplant.

Challenges for long-chain KE are the logistic and regulatory burdens; therefore, computer allocation should be encouraged over manual allocation for better quality and quantity of matching. Other challenges are having patients remaining fit for surgery and the need for an adequate surgical team for simultaneous surgery. When DRP candidates are from different states, more time is required to complete the legal permissions. If 1 patient in a long chain dies while waiting for the legal permission from different states to be completed, the entire KE chain will collapse. If 1 DRP candidate becomes medically unfit for transplant, then the entire chain needs to be postponed for simultaneous surgery. There is risk of donor renege in nonsimultaneous surgery. Multicenter simultaneous surgeries will solve the issue of a small surgical team in long-chain procedures.

What is the optimal chain length for living-donor KE transplant programs in India? It should be decided by the donor pool and the legal and regulatory logistics. Of the 300 KE transplants performed at our center, 83% (248 patients) underwent 2-way KE mainly to keep logistics simple. Longer chains should be utilized to increase transplant options for difficult to match DRP candidates like sensitized patients. In our study, 4-way KE was performed to increase the LDKT option for 2 sensitized patients and to improve quality and quantity of matching. We used 4-way KE after performing 124 two-way exchanges and 14 three-way exchanges. Therefore, we were able to overcome the logistics of a longer chain KE.

Compatible pairs increase transplant rates when the donor pool is small.^11,12 Larger donor pools and heterogeneity in antigen-antibody profiles in national or international KE programs will increase the transplant rate for sensitized patients.

Living-donor kidney transplant is recommended over DDKT. Living-donor KE should be encouraged over ABOiKT in resource-limited countries. Kidney exchange should be preferred over desensitization in sensitized patients. Deceased-donor kidney trans-plant can be made available for patients with family members who are medically unfit for kidney donation. There is a need for Indian guidelines for incompatible pairs. This guideline should focus on cost, long-term survival, availability of therapy, and local resource limitations.

To the best of our knowledge, this is the first report of single center 4-way KE transplant combined with desensitization from India, which has the potential to expand LDKT in disadvantaged groups (sensitized patients). Recipients who are hard to match in KE due to high PRA and difficult to desensitize due to strong DSA can be transplanted with a combination of KE and desensitization. Our study suggests that 4-way KE can be performed in a developing country (India) similar to that shown in KE programs in developed countries with team work, KE registry, and counseling.

Volume: 16 Issue: 5 October 2018

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