Transplantation Reports 4 (2019) 100026
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Transplantation Reports
journal homepage: www.elsevier.com/locate/tpr
Experience of starting ABO incompatible renal transplant in Nepal
Rabin Nepali , Dibya Singh Shah
⁎
Department of Nephrology, Tribhuvan University Teaching Hospital, Kathmandu, Nepal
1. Introduction
Renal transplantation is the treatment of choice for end stage renal
disease. However, the number of end stage renal disease patients are
increasing year by year while the number of kidney donors are static.
An estimated figure shows that about 3000 people develop kidney
failure every year in Nepal. But only around 5% of the patients are
undergoing renal transplant each year. This problem is aggravated by
the strictly related live donor program in Nepal. Deceased donor pro-
gram is not yet established in Nepal. So, the demand for suitable donor
is increasing year by year.
The options to expand the donor pool in living donor programs are the
following: 1) ABO- incompatible (ABOi) renal transplantation; (2) paired
donor exchange program; and (3) desensitizing highly sensitized patients.
Solid organ transplantation has traditionally been governed by the
rules of blood group compatibility. If not matched properly, the circu-
lating anti-A and/or anti-B blood group antibodies of the recipient will
bind to the antigenic moieties of the cell surface-bound A and B blood
group molecules within the kidney transplant [1]. The antibodies at-
tached will activate the complement system leading to local cell da-
mage and eventually cell and organ destruction [2]. Therefore, ABOi
renal transplantation carries a high risk for acute and irreversible an-
tibody mediated rejection and cannot be performed without pretreat-
ment of the recipient [3]. In the last 2 decades, ABOi transplantation
protocols have evolved to remove specific isoagglutinin without the
need for splenectomy, reduce production of isoagglutinins, and mod-
ulate immune response [4]. Moreover, studies have shown similar short
and long term graft and patient survival in ABOi renal transplant
compared to ABO compatible transplant [5]. So, ABOi renal trans-
plantation has evolved as a viable alternative.
Although worldwide popularity of ABOi renal transplant is in-
creasing, experience from developing world is limited. Major obstacles
are high costcompared to ABO compatible renal transplantation, in-
creased risk of antibody-mediated rejection and post-transplant infec-
tions. We started the first ABOi living donor program in Nepal on March
22nd, 2017. We hereby present the experience of starting ABOi renal
transplant at our center, a tertiary care center in Nepal.
Abbreviations: ABOi-, ABO- incompatible renal transplantation; ATG-, anti-thymocyte globulin; CDC-, complement dependent cytotoxicity; FFP-, Fresh frozen
plasma; IA-, immunoadsorption; IVIG-, Intravenous immunoglobulin; MMF-, mycophenolate mofetil; PE-, Plasma exchange
⁎
Corresponding author.
E-mail address: rabinnepali@gmail.com (R. Nepali).
https://doi.org/10.1016/j.tpr.2019.100026
Received 11 January 2019; Accepted 10 April 2019
Available online 15 April 2019
2451-9596/ © 2019 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
T
2. Materials and methods
This is a single center retrospective analysis of consecutive renal
transplants from March 22nd,2017 till October 26th, 2018. A total of 9
ABOi renal transplant were done. Written informed consent was ob-
tained from all the patients. All ABOi kidney donor-recipients were
evaluated for ABOi transplantation after routine pretransplantation
screening.
2.1. Pretransplantation desensitizing protocol
Rituximab was administered on day −14 for all the patients. Doses
varied from 375 mg/m2 to 200 mg/m2. (Table 2)
Antibody Depletion: Isoagglutinin removal was done by repeated
sessions of plasmapheresis. The plasmapheresis sessions were de-
termined by serial measurement of antibodies before and after the
procedure. Plasma exchange (PE) volume was 30 mL/kg body weight
and the replacement fluid used was 5% human albumin and fresh
frozen plasma (FFP). FFP of the donor blood group was used. For high
antibody titre, immunoadsorption (IA) was done using Glycosorb col-
umns. Apheresis or immunoadsorption was done till the target iso-
agglutinin level was reached. A titer of <= 1:8 was considered ac-
ceptable for transplantation. Isoagglutinin Measurement was done by
using gel card method. Intravenous immunoglobulin (IVIG; 100 mg/kg)
was administered after each apheresis session.
Induction: Basiliximab 20 mg on day 0 and day 4 were given for first
3 and 7th patient and anti- thymocyte globulin (ATG) at a total dose of
1 mg/kg body weight in on day 0 and day 1 post- transplantation for
remaining patients. Methyl prednisolone (500 mg) was given on day 0
to all the patients.
Maintenance Immunosuppression: Tacrolimus (0.1 mg/kg/day) and
mycophenolate mofetil (1 g per day in divided dose) was started at day
−11. Mycophenolate mofetil was increased to 2 g per day in divided
dose for 1 week after transplantation, then continued at 1500 mg per
day in divided dose. Prednisolone was started at day 1 from 20 mg per
day for 1 month. Then it was slowly tapered by 2.5 mg per week till a
maintenance dose of 5 mg/d was reached. Triple immunosuppression
R. Nepali and D.S. Shah Transplantation Reports 4 (2019) 100026

Fig. 1. Overview for desensitization protocol for ABO-incompatible (ABOi) renal transplantation.

Table 1
Clinical and demographic characteristics of patients.
Patient number Age Gender Blood Group Donor relation HLA mismatch Native kidney disease Donor DTPA GFR (ml/min) Previous Transplants
D R D R D R

1 51 25 M F A O Father 2/6 CGN 80.2 0

2 45 20 M F A O Father 3/6 CGN 91.1 0
3 36 15 F F AB B Mother 2/6 CGN 81.9 0
4 34 39 F M AB A Wife 6/6 CGN 85.7 0
5 38 21 F M A O Mother 3/6 CGN 85.3 0
6 57 35 F F A O Mother 2/6 CGN 69.6 0
7 50 32 F M A O Mother 3/6 CGN 74.1 0
8 59 33 M M A O Father 3/6 CGN 78.7 0
9 41 45 F M AB B Wife 6/6 DM 84.0 0

Table 2
Desensitizing protocol and Outcome of the patients.
Patient Induction agent Dose of Titer, Titer, PreTx PE PostTx PE PreTx IA Creatinine (micromol/L) Duration of
number Rituximab (mg) initial preop sessions sessions session, Discharge 1 month Current hospital stay (days)
duration

1 Basiliximab 500 1:128 1:4 5 1 0 94 83 79 11

2 Basiliximab 500 1:128 1:4 5 0 0 102 88 91 17
3 Basiliximab 300 1:32 1:8 2 2 0 122 124 105 18
4 ATG 300 1:32 1:2 2 0 0 130 105 96 9
5 ATG 300 1:32 1:8 9 0 0 114 126 145 13
6 ATG 300 1:1024 1:8 4 0 2, 8 h each 72 85 86 7
7 Basiliximab 300 1:1024 1:8 7 0 2, 8 h each 79 96 93 14
8 ATG 500 1:128 1:8 4 0 0 109 139 – 9
9 ATG 500 1:128 1:8 3 0 0 138 – 133 9

Table 3
Complications of the recipients.
Patient Post-operative Co-morbid conditions Infection Isolated Time of Episodes of Episodes of Follow-up
number complications organism infection(days) AMR cellular rejection (weeks)

1 – – UTI NG 20 0 0 80
2 – – UTI E.coli 420,435 0 0 77
3 – Hypothyroidism AGE,UTI NG 13,21 0 0 32
4 – – AGE NG 37,50 0 0 29
5 – – UTI, Pneumonia E.coli 14,45 0 0 11
6 – – – – – 0 0 9
7 – Hepatitis C, – – – 0 0 8
Hypothyroidism
8 – – AGE NG 23 0 0 5
9 Renal artery dissection – – – – 0 0 2

2
R. Nepali and D.S. Shah
was maintained with tacrolimus, mycophenolate mofetil and pre-
dnisolone. The overview of desensitization protocol is shown in Fig. 1.
2.1.1. Follow-up
Triple immunosuppression was continued during the follow-up. The
target trough level of tacrolimus was 10–12 ng/ml in first 2 weeks,
8–10 ng/ml in first 6 weeks, and later reduced to 6–8 ng/mL at 3
months and 6–7 ng/mL at 6 months.
Anti-viral prophylaxis was given to all patients. Valgancyclovir
(450 mg/d) was administered for 90 days. All the patients also received
sulphamethoxazole (400 mg) and trimethoprim (80 mg) once a day for
1 year as prophylaxis against Pneumocystis jirovecii pneumonia.
2.1.2. Monitoring
Surveillance biopsies were obtained at 6 months after transplanta-
tion, and when clinically indicated by rising serum creatinine or de-
creasing urine output. In addition to routine light microscopy, all spe-
cimens were evaluated by immunofluorescence for C4d.
3. Results
From the start of ABO incompatible renal transplant in March 22nd,
2017 to October 26th, 2018, a total of 9 ABO in compatible renal
transplantation were done. All the patients were complement depen-
dent cytotoxicity (CDC) cross- match negative.
Out of 9 Recipients, 5 were males and 4 females. Age of recipient
ranged from 16 to 45 years. The relationship between donor and re-
cipient were parent to child in 7 cases and spousal in 2 patients.
Regarding the donors, 6 were females and 3 were males. The age of the
donors ranged from 34 to 60. The demographic data of all the patients
is shown in Table 1. The longest follow up was 80 weeks.
Pre-treatment Anti-A/B antibody titres ranged from 1:32 to 1:1024.
Post treatment, at the time of transplant the Anti A/B antibody titres
ranged from 1:2 to 1:8. The first two patients underwent 5 pre trans-
plant plasma exchanges and 5th patient underwent 9 plasma ex-
changes, while patients 3 to 5 underwent 2 plasma exchanges. 6th and
7th patients who had anti A titres of 1:1024 underwent im-
munoadsorption using Glycosorb columns. Each session was 8 h in
duration. Both had Anti A titre of 1:8 before transplant. This procedure
was also the first of its kind to be perform in our country. They also
underwent 4 and 7 pre transplant plasma exchanges respectively. Post
transplantation, Patient 1 received 1 plasma exchange on day 2 for
increasing anti-A titres. Patient 3 also received 2 plasma exchange
treatment post transplantation on day 2 and day 4 for increasing anti-A
titres and increasing creatinine. All the other patients did not require
post-transplant plasma exchanges. Patient 7 also was a diagnosed case
of Hepatitis C. He was in sustained viral response before transplant. The
viral load was regularly monitored pre and post-transplant. Patient 9
had intraoperative main renal artery dissection. It was managed
promptly with resection and anastomosis with the branch. The post-
operative period was uneventful and the patient was discharged on day
9 with serum creatinine of 138 μmol/L.
The first two patients underwent surveillance renal biopsy at 6
months. Both showed no signs of antibody or cellular mediated rejec-
tion. Most of our patients had episodes of urinary tract infection and
acute gastroenteritis (Table 3). E. coli was mostly isolated in urine
cultures. Patient 2 was admitted post-transplant for acute appendicitis
which was managed conservatively. Patient 5 was admitted with
pneumonia and managed with IV antibiotics. No organism was isolated.
4. Discussion
Here, we have presented the outcomes of the first 9 live donor ABO
blood group incompatible kidney transplants performed in Nepal.
The early experience with ABO incompatible (ABOi) renal trans-
plantation in 1955 by Hume et al. [6] yielded poor results with most
3
Transplantation Reports 4 (2019) 100026
grafts being lost rapidly to antibody mediated rejection. Therefore, ABO
incompatibility was considered an absolute contraindication to renal
transplant.
A major breakthrough came in 1987, with the first large study on
ABOi renal transplant by Alexandre et al. from Belgium [7,8]. He in-
troduced an effective desensitization protocol based on plasmapheresis
and splenectomy to prevent hyperacute rejection across the ABO anti-
body barrier. Since then, ABOi renal transplant have gained momentum
all over the world [9]. The outcomes have improved significantly after
the introduction of tacrolimus and mycophenolate mofetil (MMF)
around 2000. When 5-year graft survival rates of ABO incompatible
renal transplant in Japan were analyzed according to the three eras
(1989–1994, 1995–2000, and 2001–2006), they were 68%, 76%, and
90%, respectively [10]. Outcomes of ABOi renal transplant between
2002 and 2008 in Japan were further improved after the introduction
of rituximab. Five-year graft survival rates of ABO compatible renal
transplant, ABOi renal transplant using splenectomy, and ABOi renal
transplant using rituximab were 88.4%, 90.3%, and 100%, respectively
[11]. In a meta-analysis of 26 single-center cohort studies, one-year
uncensored graft survival was 96% among ABOi transplant recipient
compared to 98% among ABO compatible controls [12]. However,
among ABOi grafts that survived beyond one-year post transplant, graft
survival was comparable with that of ABO-compatible controls. An-
other study which had long term follow up of 441 ABOi renal transplant
showed there was no significant difference in patient or graft survival at
years 1, 3, 5, 7 or 9 compared with ABO compatible transplants [13].
Currently, ABOi renal transplant has reached approximately 30% of all
living-donor renal transplants in Japan [9]. Following the great success
of ABOi renal transplant in Japan, many other countries such as United
States of America, Europe, Korea [14,15] and United Kingdom have
been performing this method of transplant at an increasing rate
[16,17].
In our setting, though only 9 cases have been done with maximum
follow up period of 80 weeks, the results are encouraging. The different
induction agents used in the patients were affected by the cost for the
drugs they could afford. Considering the growing number of patients
with renal failure each year, the shortage of suitable living donors and
the lack of effective deceased donor program, ABOi renal transplant has
come up as viable alternative. With the advent of newer im-
munosuppressive medication and the proven efficacy of treatment
without the need of cumbersome procedures such as splenectomy, it has
made the crossing the barrier of ABO incompatibility a good option for
needy donors. However, in a resource limited developing country like
ours, there are several challenges. First, the intensive pre-operative
immunosuppressive protocols pre and post-transplant can increase the
risk of infections. Proper anti-viral and antibacterial prophylaxis can
decrease the risk of infection to a significant degree [18]. In our short
follow, no greater risk of rejection or infection was found. However,
more number of patients and longer follow ups are required.
Secondly, the cost of such protocols are exceeding higher than the
ABO compatible renal transplant. The average cost of an ABO in-
compatible transplant in United States of America is $65,080 compared
with $32,039 for ABO compatible transplant. However, with our pro-
tocol in our setting, it costs about $8400. The government of Nepal is
also supporting the renal transplant patients by partly covering the cost
of about $5000. This has made transplantation across ABO blood group
barrier an attractive and feasible option for needful patients.
5. Conclusion
The start of a successful ABOi renal transplant program has given
hope to a large number of end stage renal patients who did not have
ABO compatible donors. This has shown that even in a developing
country like ours, ABOi renal transplantation is a viable option for
patients waiting for renal transplant without significant increase in risk
of rejection or infection and at reasonable cost.
R. Nepali and D.S. Shah
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