ABO Incompatible Transplant –

as an effective option to expand donor pool

Dr. M. Ranjanee
M.D.(GEN MED) D.M. NEPHROLOGY (SGPGIMS),
SCE Nephro (UK), FIMSA ,CHS
Senior Consultant Nephrologist & Transplant physician
Apollo Hospitals , Chennai

09/07/2023 1
 Growing need of kidney allograft!
• The prevalence of CKD is 17.2% with ~1.6% have CKD
stage 4-5 in India.
• Incidence of ESRD is 2.5 lakh /year
• Only 10,000 patients started on dialysis

• Estimated annual requirement of 2.2 lakh kidneys as

against only 7500 transplants per yr
(90% from living donors and 10% from deceased donors)

• Mere 12,000 donors available ---March 2022

Ministry of Health 2019

09/07/2023 2
5 yr waiting list for Deceased Donor Tx in TN

AB; 402; 6%

Blood Gp

O; 2429; 39% O
B; 2117; 34% A
B
AB

A; 1266; 20%

TRANSTAN REGISTRY

09/07/2023 3
 • 5,480 patients waiting for organ
transplantation at PGIMER

• Mysuru : Waiting list of patients to receive

kidney gets longer
• Aug 18, 2021, 04.36 AM IST

Indian transplant
registry
Out of 21395 kidney
transplanted between
1971-2015 ,only 783
from deceased donors
09/07/2023 4
 Healthy ,willing but
Incompatible live Donors

• 35% chance ABO incompatible.

• 10-15% (or higher) HLA incompatible
• Thousands of patients every year cannot undergo LDKT
because of incompatibilities

Segev/Gentry, JAMA, 2005 5

09/07/2023
 OPTIONS AVAILABLE

DECEASED DONOR Tx

EXTENDED CRITERIA
DONOR

ABOi TRANSPLANTATION

PAIRED KIDNEY EXCHANGE

OR SWAP
.

HLA Ab DESENSITIZATION
PROTOCOLS

Kidney Res Clin Pract. 2015 Sep; 34(3): 170–179 6

09/07/2023
 Deceased Donor Transplantation

Challenges :
• Lack of proper policy in organ sharing in different countries
• Organ retrieval and Transportation issues
• Long waiting period
• Inferior patient and graft survival as compared to live Tx
• Higher risk of delayed graft function

09/07/2023 7
 Extended Criteria Donor
• Age >60 years or

• Age 50 to 59 years old with 2 or more of the following criteria:

1) history of hypertension;
2) elevated serum creatinine at donation (1.5-2.5 mg/dl );
3) death from a cerebrovascular accident.

09/07/2023 8
 Marginal donors do increases live donor pool by 15%

09/07/2023 9
 Kidney Paired Donation (KPD)

09/07/2023 10
 Kidney Paired Donation (KPD)cont..
 Challenges :
 Age matched kidney and HLA matching ----Difficult same
setting
 Lo………..ng waiting period to obtain matching donor –
months to years unless large pool
 O and AB patients – very difficult for swapping
 Expenses while waiting for transplant :
 maintenance dialysis - Rs. 25000 to 30000/month
 Vascular issues /inferior outcomes ass.
 Option for limited population due to
 Demographic issue/logistic issues and limited number of pairs

09/07/2023 11
 So ............................. Option left

ABOI kidney
transplantation

09/07/2023 Shin M,. J Transplant.2011;2011:970421 12

 Evolution of ABOi Tx

• Tissue and blood incompatibility have traditionally been

absolute contraindications to transplantation.
Hume et al. J Clin Invest (1955) 34(2):327–82. 10.1172/JCI103085

• Increasing organ shortage enforced development of strategies

over the last 25 yrs to overcome the ABO antibody barrier .
• Has allowed donor pool expansion by up to 30%
• Death-censored graft survival rates are comparable to the rates
in compatible transplantations in current scenario.

• With currently existing protocols, as many as 90% of patients

with an ABOi living donor may effectively be desensitized and
transplanted
09/07/2023 13
 Evolution of ABOi Tx cont…

• Superior to HLA incompatible renal transplants

Pankhurst L et al .Transplant. Direct 2017; 3:e181. 

• Survival advantage when compared with matched waitlist

control -80.6 % at 8 yrs post Tx vs 30.5 % at 8 yrs on waitlist

09/07/2023 14
 Strategies of ABOi-KT
Three common principles
(1) Antibody measurement –tube method, gel card method,
flow cytometry
(2) Antibody depletion.
 Therapeutic plasma exchange,
 Double-filtration plasmapheresis,
 Antigen-specific immunoadsorption.
(3) B-Cell depletion
 Intravenous Immunoglobulin.
 Splenectomy.
 Anti-CD20 Monoclonal Antibody.

09/07/2023 15
 General Schema

09/07/2023 16
 When do we face
ABO incompatibility?

Anti-A
B

O AB No natural (IgM)
Anti- isoagglutinins
A
Anti-
B A

Anti-B

09/07/2023 17
 Isoagglutinins
• IgM isotype –natural , intrinsic ability to agglutinate erythrocytes
reacting against non-self ABO antigens

• IgG isotype induced after alloimmunisation with cell membrane

polysacchrides of gut commensal bacteria

• Blood group A consists of two subtypes, A1 (80%) and A2

• Immunogenic risk A1>B>A2
• Donor A2 kidneys can generally be successfully transplanted onto
recipients with low pretransplant anti-A titers without
desensitization
• Isoagglutinin antibody A or B titers O> A/B alone
• O recipients have a higher incidence of ABMR
09/07/2023 18
 Determination of Antibody Titre

Gel agglutination method –more sensitive , reproducible ,easy

and rapid

Titer Monitoring
• Baseline,
• Pre & post plasmapheresis
• Post Tx -Daily for first 2 weeks
Weekly for next one month
At 2, 3, 6, 12 months

09/07/2023 19
 Antibody Reduction therapies

• Plasmapheresis
• Double Filtration Plasma Exchange
• Immunoadsorption

•Apheresis session numbers based on baseline isoagglutinin titers.

•Antibody removal imperative to prevent ABMR

•>4 plasma exchange (>1:128 titre)- FFP req.(Donor group or AB Plasma);

Immunoadsorption preferable

Animal Model Exp Med. 2019;2:76–82

09/07/2023 20
 Double-filtration Plasmapheresis

Replacement fluid
(albumin + Ringers)

plasma Plasma
fractionator
Plasma
separation
blood cells
filtration/
centrifugation

IgG/IgM fraction
discarded

Using a second filter, double-filtration plasmapheresis is capable of eliminating the plasma

fraction containing the immunoglobulins and decreases the amount of plasma discarded
09/07/2023 Tyd´en, G.” Transplantation, 2007 21
 Antigen-specific Immunoadsorption

Glycosorb ABO
column
Y
Plasma system
Perfusion of plasma
anticoagulation
XXX YYY
(containing antibodies column
or immunocomplexes)
over a matrix with an Y whole blood
Y plasma
immobilized specific
ligand to eliminate
antibodies and/or
Y Y
cell separation
immunocomplexes filtration blood cells

whole blood

•Efficient
•No volume loss
•No coagulation disturbance

Using the process of immunoadsorption, the plasma is processed through a Glycosorb ABO
immunoadsorbent column and reinfused into the patient. There are no volume losses, and
thus the number of adsorption cycles has no limit.
09/07/2023 22
 Number of Apheresis Treatments

Baseline Titre Pre-Transplant Post-Transplant

PP/IVIg PP/IVIg
<16 2 2
16-32 3 2-3
64 4 3
128 5-6 4
256* 7-8 4
512* 9-10 5
>512* >10 6
* Consider exchange instead, but no exclusions
09/07/2023 23
 Various Antibody Removal Methods

20% 60-70% 56 -81%

Target IgG Ab titre <1:16

IJT,2019
09/07/2023 24
 B Cell Depletion

09/07/2023
 B-Cell depletion:
Splenectomy-Is it necessary ?

• Traditionally, it was an important prerequisite of for ABOi KT

• Reduction of Ab producing B-cell pool and some plasma cell
• Morbid procedure with inherent risk of infections
• Alexandre et al.-Splenectomised recipient had a much smaller
risk of AMR
• Ishida H et al- No significant suppression of ABO antibodies
after splenectomy v/s non spleenectomized
• Rituximab based protocol -obviates the need for splenectomy

Splenectomy may remain an effective option for refractory AMR

09/07/2023 26
 B-Cell depletion:
Rituximab

Rituximab should be used in a dose of 100–200 mg/m2

approximately 2 weeks before transplantation
Major effect between 3weeks – 6 mon post administration
PP , if required, should be performed at least 1‑week after rituximab administration

Reduces isoagglutinin rebound and acute ABMR risk

All induction therapies can be combined with rituximab

Increased infection risk with combined Rituximab‑ ATG

CD19 counts are not recommended for routine assessment.

Bhalla, et al.: ABOiKT recommendations from Indian working group
09/07/2023
 IVIG
• Prevents isoagglutinin rebound early post ABOi Tx period and
decreases ABMR risk.
• Down regulates antibody mediated immune response.
• Blocks Fc receptors on leucocyte membrane
• Direct neutralization of the alloantibody
• Inhibition of complement activation
• Pooled IVIg contains anti-A/B antibody
• Use IVIg with low anti-A/B titer- prevent hemolysis and AMR
• Use low dose(0.1gm/kg) post PLEX/IA or
Split dose – (0.5gm/kg )on D-4 and D-1

09/07/2023 World J Transplant 2014 March 24; 4(1): 18-29 28

 Preconditioning Therapy in ABOi Tx - A
Meta-analysis of 83 studies

RTX and IA superior efficacy

09/07/2023 29
Lo P et al. Transplantation 2016; 100: 933-942
 Post Transplant Period

Accommodation - presence of circulating isoagglutinins and antigens on the

graft cells with normal renal function and normal histology with C4d
positivity on the PTcs.
• Unresponsive allograft to the immune system
•Dev of resistance to complement mediated Ab damage
09/07/2023 30
 Posttransplant follow-up
• Titre monitoring imperative
• ABMR risk in 5 to 15% of patients with postoperative Ab
rebound to titres ≥1:32-1:64 Ishida H et al . Transplantation 2000; 70: 681–685
Tobian AA et al. Am J Transplant 2010; 10: 1247–1253

• 99% occur within 1st month posttransplant

• On demand PP / IVIG – graft dysfunction or Ab rebound
• No steroid free regimen (25% of ACR)
• Protocol biopsy not routine
• Tolerance- unresponsive immune system to allograft
• Eculizumab – rescue therapy for severe ABMR ,
09/07/2023 pts with high Ab titre 31
 Studies comparing outcomes in
ABOi vs ABOc Tx

09/07/2023 Maritati et al.Journal of Inflammation Research 2022:15 3095–3103 32

 SGPGI protocol

Hopkins protocol

09/07/2023 33
 Indian Experience SGPGI 2014

27/11/14 B+/AB+ AntiAIgG/M 16/4 2(1 Glycosorb) Nil 0 Nil SGF 1.25 0.9 6

09/07/2023 34
 Nadiad Experience
n= 100 (2013-2019)

ABMR -15% ABOi-KTx vs 4% in ABOc-KTx (P < 0.01)

No significant differences in infection/ malignancy and surgical complication rates

09/07/2023 Prabhakar A et al. Indian J Nephrol 2021;31:358-64 35

 Kaplan-Meier survival :ABOi vs ABOc

PS 1yr PS 5yr
ABOi 93.5% ABOi 85%
ABOc 95.4% ABOc 93%

GS 1yr PS 5yr
ABOi 73.5% ABOi 60%
ABOc 93% ABOc 83%

09/07/2023 Significant difference – inferior outcome in ABOi 36

09/07/2023 37
 Kaplan-Meier survival :ABOi vs ABOc
Patient survival Death censored graft survival

ABOi N=94
ABOc N=65

PS 4yr DCGS 4yr

ABOi 100.0% ABOi 98.4%
ABOc 99.4% ABOc 97.8%

09/07/2023 38
Biopsy‐proven rejection and complications
in ABO‐CLKT and ABO‐ILKT

09/07/2023 Kakuta et al.Clinical Transplantation.2019;33:e13591 . 39

 Higher cost in ABOi mainly due to
“Preconditioning regimen”
2 yr overall cost Tx hospitalization cost

1 yr medical cost 2 yr medical cost

09/07/2023 40
 ABOi Tx: Cost

nil

2,70000

100000

50000
30000
450000

09/07/2023 SGPGI 2014 41

 Pro and cons of ABOi Kidney Tx
Pro ABOi-KT Cons ABOi-KT

 Reduced waiting list time  Higher immunological risk

 Expands living donor pool by  Increased viral infection rates
30 %  Increased cost
 Comparable patient and  Second repeat ABOi Tx
graft survival doubtful
 May be a reasonable option  Graft nephrectomy may be
for Blood Gp O risky
 Successful Pediatric / other
organ Tx
 mTORi safe

09/07/2023 42
Strategy to minimize Immunosuppression
thereby reduced ABMR / infection rate
Tailored Desensitization Protocol

Barnett AN et al .Transpl Int 2014; 27: 187-196

09/07/2023 43
 Kaplan–Meier survival curve
Patient Survival At 3 Yr Rejection Free Survival
ABOi n=62
ABOc n=167

No difference in Survival or ABMR rates

09/07/2023 44
 Strategies to minimize ABMR rate

• Reduction of blood group antigen expression in kidney by

recombinant technology . Kobayashi et al

• Interference with the binding of anti-A/B antibodies to blood

group antigens by monoclonal anti-A or B antibody Fab
fragment

• Eculizumab – interfere with Ab triggered complement

activation

09/07/2023 45
 Strategies to reduce cost
• Rituximab free protocols

• Customized antibody depletion based on titres

• if titre < 1:8-----no PLEX/ IA or Rtx

• Reuse of Immunoadsorption filters

• Use of smaller pore sized membrane separator (SePE)

09/07/2023 46
 New ABOi Desensitization Protocols
Rituximab free protocols

09/07/2023 47
09/07/2023 48
 Summary of current standard practice

• Pre Tx Splenectomy not used

• Preconditioning-Pre Tx PP/IA/DFPP + low/standard dose IS
IVIg ± RTX
• Targeted Ab Titer 1:4 to 1:16

• Standard triple immunosuppression( steroid based ) ±

Induction (Il-2RB)

• Post Tx PP±IVIg only need based

• Post Tx splenectomy only selective cases

09/07/2023 49
 Thanks for attention !

09/07/2023 50