Seminar presentation on ABOI-KT

1. ABO incompatible renal transplant
PRESENTED BY
Dr.C.MALSAWMKIMA
DM NEPHROLOGY STUDENT
DEPT. OF NEPHROLOGY
AIIMS JODHPUR
Date: 25-07-2020

2. ABO incompatible renal transplant
 Introduction
 ABO blood groups
 Desensitization
 Target titers
 Antibody removal methods
 Immunomodulation
 B-cell depletion
 Protocols
 Outcomes

3.  ABO incompatibility was absolute contraindication to KT due to the
historical poor outcomes
 The first attempt at ABOi-KT was reported in 1955 by Chung et al. (8/10
failed in first few months)
 In 1987, when Thielke et al. showed that 12 of 20 KTRs from blood group
A2 donors into O recipients maintained long-term allograft function
 In 1987, Alexandre et al. introduced an effective desensitization protocol
(plasmapheresis). A one-year graft survival of 75% and a recipient survival
of 88%. Their results were impressive and became the basis of the next
desensitization protocols for ABOi-KT

4.  Then, in Japan, near absence of deceased donors and the only 0.15% of
living A2 donors encouraged investigation into desensitization for
ABOi/living-donor allografts (LDAs)
 Largest number of ABOi-KT since 1989, (>1000 cases) performed in
Japan. ABOi KT surgeries reached 14% of all living donor KTs performed
in Japan
 ABOi-KT began receiving new interest in Europe and the USA in the early
2000s
 Successful results from Japan, the United States and elsewhere have
renewed interest in this procedure

5.  In India, early attempts for ABOi-KT were made in the late 1980s
 Poorly utilized until a few years back, because of cost and perceived
cumbersome nature of the desensitization protocol
 First reported successful ABOi-KT from India was in 2011
 Protocols for working up and desensitization were not uniform
 Indian Working group recommendation was made in 2019

6. Date of Tx : 2.11.2011
Indian Journal of Nephrology May 2013

7.  Four common ABO blood group types- A, B, AB and O
 Blood group A consists of two subtypes- A1 and A2 (non-A1)
 Antigen is expressed on red blood cells, lymphocytes, and
platelets, as well as epithelial and endothelial cells
 Formation of blood group Ab occurs against those antigens not
native to the host
 Thus, Ab to both A and B are found in an individual with blood
type O, while an individual with blood type AB has no antibodies
to A or B antigens

9. Asian J Transfus Sci. 2014;8(2):121-125

10.  Incidence of acute ABMR after ABOi-KT has been reported in the range
of 10 to 30%
 Blood group O tends to have higher isoagglutinin Ab titers to both the A
and B antigen as compared with the formation of anti-B by blood group
A individuals or anti-A by blood group B individuals
 Blood type O recipients have a higher incidence of ABMR following
ABOi-KT
Transplantation. 2009;88(10):1186
 Initial titer of the anti-A or -B isoagglutinin Ab, rather than the antigen
targeted (A1, A2, or B), was initially reported to correlate with the risk of
ABMR in such cases
Transplantation. 2000;70(9):1331

11.  Antigenic expression of A2 is quantitatively and qualitatively
less than that of A1, and the overall immunogenic risk based
on antigen expression alone is A1 >B >A2
Transplantation. 1986;42(1):88
 Donor A2 kidneys can generally be successfully transplanted
into recipients with low pretransplant anti-A titers without the
use of desensitization
Clin Transplant. 2016;30(5):589

12.  It was initially reported that higher baseline isoagglutinin
antibody titers predispose to an increased risk of ABMR
 It is unclear whether a significantly elevated baseline Ab titer
predisposes to a poor long-term outcome, given initial
successes through desensitization
 Elevated isoagglutinin titers are generally observed during
acute ABMR, but the PPV of elevated posttransplant titers is
poor

13. Indian J Transplant 2019;13:252-8

14.  Gel column agglutination test is- method of choice for Ab titer
assessment
 More sensitive, quantitative, easy to perform, more reproducible, and is less
time-consuming
 Tube method is an acceptable alternative
 Flow cytometry has demonstrated comparable analytical performance to
that of gel column agglutination test but it is more expensive
 Indian working group recommended gel agglutination method for
determination of Ab titers

16.  Assessment of one Ab titer before Ab removal
 IgG measurement should be used to make clinical decisions
(IgM is discretionary)
 Both IgG and IgM antibodies present in the circulation of ABOi recipient
 IgG is more relevant for clinical outcomes because IgM remains confined
to vascular space which makes it amenable to easier removal

17.  Outcome of ABOi-KT depends on many factors and titers are
not the sole factors in determining outcome
 Higher pretransplant titers of IgG- lower rate of graft survival
and increased likelihood of graft rejection
 This was demonstrated by Shimmura et al.
 8-year graft survival rate at of 66.8% and 79.7% for 1:16 and 1:32–1:64
IgG Ab titer ,whereas it was 28.6% for titers 1:128 and higher
 No association between IgM titers and graft survival
Transplantation 2000;70:1331-5

18. Indian Working group recommend -Pretransplant IgG Ab titer of 1:16 as cut-off to go
ahead for ABOi-KT irrespective of the methods used for titer assessment
Indian J Transplant 2019;13:252-8

19.  Goals -to lower the immunogenicity of the incompatibility
 Most commonly used protocols employ a combination of the
following strategies (no universal protocol):
 Removal of circulating ABO antibodies with plasmapheresis or
immunoadsorption
 Immunomodulation with IVIG
 Depletion of B cell responsible for ABO Ab production with the anti-
CD20 agent rituximab

20.  Methods:
 Plasmapheresis
 Double filtration plasmapheresis
 Immunoadsorption

21.  Immunoadsorption (IA) is the method of choice for lowering
Ab titers but is expensive
 IA is more cost-effective compared to other methods when it
is predicted that more than 4 sessions of PP will be required,
such as a starting Ab titer of >1:128
 PP should be performed if IA and Double-filtration PP
(DFPP) are not possible

22.  Five factors should be considered
 Cost
 Predictability of the method
 Initial Ab titer
 Complications

23.  Widely employed for Ab removal in ABOi-KT
 Plan based on expected date of KT and baseline Ab titers
 Usually, PP is given on alternate days
 In each session of PP
 One plasma volume exchange is replaced at 100% volume with 5% human
albumin
 Calcium gluconate 0.465 mEq in 4 ml quantity is added to 500 ml of 5%
albumin
 Acid citrate dextrose-A or heparin is used as the anticoagulant (ratio of 13:1)

24. Indian J Nephrol 2019;29:151-9

25.  Duration depends on titres
 Approximately, number of cycles required to reach a target
titer of <1:16 will be:
Baseline isoagglutinin AHG titres No of PP cycles
<32 1-2
64 2-3
128 3-4
256 4-5
512 5-6
>512 >6
Indian J Transplant 2019;13:252-8

26. )
Transplantation 2009;87: 1246–1255

27.  Fixed cycle protocols can be adopted, and it has been suggested that
4 pretransplant PP sessions may be adequate
 Narumi et al. performed four and two cycles of PP those with
baseline titers of ≥1:32 and ≤1:16, respectively
 Rituximab at a low dose (100–200 mg) was given in patients with high titers
 Graft survival rate at 3 and 5 years was 96.1% and 90.7% in high-titers group and 95.8% and
95.8% in low-titers group
 The difference in graft survival was nonsignificant (P = 0.6456)
Am J Transplant 2015;15:C89
 Indian centers are not ready to accept such fixed protocols and
resort to additional sessions to achieve target Ab titers of <1:16

28.  DFPP selectively removes the Ig fraction from the serum and
helps in minimizing the volume of substitution fluid required
 Plasma is first separated by a plasma separator, and in the
second filtration, the gamma globulin fractions are separated
by plasma fractionator
 Advantages- selective removal of Igs, requirement of
smaller volumes of substitution fluid and better reduction of
Ab titers in one session (70% and 60% removal of IgM and
IgG, respectively)
Transplantation 2007;84: S30–S32

29. Transplantation 2007;84: S30–S32

33.  IA has been used for removal of agglutinins since the early
1980s
 IA can be antigen-specific or nonspecific
 Multiple procedures can be performed in a single column
with different types of columns available for different type of
agglutinins
 Glycosorb column in first treatment reduces donor specific
IgM and IgG antibodies by 81% and 56% respectively
 Multiple treatments depending on the baseline titers

34.  Advantage:
 No substitution is required
#
 Disadvantage:
 High cost of columns
(makes less attractive if the initial
Ab titers are low enough to not
require >4 PP sessions)
IA becomes more efficient in reducing Ab titers if >4 sessions are needed.
Hence, it makes sense to use this method if the initial Ab titres are >1:128

35.  Reuse has been practiced, reducing cost of treatment (but not
recommended)
 Some used saline rinsing of the Glycosorb column followed by
sterilization using ethylene oxide and storage in 2–8°C
 With immunosorba column, Schiesser et al. used 1000 mL of Buffer PA
pH 7.0 to wash the plasma, a citrate solution with 1000 mL eluate PA pH
2.2 to remove antibodies and 1000 mL buffer PA pH 7.0 for
neutralization. In the end, the column was rinsed and filled with 250 mL
Immunosorba Preservation Solution containing 0.04 polyhexamethylene
biguanide and stored in the dark at +2°C–+8°C

41.  Replacement fluid depends on the method employed
 IA - crystalloid replacement is enough
 PP and DFPP- albumin and crystalloids are recommended
 If the number PP or DFPP sessions exceed 4, FFP may be
added to mitigate the risk of coagulopathy

43.  IVIG use is not routinely recommended in ABOi-KT
 But, used in many transplant centers prior to ABOi-KT
 To replace Ig that are removed with PP or IA
 Block Fc receptors (FcR) to prevent a rebound in anti-A/B antibody titers
 Immunoregulatory properties

44.  IVIG contains anti-ABO Ab and can lead to increase in titers
 When needed, it should be used in low dose (~ 100 mg/kg),
after PP cycles, with a batch having low Ab titres
 Use declined because of its association with rising Ab titers,
likely due to the presence of anti-ABO IgG antibodies in
IVIG preparation (IVIG products may contain detectable anti-A and anti-B
isoagglutinins)
Am J Transplant 2011;11:196-202

45.  ABOi-KT desensitization protocols employ the anti-CD20
Ab rituximab along with PP or IA
 PP, if required- performed at least 1-week after rituximab
 All induction therapies can be combined with rituximab
 Increased risk of infections (with combined Rituximab-ATG)
 CD19 counts are not recommended for routine assessment

46.  B cell depletion:
 B cells are the precursors for plasma cells that produce the
anti-A/B antibodies
 Rituximab, a humanized mouse monoclonal antibody that
targets CD20 (expressed on the majority of B cells), is the
most commonly used B-cell depleting agent
 Splenectomy, which was historically used for B-cell depletion is no longer used in
most countries

47. Indian J Transplant 2019;13:252-8
 Dose and initiation time before KT varies across centers
 Optimally, RTX should be given 2 weeks before transplant or 1-week before PP
 Rituximab dose 100–200 mg/m2 approximately 2 weeks before transplantation is
recommended by Indian Working group guidelines

48. Transplantation 2008;85: 1745–1754

49.  The utility of routine rituximab administration remains
uncertain
 Evidence suggests that complete avoidance of rituximab may
not have adverse effect on outcomes
 However, more data is needed before this course of action
can be recommended
Am J Transplant 2005;5:2570-5

50.  Induction therapy - Optimal induction therapy unknown for ABOi-KT
 Maintenance therapy- Triple IST as per standard currently practiced for
ABOc-KT
 Triple therapy -steroids, mycophenolate mofetil and cyclosporine, or preferably tacrolimus
(Tac) is the standard approach in renal transplant
The 2017 National Institute for Health and Care Excellence guidelines
2009 KDIGO
 Use of 12 h trough levels for TAC(5–15 ng/ml – mean 10 ng/ml) (KDIGO)
 Initiation time of IST- variable in different studies but it has been
suggested initiation 7–14 days prior to transplant is helpful in adequate
inhibition of Ab production
 No evidence to suggest any change in the IST schedule for ABOi-KT

51.  Candidates must meet center-specific, general transplant
candidate selection criteria in addition to ABOi-specific
criteria
 No established ABOi-specific selection criteria for recipients
 Some select initial ABO isoagglutinin titer of ≤1:128 (at some transplant
centers, an initial titer of ≤1:256 may be acceptable)
 Must be willing to undergo ABOi-KT and all the therapies associated
 Must not be undergoing concurrent HLA desensitization (practice may vary
from center to center, and simultaneous HLA incompatible and ABOI
transplants are performed at some institutions)

52.  Pretransplant desensitization
 Begins one month prior to the scheduled transplant
surgery(center to center variation)
 Transplantation is performed when the isoagglutinin
antibody titer is ≤1:8 (1:4 to 1:32)

53.  One approach is…..
 At four weeks prior to KT
 Single dose of rituximab 200 mg
 (premedicate for with IV MP 250 mg, acetaminophen 325 mg given
orally, and diphenhydramine 25 mg given orally)
 At four weeks prior to KT
 Oral enteric-coated mycophenolate sodium (EC-MPS) 360 mg twice
daily (mycophenolate mofetil [MMF] 500 mg twice daily)
 Initiate antimicrobial and antiviral prophylaxis with trimethoprim-
sulfamethoxazole and acyclovir (both dose adjusted for kidney function)

54.  At two weeks prior to KT
 Obtain an isoagglutinin titer and a final crossmatch
 Plan for pretransplant PP to achieve a goal isoagglutinin titer
≤1:8 by the time of transplant surgery
 Expected to decrease by one dilution with each session of PP
 Can estimate the number of PP sessions necessary to achieve the target
titer. Example, if starting titer is 1:64, it will take three plasmapheresis
sessions to achieve a titer of 1:8 (1:64 to 1:32, 1:32 to 1:16, and 1:16 to
1:8).

55.  Admit patients three to four days prior to the scheduled
transplant surgery date, depending upon the isoagglutinin
titer and how many PP sessions are planned
 Obtain- KFT, electrolytes, CBC, PT-INR, APTT, and
isoagglutinin titer, and isoagglutinin titer on a daily basis
while the patient is admitted

56.  Daily PP-1.5 volume exchanges with 5% albumin (FFP if INR elevated)
 IVIG 10g after each PP- to prevent rebound antibody formation. At the
last PP session prior to Tx, IVIG 500 mg/kg, rounded to the nearest 10
grams (to correct preoperative hypogammaglobulinemic state)
 Alternatively, administer two units of donor blood type or AB-negative
blood type plasma. Each unit contains approximately 5 grams of IgG
 On completion of this desensitization protocol, transplant surgery can be
performed.

57. Ritux- 2 weeks before transplant or 1-week before PP

58.  Same approach as in recipients of ABOc-KTR
 Monitor isoagglutinin titers daily while the patient is in the hospital, 2-
3/week for the first month posttransplant, weekly for months 2 to 3
posttransplant, and then yearly thereafter
 In patients with a posttransplant isoagglutinin titer ≥1:16, a kidney biopsy
and/or preemptive plasmapheresis should be performed, particularly if
there is evidence of graft dysfunction (eg, delayed/slow graft function or
rising serum creatinine)
 Transplant centers vary in the use and timing of protocol renal allograft
biopsies (some centres-14 days and again at one year posttransplant)

59.  Routine measurement of titers after transplantation is not
recommended
 Indian Working group unanimously agreed that postoperative
titers may not be essential and these do not alter the
outcomes of the patient
 Posttransplant PP may be necessary if there is graft
dysfunction with increasing titers (>1:64 or 4-fold increase
from baseline)
Indian J Transplant 2019;13:252-8

60.  Presence of detectable isoagglutinin titers, AB endothelial antigen
expression, and positive PTC C4d staining despite the absence of any
histologic evidence of ABMR has been thought to represent ABOI
immunologic accommodation
Am J Transplant. 2003;3(8):952
 No therapy needed for isolated positive PTC C4d staining in ABOi-KT
 When graft dysfunction secondary to ABMR is present in the setting of
ABOi-KT, PTC C4d is likely to be positive, but histologic manifestations
associated with ABMR are also likely to be present
Transplantation. 2003;75(7):971
 The C4d result must be interpreted with other histologic parameters as
well as the clinical scenario in order to distinguish immunologic
accommodation versus ABMR

61.  In one study, C4d staining were examined on surveillance biopsies
performed 1 and 5 years posttransplant in 73 ABOi, 102 crossmatch-
positive
 At 5 years, ABOI kidneys showed higher rates of C4d deposition, compared with
crossmatch-positive kidneys (77.8 versus 18.9 percent)
 Death-censored graft survival was superior in ABOi (79.5 versus 70.7 percent)
 eGFR in surviving grafts was superior in ABOI, compared with XM-positive (51.3
versus 44.4 mL/min), and closely resembled conventional transplants (48.5
mL/min)
Transplantation 2014 Nov 27;98:1089-96

62.  Another analysis found that C4d-positive staining was present
in 80 percent of protocol ABOi allograft biopsies and in 58
percent of ABOi biopsies performed for graft dysfunction
 There was no correlation between this finding and histologic evidence of
ABMR or graft injury
Am J Transplant. 2006;6(8):1829

63. Staining of glomerular capillaries (A) and circumferential staining of peritubular
capillaries (B)

64.  Higher rates of perioperative bleeding likely due to the
loss of clotting factors due to the pheresis procedure
 Higher rate of lymphoceles (19 to 50 percent) has been
reported in ABOi-KTR (reason for this is unclear,? early
initiation of mycophenolate )
 Higher risk for infectious complications including
pneumonia, UTIs, and/or pyelonephritis, wound
infection, and BK nephropathy

65.  Compared with ABO-compatible KT, ABOi-KT has been
associated with lower graft and patient survival within the
first three years posttransplant
 However, longer-term graft and patient survival rates after
ABOi-KT appear to be comparable to those after ABO-
compatible KT

66. CJASN August 2018, 13 (8) 1234-1243

67. Lancet 2019;393(10185):2059-2072
 The best data come from a 2019 meta-analysis of 40 observational studies that
compared patient and graft outcomes among 7098 ABOi-KTRs and 57,965 ABOc-
KTRs

68.  Compared with ABOc-KT, ABOi-KTRs have…….
 Higher risk of mortality at one (odds ratio [OR] 2.17, 95% CI 1.63-2.90), three (OR 1.89,
95% CI 1.46-2.45), and five (OR 1.47, 95% CI 1.08-2.00) years posttransplant but not at
eight or more years posttransplant
 Death-censored graft survival was lower for ABOi-KTRs at one (OR 2.52, 95% CI 1.80-
3.54) and three (OR 1.59, 95% CI 1.15-2.18) years posttransplant but was comparable
between the two groups after five years posttransplant
 Higher risk of sepsis (OR 2.14, 95% CI 1.37-3.33) (no differences in the risks of UTI, CMV
infection, BKPyV infection, and Pneumocystis pneumonia between the two groups
 Higher risks of surgical revision (OR 1.92, 95% CI 1.65-2.23), bleeding or hematomas (OR
1.76, 95% CI 1.18-2.63), and lymphoceles (OR 2.10, 95% CI 1.41-3.12)
 Higher risk of antibody-mediated rejection (ABMR; OR 3.06, 95% CI 1.97-4.75).
 No difference in the risks of overall, borderline, or T cell-mediated (cellular) rejection

69. Indian J Nephrol 2016;26:113-8.

70. Open Access Library Journal, 3:e2544.http://dx.doi.org/10.4236/oalib.1102544

71.  Regimens using PP and lVIG alone may be equally effective
compared with those involving anti-CD20 therapy or, less
commonly, splenectomy
 In one single-center study, outcomes with protocols involving
splenectomy and/or pretransplant rituximab in addition to PP
and IVIG were compared with their current protocol of PP
and IVIG alone. Graft survival and rates of ABMR were
similar in both groups
 Long-term follow-up is needed
Transplantation. 2009;87(8):1246
Am J Transplant. 2005;5(10):2570

72.  Concerns for high costs of the necessary preconditioning and
posttransplant care
 Exact cost in India??

73. Thanks