ABO Incompatible Kidney Transplantation, Michael Casey, MD (W-0007)

ABO Incompatible Kidney
Transplantation
Michael J. Casey, MD, MS
January 2016

Outline
• Describe ABO incompatibility and the challenges it presents to kidney
transplantation
• Review the evolving ideas on how to overcome ABO incompatibility
• Propose a new ABO incompatible protocol for our center

Adult Deceased Donor Kidney Wait List
American Journal of Transplantation
pages 11-46, 11 JAN 2016 DOI: 10.1111/ajt.13666
http://onlinelibrary.wiley.com/doi/10.1111/ajt.13666/full#ajt13666-fig-0001
Waitlist times for kidney
transplants are getting longer!

Incompatible ABO Living Donors
• Based upon the distribution of blood groups in the United States,
approximately one-third of potential living donors are eliminated
from consideration based on ABOi.
2008 OPTN/SRTR Annual Data Report

ABO Blood Antigens and Antibodies
www.medical-labs.net/abo-blood-types-with-antigens-and-antibodies-454/ viewed 1/20/16

ABO Recipient-Donor Compatibility
Recipient Blood Type Compatible Donor Blood
Types
Incompatible Donor Blood
Types
A A, O B, AB
B B, O A, AB
AB A, B, AB, O none
O O A, B, AB
Besides RBC’s, blood type antigens also exist on lymphocytes, platelets, epithelial
and endothelial cells.

Special Groups: Blood type O Recipients
• Type O recipients have a higher incidence of AMR following ABOi-KT
(1)
• They have been shown to produce higher levels of anti-A/anti-B IgG
than blood type A or B recipients, and IgG is thought to be largely
responsible for both acute AMR and chronic rejection (2).
1. Toki D, et al. Transplantation. 2009;88(10):1186.
2. Montgomery JR, et al. Transplantation. 2012 March 27; 93(6): 603–609.

Special Groups: Blood type A2 Donors
• Blood group A consists of two subtypes, A1 and A2.
• 20% of U.S. individuals with blood group A express A2
• The antigenic expression of A2 is less than that of A1 (including on the
renal endothelium surface), so A2 is considered less immunogenic.
• Donor A2 kidneys can generally be transplanted into recipients of low
anti-A titers without desensitization

First Report on the OPTN National Variance: Allocation of A2/A2B Deceased Donor Kidneys to Blood Group B Increases Minority
Transplantation
Volume 15, Issue 12, pages 3134-3142, 4 AUG 2015 DOI: 10.1111/ajt.13409
http://onlinelibrary.wiley.com/doi/10.1111/ajt.13409/full#ajt13409-fig-0002
• In 2002, the OPTN Minority Affairs
Committee implemented a “variance of
practice” to allow deceased donor ABOi-KT
with an A2 donor for blood group B
recipients
• Only B recipients with anti-A IgG titers <8
were eligible

History
• Initial forays into ABO incompatible kidney transplantation (ABOi-KT)
resulted in disastrous hyperacute rejection (1)
• In 1955, 8 of 10 ABOi-KTs did not work within the first few postoperative days
(2)
• Further attempts at ABOi KT had similar poor outcomes (3)
• Therefore, ABOi-KT was considered contraindicated for many years
1. Rydberg L. ABO-incompatibility in solid organ transplantation. Transfus Med 2001; 11: 325–342.
2. Chung BH, et al. Renal Failure, vol. 33, no. 2, pp. 150–158, 2011.
3. Shin MJ, Kim SJ. J Transplant. 2011;2011:970421. doi: 10.1155/2011/970421. Epub 2011 Dec 10.

History
• Initial reports of successful ABOi-KT’s sprung up in the late 1980’s
• In Japan, a severe lack of deceased donors encouraged investigation
into live donor ABOi-KT
• Desensitization protocols have been in use in Japan since 1989
• ABOi-KT accounts for 30% of all live donor kidneys (1)
1. Takahashi K, Saito K. ABO-incompatible kidney transplantation. Transplant Rev (Orlando). 2013 Jan; 27(1):1-8.

History
• However in the U.S., ABOi-KT remained limited accounting for <1% of
all KT between 1995-2010 (1)
• Concerns over
• Ab mediated rejection
• Graft loss
• Death in ABOi recipients compared to ABO compatible counterparts (2, 3)
• Splenectomy
1. Montgomery JR, et al. Transplantation. 2012;93:603–609.
2. Goodwin WE, et al. J Urol. 1963; 89:349–356.
3. Kawase T, et al. Transplant Proc. 2002; 34(7):2773.

Complications of ABOi-KT
• Acute antibody mediated rejection (The major complication)
• Perioperative bleeding likely due to the loss of clotting
factors from apheresis
• Infectious complications including
• pneumonia, UTIs and/or pyelonephritis, wound infection, and BK
nephropathy

The Japanese Experience
• A single center report of 67 recipients of a live donor ABOi-KT from
1989-1995.
• 1-2 Plasmapheresis and 3-4 immunoadsorption were carried out before
transplantation.
• Induction phase: methylprednisolone, cyclosporine, azathioprine,
antilymphocyte globulin, and deoxyspergualin were used
• Splenectomy at the time of transplant
• Local irradiation on the first, third, and fifth days after Txp
Tanabe K. et al. Transplantation. 1998;65(2):224.

© Williams & Wilkins 1998. All Rights Reserved. Published by Lippincott Williams & Wilkins, Inc. 2
Table 1
LONG-TERM RESULTS OF ABO-INCOMPATIBLE LIVING KIDNEY
TRANSPLANTATION: A Single-Center Experience 1.
Tanabe, Kazunari; Takahashi, Kota; Sonda, Kazunori; Tokumoto, Tadahiko;
Ishikawa, Nobuo; Kawai, Tasuo; Fuchinoue, Shouhei; Oshima, Tadashi;
Yagisawa, Takashi; Nakazawa, Hayakazu; Goya, Nobuyuki; Koga, Shoji;
Kawaguchi, Hiroshi; Ito, Katsumi; Toma, Hiroshi; Agishi, Tetsuzo; Ota, Kazuo
Transplantation. 65(2):224-228, January 27, 1998.
Table 1 . Patient characteristics

Figure 1
Figure 1 . Patient survival. Patient survival was 93% at 1 year and 91% at 8
years. Patient survival was not significantly different from those of ABO-
compatible patients.
Patient survival was not significantly different from ABO-compatible patients.

Table 3
Table 3 . Cause of death

Figure 2
Figure 2 . Graft survival. Graft survival was 79% at 1, 2, 3, and 4 years, 75% at
5 and 6 years, and 73% at 7 and 8 years. Graft survival was significantly
different between ABO-incompatible grafts and ABO-compatible grafts up to
3 years, but no significant difference was seen after 4 years up to 8 years.
ABOi-KT recipients experienced a higher rate of early graft loss up to 3 years
but showed an equivalent graft loss by year 4.

Table 2: Cause of Graft Loss
• Among 67 patients, 16 grafts failed of which 15 failed within 1 year
• Long-term renal function was strongly influenced by acute rejection
within 6 months

Table 4
Table 4 . Infectious complications
• There was no fatal infectious complication
• 15% patients had non-tissue-invasive CMV infection

• Multicenter study of 441 live donor ABOi-KT recipients between
1989-2001 from 55 centers
• Control group was historical data from 1055 recipients of living kidney
transplantation.
Takahashi K, et al. Am J Transplant. 2004;4(7):1089.

Excellent Long‐term Outcome of ABO‐Incompatible Living Donor Kidney Transplantation in Japan
Volume 4, Issue 7, pages 1089-1096, 21 APR 2004 DOI: 10.1111/j.1600-6143.2004.00464.x
http://onlinelibrary.wiley.com/doi/10.1111/j.1600-6143.2004.00464.x/full#f2
The graft survival rate was slightly but not significantly lower for
ABOi‐KT than for historical controls.

• An even larger multicenter study of 851 live donor ABOi-KTs
performed at 82 institutions from 1989-2005
• We see an evolving immunosuppression strategy away from
cyclosporine and towards tacrolimus and MMF
• In most cases, 3-4 preTxp sessions of plasmapheresis or double-
filtration plasmapheresis
• Splenectomy was performed in most recipients
Tanabe K. Transplantation. 2007;84(12 Suppl):S4.

© 2007 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2
FIGURE 1.
Japanese Experience of ABO-Incompatible Living Kidney Transplantation.
Tanabe, Kazunari
DOI: 10.1097/01.tp.0000296008.08452.4c
FIGURE 1. The immunosuppressive regimen at Tokyo Women's Medical
University, 2001-2004. DFPP, double-filtration plasmapheresis; FK, tacrolimus
(FK-506); MMF, mycophenolate mofetil; MP, methylprednisolone; Tx,
transplantation.

95 92 90
85
89
85
79
61
0
10
20
30
40
50
60
70
80
90
100
Year 1 Year 3 Year 5 Year 10
(%) Patient Survival
Overall Graft Survival
Tanabe K. Transplantation. 2007;84(12 Suppl):S4.

The Spleen: In or Out?
• Putative benefits of splenectomy include reduction of lymphoid mass
and suppression of B-cell activation and Ab production (1,2)
• Early reports described hyperacute irreversible vascular rejection
without splenectomy (3)
• Splenectomy has been commonly used in early ABOi desensitization
protocols in Japan
1. Starzl TE, et al. Proc Soc Exp Biol Med 1963; 113: 929–932.
2. Alexandre GP, et al. Transplant Proc 1985; 17: 138–143.
3. Alexandre GP, et al. Transplant Proc. 1987;19(6):4538.

The Spleen: In or Out?
• But, Ishida and colleagues found that the suppression of ABO
antibodies after splenectomy was not significantly different from ABO
antibody levels reported from centers that did not utilize splenectomy
(1)
• The increased mortality rate of post-splenectomy sepsis, particularly
secondary to encapsulated bacteria, is well documented in the
trauma literature (2)
• Additional surgical risk
1. Ishida H, et al. Transplantation. 2000;70(4):681.
2. Malangoni MA, et al. Surgery 1984; 96: 775–783.

Avoiding Splenectomy with Rituximab
• Rituximab is a humanized mouse monoclonal Ab that targets CD20,
which is expressed on the majority of B cells.
• Deletion of plasma cell precursors (B cells) may result in a partial
medical splenectomy and decrease the risk of AMR
• Infection is a concern with specific predisposition to Pneumocystis
pneumonia reported (1)
1. Shelton E, Yong M, Cohney S. Late onset Pneumocystis pneumonia in patients receiving rituximab for
humoral renal transplant rejection. Nephrology (Carlton) 2009; 14: 696–699.

Sonnenday 2004 (Johns Hopkins)
• A splenectomy-sparing ABOi-KT protocol with Rituximab
• Six ABOi-KT recipients were described with successful transplantation
without any evidence of AMR through a median follow-up of one year
• All patients had a negative flow and cytotoxic crossmatch
Sonnenday CJ, et al. Am J Transplant. 2004;4(8):1315.

Plasmapheresis, CMV Hyperimmune Globulin, and Anti‐CD20 Allow ABO‐Incompatible Renal Transplantation
Without Splenectomy
Volume 4, Issue 8, pages 1315-1322, 10 JUN 2004 DOI: 10.1111/j.1600-6143.2004.00507.x
• Plasmapheresis (PP): 1–1.5 plasma volumes removed per treatment with 100% volume replacement
using either 5% albumin or FFP
• CMVIg was administered at 100 mg/kg following each PP
• Pre-transplant treatments were given every other day on an outpatient basis until an ABO antibody titer
≤16 was achieved.
• A single dose of rituximab (375 mg/m2) given after the last preTxp PP but before transplant surgery

Without Splenectomy
• FK (0.1 mg/kg/day) and MMF (2 g/day in divided doses) were started at the initiation of
preoperative PP/CMVIg treatments.
• Daclizumab 2 mg/kg prior to reperfusion then 1 mg/kg every other week for four doses
• methylprednisolone 500mg intra-operative then 125mgevery 6 h for six doses; followed by
prednisone 30 mg/day) were begun at the time of transplantation. When FK reached target
levels (10–12 ng/mL) post-transplant, prednisone was decreased to 20 mg/day.
• After transplantation, protocol PP/CMVIg treatments were given on postop days 1, 3, and 5.

Without Splenectomy

Patient 4
Day 4: no rejection Trace C4d
Month 1: no rejection 2+ C4d (diffuse, linear in PTC)
Month 3: 2A rejection 2+ C4d
Rx: ATG
Month 6: rejection resolved C4d persists

• 65% of biopsies were stained for C4d but the patient did not
demonstrate clinical or histologic evidence of AMR.
• This phenomenon has also been described by others (1) and is
thought to represent ABOi immunologic “accommodation”
• Whether the early presence of PTC C4d impacts on long-term graft
function remains to be determined
1. Bentall A, et al. Transplantation. 2014;98(10):1089.

Tyden 2005 (Sweden)
• Further encouraging findings were noted in a Swedish series of 11
ABOi-KT recipients using a splenectomy-free protocol employing
rituximab and immunoadsorption (IA)
• IA: Glycosorb ABO carbohydrate column with A or B blood group
antigen specifically depletes anti-A or anti-B antibodies without side
effects typically associated with TPE
• Ab titers against other Ag (i.e. viruses, vaccinations) are not affected
• No coagulation disorders
• Excluded patients with ABO antibody titer >128
• Target ABO antibody titer < 8
Tydén G, et al. Am J Transplant. 2005;5(1):145.

ABO Incompatible Kidney Transplantations Without Splenectomy, Using Antigen‐Specific Immunoadsorption
and Rituximab
Volume 5, Issue 1, pages 145-148, 4 OCT 2004 DOI: 10.1111/j.1600-6143.2004.00653.x
• Rituximab (375 mg/m2) given 1
month prior to transplant
• 1 week prior to IA, start
conventional triple
immunosuppression:

and Rituximab
• Four preTxp apheresis sessions
(day -6, -5, -2, -1)
• If target titer <8 was not achieved
after four sessions, the Txp was
postponed for 1 week and four more
sessions were performed.
• After last preop apheresis, 0.5 g/kg of
IVIG was administered

and Rituximab
• Postop, 3 more apheresis
sessions on day +3, +6, and +9
• If there was a 2 step increase in
Ab titer, extra sessions were
considered.

Tyden 2005 (Sweden)
• No acute rejection episodes, either humoral or cellular.
• No late reappearance of antibodies
• No serious infection complications

Is Rituximab Necessary?
• Rituximab negatives
•Increased infection risk
•Increased malignancy risk
•Cost

Montgomery 2009
• Splenectomy-free and Rituximab-free ABOi-KT protocol
• Each plasmapheresis treatment is immediately followed by 100
mg/kg of CMVIg (IVIg)
• In all cases, the titer was reduced to ≤ 16 before transplant.
• Number of treatments was estimated based on the starting Ab titer
Montgomery RA, et al. Transplantation. 2009;87(8):1246.

TABLE 1.
ABO Incompatible Renal Transplantation: A Paradigm Ready for Broad
Implementation.
Montgomery, Robert; Locke, Jayme; King, Karen; Segev, Dorry; Warren,
Daniel; Kraus, Edward; Cooper, Matthew; Simpkins, Christopher; Singer,
Andrew; Stewart, Zoe; Melancon, J; Ratner, Lloyd; Zachary, Andrea; Haas,
Mark
DOI: 10.1097/TP.0b013e31819f2024
• Additional postTxp treatments were delivered for high starting titers, antibody rebound, or AMR.

ABO Incompatible High‐Titer Renal Transplantation without Splenectomy or Anti‐CD20 Treatment
Volume 5, Issue 10, pages 2570-2575, 28 JUL 2005 DOI: 10.1111/j.1600-6143.2005.01031.x
• FK and MMF begin on the first day of preTxp PP/IVIg
• Induction with daclizumab (as previously described)

ABO Incompatible High‐Titer Renal Transplantation without Splenectomy or Anti‐CD20 Treatment
Volume 5, Issue 10, pages 2570-2575, 28 JUL 2005 DOI: 10.1111/j.1600-6143.2005.01031.x
• Ab titers were determined using
standard serological techniques (tube
test) and then converted to the anti-
human globulin test phase.
• Ab titers were monitored
• before and after each PP/IVIg
• 72 hrs after the last PP/IVIg
• weekly for the first month
• at 2, 3, 6, and 12 months.

Montgomery 2009
Subjects
• Between 1999-2007, 60 patients received a live donor ABOi-KT
• 28 patients were on a splenectomy-free and rituximab-free
protocol (Second Era)
• Surveillance biopsies were performed 1 hr post-reperfusion and at
1, 3, 6, and 12 months

TABLE 2.

TABLE 3.

TABLE 4.
Implementation.
Mark
DOI: 10.1097/TP.0b013e31819f2024
No death censored graft losses in the Second Era

TABLE 5.

TABLE 6.
Implementation.
Mark
DOI: 10.1097/TP.0b013e31819f2024
TABLE 6. Incidences of acute rejection episodes among ABO incompatible
kidney transplant recipients transplanted at Johns Hopkins Hospital between
1999 and 2007
No DGF, hyperacute
rejection, or graft
losses from AMR.

Montgomery 2009
Second Era-No Splenectomy or Rituximab
• 28 patients desensitized without splenectomy and anti-CD20.
• Median starting titer was 128 (range, 16–512)--same as the first era.
• 5 clinical and 3 subclinical cases of AMR.
• Median SCr and CrCl are 1.3 mg/dL (range, 0.7–2.7 mg/dL) and 60.5
mL/min (range, 32.6–167.5 mL/min), respectively.
• Mean 1-year delta SUM score was 1.7.
• The only statistically significant difference between the two eras was
the length of follow-up, which was 21 months (range, 0.4–43.5
months) in era 2.

Montgomery 2009
Overall Cohort Summary
• The 1-, 3-, and 5-year graft survival rates for the entire ABOi-KT
cohort is comparable with UNOS data for compatible live donor
transplants.
• No hyperacute rejection, no grafts lost to AMR
• <15% of recipients had clinical AMR and rejections were mild.
• Elimination of B-cell ablative therapies did not result in an increased
AMR.
• Excellent graft function persists with a current median creatinine
clearance of 60 mL/min.

SRTR Analysis
• 738 U.S. patients underwent
live donor ABOi-KT between
1995-2010
• Compared to matched ABO
compatible (ABOc) live donor
kidney recipients
Montgomery JR, et al. Transplantation. 2012 March 27; 93(6): 603–609.

• Patient survival was not significantly different
• Graft loss was significantly higher with ABOi-KT, particularly in the first 14 days
post-transplant, with little to no difference beyond day 14.

SRTR Analysis
• In subgroup analyses among ABOi recipients, no differences in
survival were seen by
• donor blood type,
• recipient blood type,
• or transplant center ABOi volume

Other Experimental ABOi-KT Protocols
• An Australian center reported a series of ABOi-KT using conventional
immunosuppression alone (no TPE, no B-cell depletion) in patients
with low baseline Ab titers (1)
• The Stanford group reported a series using preTxp TPE but no postTxp
TPE.
• They also utilized high-dose IVIG, rituximab and ATG in addition to FK, MMF,
and prednisone (2)
1. Masterson R, et al. Am J Transplant. 2014 Dec;14(12):2807-13.
2. Yabu JM, Fontaine MJ. J Clin Apher. 2015 Mar 5. doi: 10.1002/jca.21390. [Epub ahead of print]

UF Health ABO Incompatible Living Donor
Kidney Transplant Protocol Proposal
• Model after the Johns Hopkins protocol (Montgomery 2009)
• No splenectomy and no rituximab
• Each TPE (1-1.5 plasma volume) followed by low dose IVIG (100mg/kg)
• PreTxp TPE/IVIG on even days prior to surgery (day -2, -4, etc.)
• PostTxp TPE/IVIG on odd days after surgery (day +1, +3, etc.)

• # pre/post treatments determined by sliding scale

• FK (0.1mg/kg/day) and MMF (2g/day) to start on first day of TPE/IVIG
or 1 week prior to transplant, whichever first
• Instead of daclizumab, induction with basiliximab 20 mg IV on POD #0
and POD #4
Segev DL, et al.
Am J Transplant. 2005 Oct;5(10):2570-5.

• Target preTxp ABO Ab titer ≤ 8. If titer >8, then additional TPE/IVIG
therapies may be required
• ABO Antibody Monitoring Schedule
Time
Period
Pre-Transplant Immediate Post-
Transplant
Post
Discharge
Month
2
Month
3
Month
6
Long Term
Testing
Frequency
-Before and After
every TPE
(or only before
initial TPE and
after every TPE?)
-Day of Transplant
Prior to surgery
-Before and After
every TPE
(or only before first
post TPE and after
every TPE?)
-72 hours after last
TPE
Weekly up
to 1 month
once once once For Cause
Only

ABO Incompatible Kidney Transplantation, Michael Casey, MD (W-0007)

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