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ABO incompatible kidney ABO incompatible kidney transplantationtransplantation
Ulla B. Berg, Division of PediatricsUlla B. Berg, Division of Pediatrics
The presentation is based on slides from Gunnar Tydén and Helena The presentation is based on slides from Gunnar Tydén and Helena Genberg, Division of Transplantation Surgery,Genberg, Division of Transplantation Surgery,
Dept. of Clinical Science, Intervention and Technology, Dept. of Clinical Science, Intervention and Technology,
Karolinska University Hospital Huddinge, Stockholm, SwedenKarolinska University Hospital Huddinge, Stockholm, Sweden
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2
Reasons to increase the number of Reasons to increase the number of living donor renal transplantsliving donor renal transplants
The increasing discrepancy between the The increasing discrepancy between the number of available deceased donor organs number of available deceased donor organs and the number of patients on the waiting listand the number of patients on the waiting list
The superior graft and patient survival rates The superior graft and patient survival rates obtained with living donor transplantsobtained with living donor transplants
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0102030405060708090
100
0 2 4 6 8 10Years after transplantation
Gra
ft s
urv
iva
l, %
LD (n=363)DD (n=626)
0102030405060708090
100
0 2 4 6 8 10Years after transplantation
Gra
ft s
urv
iva
l, %
LD (n=363)DD (n=626)
Kidney transplantations in Stockholm Kidney transplantations in Stockholm 1990-20021990-2002
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Kidney transplantations in Stockholm Kidney transplantations in Stockholm 1990-20021990-2002
10 year survival10 year survival
Graft (%)Graft (%) Patient (%)Patient (%)
Living donorLiving donor 7070 8585
Deceased donorDeceased donor 4040 5555
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5
Evolution of living donor programmesEvolution of living donor programmes
Parents, HLA- identical or Parents, HLA- identical or haploidentical siblingshaploidentical siblings
SpousesSpousesHLA-incompatible siblingsHLA-incompatible siblings
Emotionally related donorsEmotionally related donors
Non-directed donationNon-directed donationPaired exchangePaired exchange
Blood group incompatibleBlood group incompatible
Cross match positiveCross match positive
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6
Oag
anti A Abanti B Ab
AagBag
no Ab
Aag
(A1 ~36%, A2 ~9%)
anti B Ab
Bag
anti A ab
40%
5%
45% 10%
The likelihood that two The likelihood that two unrelated individuals are:unrelated individuals are:- identical is 37.5%- identical is 37.5%- compatible is 26.75%- compatible is 26.75%- incompatible is 35.75%- incompatible is 35.75%
The likelihood that two The likelihood that two unrelated individuals are:unrelated individuals are:- identical is 37.5%- identical is 37.5%- compatible is 26.75%- compatible is 26.75%- incompatible is 35.75%- incompatible is 35.75%
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Immunohistochemistry for detection of Immunohistochemistry for detection of A antigen in a blood group AA antigen in a blood group A11 kidney kidney
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8
A1 A2A2
Breimer et al Transplantation 82: 479, 2006
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Previous experience in APrevious experience in A11 and B and B
AB0-incompatible kidney transplantationAB0-incompatible kidney transplantation
Year of first transplantation:Year of first transplantation:
1955: Boston, Massachussets, USA, (Hume et al.)1955: Boston, Massachussets, USA, (Hume et al.)
8/10 grafts were lost in hyperacute rejection within the first week8/10 grafts were lost in hyperacute rejection within the first week
1960: Murray1960: Murray
1964 Starzl 1964 Starzl
Occassional patients survivedOccassional patients survived
Overall very poor resultsOverall very poor results
Therefore ABO incompatibility was considered an absolute Therefore ABO incompatibility was considered an absolute
contraindication to kidney transplantationcontraindication to kidney transplantation
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Previous experience in APrevious experience in A2 2 AB0-incompatible AB0-incompatible
kidney transplantationkidney transplantation Year of publication:Year of publication: 1987: Gothenburg, Sweden (Breimer, Rydberg et al) (n=23)1987: Gothenburg, Sweden (Breimer, Rydberg et al) (n=23) 1987: London, UK (Welsh et al.) (n=16)1987: London, UK (Welsh et al.) (n=16) 1998: Kansas, USA (Nelson et al.) (n=50)1998: Kansas, USA (Nelson et al.) (n=50) 1999: Portland, Oregon, USA (Alkhunaizi et al.) (n=15)1999: Portland, Oregon, USA (Alkhunaizi et al.) (n=15) 2001: Salt Lake City, Utah, USA (Sorensen et al.) (n=15)2001: Salt Lake City, Utah, USA (Sorensen et al.) (n=15)
Between 1974-1988 23 DD kidney Between 1974-1988 23 DD kidney transplantations across the Atransplantations across the A22 barrier were barrier were
performed, using regular immunosuppression performed, using regular immunosuppression
1-year graft survival was approx. 55%.1-year graft survival was approx. 55%.
Between 1974-1988 23 DD kidney Between 1974-1988 23 DD kidney transplantations across the Atransplantations across the A22 barrier were barrier were
performed, using regular immunosuppression performed, using regular immunosuppression
1-year graft survival was approx. 55%.1-year graft survival was approx. 55%.
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11
Previous experience in APrevious experience in A11 and B and B
AB0-incompatible kidney transplantationAB0-incompatible kidney transplantationYear of first transplantation:Year of first transplantation:
1955: Boston, Massachussets, USA, (Hume et al.)1955: Boston, Massachussets, USA, (Hume et al.)
1960: Murray1960: Murray
1964 Starzl 1964 Starzl
1981: Portsmouth, UK (Slapak et al.)1981: Portsmouth, UK (Slapak et al.)
1982: Brussels, Belgium (Alexandre et al.) (n=26)1982: Brussels, Belgium (Alexandre et al.) (n=26)
1989: Japan (Tanabe et al.)1989: Japan (Tanabe et al.)
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Present experiences in a series of 26 ABO-incompatible Present experiences in a series of 26 ABO-incompatible living donor renal allograftsliving donor renal allografts
Alexandre GPJ, Squifflet JP et alAlexandre GPJ, Squifflet JP et alTranplantation Proceedings vol XIX no 6 1987 pp 4538-4542Tranplantation Proceedings vol XIX no 6 1987 pp 4538-4542
donor specific platelet transfusiondonor specific platelet transfusion
plasmapheresis plasmapheresis
splenectomysplenectomy
cyclosporin A, prednisolone, azathioprine cyclosporin A, prednisolone, azathioprine
polyclonal Abs (ALG or ATG)polyclonal Abs (ALG or ATG)
substance A or B substance A or B
3 not splenectomized recipients hyperacutely rejected 3 not splenectomized recipients hyperacutely rejected their grafts during the first postoperative week their grafts during the first postoperative week
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Plasma separation
Replacement fluid(albumin, plasma)
Plasma discarded
Plasma exchangePlasma exchange
blood cells
plasma
Disadvantages:Disadvantages:
LimitedLimited efficacy due to restrictions to the plasma volume processed. efficacy due to restrictions to the plasma volume processed.
All plasma components are reduced including coagulation factors.All plasma components are reduced including coagulation factors.
Fluid replacement is necessary.Fluid replacement is necessary.
Disadvantages:Disadvantages:
LimitedLimited efficacy due to restrictions to the plasma volume processed. efficacy due to restrictions to the plasma volume processed.
All plasma components are reduced including coagulation factors.All plasma components are reduced including coagulation factors.
Fluid replacement is necessary.Fluid replacement is necessary.
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Lessons learned from ABO-incompatible living donor Lessons learned from ABO-incompatible living donor kidney transplantation: 20 years later.kidney transplantation: 20 years later.
Squifflet JP, De Meyer M, Malaise J, Latinne D, Pirson Y, Alexandre GPSquifflet JP, De Meyer M, Malaise J, Latinne D, Pirson Y, Alexandre GP. . Exp Clin Transplant. 2004 2:208-13.Exp Clin Transplant. 2004 2:208-13.
– ““Pretransplant therapies included Pretransplant therapies included platelets donor platelets donor transfusiontransfusion, 2 to 5 , 2 to 5 plasmapheresisplasmapheresis sessions, sessions, cyclosporin cyclosporin A with or without azathioprineA with or without azathioprine along with along with polyclonal Abspolyclonal Abs and and splenectomy splenectomy at the time of transplantation. After the at the time of transplantation. After the last plasmapheresis session, when the level of 1/4 (ABO last plasmapheresis session, when the level of 1/4 (ABO antibodies) was reached, all recipients received antibodies) was reached, all recipients received 5 mL of 5 mL of substance A or B.” substance A or B.”
39 ABO incompatible living donor grafts39 ABO incompatible living donor grafts
Exp Clin Transplant. 2004 2:208-13.
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15Exp Clin Transplant. 2004 2:208-13
<15 y
>15 y
78%
59%
39 ABOi tx
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16
39 ABOi tx Rec. <15 y
N=38
N=8
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RRemoval ofemoval of A Antinti-A/B -A/B antibodies antibodies
Double-filtration plasmapheresisDouble-filtration plasmapheresis (390) (390)
Protein A immunoadsorptionProtein A immunoadsorption (51) (51)
Cessation of the Cessation of the AAntinti-A/B -A/B antibody productionantibody production
SplenectomySplenectomy (433)(433)
((CyclophosphamideCyclophosphamide))
((DeoxyspergualinDeoxyspergualin))
Anticoagulation therapyAnticoagulation therapy
(ATG or ALG)(ATG or ALG)
Maintenance Maintenance triple triple immunosuppressionimmunosuppression
PProtocol for AB0i transplantationrotocol for AB0i transplantation in Japan in Japan
Takahashi K, et al. Am J Transplant 2004;4:1089–96
441 patients 1989 - 2001 441 patients 1989 - 2001
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Plasma separation
filtration/centrifugation
Replacement fluid(albumin + Ringers)
IgG/IgM fraction discarded
Double-filtration Double-filtration plasmapheresisplasmapheresis
blood cells
plasma Plasma fractionator
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RRemoval ofemoval of A Antinti-A/B -A/B antibodies antibodies
Double-filtration plasmapheresisDouble-filtration plasmapheresis (390) (390)
Protein A immunoadsorptionProtein A immunoadsorption (51) (51)
Cessation of the Cessation of the AAntinti-A/B -A/B antibody productionantibody production
SplenectomySplenectomy (433)(433)
((CyclophosphamideCyclophosphamide))
((DeoxyspergualinDeoxyspergualin))
Anticoagulation therapyAnticoagulation therapy
(ATG or ALG)(ATG or ALG)
Maintenance Maintenance triple triple immunosuppressionimmunosuppression
PProtocol for AB0i transplantationrotocol for AB0i transplantation in Japan in Japan
Takahashi K, et al. Am J Transplant 2004;4:1089–96
441 patients 1989 - 2001 441 patients 1989 - 2001
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ABO-incompatible kidney transplantations in JapanABO-incompatible kidney transplantations in Japan NN YearYear
Incomp. Tx Incomp. Tx 441 441 1989-20011989-2001Historical controlsHistorical controls 10551055 1986-19951986-1995
Takahashi K, et al. Am J Transplant 2004;4:1089–96
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21Takahashi K, et al. Am J Transplant 2004;4:1089–96
Graft survival rate according to recipient ageGraft survival rate according to recipient age
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Present protocol for ABO- incompatible Present protocol for ABO- incompatible kidney transplantationskidney transplantations
Removing existing ABO-antibodiesRemoving existing ABO-antibodiesAntigen-specific immunoadsorption (GlycosorbAB0®)Antigen-specific immunoadsorption (GlycosorbAB0®)
Preventing rebound of ABO-antibodiesPreventing rebound of ABO-antibodies
Rituximab (MabtheraRituximab (Mabthera®®))
Tacrolimus/MMF/prednisoloneTacrolimus/MMF/prednisolone
IVIG (GammagardIVIG (Gammagard®®))
Postop preemptive immunadsorptionPostop preemptive immunadsorption
Am J Transplant. (2005) 5:145-8
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Antigen-specific immunoadsorption Antigen-specific immunoadsorption
XXX
Glycosorb ABO column
Y YY
Y
Y
YYY
Transplantation 2003 ;76:730-731
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Present protocol for ABO- incompatible Present protocol for ABO- incompatible kidney transplantationskidney transplantations
Removing existing ABO-antibodiesRemoving existing ABO-antibodiesAntigen-specific immunoadsorption (GlycosorbAB0®)Antigen-specific immunoadsorption (GlycosorbAB0®)
Preventing rebound of ABO-antibodiesPreventing rebound of ABO-antibodies
Rituximab (MabtheraRituximab (Mabthera®®))
Tacrolimus/MMF/prednisoloneTacrolimus/MMF/prednisolone
IVIG (GammagardIVIG (Gammagard®®))
Postop preemptive immunadsorptionPostop preemptive immunadsorption
Am J Transplant. (2005) 5:145-8
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25
–30 –13 –6 –4 –2 Tx 2 4 6 8 10 12
1:128
1:64
1:32
1:16
1:8
1:4
1:21:1
<1:1
An
ti-A
1 Ig
G t
itre
Glycosorb
IVIG (0.5 g/kg)Rituximab 375 mg/kg
Tacrolimus/MMF/prednisolone
Time (days)
Am J Transplant. (2005) 5:145-8
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26Am J Transplant. (2005) 5:145-8
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AB0 -incompatible kidney transplantation AB0 -incompatible kidney transplantation using antigen-specific immunoadsorption and using antigen-specific immunoadsorption and rituximab: a 3-year follow-uprituximab: a 3-year follow-up
Genberg H et al Transplantation 85:1745-1754, 2008
ABO-incomp.ABO-incomp. ABO-compABO-comp..
AdultsAdults 1515 3030
Mean rec.ageMean rec.age 35.135.1 42.442.4
Mean don.ageMean don.age 52.852.8 49.049.0
ChildrenChildren 5 5 1818
Mean rec.ageMean rec.age 8.6 8.6 7.8 7.8
Mean don.ageMean don.age 42.542.5 42.842.8
Grafted during the same time periodGrafted during the same time period
In adults: the same basic immunosuppression In adults: the same basic immunosuppression
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Rejection episodes in adult kidney recipients Rejection episodes in adult kidney recipients
ABO-incomp.ABO-incomp. ABO-comp.ABO-comp.
N=15N=15 N=30N=30
Acute rejection (total)Acute rejection (total) 11 (7%)(7%) 44 (13%)(13%) n.s.n.s.
Antibody-mediated rej.Antibody-mediated rej. 00 (0%)(0%) 11 (3%)(3%) n.s.n.s.
Cellular rejectionsCellular rejections 11 (7%)(7%) 33 (10%)(10%) n.s.n.s.
Chronic allograft nephrop.Chronic allograft nephrop. 00 (0%)(0%) 22 (7%)(7%) n.s.n.s.
Genberg H et al Transplantation 85:1745-1754, 2008
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Rejection episodes in child kidney recipients Rejection episodes in child kidney recipients
ABO-incomp.ABO-incomp. ABO-comp.ABO-comp.
N=5N=5 N=18N=18
Acute rejection (total)Acute rejection (total) 00 (0%)(0%) 33 (17%)(17%) n.s.n.s.
Antibody-mediated rej.Antibody-mediated rej. 00 (0%)(0%) 00 (0%)(0%) n.s.n.s.
Cellular rejectionsCellular rejections 00 (0%)(0%) 33 (17%)(17%) n.s.n.s.
Patient survivalPatient survival 100%100% 100%100%
Graft survivalGraft survival 100%100% 95% 95%
Genberg H et al Transplantation 85:1745-1754, 2008
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30
0.0
0.2
0.4
0.6
0.8
1.0
0 12 24 36 48 60
ABOi: n=15
ABOc: n=30
Patients at risk: Day 0 12M 24M 36M 48M 60MAB0i 15 13 10 7 4 1AB0c 30 23 22 18 8 4
Time after transplantation in months
Using chi-square test: p=ns
Cumulative event-free survival (months) in adult Cumulative event-free survival (months) in adult kidney recipients kidney recipients
Event: rejection, graft loss or deathEvent: rejection, graft loss or death
Genberg H et al Transplantation 85:1745-1754, 2008
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Post-transplant infections (adults)Post-transplant infections (adults)
0%
10%
20%
30%
40%% of patients
UTI Sepsis CMV Surgicalwound
infection
Clostridiumdifficile
EBV BKVAN Invasivefungal
infection
Otherserious
infections
ABOc (n=30)
ABOi (n=15)
p=ns
Genberg H et al Transplantation 85:1745-1754, 2008
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32
0
25
50
75
100
125
1 year 2 years 3 years
ABOi (mean)
ABOc (mean)
p=ns
Mean-GFR and 95% CI in adults Mean-GFR and 95% CI in adults
-comparing AB0i and AB0c kidney recipients-comparing AB0i and AB0c kidney recipients
Genberg H et al Transplantation 85:1745-1754, 2008
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33
0
20
40
60
80
100
120
140
160
180
3 m 1 2 3
ABOi
ABOc
GF
R (
ml/m
in/1
.73
m2
Time after transplantation (years)
GFR after tx in AB0c and AB0i childrenGFR after tx in AB0c and AB0i children
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34
Growth after tx in AB0c and AB0i childrenGrowth after tx in AB0c and AB0i children
A t tx 1 2 3
T ime (years)
-3 ,0
-2 ,5
-2 ,0
-1 ,5
-1 ,0
-0 ,5
0,0
0,5
1,0
1,5
He
ight S
DS
A B O c
A B O i
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35
What happens to the A/B antibodies followingWhat happens to the A/B antibodies following
AB0i kidney transplantation using antigen-specificAB0i kidney transplantation using antigen-specific
immunoadsorption and rituximab?immunoadsorption and rituximab?
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B O
0
8
-10 -8 -6 -4 -2 0 2 4 6 8 10 12
Days
An
ti B
Ig
G t
ite
r
128
64
32
16
8
4
2
1<1
Glucosorb
IVIG
Prograf/Cellcept/Prednisolone
Rituximab
-13-30 Tx
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A1 O
0
8
-10 -8 -6 -4 -2 0 2 4 6 8 10 12
Days
An
ti A
1 I
gG
tit
er
128
64
32
16
8
4
2
1<1
GlucosorbTx
IVIG
Prograf/Cellcept/Prednisolone
Rituximab
-13-30 Tx
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0
2
4
6
8
0 17
Months
LO
G 2
An
ti A
/B I
gG
tit
re
Pre tx 3 - 4 5 - 7 13 - 24
Median Ig G, n=20
8 - 12 >24
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0
1
2
3
4
5
6
7
8
9
0 4L
OG
2 A
nti
A Ig
G t
itre
0
1
2
3
4
5
6
7
0 4
LO
G 2
An
ti B
Ig
G t
itre
Tx cancelled
Tx cancelled
Tx cancelled
RituximabGlycosorb2005-05
RituximabGlycosorb2003-10
RituximabGlycosorb2003-09
Follow up2006-03
Follow up2006-05
Follow up2006-03
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0
2
4
6
8
0 2 4 6 8 10 12 14 16 18 20 22Days
LO
G 2
An
ti A
Ig
G t
itre
TxTx ectArterial thrombosis
0
2
4
6
8
0 2 4 6 8 10 12 14 16 18 20 22Days
LO
G 2
An
ti B
Ig
G t
itre Tx
Tx ectVenous thrombosis
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LD
0
2
4
6
8
0 2 4 6 8 10 12 14 16 18 20 22
LO
G 2
An
ti B
Ig
G t
itre
Tx
2007-01 2007-04
HD
Days
2006-01
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42
60 consecutive transplantations60 consecutive transplantations
27 A1 (A/O, A/B, AB/B)
24 B (B/O, B/A, AB/A)
9 A2 (A/O,A/B) major incompatibilities
One patient died with functioning graft after 4 months
One graft was lost in non compliance after 22 months
All the remaining 58 grafts have normal function at a
follow up of 1 - 60 months
Tydén G et al Transplantation 2007 83:1153-1155
The Stockholm/Freiburg/Uppsala experience with The Stockholm/Freiburg/Uppsala experience with ABO incompatible transplantationsABO incompatible transplantations
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43Tydén G et al Transplantation 2007 83:1153-1155
NN ActualActual graftgraft ActualActual Follow-upFollow-upsurvivalsurvival S-creatinineS-creatinine monthsmonths
(mean (min-max)(mean (min-max)
ABO incomp.ABO incomp. 6060 97%97% 127 127 (42-203)(42-203) 17.5 17.5 (2-61) (2-61)
ABO comp.ABO comp. 274274 95%95% 133 133 (53-360)(53-360) 21.1 21.1 (2-63) (2-63)
The Stockholm/Freiburg/Uppsala experience with The Stockholm/Freiburg/Uppsala experience with LD kidney transplantations performed 2002-2006LD kidney transplantations performed 2002-2006
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44
nn Ab-titreAb-titre Ab-titreAb-titre Cancelled txCancelled tx Mean no Mean no preop.preop.
rangerange medianmedian >8 adsorp.>8 adsorp. adsorptionsadsorptions
StockholmStockholm 2626 1:1-1:1281:1-1:128 1:321:32 33 4.24.2
FreiburgFreiburg 2121 1:8-1:10241:8-1:1024 1:1281:128 55 77
UppsalaUppsala 1313 1:1-1:321:1-1:32 1:81:8 00 3.93.9
Tydén G et al Transplantation 2007 83:1153-1155
The Stockholm/Freiburg/Uppsala experience with The Stockholm/Freiburg/Uppsala experience with ABO incompatible transplantationsABO incompatible transplantations
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The European experienceThe European experience
– SwedenSweden– StockholmStockholm– GothenburgGothenburg– UppsalaUppsala– MalmöMalmö– GermanyGermany– FreiburgFreiburg– HannoverHannover– BerlinBerlin– HeidelbergHeidelberg– MannheimMannheim– HamburgHamburg– StuttgartStuttgart– ErlangenErlangen– FrankfurtFrankfurt– BochumBochum– The NetherlandsThe Netherlands– RotterdamRotterdam
– United KingdomUnited Kingdom– LondonLondon– BirminghamBirmingham– CoventryCoventry– SwitzerlandSwitzerland– BaselBasel– ZurichZurich– NorwayNorway– OsloOslo– DenmarkDenmark– CopenhagenCopenhagen– GreeceGreece– AthensAthens– SpainSpain– BarcelonaBarcelona– AustraliaAustralia– MelbourneMelbourne
25 centres 25 centres
> 200 kidney > 200 kidney transplantationstransplantations
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46
General conclusionGeneral conclusion
AB0i renal transplantation without splenectomy, canAB0i renal transplantation without splenectomy, can be be
performed with excellent results, using antigen-specific performed with excellent results, using antigen-specific
immunoadsorption in combination with a single-dose of immunoadsorption in combination with a single-dose of
rituximab and a single-dose of IVIG in combination with rituximab and a single-dose of IVIG in combination with
standard immunosuppression standard immunosuppression
5 year graft survival is equivalent to standard AB0 5 year graft survival is equivalent to standard AB0
compatible living donorscompatible living donors
Antigen-specific immunoadsorption in combination with Antigen-specific immunoadsorption in combination with
rituximab effectively depletes anti-A/B antibodiesrituximab effectively depletes anti-A/B antibodies
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47
General conclusionGeneral conclusion
There is no significant rebound of anti-A/B antibodies although There is no significant rebound of anti-A/B antibodies although
splenectomy is not performed splenectomy is not performed
A persistent low-grade anti-A/B antibody production following A persistent low-grade anti-A/B antibody production following
AB0i kidney transplantation is common but does not have any AB0i kidney transplantation is common but does not have any
negative impact on graft functionnegative impact on graft function
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AcknowledgementAcknowledgement
Gunnar TydénGunnar Tydén Transplantation surgery, Karolinska University Hospital Transplantation surgery, Karolinska University Hospital
Gunilla Kumlien Transfusion medicine, Karolinska University HospitalGunilla Kumlien Transfusion medicine, Karolinska University Hospital
Helena Genberg Transplantation surgery, Karolinska University Hospital Helena Genberg Transplantation surgery, Karolinska University Hospital
John SandbergJohn Sandberg
Amir SedighAmir Sedigh
Torbjorn LundgrenTorbjorn Lundgren
Lars WennbergLars Wennberg
Henrik GjertsenHenrik Gjertsen
Ingela Fehrman Nephrology, Karolinska University Hospital Ingela Fehrman Nephrology, Karolinska University Hospital
Gunnar Tufveson Transplantation, Uppsala Academic HospitalGunnar Tufveson Transplantation, Uppsala Academic Hospital
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49
Extra costs for the Extra costs for the procedureprocedure
€ €
GlycosorbGlycosorb 10.000 – 10.000 – 40.00040.000
Apheresis (seven sessions at €1,000)Apheresis (seven sessions at €1,000) 4.000 – 4.000 – 12.00012.000
Rituximab (one dose)Rituximab (one dose) 1.8001.800
IVIG 0.5g/kg (one dose)IVIG 0.5g/kg (one dose) 1.0001.000
TotalTotal 16.800 – 16.800 – 54.80054.800