ABO-Incompatible Kidney Transplant Outcomes: A Meta-Analysis : Clinical Journal of the American Society of Nephrology

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Original Articles: Transplantation

ABO-Incompatible Kidney Transplant Outcomes

A Meta-Analysis

de Weerd, Annelies E.; Betjes, Michiel G.H.

Author Information

Department of Nephrology and Kidney Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands

Correspondence: Dr. Annelies E. de Weerd, Department of Nephrology and Transplantation, Erasmus Medical Center, Room Rg-529, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Email: [email protected]

Clinical Journal of the American Society of Nephrology 13(8):p 1234-1243, August 2018. | DOI: 10.2215/CJN.00540118
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Abstract

Introduction

Desensitization protocols have allowed for successful transplantation of kidney allografts across the ABO blood group barrier. Pioneering centers in ABO-incompatible kidney transplantation have published patient and graft survival rates comparable to ABO-compatible transplantations (1–3). These reassuring outcomes combined with long waiting times for deceased-donor kidneys and the shortage of available living donors have led to a broader implementation of ABO-incompatible transplantation. It accounts for one fourth of living donor transplantations in German centers (4,5) and almost one third of procedures in Japanese centers (6,7).

Therefore, a kidney transplant candidate with an ABO-incompatible living donor has options to wait for a deceased ABO-compatible donor (remain on dialysis), participate in a kidney exchange program (if operative), or proceed with desensitization for ABO-incompatible transplantation. In order to ensure the ability to make an informed decision about which option to choose, the additive risk of desensitization for ABO-incompatible donor-recipient pairs should be known.

Data on the potential additive risk of ABO-incompatible kidney transplantation have been deduced from registry and cohort studies. Recent cohort studies have shown no significant difference in graft and patient survival compared with ABO-compatible kidney transplantation (5,8,9). The largest registry study with ABO-compatible controls is from the Collaborative Transplant Study (10,11). Three-year patient survival was not significantly lower; however, there was more infection-related mortality. A registry study from Korea reports comparable graft survival rates, with a trend toward inferior patient survival (12). Registries from the United States reveal somewhat different results with more early graft loss and equal or inferior patient survival (13,14), but these registries also contain splenectomized patients. A disadvantage of these registries is the uncertainty about completeness and quality of data, and inclusion of patients treated with different desensitization protocols, limiting external validity.

For these reasons we have performed a meta-analysis of single-center cohort studies published with a control group consisting of patients who were ABO-compatible from the same hospital. Information from such a meta-analysis includes a large number of patients allowing the ability to identify risk differences in relative rare events like patient death and graft loss across different desensitization regimes.

The primary objective of the meta-analysis was to compare the risk for graft and patient survival after ABO-incompatible versus ABO-compatible kidney transplantation. As secondary outcomes the differences in risk for acute rejection, infectious complications, and postoperative bleeding were analyzed.

Materials and Methods

We have performed the meta-analysis according to guidelines for observational studies as described in the Meta-analyses Of Observational Studies in Epidemiology study (15).

Literature Search Strategy

Research Database.

The meta-analysis is a sequel of a systematic literature search to create an ABO-incompatible research database. This original search was carried out in Embase, Medline, Cochrane, Web-of-Science, and Google Scholar. The broad index terms are described in Supplemental Table 1 and identified all studies on ABO-incompatible kidney transplantation published till July 1st 2017. Studies were screened for relevance to this database: eligibility criteria were medical aspects of kidney transplantation (excluding studies on financial aspects). A limitation was English language only and case reports were excluded. Search results were analyzed in Endnote. This database was built in Excel and categorized studies according to topic(s).

Meta-Analysis.

Next, studies in this database were screened for inclusion in the meta-analysis by two independent researchers, A.E.d.W. and M.G.H.B. (both nephrologists). Eligible were all single-center studies comparing patients who were ABO-incompatible with ABO-compatible controls reporting patient and graft survival. Conference abstracts were excluded. Reports usually define an era with splenectomy and a “modern” era with rituximab induction, with improved outcomes in the latter (7,16). For this reason the older studies using splenectomy were excluded. Studies on combined HLA-incompatible and ABO-incompatible transplantation were excluded, as were studies on deceased donor kidney allografts. The final step was to identify unique patients by excluding overlapping reports from the same center. Authors were contacted via Email and ResearchGate to ask for missing data and (if available) for 3-year follow-up data.

Data Collection and Data Items

The following items were identified in the included studies and reported in Excel:

Patients and Controls.

Patients were all living patients who received ABO-incompatible kidney transplant during the study period of the included study who were treated without splenectomy. Controls were either consecutive (all patients with a living ABO-compatible kidney transplant during the study period) or matched according to the matching criteria of the included study (see quality assessment). In general, studies excluded HLA-incompatible transplantations from their analyses.

Immunoadsorption and Plasmapheresis.

There is no universal ABO-incompatible desensitization protocol and centers differ in immune suppressive therapy and isoagglutinin removal technique. For analysis, studies were divided into centers using (mainly) plasmapheresis versus (mainly) immunoadsorption.

Baseline Patient Characteristics.

Number of patients, recipient and donor age, level of panel-reactive antibodies, donor-specific antibodies, percentage of retransplant, and pre-emptive transplantations were recorded.

Uncensored Graft Survival, Patient Survival.

These outcomes were deduced from Kaplan–Meier survival curves and from numbers and percentages described in the results sections. Uncensored graft survival was established as follows: its numerator was determined by either graft loss or patient death and the denominator was the total number of patients censored for loss to follow-up.

Uncensored graft survival was determined for year 1 and if available year 3. In case of availability of year 3 data, graft survival after 1 year was determined as follows: the numerator was graft survival at year 3 and the denominator was the number of patients censored for follow-up at year 3 and for graft loss and patient death at year 1.

Cause of Death.

Infectious origin versus noninfectious origin (including unknown) causes of death were extracted from the included studies.

Biopsy-proven acute rejections included all (mainly 1-year) biopsy-proven rejections, excluding subclinical and borderline rejections.

BK Viremia.

Studies described any viremia, viremia from a cut-off level onwards, or BK nephropathy. If various BK outcomes were reported, any BK viremia was scored. The outcome BK therefore is heterogeneous, but comparable between patients from the same center. This holds true for cytomegalovirus (CMV) viremia as well.

Severe Nonviral Infection.

For this item heterogeneous outcomes were combined: sepsis, hospitalization for infection for 7 or more days, bacterial infection, sepsis, pneumonia, fungal infection, Pneumocystisjirovecii pneumonia, bacterial requiring hospitalization. Urinary tract infections were excluded.

Bleeding.

This was a combination of postoperative blood transfusion or bleeding leading to surgical intervention, whichever was reported in the included studies.

Follow-up.

Graft survival was analyzed at year 1 and if available year 3. Rejection, infection, and bleeding were censored at year 1 if this information was provided. If not, these outcomes were reported during total follow-up of the individual studies. Studies reported either mean or median follow-up, making it impossible to determine the mean follow-up of patients in the meta-analysis. This mean follow-up was established by approximation: mean follow-up was determined by multiplying the total number of patients in each study by their corresponding (mean or median) follow-up in months, divided by the total number of patients in all included studies.

Risk of Bias Assessment

The Newcastle–Ottawa scale was adopted to assess the quality of the retrospective cohort studies (http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp). Studies were graded according to selection of study groups, comparability of groups, and ascertainment of exposure and outcomes. A maximum of nine stars represents the lowest risk of bias (Supplemental Table 2 Newcastle–Ottawa checklist).

Statistical Analyses

The meta-analysis was performed using Review Manager 5.3 (The Nordic Cochrane Centre, Copenhagen, Denmark). Baseline characteristics were descriptive for continuous variables and reported group means weighed for number of included patients. For the meta-analysis the Mantel–Haenszel analysis method was used. We divided the included studies into two subgroups in advance, defining studies with (mainly) immunoadsorption versus studies with (mainly) plasmapheresis as antibody removal technique. This subgroup analysis was planned because the only meta-analysis about ABO-incompatible kidney transplantation so far compared these desensitization techniques (17). Lo et al. demonstrated inferior outcomes after plasmapheresis. Statistical heterogeneity was formally assessed with I2 (where 0%–40% was considered low heterogeneity) and visually by judging overlap in 95% confidence intervals. Differences between groups were analyzed with relative risk (RR) ratios at fixed time spans. Risk ratios were calculated using a fixed-effect model. If heterogeneity was, however, >40%, a random-effect model was used. Forest plots represent studies in order of year of publication. P<0.05 was considered statistically significant.

Results

Literature Search Results

Figure 1 presents the PRISMA flow chart. After removing duplicates a total of 2728 unique studies were identified. Seven hundred fifty studies were selected for the ABO-incompatible research database, of which 36 described center-matched ABO-incompatible cohorts. Of these, nine were excluded because of missing data on patient and graft survival (18), bias due to description of the ABO-incompatible cohort by selecting only surviving grafts (19), and because of overlap in patients (20–26). Finally, 26 studies were included in the meta-analysis. In these 26 articles, a total of 1346 unique patients who were ABO-incompatible were compared with 4943 center-matched controls. The characteristics of the included studies are shown in Table 1.

fig1
Figure 1.:
Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart of the systematic literature search. ABOc, ABO-compatible; ABOi, ABO-incompatible; vs, versus.
Table 1. - Overview of the included studies in the meta-analysis
Study Period Country ABO-incompatible ABO compatible Controls Desensitization Induction Follow-Up (mo)
Ashimine et al. (16) 2005–09 Japan 51 228 consecutive DFPP all: BAS ABOi: 36
ABOi with titer>8: RTX ABOc: 52
2×200 mg
Barnett et al. (34) 2005–11 England 62 167 consecutive >64: IA all: BAS ABOi: 26
16–64: DFPP ABOi with titer≥8: RTX ABOc: 33
≤8: none 375 mg/m2 (n=2 ABOi: ATZ)
<2008: IVIG
Becker et al. (32) 2005–13 Germany 34 86 Matched IA with IVIG all: BAS ABOi: 22
ABOi: RTX 375 mg/m2 ABOc: 20
Naciri Bennani et al. (35) 2011–15 France 44 44 matched ≥128: DFPP and IA all: DSA or PRA>25%: ATG ABOi: 6
32–64: IA no DSA and PRA≤25%: BAS ABOc: 6
8–16: PE ABOi: RTX 375 mg/m2
≤4 none
Bentall et al. (36) 1999–2006 United States 73 652 consecutive PE with IVIG all: ATG ABOi: 67
ABOc: 73
Flint et al. (37) 2005–08 Australia 37 52 matched PE all: BAS ABOi: 26
<2008: IVIG ABOc: 22
Genberg et al. (1) 2001–05 Sweden 15 30 matched IA with IVIG ABOc: none ABOi: 41
ABOi: RTX 375 mg/m2 ABOc 48
Habicht et al. (38) 2007–09 Germany 21 47 consecutive IA all: BAS ABOi: 17
ABOi: RTX 375 mg/m2 ABOc: 15
Hatakeyama et al. (6) 2006–13 Japan 13 29 consecutive DFPP all: BAS ABOi: 28
ABOi: RTX 100 mg/m2 ABOc: 37
Hwang et al. (39) 2009–11 Korea 35 138 matched PE with IVIG all: BAS ABOi: 24
ABOi: RTX 100–375 mg/m2 ABOc: 24
Iwai et al. (40) 2001–14 Japan 4 16 consecutive DFPP or PE all: BAS ABOi: 39
ABOi: RTX 150 mg/m2 ABOc: 38
Jha et al. (41) 2011–14 India 20 669 consecutive 5 pts: PE with IVIG ABOc: ABOi: 10
12 pts: DFPP 55% BAS, 5% ATG, 40% none ABOc: 17
3 pts: none ABOi: BAS and RTX 200 mg
Kauke et al. (42) 2007–12 Germany 26 52 matched IA ABOc: ABOi: 12
PRA>5%: ATG and BAS ABOc:12
PRA≤5%: none
ABOi: ATG and RTX
Kim et al. (43) 2010–16 Korea 71 726 consecutive PE and IVIG all: BAS ABOi: 27
ABOi: RTX 200 mg ABOc: 42
Kwon et al. (44) 2012–15 Korea 234 600 consecutive PE all: BAS ABOi: 36
ABOi: RTX (n=67: 500 mg; ABOc: 36
n=167: 200 mg)
Lee et al. (45) 2010–14 Korea 97 118 consecutive PE all: BAS ABOi: 34
>128: IVIG ABOi: RTX ABOc: 36
≥128: 375 mg/m2
<128: 200 mg RTX
Melexopoulou et al. (46) 2005–13 Greece 30 30 matched IA or DFPP all: BAS or daclizumab ABOi: 74
ABOi: RTX 375 mg/m2 ABOc: 78
Okumi et al. (7) 2005–13 Japan 144 333 consecutive DFPP all: BAS ABOi: 48
ABOi: RTX 200 mg ABOc: 56
Park et al. (47) 2011–13 Korea 11 21 consecutive DFPP and once PE all: BAS ABOi: 15
ABOi: RTX 200 mg ABOc: 15
Sanchez-Escuredo et al. (48) 2011–13 Spain 30 146 consecutive PE or IA all: BAS or ATG depending on immunologic risk ABOi: 21
ABOi: RTX 2×200 mg ABOc: 21
Schachtner et al. (4) 2005–12 Germany 35 62 matched IA, IVIG all: BAS ABOi: 42
ABOi: RTX 375 mg/m2 ABOc: 37
Shin et al. (8) 2009–12 Korea 73 396 consecutive PE all: BAS ABOi: 39
ABOi: RTX 500 or 200 mg ABOc: 46
Subramanian et al. (9) 2007–12 United States 18 45 matched PE and IVIG all: ATG ABOi: 29
ABOi: RTX 200 mg ABOc: 29
Van Agteren (49) 2006–12 Netherlands 50 100 matched IA and IVIG ABOc: BAS ABOi: 38
ABOi: RTX 375 mg/m2 ABOc: 38
Yokoyama et al. (50) 2008–13 Japan 21 50 consecutive PE all: BAS ABOi: 12
ABOi: RTX ABOc: 12
Zschiedrich et al. (5) 2004–14 Germany 97 106 consecutive IA all: BAS ABOi: 58
ABOi: RTX 375 mg/m2 ABOc: 48
Total 1346 4943
ABOi, ABO-incompatible; ABOc, ABO-compatible; DFPP, double-filtration plasmapheresis; BAS, basiliximab; RTX, rituximab; IA, immunoadsorption; IVIG, intravenous immunoglobulin; ATZ, alemtuzumab; DSA, donor-specific antibodies; PRA, panel-reactive antibodies; ATG, anti-thymoglobulin; PE, plasma exchange.

Baseline Characteristics of Patients Included

Follow-up of ABO-incompatible patients was 37 months versus 40 months in controls (Supplemental Table 4, Table 2). Recipients of ABO-incompatible kidney allografts were slightly older and had younger donors than ABO-compatible controls (recipients 47 versus 45 years and donors 48 versus 49 years in ABO-incompatible versus ABO-compatible). Because the majority of studies lacked SDs for these items, no significance level could be determined. This holds true for total number of HLA mismatches on A, B, and DR loci (3.6 versus 3.1). There were no differences in level of panel-reactive antibodies, donor-specific antibodies, retransplants, and pre-emptive transplantations between patients who were ABO-incompatible and those who were ABO-compatible. As expected, patients who were ABO-incompatible more often received unrelated transplants, although this characteristic was only reported on in the minority of studies.

Table 2. - Baseline characteristics of patients included in the meta-analysis
Characteristic ABO-Incompatible Patients (Studies) ABO-Compatible Patients (Studies)
Follow-up, mo 37 1346 (26) 40 4943 (26)
Age 47 1346 (26) 45 4943 (26)
Donor age 48 940 (22) 49 4029 (22)
Total HLA mismatch 3.6 1208 (23) 3.1 4083 (23)
PRA “any prespecified,” % 15 783 (13) 15 2499 (13)
Donor-specific antibody, % 4 689 (10) 4 2312 (10)
Retransplantation, % 10 1004 (17) 10 3592 (17)
Pre-emptive, % 27 999 (18) 28 4138 (17)
Living-related, % 47 255 (6) 62 a 593 (6)
HLA, human leukocyte antigen; PRA, panel-reactive antibody.
aP<0.001.

Risk of Bias

The risk of bias was low: the majority of studies (13) had no bias item, ten studies had one bias item, and three studies had two bias items (Supplemental Table 3). Examples of these bias items were the use of different calcineurin inhibitors and a shorter follow-up of patients who were ABO-incompatible. Studies were equally divided in consecutive and matched control groups. In the majority of studies criteria for matching were scarcely explained. Supplemental Table 5 provides detailed matching information.

Graft Survival (Uncensored)

All 26 studies reported 1-year graft survival. No study found significant differences between ABO-incompatible and ABO-compatible uncensored graft survival. Combining these data revealed inferior graft survival for patients who were ABO-incompatible (96% versus 98% for controls, P=0.002). The RR for 1-year graft survival was lower in patients who were ABO-incompatible (RR, 0.97; 95% confidence interval [95% CI], 0.96 to 0.98; P<0.001; I2=0%; P=0.47; Figure 2). The subgroup analysis dividing plasmapheresis and immunoadsorption revealed the same pattern (I2=0%; P=0.66 for subgroup differences). Graft survival remained inferior at 3 years (92% versus 94%, P=0.04, Supplemental Figure 1). However, ABO-incompatible grafts surviving after 1 year had comparable outcomes to ABO-compatible controls 3 years after transplantation: uncensored graft survival between 1 and 3 years was 97% for both patients who were ABO-incompatible and those who were ABO-compatible (P=0.70, Supplemental Figure 2).

fig2
Figure 2.:
Forest plot of comparison: Patients with an ABO-incompatible kidney transplant have inferior 1-year uncensored graft survival compared to center-matched ABO-compatible control patients. Subgroup analysis: plasmapheresis versus immunoadsorption. ABOc, ABO-compatible; ABOi, ABO-incompatible; 95% CI, 95% confidence interval; M-H, Mantel-Haenszel.

Patient Survival

One-year patient survival was lower for patients who were ABO-incompatible (98% versus 99%, P=0.03). The RR for 1-year patient survival in patients who were ABO-incompatible was 0.99 (95% CI, 0.98 to 1.00; P<0.01; I2=0%; P=0.66) (Figure 3). Fifteen articles reported on causes of death during the follow-up period. In patients who were ABO-incompatible, 49% of reported causes of death were of infectious origin, versus only 13% in patients who were ABO-compatible (P=0.02; ABO-incompatible: 18 infection, one malignancy, 15 miscellaneous, three unknown versus ABO-compatible: six infection, five malignancy, 24 miscellaneous, three unknown, nine not reported).

fig3
Figure 3.:
Forest plot of comparison: Patients with an ABO-incompatible kidney transplant have lower 1-year patient survival compared to center-matched ABO-compatible control patients. Subgroup analysis: plasmapheresis versus immunoadsorption. ABOc, ABO-compatible; ABOi, ABO-incompatible; 95% CI, 95% confidence interval; M-H, Mantel-Haenszel.

Rejection

Twenty-two studies reported on rejection. Biopsy-proven acute rejection was more common in ABO-incompatible (RR, 1.39; 95% CI, 1.19 to 1.61; P<0.001; I2=38%; P=0.05; Table 3), especially antibody-mediated rejection (RR, 3.86; 95% CI, 2.05 to 7.29; P<0.001; I2=60%; P=0.001; random-effect model; Figure 4, Table 3).

Table 3. - Comparison of complications after ABO-incompatible versus ABO-compatible kidney transplantation
Variable % ABO-Incompatible (Events/Total) % ABO-Compatible (Events/Total) RR (95% CI) P Value
Infection
 Severe nonviral infection 12 (105 of 876) 6 (163 of 2666) 1.44 (1.13 to 1.82) <0.01
 CMV 22 (210 of 976) 19 (465 of 2462) 1·0.20 (1.04 to 1.37) 0.01
 BK 14 (121 of 875) 8 (215 of 2644) 1.70 (1.14 to 2.56) 0.01
Biopsy-proven acute rejection 24 (193 of 806) 17 (523 of 3117) 1.39 (1.19 to 1.61) <0.001
Antibody-mediated rejection 10 (75 of 744) 2 (65 of 2839) 3.86 (2.05 to 7.29) <0.001
Bleeding 11 (63 of 579) 4 (53 of 1450) 1.92 (1.36 to 2.72) <0.001
RR, relative risk; 95% CI, 95% confidence interval; CMV, cytomegalovirus.

fig4
Figure 4.:
Forest plot of comparison: Patients with an ABO-incompatible kidney transplant have a higher risk of antibody-mediated rejection compared to center-matched ABO-compatible control patients. ABMR, antibody-mediated rejection; ABOc, ABO-compatible; ABOi, ABO-incompatible; 95% CI, 95% confidence interval; M-H, Mantel-Haenszel.

Infection

Severe Nonviral Infection.

Seventeen studies reported infectious episodes. Severe nonviral infections occurred more often in ABO-incompatible recipients (RR, 1.44; 95% CI, 1.13 to 1.82; P=0.003; I2=39%; P=0.06; Table 3).

Viral Infection.

Eighteen studies reported CMV, either viremia or disease. CMV viremia was slightly more common in patients who were ABO-incompatible (RR, 1.20; 95% CI, 1.04 to 1.37; P=0.01; I2=17%; P=0.26; Table 3).

BK viremia was more common in patients who were ABO-incompatible in nine studies, did not occur in two studies, and was less common in four studies (RR, 1.70; 95% CI, 1.14 to 2.56; P=0.01; I2=45%; P=0.03; random-effect model; Table 3).

Bleeding

Nine studies included a table with bleeding-related parameters. These outcomes occurred almost twice as often in patients who were ABO-incompatible versus those who were ABO-compatible (RR, 1.92; 95% CI, 1.36 to 2.72; P<0.001; I2=10%; P=0.35; Table 3), both with immunoadsorption and with plasmapheresis (I2=0%, P=0.84 for subgroup differences; Supplemental Figure 3).

Discussion

ABO-incompatible kidney transplantation, as performed in the last decade, is considered safe as compared with ABO-compatible transplantation. The current meta-analysis shows that ABO-incompatible kidney transplant recipients have very good outcomes, but with a higher risk of losing their allograft within 1 year after kidney transplantation compared with center-matched ABO-compatible controls. In addition, the risks for severe infection, viral infection, antibody-mediated rejection, and postoperative bleeding were all higher in the ABO-incompatible patient group.

Although inferior graft survival in the ABO-incompatible group was a consistent finding in the 26 studies included for analysis, it was NS in any of these studies, because of insufficient number of patients per study. However, inferior graft survival has been described in some registry studies. United Network for Organ Sharing data, for instance, reveal inferior graft survival within the first year and, similar to the results of the meta-analysis, grafts surviving thereafter had comparable outcomes to patients who were ABO-compatible (27). Early graft losses occurred in the direct postoperative period (within 14 days) in a relatively large cohort of patients who were ABO-incompatible described by Montgomery et al. (13). A Japanese registry also revealed inferior 1-year graft survival (28), but both of these Japanese and American cohorts contained patients treated with splenectomy.

The largest registry study, especially in the modern era without splenectomy, the Collaborative Transplant Study (CTS) by Opelz et al. and Morath et al. (10,11), described 1420 patients who were ABO-incompatible. Their outcomes show similar death-censored graft survival rates for ABO-incompatible versus ABO-compatible transplantation. However, there was a slightly lower 1-year patient survival in the ABO-incompatible group owing to infection-related deaths. Our data are limited on cause of death but reveal the same pattern, with infection as cause of death in half of the patients who were ABO-incompatible versus only 13% of patients who were ABO-compatible. These findings are in accordance with a Korean ABO-incompatible registry reporting inferior patient survival due to 83% infection-related deaths compared with only 27% in ABO-compatible controls (12).

These registry studies lack a comparison of baseline characteristics between the ABO-incompatible and ABO-compatible cohorts but their outcomes strengthen the results of our meta-analysis: ABO-compatible controls in the meta-analysis were either matched or consecutive, leading to similar baseline clinical and demographic characteristics between the groups. Therefore, it seems that the inferior outcomes after ABO-incompatible kidney transplantation cannot be contributed to “unchangeable” patient characteristics but to the procedure itself.

The explanation for the higher infection-related 1-year mortality after ABO-incompatible kidney transplantation is speculative because data analysis on the single-patient level was not possible. For example, it could not be deciphered if antibody-mediated rejection and patient death coincided. Other potential factors that may have resulted in a higher risk of severe infection are induction therapy and plasmapheresis. The vast majority of patients in the included studies received rituximab induction. Rituximab induction on top of a standard immunosuppressive regime is considered relatively safe and was not associated with infection in a large, randomized trial in kidney transplant recipients (29). In the CTS registry, rituximab resulted in better death-censored graft survival compared with no induction therapy, arguing against a major effect of rituximab on infectious complications (11). The removal of protective Igs by plasmapheresis may contribute to a higher risk for infection. However, there was no difference in mortality and infectious complications between patients receiving immunoadsorption versus plasmapheresis. This is contrary to a meta-analysis of 4810 patients who were ABO-incompatible stratified according to desensitization technique (17): in this study by Lo et al., after a mean of 26 months follow-up, overall graft survival was significantly worse after plasmapheresis compared with immunoadsorption.

Of note is the doubled risk of bleeding in patients who were ABO-incompatible, irrespective of plasmapheresis technique used. This is a consistent finding in Dutch immunoadsorption patients (30).

This meta-analysis reveals that ABO-incompatible transplantation has very good outcomes, albeit inferior to ABO-compatible transplantation: the overall uncensored graft loss at 1 year post-transplantation was 4.2% in the ABO-incompatible and 2.5% in the ABO-compatible patient group. These outcomes are favorable compared with remaining on dialysis or receiving a deceased donor kidney allograft (31). However, it also indicates that the ABO-incompatible procedure with its specific complications is associated with a higher 1-year graft loss and mortality, although the absolute numbers remain low. In this is the strength of this meta-analysis, because the ABO-incompatible literature lacks randomized, controlled trials and guidelines are on the basis of cohort studies generally lacking power to detect low-frequency, clinically relevant differences. Statistical heterogeneity for graft and patient survival was very low in this meta-analysis. This information can assist transplant candidates and their doctors in balanced clinical decision making. It is also a further incentive to promote the use of kidney exchange programs allowing for ABO-compatible matches to be made in case of ABO incompatibility.

Publication bias is a limitation of this meta-analysis. The discussions of the included studies generally conclude favorable ABO-incompatible outcomes. Less favorable ABO-incompatible outcomes might be left unpublished and the true additive risk of ABO-incompatibility might be higher. An important consideration is that some patients cannot proceed to transplantation despite ABO-incompatible desensitization. Becker et al. (32), for example, report desensitization failures in five of 39 procedures. Because this meta-analysis only includes patients who were transplanted, the true burden of ABO-incompatible desensitization is probably higher. Other limitations are the lack of individual patient data and the inconclusive reporting of match criteria. Completeness of reporting of adverse events and the observation period after transplantation differed between studies. Follow-up of patients who were ABO-incompatible was shorter than controls. This, however, may suggest that the higher incidence of complications observed after ABO-incompatible kidney transplantation is a conservative estimation. Given the slightly inferior results of ABO-incompatible kidney transplantation, it is important to optimize the possibilities for compatible transplantation: national or regional kidney exchange programs are therefore of proven value and utmost importance to improve outcomes after living kidney transplantation (33).

In conclusion, ABO-incompatible kidney transplantation has very good outcomes but is associated with a greater risk for graft loss and lower patient survival within the first year after transplantation compared with ABO-compatible controls.

Disclosures

None.

Published online ahead of print. Publication date available at www.cjasn.org.

See related editorial, “Expand the Pool of Living Donors for Kidney Transplantation,” on pages .

This article contains supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.00540118/-/DCSupplemental.

Acknowledgments

We gratefully thank Solomon Cohney, Shingo Hatakeyama, Jeongkye Hwang, Pranaw Kr. Jha, Kyu Ha Huh, Christine Melexopoulou, and Seungyeup Han for providing us with additional data. We thank Maryse Cnossen for her statistical advice.

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Keywords:

ABO Blood-group system; acute rejection; Antibodies; Bias; Blood Group Incompatibility; Cause of Death; Cohort Studies; Graft Survival; Humans; kidney transplantation; transplant outcomes

Copyright © 2018 by the American Society of Nephrology