ABO incompatibility in renal transplantation

Table 1 Literature review of studies reporting the ABO blood group incompatibility transplants, complications and outcome

	Study type	Ref.	Sample size	Desensitization/immunosuppression protocols	Complications	Success rate
1	Systemic review and meta-analysis	Scurt et al[37]	65063 of which 7098 undergone ABOi-rTx (ABO-incompatible renal transplantation)	Rituximab based protocols vs non-rituximab; splenectomy groups	Risk of bleeding; the proportion of patients with sepsis was higher after ABOi-rTx than after ABOc-rTx; no statistically significant difference was observed in the risk of UTI (D2 = 48%), CMV infection (D2 = 71%), BK polyomavirus infection (D2)	Death censored graft survival became similar to that of ABOc-rTx within the first year; compared with ABOc-rTx, ABOi-rTx was associated with significantly higher 1-yr mortality (OR: 2∙17; 95%CI: 1∙63-2∙90), P < 0.0001
2	Single-center retrospective study	Lee et al[54]	56	RP group (n = 26) vs RO group (n = 30)	No difference in complications such as antibody-mediated rejection, biliary stricture, hepatic artery thrombosis, infection, poor graft and patient survival; biliary stricture was most common 23.1% of patients (n = 6) in the RP group; 16.7% in RO group (P = 0.990); hepatic artery thrombosis: 6.7% of patients (n = 2) in the RO group only; infection: 7.7% in RP group (n = 2) and 6.7% (n = 2) in the RO group, P = 0.791	6-, 12-, and 18-mo overall survival rates were 92.3%, 80.8% and 76.9% in the RP group and 96.6%, 85.4% and 85.4% in the RO group (P = 0.5744)
3	Systemic review and meta-analysis	Lo et al[55]	4810	Immunoadsorption or apheresis; splenectomy or underwent splenectomy	From 68 studies: 878 of 2672 recipients (32.9%) experienced acute, rejections; of the above 878 recipients with biopsy-proven acute rejection episodes, there were 304 (34.6%) reported cases of acute antibody-mediated rejection, 213 (24.3%) reported cases of acute cellular rejection and 400 (45.6%) cases of undifferentiated acute rejection; 46 of 83 studies with 785 recipients reported on posttransplant infective complications. CMV is the most frequently reported infection, followed by urinary tract infections, polyomavirus, and BK nephropathy	Follow up time of 28 mo (SD: 26.6); immunoadsorption or apheresis: Graft survival 94.1% (95%CI: 88.2%-98.1%) and 88% (95%CI: 82.6%-91.8%); splenectomy or underwent splenectomy: Graft survival: 94.5% (95%CI: 91.6–96.5%) and 79.7% (95%CI: 72.9% -85.1%)
4	Single center	Tanabe et al[52]	67	Plasmapheresis and immunoadsorption to remove anti-AB antibodies prior to kidney transplantation; induction phase with methylprednisolone, cyclosporine, azathioprine, antilymphocyte globulin, and deoxyspergualin were used for immunosuppression; splenectomy at the time of kidney transplantation in all cases	5 dies during observation.; 3 of uncontrolled bleeding due to duodenal ulcer, malignant lymphoma, cerebral hemorrhage (one each); 10 had non-tissue invasive CMV infection	Survival: 93% at 1 yr; 91% at 8 yr; graft survival 79% at 1, 2, 3 and 4 yr, 75% at 5, 6 yr, and 73% at 7 and 8 yr
5	Retrospective cohort study	Okumi et al[53]	Study population: 1032; 555 LKT recipients (between 1989–2004), 452/555 were ABO-CLKT & 103 were ABO-ILKT; 477 LKT recipients (between 2005–2013), ABO-CLKT: 333 and ABO-ILKT: 144.; (247/1032 ABO-ILKT)	All of the patients were administered a triple immunosuppressive protocol comprising CNI, antimetabolite drugs, and MP; patients transplanted between 1989 and 1997 received cyclosporine and AZA, those transplanted between 1998 and 2000 received TAC and AZA, and those transplanted after 2001 received TAC and MMF; after 2002, all patients received basiliximab perioperatively; splenectomies were performed at the time of transplantation between 1989 and 2004; as an alternative to splenectomy, one dose of rituximab was administered 5-7 d before transplantation	Significantly higher CMV rates and adenovirus infections were observed in the ABO-ILKT recipients compared with the ABO-CLKT recipients before 2004. There were no differences in the frequencies between the ABO-CLKT and ABO-ILKT recipients after 2005	There were 32 graft losses among the patients who underwent ABO-ILKT before 2004 and 99 graft losses in the ABO-CLKT group; the Kaplan–Meier cumulative graft survival rates at 9 years were 68.9% and 78.1% for the ABO-ILKT and ABO-CLKT groups, respectively, a difference that was significant (log-rank test: P = 0.026). After 2005, the 9-yr graft survival rates were 86.9% and 92.0% for the ABO-ILKT and ABO-CLKT groups, respectively, a difference that was not significant (log-rank test: P = 0.279); no particular causes of graft failure predominantly affected the ABO-CLKT or ABO-ILKT groups in either era
6	Retrospective cohort study	Takahashi et al[56]	441 (Mean age 34)	Standard immunosuppressive therapy used: (1) Extracorpeal immunomodulation to remove serum A, anti-B antibodies before transplantation; (2) Pharmacotherapy (triple-drug regiment combining calcineurin inhibitor with a steroid and an antimetabolite) 66% received cyclosporin and 34% tacrolimus; (3) Splenectomy (433 of 441 patients except 8 who were children); and (4) Anticoagulation therapy (223 patients 51% received anticoagulation; 218 patients, 49% did not)	60 patients died; 14 patients died of pneumonia; 8 of hepatic failure; 7 of heart failure; 6 of a cerebral hemorrhage; 3 with multiorgan failure with DIC; 2 patients in each: Malignant lymphoma, gastric cancer, brain tumor, gastroduodenal ulcer, acute pancreatitis, pulmonary edema, sepsis, cerebral meningitis; 1 each: Hydrocephalus, virus-associated hemophagocytic syndrome, rupture of aorta aneurysm, hemorrhage after aortic valve replacement, ileus, and suicide	Patient survival rates were 93%, 89%, 87%, 85%, and 84% at 1, 3, 5, 7, and 9 yr, respectively; corresponding graft survival rates were 84%, 80%, 71%, 65%, and 59%
7	Prospective study	Tydén et al[18]	67 (mean age 34.9)	Plasmapheresis and immunoadsorption were carried out to remove the anti-AB antibodies before transplantation; induction phase: Methylprednisolone, cyclosporine, azathioprine, antilymphocyte globulin and deoxyspergualin were used for immunosuppression; local irradiation of graft of 150 rad on the 1st, 3rd and 5th day after transplantation; splenectomy at the time of transplantation	5 died during observation; 3 patients with functioning grafts died of uncontrolled bleeding due to duodenal ulcer, malignant lymphoma, and cerebral hemorrhage (one patient each); 1 patient died of ischemic colitis due to secondary amyloidosis; 1 patient of a cerebral hemorrhage after graft loss due to humoral rejection; there was no fatal infectious complication; 10 patients had a non-tissue-invasive cytomegalovirus infection	Patient survival was 93% at 1 yr and 91% at 8 yr; graft survival was 79% at 1, 2, 3, and 4 yr, 75% at 5 and 6 yr, and 73% at 7 and 8 yr; patient survival was not significantly different from that of ABO-compatible patients. Graft survival was significantly different between ABO-incompatible grafts and ABO-compatible grafts
8	Prospective observational study	Masterson et al[50]	Study population: 84	Standard immunosuppression without antibody removal with steroids, mycophenolate, tacrolimus, and basiliximab; mycophenolate mofetil 500 mg, BID initiated 7-14 d pretransplant; then 1000 mg, BID as tolerated or at time of transplant then taper dose of 1500 mg/day by weeks 3-6, then 1000 mg/d by week 10-12; tacrolimus 0.05 mg/kg bid 2-3 d pretransplant, followed by 9-12 ng/mL for 2 weeks, 8-10 ng/mL weeks 3-4, 5-8 ng/mL weeks 5-24, 3-7 ng/mL weeks 25-52 and 2-4 ng/mL beyond 1 yr; Basilizumab 20 mg days 0 and 4; prophylaxis against CMV and pneumocystis jiroveci pneumonia	One patient had recurrent urinary tract infections; BK viremia in four patients by screening with spontaneous resolution following a reduction in immunosuppression; no cases of CMV disease or other opportunistic infections	At 36 mo posttransplant, patient and graft survival was 100%; at 12 mo, median (IQR) serum creatinine and eGFR were 110.5 μmol/L 77–127 and 56.5 mL/min/1.73 m2 (48–71), respectively; at 36 mo, there was no significant change in graft function with median creatinine 104 μmol/L (82-129), eGFR 57 mL/min/1.73 m2, and urinary albumin/creatinine ratio 2.5 mg/mmol (0.98-4.25)
9	Retrospective	Egawa et al[57]	66 patients (10 mo to 55 yr old)	The basic immunosuppressive regimen consisted of tacrolimus and steroids in all groups with a target tacrolimus trough level between 10 to 15 ng/mL in the first week, 5-10 ng/mL during the first post-treatment month; methylprednisolone was administered- at different doses throughout each stage; prostaglandin E1 was infused for 7 to 14 d after transplantation; cyclophosphamide was initiated 1-week pretransplant and given daily one month after transplantation, then converted to azathioprine; splenectomy was performed in all patients aged five years and older without contraindications	Incidence of intrahepatic biliary complications and hepatic necrosis in ABO-incompatible living-related grafts (18% and 8%, respectively) was significantly (P < 0.0001) greater than in ABO-compatible and ABO-identical grafts (both 0.6% and 0%, respectively)	Antibody titer and the clinical course followed prospectively during a period of 3 to 11 yr; 5-yr patient survival was 59%, 76%, and 80% for ABO-incompatible, ABO-compatible, and ABO-identical grafts, respectively (P < 0.01); in patients < 1 yr old, > or = 1 to < 8, > or = 8 to < 16, and > or = 16 yr old, 5-yr survival was 76%, 68%, 53%, and 22%, respectively
10	Retrospective study	Kimura et al[58]	5549 patients (ABO matched n = 2820 and major incompatible n = 1384 and bidirectional incompatible n = 143)	Among the four groups of ABO compatibility, there were no significant differences in the gender distributions of patients and donors, the number of transplantations, performance status before transplantation, conditioning regimen, GVHD prophylaxis, administration of colony-stimulating factors	The cumulative incidences of transplant-related mortality differed significantly among the four groups P < 0.0001), with the 1-yr rates being 27.9% (AB0-matched), 35.8% (major incompatibility), 34.2% (minor incompatibility), and 30.7% (bidirectional incompatibility)	Survival rates in the group with major and minor mismatches were significantly lower than the rate in the AB0-identical group (AB0-identical 63.0%; major mismatch, 56.9%; minor mismatch, 57.1% at one year)
11	Retrospective	Kim et al[59]	89 adult patients	Acute GVHD prophylaxis consisted of cyclosporin A (CyA) + Methotrexate (n = 57), CYA alone (n = 20), CyA plus mycophenolate mofetil (n = 11); infection prophylaxis consisting of ciprofloxacin/metronidazole/fluconazole and acyclovir	Within the first 30 d after allogeneic PBSCT, bacteremia occurred in 10 (11.2%) patients, viral infections including cytomegalovirus in 20 (22.5%) patients, and fungal infections in 12 (13.5%) patients, although the incidence of infection was not statistically different between the different groups of transplantation; bleeding occurred in 3 cases; graft failure in 3 cases; toxic hepatitis 1 case	With a median follow-up duration of 13 mo (range, 0.5–61 mo); 3-yr overall survival estimates for the ABO-identical, major/bidirectional, and the minor group were 44.6.0 ± 9.0, 43.1 ± 11.6, and 43.8 ± 13.5%, respectively (P = 0.8652)
12	Series	Montgomery et al[22]	60 patients	Pre-and posttransplant PP/CMV IV immunoglobulin; quadruple, sequential immunosuppression with tacrolimus and mycophenolate mofetil. Steroids were used perioperatively. Daclizumab was used for induction; splenectomy at the time of transplant was then replaced by a single dose of anti-CD20 the night prior to transplantation	3 patient deaths in the series; all 3 patients died with functioning grafts; cause of death included West Nile encephalitis (likely acquired from FFP transfusion). metastatic liver cancer	Patient survival at 1, 3, and 5 yr was 96.3%, 96.3%, and 89.4%, respectively; using a short course of PP and low-dose IVIG with standard maintenance immunosuppression, the death-censored graft survival of 60 consecutive ABO-I kidney transplants at 1, 3, and 5 yr was 98.3%, 92.9%, and 88.7%, respectively
13	Retrospective observational	Okada et al[60]	412; ABO-I: n = 205	ABO-I cases treated with Rituximab (n = 131); splenectomy (n = 21)	The incidence of infection was significantly higher in the ABO incompatible treated with Rituximab group than in the ABO-incompatible treated with neither rituximab nor splenectomy group [28.2% (37/131) vs 9.4% (5/53), P = 0.006]	Graft survival for ABO-I was significantly lower than that for ABO compatible renal transplantation (92.8% vs 97.2% after five years P = 0.0037)
14	Retrospective study	Rowley et al[61]	158 allogeneic hematopoietic stem cell transplants from ABO-incompatible	The majority received busulfan or TBI-based conditioning regimen. 9 patients received a variety of other myeloablative conditioning regimes; 150 patients received GVHD prophylaxis consisting of cyclosporine followed by methotrexate (CSPMTX); 2 patients received MTX alone, 1 patient received cyclosporine + methotrexate, 2 patients received CSPMTX with prednisone, 3 patients received CSP and prednisone	6 patients with suspected hemolysis due to elevated bilirubin; unable to demonstrate adverse effects from hemolysis during the first 21 d of transplantation	The study was to demonstrate the risk of hemolysis

ABOi-rTX: ABO-incompatible renal transplantation; ABOc-rTX: ABO-compatible renal transplantation; ABO-CLKT: ABO-compatible living kidney transplant; ABO-ILKT: ABO-incompatible living kidney transplant; RP: Rituximab with plasmapheresis; RO: Rituximab only without plasmapheresis; OR: Odds ratio; CMV: Cytomegalovirus; CNI: Calcineurin inhibitors; CyA: Cyclosporin; CSP: Cyclosporin A; MP: Methylprednisolone; AZA: Azathioprine; TAC: Tacrolimus; MMF: Mycophenolate mofetil; CSPMTX: Cyclosporine followed by methotrexate; GVHD: Graft versus host disease; TBI: Total body irradiation; yr: year; mo: month; FFP: Fresh frozen plasma; PP: Plasmapheresis.