|Year : 2019 | Volume
| Issue : 3 | Page : 655-662
|ABO incompatible kidney transplantation: the Saudi experience
Tariq Ali1, Dieter Broering1, Hassan Aleid1, Jens Brockmann1, Hind Alhumaidan2, Ehab Hammad1, Yaser Shah1, Hazem Elgamal1, Ibrahim Alahmadi1, Mohamed Hussein1, Syed Raza1, Amira Alabassi1, Ihab Ibrahim1, Mohamed Shoukri3, Khalid Almeshari1
1 Department of Kidney and Pancreas Transplant, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
2 Department of Blood Transfusion Services, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
3 Department of Cell Biology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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|Date of Submission||04-Apr-2018|
|Date of Decision||17-May-2018|
|Date of Acceptance||02-Jul-2018|
|Date of Web Publication||26-Jun-2019|
| Abstract|| |
Although the outcomes of ABO-incompatible (ABOi) kidney transplant recipients are quite favorable, these patients are at increased risk of early antibody-mediated rejection (AMR) and graft loss. Some studies have also shown high mortality in the ABOi group mainly due to increased risk of infections. The AMR rates have been reported anywhere from <10% to >50% in the literature. The outcomes of the ABOi kidney transplants in the Saudi population are not known. In this study, we aimed to determine the graft and patient survival in ABOi kidney transplant recipients in the Saudi population. We included all adult patients who underwent ABOi transplantation between 2007 and 2016. All patients received rituximab, therapeutic plasma exchange, thymoglobulin, intravenous antibiotics, and intravenous immunoglobulin. The maintenance immunosuppression was prednisone, mycophenolate mofetil, and tacrolimus. The data were collected from a prospectively maintained database. A total of 77 patients were included in the study. The most common blood group mismatch was A to O (44.2%), followed by B to O (26.0%) and A to B (16.9%). In the 1st year, 17% of patients developed acute cellular rejection and AMR occurred in 7.8% of patients. Two patients were diagnosed with BK nephropathy. In the 1st year, urinary tract infection occurred in 25 (32.5%) patients. No patient was diagnosed severe viral or fungal infection. In the 1st year, four grafts were lost (graft survival of 94.8%); all grafts were lost within two weeks, three due to AMR and one due to technical reason. One year patient survival was 100%. In this study of ABOi kidney transplant recipients, we observed low risks of infectious complications with excellent patient and graft survival. Our immunosuppressive protocol can be considered safe.
|How to cite this article:|
Ali T, Broering D, Aleid H, Brockmann J, Alhumaidan H, Hammad E, Shah Y, Elgamal H, Alahmadi I, Hussein M, Raza S, Alabassi A, Ibrahim I, Shoukri M, Almeshari K. ABO incompatible kidney transplantation: the Saudi experience. Saudi J Kidney Dis Transpl 2019;30:655-62
|How to cite this URL:|
Ali T, Broering D, Aleid H, Brockmann J, Alhumaidan H, Hammad E, Shah Y, Elgamal H, Alahmadi I, Hussein M, Raza S, Alabassi A, Ibrahim I, Shoukri M, Almeshari K. ABO incompatible kidney transplantation: the Saudi experience. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Jul 23];30:655-62. Available from: http://www.sjkdt.org/text.asp?2019/30/3/655/261340
| Introduction|| |
ABO-incompatible (ABOi) transplant was considered to be a contraindication to kidney transplants because of early graft losses. However, with better understanding of the immune mechanisms and ability to remove the antibodies at the time of transplantation, successful kidney transplantations from ABOi donors have been performed across the world.,,, The risk of graft loss and antibody-mediated rejection (AMR) remains high in ABOi transplant recipients. To reduce the risk of early AMR, these recipients require potent immunosuppression which increases the risk of infections and possibly malignancies.
The incidence of AMR in the ABOi recipients was reported to be 18% compared to 1% in the ABO-compatible transplant reci-pients. Takahashi et al reported that the incidence of AMR in the first three months was 58% in the ABOi transplant recipients. A total of 41 (9%) grafts were lost due to acute rejection episodes. Gloor et al found that 50% of ABOi recipients developed acute rejection compared to 14% in the ABO-compatible group. In those who developed acute rejection, 71% were due to AMR.
Patient and graft survival has been reported to be quite good in the ABOi kidney transplant recipients. However, a landmark Japanese study reported an increased risk of graft loss in the early posttransplant period. The US Scientific Registry data also cautioned about the early risk of graft loss in ABOi transplant recipients. A multicenter study of 1420 patients showed that graft survival rates of ABOi transplants at three years were comparable to the ABO-compatible transplants. However, they noticed a small but significant lower patient survival in the ABOi group in the 1st year. Similarly, a UK-based study showed high mortality in ABOi group and the majority of the patients died due to infections.
Previously, we have published the outcomes of our immunosuppressive protocol for patients who underwent antibody-incompatible transplants. However, in that study, only small number of ABOi transplant recipients were included. Hence, the outcomes of ABOi kidney transplant recipients in our population are not well studied or reported in the literature.
In our institution, the first ABOi kidney transplant was performed in 2007. We have a stable induction immunosuppressive protocol since then. This protocol consists of administering rituximab, thymoglobulin, therapeutic plasma exchange (TPE) and high-dose immunoglobulin (IVIG). This protocol has not changed in the past 10 years. Hence, in this study, we aimed to determine the effectiveness of our immuno-suppressive protocol and outcomes of ABOi transplant recipients in the Saudi population.
| Methods|| |
In this study, we included all adult patients who underwent ABOi transplantation between November 2007 and June 2016. All patients completed at least one-year follow-up. We collected demographic and other relevant data from a prospectively maintained database for the donors and the recipients. The missing or additional data were collected from the electronic database of the institution.
All patients received a fixed dose of ritu-ximab 500 mg two weeks before transplant. Patients were admitted one week before surgery and underwent TPE. Usually, 1.5 volume exchanges were performed and albumin was used as the replacement solution. Each session of TPE was followed by intravenous IVIG in a dose of 100 mg/kg. A number of sessions were planned according to the baseline isotiters. Isotiters were checked daily along with coagulation profile and fibrinogen level. Post-transplant TPE was used on demand (if isotiters rebounded).
All patients received 1.5 mg/kg body weight infusions of thymoglobulin [antithymocyte globulin (rabbit)] at induction. The first dose was commenced just before releasing the arterial clamps (before graft reperfusion). A total of three doses were given on the daily basis (adjusted for platelet and white cell count). Further doses were given if CD3 count was above 20 or lymphocyte count was above 200 (if CD3 count was not available) to a maximum dose of 7 mg/kg. Mycophenolate mofetil was started 24 h before transplant at a dose of 500 mg twice daily. The dose was increased to 750 mg twice daily after completion of thymoglobulin doses. Tacrolimus was introduced on the first postoperative day; its introduction was delayed in the event of delayed graft function. In the first three months, we aimed to keep tacrolimus trough level of 8–10 ng/mL and subsequently 6–8 ng/mL. All patients received methylpredni-solone intravenously at a dose of 5 mg/kg at induction and 80 mg on day 1. Thereafter, patients received oral prednisone, and the dose was gradually reduced to 5 mg by six weeks. This dose was continued in the long term.
Six cryoprecipitate units were infused if fibrinogen level was below 1 g/L before a TPE session or <2 g/L on the evening before surgery (normal value, 1.4–4.4 g/L). Six units of cryoprecipitate were transfused, if required, during surgical procedure (e.g., if the patient was oozing blood more than usual and this administration was at the discretion of the operating surgeon).
Patients also received prophylaxis against pneumocystis (sulfamethoxazole and trimetho-prim or pentamidine for six months) and cyto-megalovirus (CMV) infection (valganciclovir for three months). Isoniazid was used for nine months unless purified protein derivative skin test for tuberculosis was negative for the donor and the recipient.
Antibiotics and IVIG protocol
All patients received intravenous antibiotics (piperacillin/tazobactam or cefoxitin) from admission day till discharge to avoid bacterial infections. Before June 2013, patients received piperacillin/tazobactam at a dose of 2.25 g three times a day. However, subsequently, patients received cefoxitin at a dose of 1 g/day. This change was in keeping up with the hospital policy of deescalating to second-generation cephalosporin.
Patients were given 100 mg/kg of IVIG after each TPE session. After two weeks of transplant surgery, further dose of IVIG was given to complete the total dose of 2 g/kg from the first dose.
Before July 2013, we used IgM titers, but after that, both IgM and IgG titers were used. The aim was to keep IgM titer <1:8 or IgG <1:16 before surgery.
We used ABO titration, which was performed as a tube method. It is a semiquantitative technique for measuring the amount of ABO antibodies titrated for IgM and IgG. The titer of antibody was determined by testing serial two-fold dilutions of the serum with selected known red cells. The score was calculated by assigning each agglutination with a score value, and the total of all scores was reported. The reporting of the titer was the reciprocal of the highest dilution that showed 1+ macroscopic agglutination. Titration values provide information about the relative amount of antibody present in the serum. After transplant surgery, isotiters were checked on the daily basis and monitoring was stopped after two weeks.
Acute rejection was defined according to the latest available Banff classification at that specific period.,
This study was approved by the institution’s local ethics committee.
| Statistical Analysis|| |
The data were reported as mean ± standard deviation or median with ranges for continuous variables and as number and proportion for categorical variables. Patient and graft survival were estimated by Kaplan–Meier survival analysis.
| Results|| |
A total of 77 patients underwent ABOi kidney transplant during the study period (after excluding one patient due to lack of comprehensive data). The mean age of the donor was 29 years, and the majority (79.2%) of the donors were male [Table 1]. The mean age of the recipient was 39 years and 55.8% were male patients. The most common cause of end-stage renal disease (ESRD) (after excluding those with unknown etiology) was glomerulonephritis (28.6%), followed by diabetes (10.4%) and hypertension (10.4%) [Table 1].
The median length of stay was 16 days. The median length of stay from the day of surgery to discharge was seven days.
The most common blood group mismatch was A to O (44.2%), followed by B to O (26.0%) and A to B (16.9%) [Table 1]. A total of 47 donors were of blood Group A and 32 of those had subtype A1 and 15 were of subtype A2. Twenty-two (28.6%) recipients of blood Group O received kidneys from donors of blood Group A1.
Baseline ABO isotiter was >1:16 in 58 (75.3%) patients and 11.8% had a baseline titer of >1:128. On average, patients received 3.6 sessions of TPE before transplant and around 50% of the patients required >4 sessions. After transplantation, 34 (44.2%) patients required TPE with mean sessions of 1.85.
In the 1st year, urinary tract infection (UTI) occurred in 25 (32.5%) patients, 32% of whom had a single episode. The second most common complication was drop in hemoglobin requiring blood transfusion in 7.8%. Urological complications occurred in 5 (6.5%) patients. A total of 18 (23.4%) patients were admitted in the 1st year. Five (6.5%) patients were admitted with urological issues and another five patients were admitted with sepsis (three with UTI, one patient with influenza, and one with wound infection). Four (5.2%) patients were admitted to receive treatment for acute rejection, three (3.9%) for TPE, and one patient with gastroenteritis.
A total of 61 (79.2%) patients underwent at least one kidney biopsy. In the 1st year, acute cellular rejection occurred in 16.9% of patients (9.1% after excluding borderline rejection). AMR was observed in six (7.8%) patients (blood group incompatibility was B to O in four patients, A1 to O in one patient, and A1B to O in the other recipients).
Two patients were diagnosed with BK nephropathy (one at day 175 and the other at day 643). No patient was diagnosed with pneumocystis infection, CMV disease, herpes simplex, varicella zoster, or fungal infection. None of the patients had developed malignancy in the follow-up period.
One-year graft survival was 94.8% [Figure 1]. In the 1st year, four grafts were lost [three due to AMR and one patient had primary non-function (technical)]. All these grafts were lost within two weeks. Beyond one year, two more grafts were lost, both due to noncompliance [Figure 1]. The mean serum creatinine values are shown in [Table 2].
One-year patient survival was 100%. In long-term follow-up, only one patient died (day 1533) due to pneumonia [Figure 1].
| Discussion|| |
This large, single-center study of ABOi kidney transplant recipients shows excellent patient and graft survival in the Saudi population. Around 8% of patients developed AMR, but graft survival was around 95% and no mortality was observed in the 1st year. Although rates of UTIs were high, the risk of other severe infections was very low. Our immunosuppressive protocol appears to be safe with excellent outcomes.
ABO incompatibility was once an absolute contraindication for kidney transplantation due to very high risk of graft loss. However, subsequently, with better understanding and advances in the immunosuppressive medications, a significant number of ABOi kidney transplants have been carried out worldwide.,, According to a Japanese study, 30% of living donor kidney transplants are being performed from ABOi donors. Even there is some evidence of favorable outcomes of ABOi transplants from deceased donors. However, ABOi transplantation is associated with higher rates of AMR and graft loss, as well as high rates of morbidity and mortality mainly due to infectious complications.,, The best induction immunosuppressive therapy for ABOi renal transplant recipient is unknown. Previous studies have reported using various combinations including splenectomy without IVIG, without anti-CD20 therapy, or tailored desensitization. In the present study, we have reported the outcomes of our induction immunosuppressive protocol (stable protocol for around 10 years) that includes administering rituximab, TPE, thymoglobulin, steroids, and high-dose IVIG.
The study by Habicht et al, has shown that the rate of viral infections including CMV, herpes simplex virus, varicella zoster virus, and polyoma virus was significantly increased among the ABOi recipients. Of note, 60% of patients developed BK nephropathy within three to six months after transplantation. In a UK-based study, the mortality in the ABOi group was 6.5% and all deaths were attributed to infections (mainly Pneumocystis infection). Our study has shown significantly low risk of infections (except UTIs), especially extremely low risk of viral infections.
Patient survival in the ABOi group has been studied in a multicenter study of 1420 patients who underwent ABOi transplants. The author concluded that early patient survival was significantly lower in the ABOi group. Similarly, higher mortality was observed in the ABOi group (patients survival of 93.5% in the 1st year) in a UK-based study. In both studies, deaths were due to infectious complications., The US registry data study showed that patient survival was 96.8% at one year and was 74.5% at five years. Patient survival in our patients was 100% in the 1st year, and in the long-term follow-up, only one patient had died. We think that initial low mortality in our cohort was due to low incidence of severe infectious complications.
Death uncensored graft survival was found to be around 93% in a study of 62 ABOi transplants. Graft survival was 89% in young ABOi transplant recipients in a Japanese study. A multicenter study of ABOi transplants shows graft survival of 89% at three years. In a US-based study, graft loss in the 1st year was observed in 5.9%; however, the authors did not specify the reasons for graft losses. In the present study, graft survival is around 95%, which is comparable to the international reports. All the grafts were lost in the first two weeks, similar to the experience of other centers.
A major concern in ABOi transplantation is risk of AMR which usually develops within the first two to three weeks of transplantation. In a study from the UK, AMR was observed in 6.5% of patients who received kidneys from ABOi donors. Another study reported that AMR occurred in 18% of patients who underwent ABOi transplant. Takahashi et al reported that the incidence of AMR in the first three months was 58% in the ABOi transplant recipients and 9% grafts were lost due to rejection. In our study, we observed AMR in 7.8% of patients; these rates are within acceptable range when compared to the international literature. However, graft loss due to AMR was seen in around 4% of patients.
Our study has some limitations. We did not compare the outcomes with the control group. We felt that there was no group that received such potent preconditioning; hence, fair comparison was not possible. However, as the graft losses and mortality in our study are extremely low, even without control group, the findings are very significant. Due to low incidence of graft loss and mortality, we could not perform meaningful multivariate analysis.
In conclusion, the outcomes of ABOi transplant recipients in the Saudi population are extremely good. We think that our immuno-suppressive protocol is safe with low risk of infections and excellent patient and graft survival.
Conflict of interest: None declared.
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Department of Kidney and Pancreas Transplant, King Faisal Specialist Hospital and Research Center, MBC 37, P. O. Box 3354, Riyadh 11211
[Table 1], [Table 2]
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