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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 16  |  Issue : 2  |  Page : 205-210

Outcomes of ABO-Incompatible kidney transplantation with respect to baseline isoagglutinin immunoglobulin G titers: A retrospective observational study


1 Department of Nephrology, Sir Gangaram Hospital, New Delhi, India
2 Department of Pathology, Sir Gangaram Hospital, New Delhi, India
3 Department of Urology and Kidney Transplant Surgery, Sir Gangaram Hospital, New Delhi, India
4 Department of Blood Transfusion Medicine, Sir Gangaram Hospital, New Delhi, India

Date of Submission24-Jun-2020
Date of Acceptance17-Sep-2021
Date of Web Publication30-Jun-2022

Correspondence Address:
Dr. Lovy Gaur
A-1102, Sunbreeze Apartment, Sector-5, Vaishali, Ghaziabad - 201 010, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_64_20

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  Abstract 


Background: ABO-incompatible kidney transplantation is one of the ways to increase the donor pool by as much as 30%–35%. Studies comparing baseline titers have shown conflicting results with respect to graft outcomes. This study attempts to evaluate the outcomes of ABO-incompatible transplant with high and low baseline immunoglobulin G (IgG) isoagglutinin titers to the outcomes of ABO compatible transplant. Materials and Methods: This was a retrospective observational study, in which 954 renal transplant recipients were included in the study. Of these, 873 patients had undergone ABO compatible kidney transplantation. Of the 81 patients who underwent an ABO-incompatible transplantation, 67 belonged to the low titer group (defined as the baseline IgG ≤ 1:64) and 14 belonged to the high titer group (defined as baseline IgG ≥ 1:128). Patients were followed up for a period of 1 year. Laboratory assessments were performed at baseline and at each visit. Graft survival, rejection episodes, patient survival, and infections were assessed on a continuous basis. Graft loss was defined by the need to return to dialysis. Results: Death censored graft survival was 92.3% in the high titer group as compared to 98.2% in ABO compatible group, but this difference was not significant (P = 0.231). Graft survival in the low titer group (96.8%) was comparable to the compatible group (P = 0.328). The proportion of patients who developed biopsy-proven rejections was lower in ABO compatible groups (6.5%) when compared to ABOi high (21.4%) and low titer groups (13.4%), respectively (P = 0.063 and 0.033, respectively). Antibody-mediated rejections were significantly fewer in ABO compatible group (1.8%) versus high titer group (21.4%) and low titer group (11.9%) (P = 0.003 and P < 0.001, respectively). Patient survival was higher in ABOc group (97.9%) as compared to high (92.9%) and low titer (94.0%) groups though the difference did not achieve statistical significance. Most of the deaths were attributed to infections. Conclusion: ABO-incompatible transplantation is an acceptable treatment for those with end-stage renal disease; however, this comes with a caveat of increased risk of acute rejections and infections in patients with baseline titers of 1:128 or higher.

Keywords: ABO-incompatible, graft survival, hemagglutinin titers, isoagglutinin titers, kidney transplantation


How to cite this article:
Gaur L, Bhalla AK, Shingada A, Gupta A, Malik M, Gupta A, Bhargava V, Gupta P, Joshi A, Jauhari H, Ranjan V, Khillan K, Rana D S. Outcomes of ABO-Incompatible kidney transplantation with respect to baseline isoagglutinin immunoglobulin G titers: A retrospective observational study. Indian J Transplant 2022;16:205-10

How to cite this URL:
Gaur L, Bhalla AK, Shingada A, Gupta A, Malik M, Gupta A, Bhargava V, Gupta P, Joshi A, Jauhari H, Ranjan V, Khillan K, Rana D S. Outcomes of ABO-Incompatible kidney transplantation with respect to baseline isoagglutinin immunoglobulin G titers: A retrospective observational study. Indian J Transplant [serial online] 2022 [cited 2022 Oct 4];16:205-10. Available from: https://www.ijtonline.in/text.asp?2022/16/2/205/349356




  Introduction Top


Kidney transplant is a standard therapy for patients with end-stage kidney disease. For potential donors and recipients who are mismatched with respect to ABO blood groups, the patient has option of either getting listed into the cadaveric donor wait list, or enter into the paired donor exchange program or alternatively undergo desensitization regimen to eventually receive an ABO-incompatible graft.[1]

The deceased donor transplantation program in India is picking up pace, but the current rate stands low at 0.34 per million population.[2] Meanwhile, increased time on dialysis has been demonstrated to have a detrimental effect on patient and graft survival.[3] While paired kidney donation programs offer several advantages, implementation is laborious owing to logistic issues, absence of dedicated registries, policies to reduce reneging, and strategies to stay favorable to potential recipients with O-blood group.[4]

From the time Alexandre et al. demonstrated the feasibility of ABO-incompatible kidney transplant, we have certainly come a long way.[5] Several studies have demonstrated good outcomes of ABO-incompatible in Indian settings.[6],[7],[8]

However, the effect of baseline isoagglutinin titers on the outcome of transplants remains a matter of conflict.

To our knowledge, there is no published study which has compared the outcomes of ABO-incompatible transplantation with high and low baseline titers to the outcomes of ABO compatible kidney transplants. This study attempts to explore the same.


  Materials and Methods Top


This is a retrospective observational study conducted from June 2012 to March 2017 at Sir Gangaram Hospital, New Delhi, India. The study was approved by the Ethical Committee of the Institution (vide EC/06/16/1019). Medical records of the patients were studied retrospectively. Additional information wherever needed was retrieved by interviewing patients on follow-up visits whenever possible.

All the adult patients who underwent the first live donor kidney transplantation during the prespecified period (June 2012 to March 2017) were included in the study and were followed up for 1-year posttransplant. Patients who underwent ABO-compatible kidney transplantation were classified as the control group, and those who underwent ABO-incompatible transplants formed the test group. The patients in the test group were further divided into two groups based on baseline immunoglobulin G (IgG) titer– Low titer group defined by baseline IgG titer of 1:64 or lower and high titer group defined as the baseline IgG titer of 1:128 or higher.

Patients who were transplanted organs in addition to kidney, those who were human leukocyte antigen (HLA)-incompatible and pediatric patients (<18 years) were excluded from the study.

Pretransplant conditioning protocol

Immunomodulation

Anti-CD20 monoclonal antibody, rituximab was administered at a dose of 375 mg/m2 14 days before transplantation.

Antibody depletion

Plasma exchanges were initiated 2 days after the administration of rituximab. In each plasma-exchange session, one plasma volume was removed and replaced with 20% human albumin solution and normal saline. If plasma exchanges were required a day before the transplantation or in the immediate posttransplant period, the replacement was done with fresh frozen plasma (of the donor blood group or AB blood group). Intravenous immune globulin (10 gm) was infused 1 h after each session.

Immunoadsorption

For patients with high baseline titer or those in whom titer did not decline by 2 logs after 3 plasma exchanges, immunoadsorption was done with either Glycosorb (GlycosorbABO; Glycorex, Lund, Sweden) or Adsopak (AB0-Adsopak, Pocard, Moscow).

Induction

Antithymocyte globulin (thymoglobulin-rabbit- [ATG], Sanofi) or basiliximab (Simulect; Novartis Pharmaceuticals, East 2Hanover, NJ, USA) was used for the induction therapy. The type of induction agent was decided based on baseline immunological risk. Patients with prior sensitizing events (blood transfusions, pregnancy) or those with four or more HLA mismatches were considered to be at high immunological risk and were administered ATG. Those with three or fewer HLA mismatches and without any such sensitization history were considered to be at low immunological risk and were administered basiliximab.

The first dose of ATG induction was given in the morning on the day of surgery. ATG was given at a dose of 0.9–1.0 mg/kg/dose diluted in 250 ml of 5% dextrose administered intravenously over 4–6 h after premedication with 100 mg hydrocortisone and 25 mg pheniramine to reduce cytokine release. Subsequent dose of ATG was determined by the absolute lymphocyte count (targeted to <100/cumm), graft function, number of HLA mismatches, and degree of sensitization.

Immunologically low-risk patients were administered two doses of basiliximab 20 mg each the first dose was administered immediately pretransplant and the second dose on the fourth postoperative day.

Immunosuppression

Tacrolimus and mycophenolate mofetil (MMF) were started on the day (−2) for those undergoing ABOcKT. It was administered orally as capsules in a total dose of 0.1 mg/kg/day in two divided doses. Mycophenolate was initiated at 1.5–2.0 g/day.

For patients undergoing ABOi kidney transplant, tacrolimus (0.05 mg/kg/day) and mycophenolate (500 mg/day) were started 2 weeks before the anticipated date of surgery and the dose was increased to 0.1 mg/kg/day and 1.0–1.5 gm/day 2 days before transplant.

Methylprednisolone was administered at a dose of 250 mg/day in two divided doses just before transplantation surgery, before declamping, and for 3 days postoperatively to a total dose of 1 gm; following which patients were initiated on 20 mg prednisolone daily which was subsequently tapered after 3rd month at a rate of 2.5 mg/week targeted to a dose of 5–7.5 mg/day.

Isoagglutinin measurement

The anti-A/B antibody titers were estimated by column agglutination technology using ID-Card LISS/Coombs (Dia-Med AG, Cressier, Switzerland) for IgG antibody. About 3–5 ml of patient's blood was sampled in a plain vial. It was then centrifuged at 2500 rpm for 3–5 min to obtain serum. About 200 μl of serum was incubated with dithiothreitol for 45 min and subsequently, serial dilutions were prepared in low ionic strength solution. From every dilution in the test tube, 25 μl serum was transferred to respective microcolumns of the DiaMed Coombs anti-IgG gel cards along with 50 μl of red cell suspension. The cards were then incubated at 37°C for 15 min followed by centrifugation at 1500 rpm for 10 min. A 1+ reaction, defined as the presence of small-sized agglutination in the column, was used as the endpoint; titer value was the reciprocal of the highest dilution that gave a 1+ result.

The titer was measured at baseline and subsequently 24 h after each plasma exchange. The target titer at transplantation was 1:8.

Follow-up

All the patients were assessed daily from the day of surgery till discharge, twice a week for 1 month, weekly for 2 months, fortnightly for 3–6 months, and monthly for the rest of the study period. The target trough level of tacrolimus was 10–12 ng/ml, 6–8 ng/ml at 3 months, and 3–5 ng/ml at 6–12 months. After 6 months, MMF was reduced to 1 gm/day.

Prophylaxis

All the patients were given prophylaxis against cytomegalovirus and pneumocystis jirovecii with valganciclovir (for 3 months) and cotrimoxazole (for 1 year), respectively.

Statistical analysis

Data were analyzed using the SPSS software 16.0 (Statistical Package for Social Sciences; SPSS, Inc., Chicago, IL, USA). Categorical variables were expressed as count and percentage, and continuous variables were expressed as median or range. Statistical significance of quantitative variables across three groups (ABO compatible, ABO-incompatible high and low titer groups) was done by ANOVA. Nonparametric variables were compared using Kruskal–Wallis test and if found significant further paired comparison was done using Mann–Whitney U-test. The statistical significance of qualitative variables was determined by Chi-square test. Graft and patient survival curves were plotted using Kaplan-Meier method and curves were compared using the log run test.

Patient consent

The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that their names and initials would not be published, and all standard protocols will be followed to conceal their identity.

Ethics statement

The study was approved by the Ethical Committee of the Institution (vide EC/06/16/1019). The study was performed according to the guidelines in Declaration of Helsinki.


  Results Top


Patient characteristics and demographics

The final study population included a total of 954 patients-873 patients had received kidney from ABO compatible donor, whereas 81 patients underwent an ABO-incompatible transplantation [Figure 1]. Of these, 67 patients had baseline IgG titer of 1:64 or lower, whereas the remaining 14 patients belonged to the high titer group defined as baseline IgG titer of 1:128 or higher.
Figure 1: Study population

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Baseline demographic characteristics of the patients were as described in [Table 1]. The groups were similar in all respects except that the degree of HLA mismatch was greater in patients who underwent ABOi kidney transplant, primarily accounted for by HLA-A mismatch between when ABO compatible and ABOi-low titer groups (P < 0.001).
Table 1: Baseline demographic data of the patients belonging to each group

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Patient survival

One-year patient survival was higher, albeit statistically insignificant, in ABO compatible group (97.9%) as compared to those who underwent ABO-incompatible transplantation – both high (92.9%) and low titer (94%) groups (P = 0.263 and 0.65, respectively).

In the patients who underwent ABO-compatible kidney transplant, the most common cause of death was infections accounting for 14 deaths out of a total of 18 (77.8%). Three deaths were attributed to cardiovascular cause. One of these patients had undergone percutaneous coronary artery stenting 3 years before transplant. Postoperatively, the patient developed 100% stent thrombosis and cardiogenic shock and succumbed to his illness on 7th postoperative day. Only one patient developed malignancy in the 1st-year posttransplant detected to be periampullary pancreatic adenocarcinoma.

In the ABO-incompatible group, all the deaths were attributed to infections.

Graft survival

The overall graft survival in ABO-incompatible group was 96.05%–92.3% in the high titer group and 96.8% in the low titer group. This was lower but not significantly, so when compared to the graft in survival in ABOc group (98.2%).

In the high titer group, only one graft was lost; this was secondary to antibody-mediated rejection on 11th postoperative day.

In the low titer group, two grafts were lost in the 1st year. The first patient developed slow graft function with biopsy revealing features of acute tubular necrosis. Further course of patient was remarkable for the development of pulmonary mucormycosis– immunosuppressants were tapered along with the standard antifungal treatment and lobectomy of the affected segment. Graft was lost at about 6-month posttransplant. Another graft was lost to antibody-mediated rejection, with the patient returning to dialysis at 1.5 months after transplant.

In the ABO compatible cohort, the death censored graft survival was 98.2%, with 9 grafts lost secondary to antibody-mediated rejection. Four patients developed acute cortical necrosis, one of them developed antiphospholipid antibody-related thrombotic microangiopathy, and the other graft was lost to pyelonephritis. A single case of recurrence occurred in a patient whose primary disease was focal segmental glomerulosclerosis. Graft function failed to recover despite plasma exchanges.

When the mean serum creatinine of the functioning grafts in the three groups were compared, the difference was not significant at any of the time periods studied, i.e. after discharge from the hospital, 3 months, 6 months, 9 months, and 12 months.[Table 2] and [Figure 2].
Table 2: Mean serum creatinine at different observation times

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Figure 2: Mean serum creatinine over 1 year

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Rejections

Biopsy-proven acute rejections occurred in three patients (21.4%) with high baseline isoagglutinin titers and in nine patients (13.4%) with baseline titers of 1:64 or lower. Fifty-seven patients (6.5%) developed acute rejections in the ABO compatible group. Overall, antibody-mediated rejection occurred more commonly with ABO-incompatible transplants. This difference was significant when ABOi high titer group (21.4%) and ABOi low titer (11.9%) groups were compared to ABOc group (1.8%) with P values of 0.003 and P < 0.001, respectively [Table 3].
Table 3: Key outcomes of ABO incompatible transplant compared to ABO compatible transplant

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All the rejections in high titer group were antibody mediated; one graft was lost despite plasma exchange and IV immunoglobulin. Only one out of total seven grafts in low titer group which developed antibody-mediated rejection was lost. Median number of plasma exchanges which were required for the treatment of antibody-mediated rejection was 5 (mean 5) and 4 (mean 3.57) for high titer and low titer group, respectively. Of these, patients with antibody-mediated rejection (ABMR), one patient in the high-titer group, and three patients in the low-titer group also had elevations in isoagglutinin titers for which they underwent a single session of immunoadsorption each. Due to the low sample size and low event rate (ABMR) in respective groups, the statistical significance of this difference in therapy could not be reliably estimated.

All other cases of acute cellular rejections responded to steroid pulse. None of the patients in any group required additional ATG.

Infections

Nearly 35% of the patients in the entire study group developed infections in the first-year posttransplant. This figure includes infections treated on outpatient basis as well as those requiring hospitalization. However, significantly greater proportion of patients were infection-free in ABO compatible group (68%) and this was significant when compared to ABOi high titer group (21.4%, P = 0.001) and low titer groups (32.8%, P < 0.001).

Overall, the most common infections were urinary tract infections followed by lower respiratory tract infections.

While just 2% of patients in ABO compatible patients developed CMV infection, the proportion of those infected in high and low titer groups was significantly greater– 14.3% (P = 0.034) versus 10.4%(P = 0.001), respectively.

Only two cases of BK virus nephropathy occurred during the first-year posttransplant. Both cases were reported in patients who underwent ABO compatible kidney transplant. Overall rate was low the reasons could be limited follow-up, application of SV40 stain only in biopsies with suspicious findings (e. g. Cytopathic changes, and plasma cell-rich interstitial infiltrates.).

Bleeding

Postsurgical major bleeding complications requiring blood transfusions occurred in 21 patients in ABO compatible group; out of these, four patients required reexploration surgery and repair of anastomotic site. Three patients who underwent ABO-incompatible transplant had major bleeding episodes, one patient in the high titer group who developed this complication required reexploration whereas two patients belonging to low titer group were managed conservatively with blood transfusion.


  Discussion Top


Various studies with conflicting results have been published regarding the effect of baseline isoagglutinin titers on the outcomes on the graft outcomes. Early studies in the “pre-calcineurin inhibitor era” indicated that high preoperative anti-A/B IgG titers are associated with poor long-term allograft survival.[9] Study by Gloor et al.,[10] which employed splenectomy, ATG, and calcineurin inhibitors (but not rituximab) also showed that preoperative high titers are a predictor for ABMR.

In the relatively newer study by Chung et al.,[11] the desensitization protocol was quite heterogeneous with respect to dose and frequency of rituximab administration and the use of bortezomib in those with baseline titers exceeding 1:1024. None of the patients developed antibody-mediated rejection; however, antibody rebound and acute cellular rejections were more frequent in the high-titer group than in the low-titer groups.

In this study, 1-year death censored graft survival in ABOiKT was 96.05% which is comparable to those reported by Montgomery et al. (94.1%).[12] Graft survival was lower for those with high baseline titers but the difference was not significant, but this needs to be validated in a larger cohort.

The overall patient survival was 92.9% in high titer group. The annual death rate among waitlisted candidates has been estimated to be 6% and is even greater for the elderly and those with diabetic kidney disease.[13] Furthermore, in keeping with the fact that the “end stage renal disease-time” is one of the strongest modifiable risk factors for patient and graft outcomes postkidney transplantation, ABOi kidney transplantation may be a reasonable choice if paired kidney donation is not feasible.

Infection-related complications were seen more commonly in patients receiving an ABO-incompatible graft; more so in those with high baseline titers. This is in agreement with the study by Habicht et al.[14] which demonstrated that intensified desensitization was associated with increased risk of infections in ABO-incompatible transplantation. With this respect, lower doses of rituximab have been demonstrated to reduce the risk of infections.[15] This has been adopted as a modified protocol at our center too.

Limitations

This study has its own limitations. First, this study is a retrospective observational study done at a single center. The sample size is small particularly with regards to those with high baseline titers. Despite these limitations, this study is one of the largest single-center studies reported from a developing country and lays a ground work for the subject to be studied in a larger cohort of patients.


  Conclusion Top


ABO-incompatible transplantation is an acceptable treatment for those with end-stage renal disease; however, this comes with a caveat of increased risk of acute rejections and infections in patients with baseline titers of 1:128 or higher.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Stegall MD, Dean PG, Gloor JM. ABO-incompatible kidney transplantation. Transplantation 2004;78:635-40.  Back to cited text no. 1
    
2.
Abraham G, Vijayan M, Gopalakrishnan N, Shroff S, Amalorpavanathan J, Yuvaraj A, et al. State of deceased donor transplantation in India: A model for developing countries around the world. World J Transplant 2016;6:331-5.  Back to cited text no. 2
    
3.
Meier-Kriesche HU, Kaplan B. Waiting time on dialysis as the strongest modifiable risk factor for renal transplant outcomes: A paired donor kidney analysis. Transplantation 2002;74:1377-81.  Back to cited text no. 3
    
4.
Ferrari P, Weimar W, Johnson RJ, Lim WH, Tinckam KJ. Kidney paired donation: Principles, protocols and programs. Nephrol Dial Transplant 2015;30:1276-85.  Back to cited text no. 4
    
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Alexandre GP, Latinne D, Carlier M, Moriau M, Pirson Y, Gianello P, et al. ABO-incompatibility and organ transplantation. Transplantation Reviews 1991;5:230-41.  Back to cited text no. 5
    
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Ray DS, Thukral S. Outcome of ABO-incompatible living donor renal transplantations: A single-center experience from eastern India. Transplant Proc 2016;48:2622-8.  Back to cited text no. 6
    
7.
Jha PK, Bansal SB, Sethi SK, Jain M, Sharma R, Nandwani A, et al. ABO-incompatible renal transplantation in developing world – Crossing the immunological (and mental) barrier. Indian J Nephrol 2016;26:113-8.  Back to cited text no. 7
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8.
Thukral S, Kumar D, Ray DS. Comparative analysis of ABO-incompatible kidney transplantation with ABO-compatible transplantation: A single-center experience from Eastern India. Saudi J Kidney Dis Transpl 2019;30:97-107.  Back to cited text no. 8
[PUBMED]  [Full text]  
9.
Shimmura H, Tanabe K, Ishikawa N, Tokumoto T, Takahashi K, Toma H. Role of anti-A/B antibody titers in results of ABO-incompatible kidney transplantation. Transplantation 2000;70:1331-5.  Back to cited text no. 9
    
10.
Gloor JM, Lager DJ, Moore SB, Pineda AA, Fidler ME, Larson TS, et al. ABO-incompatible kidney transplantation using both A2 and non-A2 living donors. Transplantation 2003;75:971-7.  Back to cited text no. 10
    
11.
Chung BH, Lee JY, Kang SH, Sun IO, Choi SR, Park HS, et al. Comparison of clinical outcome between high and low baseline anti-ABO antibody titers in ABO-incompatible kidney transplantation. Ren Fail 2011;33:150-8.  Back to cited text no. 11
    
12.
Montgomery JR, Berger JC, Warren DS, James NT, Montgomery RA, Segev DL. Outcomes of ABO-incompatible kidney transplantation in the United States. Transplantation 2012;93:603-9.  Back to cited text no. 12
    
13.
Ojo AO, Hanson JA, Meier-Kriesche HU, Okechukwu CN, Wolfe RA, Leichtman AB, et al. Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait-listed transplant candidates. J Am Soc Nephrol 2001;12:589-97.  Back to cited text no. 13
    
14.
Habicht A, Bröker V, Blume C, Lorenzen J, Schiffer M, Richter N, et al. Increase of infectious complications in ABO-incompatible kidney transplant recipients – A single centre experience. Nephrol Dial Transplant 2011;26:4124-31.  Back to cited text no. 14
    
15.
Lee J, Lee JG, Kim S, Song SH, Kim BS, Kim HO, et al. The effect of rituximab dose on infectious complications in ABO-incompatible kidney transplantation. Nephrol Dial Transplant 2016;31:1013-21.  Back to cited text no. 15
    


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