Impact of ABO Compatibility/Incompatibility on the Perioperative Anti-SARS-CoV-2 Immunoglobulin G Levels in 2 Preoperatively Vaccinated Patients Undergoing Kidney Transplant: A Case Report.

Herein, we monitored the perioperative anti-SARS-CoV-2 spike immunoglobulin G titers in patients who were preoperatively vaccinated with 2 doses of a COVID-19 messenger RNA vaccine. Additionally, we compared the clinical settings between ABO-incompatible and ABO-compatible pre-emptive kidney transplant (KTx). Case 1 was of a 45-year-old man who was an ABO-incompatible KTx recipient. Before transplant, his serum antibody titers decreased from 278 U/mL at baseline to 41.9 U/mL after desensitization therapy (84.9% lower) and 54.7 U/mL (80.3% lower) at day 8; it is now maintained at 4.1 U/mL at 6 months posttransplant (98.5% lower). Case 2 was of a 50-year-old man who was an ABO-compatible KTx recipient. His serum antibody titer level decreased from 786 U/mL at baseline to 386 U/mL on day 8 (50.8% lower) and is now maintained at 156 U/mL at 6 months posttransplant (80.1% lower). We suggest that anti-SARS-CoV-2 spike immunoglobulin G titers should be monitored during the perioperative period to determine the optimal timing of COVID-19 vaccine booster doses for the maintenance of protective immunity, particularly in ABO-incompatible KTx recipients who require desensitization therapy.

Introduction

The immune response to coronavirus disease (COVID-19) vaccination of patients with chronic kidney disease (CKD) receiving renal replacement therapy (RRT) was significantly lower than that of the general population, particularly in patients undergoing kidney transplantation (KTx) 1-3. Recent studies have shown immune responses to post-transplantation COVID-19 vaccination in unvaccinated KTx patients 4-7 and not highlighted the importance of preoperative vaccination in patients undergoing KTx. Although it is recommended that vaccination should be prioritized during the pre-transplant period, there are no reports regarding the monitoring of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) antibody titers.

Herein, we report two cases of patients who were preoperatively vaccinated with two doses of the Comirnaty COVID-19 vaccine (BioNTech-Pfizer BNT162b2) in whom the anti-SARS-CoV-2 S IgG titers were monitored before undergoing ABO-incompatible (Case 1) and ABO-compatible (Case 2) pre-emptive KTx. Additionally, the clinical settings between the two cases were compared.

Case report

Case 1

The patient was a 45-year-old Japanese man who was diagnosed with end-stage kidney disease (ESKD) due to diabetic nephropathy. At 41 years old, he was diagnosed with diabetes mellitus and began treatment with diet modification and medication. At this point, proteinuria was already noted, and his serum creatinine (Cr) level gradually increased to 1.36 mg/dL. Thereafter, his renal function gradually declined, ultimately leading to ESKD. At 45 years old, he was referred to our hospital for further evaluation and treatment, including pre-emptive living donor KTx.

The two-dose COVID-19 mRNA vaccination was completed 3 months prior to transplantation, and the preoperative antibody titer against the SARS-CoV-2 spike protein was 278 U/mL (Elecsys® Anti-SARS-CoV-2 S RUO, Roche Diagnostics, Basel, Switzerland; positive threshold, ≥0.8 U/mL).

The proposed transplant was ABO-incompatible as the donor had type B blood while the recipient had type A blood. The ABO titer for anti-B before desensitization therapy was 1:16.

Tacrolimus (TAC), mycophenolate mofetil (MMF, 2,000 mg/day), and methylprednisolone (mPSL) were administered 1 week before transplantation (Fig. 1 ). Additionally, the anti-CD20 monoclonal antibody rituximab (100 mg) was also administered at 1 week and 3 days prior to transplantation, according to our pre-transplantation regimen (Fig. 1). TAC was started at a dose of 0.1 mg/kg/day, and the trough level was maintained at 8 to 12 ng/mL for the first few weeks after transplantation. After 1 week of oral immunosuppressant therapy, the patient underwent three sessions of hemodialysis with two sessions of double filtration plasmapheresis (DFPP) and one session of plasma exchange (PE) using fresh frozen plasma as desensitization therapy before transplantation. Induction therapy with intravenous mPSL (500 mg) and basiliximab (20 mg), which was also administered 4 days after transplantation, was administered on the day of transplantation. The dose of mPSL was gradually tapered to 40 mg and switched to an oral formulation at the end of the first post-transplantation week. The patients’ anti-B titers remained below the target value.

Figure 1

Antibody titers after preoperative desensitization therapy and tapering of triple immunosuppression in post-transplantation patients. Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antibody titers markedly decreased prior to transplantation after the first and second sessions of DFPP, first session of PE, and 2 doses of rituximab. At days −5, −3, and −1, antibody titers were 215 U/mL, 133 U/mL, and 41.9 U/mL, respectively. Six months after transplantation, the antibody titers did not decrease below the sensitivity level (<0.8 U/mL) and was maintained at 4.1 U/mL.

The serum antibody titers are shown in Figure 1. The antibody titers markedly decreased after the first and second DFPP sessions, first session of PE, and administration of two doses of rituximab (215 U/mL, 133 U/mL, and 41.9 U/mL on days −5, −3, and −1, respectively). The antibody titers on days −5, −3, and −1 were 22.6%, 52.1%, and 84.9% lower than the titer before desensitization therapy, respectively. After transplantation, the antibody titer gradually declined; however, it did not decrease below the sensitivity level and was maintained at 4.1 U/mL (98.5% lower than preoperative titer) at 6 months postoperatively.

Case 2

A 50-year-old Japanese man was diagnosed with ESKD secondary to immunoglobulin A (IgA) nephropathy. At 44 years old, he presented with hematuria and proteinuria and was treated with diet modification and medication; however, his outpatient follow-ups were irregular. At 46 years old, his eGFR decreased to 41 mL/min/1.73 m2 and proteinuria increased to 3.3 g/gCr. Kidney biopsy was performed and revealed IgA nephropathy. Although CKD was adequately managed, his renal function gradually declined, ultimately leading to ESKD. At 50 years old, he was referred to our hospital for further evaluation and treatment, including for pre-emptive living donor KTx.

Two doses of COVID-19 mRNA vaccination were administered 5 months prior to transplantation, and the preoperative serum antibody titer against the SARS-CoV-2 spike protein was 786 U/mL.

The proposed transplant was ABO-compatible as both the donor and recipient had type A blood. Administration of TAC, MMF (2,000 mg/day), and mPSL was initiated 1 week before transplantation (Fig. 2 ). TAC was started at a dose of 0.1 mg/kg/day, and the trough level was maintained at 8 to 12 ng/mL for the first few weeks after transplantation.

Figure 2

Antibody titers after transplantation with tapering of triple immunosuppression. Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antibody titers decreased from the preoperative level of 786 U/mL to 386 U/mL on postoperative day 8. Six months after transplantation, the antibody titers did not decrease below the sensitivity level (<0.8 U/mL) and was maintained at 156 U/mL.

Induction with intravenous mPSL (500 mg) and basiliximab (20 mg) was initiated on the day of transplantation. Basiliximab was administered for 4 days after transplantation, while mPSL was gradually tapered to 40 mg and switched to an oral formulation at the end of the first post-transplantation week.

The serum antibody titers are shown in Figure 2. The antibody titer on day 8 was 386 U/mL, which is 50.8% lower from the preoperative titer. After transplantation, the antibody titer gradually declined; however, it did not fall below the sensitivity level and was maintained at 156 U/mL (80.1% decrease) at 6 months postoperatively.

Discussion

We describe two patients who were vaccinated against COVID-19 before KTx in whom the serum anti-SARS-CoV-2 S IgG titers were monitored. Additionally, we compared the clinical settings between Case 1 (ABO-incompatible) and Case 2 (ABO-compatible) wherein the serum antibody titers decreased by 98.5% and 80.1%, respectively, from pre-transplantation to 6 months post-transplantation.

This case report has two important clinical implications. First, ABO-incompatible patients are more likely to have lower postoperative serum antibody titers than ABO-compatible patients because of preoperative desensitization therapy. Second, compared with post-transplantation vaccination, COVID-19 vaccination prior to transplantation may allow patients to produce high levels of antibody titers that prevent its decrease to below the sensitivity level (<0.8 U/mL) 6 months after transplantation.

Similar to our report, antibody titers in patients who underwent KTx following the second dose of SARS-CoV-2 mRNA vaccine decreased by 54% and 85% on days 28 and 100, respectively, compared with the titer on day 0 8. However, this report did not compare ABO-incompatible and -compatible transplantation settings.

In ABO-incompatible KTx, desensitization protocols with potent therapeutic apheresis have been used for anti-A/B antibody removal 9, 10. Therapeutic apheresis is not specific for IgG; hence, it reduces the levels of all plasma proteins, with total IgG and IgM and anti-A/B antibody being significantly reduced 10. Additionally, antibodies against Pneumococcus and Haemophilus polysaccharide antigens are significantly reduced, whereas those against tetanus and diphtheria protein antigens are not 10. Our findings confirm that anti-SARS-CoV-2 S IgG titers in ABO-incompatible patients decreased more than that in ABO-compatible patients, which could theoretically be due to the elimination of anti-SARS-CoV-2 S IgG.

Although no optimal threshold has been established for achieving protective immunity, early reports have indicated that higher levels of antibody titers after the second COVID-19 vaccine dose were correlated with a reduced risk of symptomatic infection. A vaccine efficacy of 80% against symptomatic infection with SARS-CoV-2 was achieved with an anti-spike antibody titer of 264 binding antibody units (BAU)/mL 11. Note that BAU/mL was converted to U/mL (U/mL = 0.972  ×  BAU/mL) 12. In our two patients, antibody titers declined throughout the perioperative period, particularly in ABO-incompatible patients, and both antibody titers were below the threshold (256 U/mL) at 6 months postoperatively. Thus, regarding the strategy of booster vaccination for post-transplantation patients with low antibody titers, the ABO compatibility/incompatibility should be considered instead of the current conventional vaccination strategy.

We recently reported the evaluation of immune responses to post-transplantation COVID-19 vaccination and their possible relationship with other co-factors in KTx recipients; 44.8% of KTx recipients did not develop antibody response (<0.8 U/mL) after receiving the second dose of COVID-19 vaccine. Factors that may significantly affect the inadequacy of response to the COVID-19 vaccine in these patients are older age, shorter duration after KTx, and use of a higher dosage of MMF for maintenance immunosuppression 13.

In our two patients, COVID-19 vaccination prior to transplantation may have induced antibody production. Additionally, the antibody titers did not decrease below the sensitivity level (<0.8 U/mL) even at 6 months post-transplantation. This result is consistent with that of our another study wherein following the second dose of COVID-19 mRNA vaccine in elderly patients with late-stage CKD, the antibody titers tended to be lower in patients with CKD stage G5D than in patients with CKD stages G4 and G5 14; therefore, CKD progression may cause antibody titers to decline, and administering the COVID-19 vaccine is strongly recommended prior to the commencement of RRT.

In summary, although our patients had both preoperatively received the second dose of the COVID-19 mRNA vaccine and produced antibodies, continuous and regular monitoring of the SARS-CoV-2 S antibody titers during the perioperative period is important as the titers may decline 6 months post-transplantation. We strongly suggest that this strategy be applied for ABO-incompatible transplantation patients, particularly those undergoing desensitization therapy, to determine the optimal timing for COVID-19 booster vaccination to maintain the protective immunity obtained from COVID-19 vaccination.

Acknowledgments

The authors are grateful to Masahiro Doi and Tomoe Ando for their technical assistance during immunological evaluation of the samples.

Grant information

No funding was obtained for this study.

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