Ideally, immediate graft function should be expected after living donor kidney transplantation. We present a case of early Banff 2A cellular rejection 24 hours after an ABO blood group-compatible, HLA crossmatch-negative living donor kidney transplant. We speculate that the development of acute rejection in this low-risk patient was likely due to the HLA mismatches and possible induction with basiliximab. This case report poses the question of whether more intensive induction therapy should be considered in low-risk patients with the presence of HLA mismatches and discusses the long-term allograft outcomes following early acute rejection.
Key words : Acute rejection, Banff, Basiliximab, Living kidney transplant, Thymoglobulin
With the introduction of potent immunosuppression, the incidence of acute allograft rejection has dramatically decreased in recipients of both living and deceased donor kidney transplant.1 Ideally, immediate graft function should be expected after living donor kidney transplant. Thus, acute rejection is not expected immediately after living donor transplant. We present a case of early acute cellular rejection 24 hours after an ABO-compatible, human leukocyte antigen (HLA) crossmatch-negative living donor kidney transplant.
A 65-year-old White man with medical history of end-stage renal disease due to biopsy-proven anti-glomerular basement membrane (anti-GBM) disease underwent a living donor kidney transplant from his 68-year-old wife. The recipient’s blood group was AB positive, and his HLA tissue typing is shown in Table 1. A flow panel reactive antibody (PRA) screen done 3 months before transplant was 0% for both T-flow and B-flow PRA. The donor was a 68-year-old White woman with blood type A positive. She had a history of osteoporosis and had smoked 1 pack of cigarettes every 3 days for over 20 years. Her estimated glomerular filtration rate calculated using chronic kidney disease epidemiology collaboration was 80 mL/min/1.73 m2 with a 24-hour creatinine clearance of 91 mL/min. As expected, both complement-dependent cytotoxic and flow crossmatches for T and B cells were negative.
The donor had normal anatomy of both kidneys, each with a single artery and vein. The right donor kidney was selected for donation. Donor nephrectomy was uneventful. Kidney transplant surgery was performed uneventfully. Induction with basiliximab (20 mg) and methylprednisolone (500 mg) was performed at the time of surgery. At the time of revascularization, the patient received furosemide (Lasix [Pfizer], 80 mg) and mannitol (20 mg) with immediate diuresis. No implant biopsy was done. After surgery, urine output was 600 mL/h, which decreased over the next 3 hours to 375 mL/h. At 5 hours postsurgery, urine output continued to fall to 100 mL/h. By hour 16, the patient was anuric. Mycophenolate mofetil was started on postoperative day (POD) 0 at a dose of 500 mg twice daily. Tacrolimus was initiated on POD 1 at a dose of 1 mg twice daily. A renal allograft duplex ultrasonography scan on POD 1 showed normal renal transplant with patent transplant vessels with normal waveforms and velocities. Serum creatinine level immediately trended downward after surgery, from 862 mol/L (9.75 mg/dL) to 627 mol/L (7.10 mg/dL). However, repeat laboratory results 24 hours after surgery showed an increase in serum creatinine level to 831 mol/L (9.40 mg/dL). A transplant duplex ultrasonography showed diffusely elevated intrarenal resistive indices measuring 1.0 with reversal of diastolic flow at the upper pole (Figure 1). Additional laboratory studies were conducted. Lactate dehydrogenase and haptoglobin levels were normal. Antineutrophil cytoplasmic antibody and complement C3 and C4 levels were normal. Anti-GBM antibody and anti-phospholipase A2 receptor antibody tests were both negative.
Because of persistent anuria and rising serum creatinine level, a for-cause biopsy was done on POD 2 that showed Banff 2A acute cellular rejection that was C4d negative (Figure 2). Donor-specific antibodies (DSA) were not present.
For treatment of Banff 2A rejection, basiliximab was stopped and the patient was given rabbit anti-thymocyte globulin (rATG) at a total dose of 3 mg/kg and pulse intravenous steroid at 250 mg for 5 days. Immunosuppression was intensified, and target tacrolimus levels were increased to achieve trough levels between 10 and 12 ng/mL. By POD 15, the serum creatinine level improved to 274 mol/L (3.10 mg/dL) from 848 ?mol/L (9.60 mg/dL) on POD 7. Six months posttransplant, the patient maintained stable allograft function with a baseline serum creatinine level of 159 to 1761 ?mol/L (1.8-2.0 mg/dL). At 15, 30, 60, and 90 days posttransplant, DSA remained undetected.
Although acute cellular rejection commonly presents within the first 3 to 6 months posttransplant, it can also present within the first week posttransplant.2 However, this case report demonstrates acute cellular rejection very early posttransplant in an ABO-compatible, HLA crossmatch-negative living donor kidney transplant.
Factors that indicate high risk for acute rejection include multiple HLA mismatches, a high PRA value, the presence of DSA, ABO blood group incompatibility, a prolonged cold ischemia time greater than 24 hours, African American ethnicity, and an inadequate induction regimen.3 Factors indicating low risk for acute rejection include living donor transplants, White ethnicity, ABO compatibility, and a negative crossmatch. For patients with
factors for high risk of rejection, the 2009 Kidney Disease: Improving Global Outcomes guidelines recommend an induction regimen with lymphocyte-depleting agents such as rATG rather than an interleukin-2 receptor monoclonal antibody such as basiliximab.
It should be noted that basiliximab has become the preferred induction therapy for living donor kidney transplants because these cases are considered to have low risk for rejection.4 In 2016, nearly 75% of kidney recipients received rATG and 20% received basiliximab.5 A prior study by Brennan and colleagues6 compared the efficacy of rATG versus basiliximab in deceased donor kidney transplants. In that study, it was shown that, 5 years posttransplant, the rATG group had a lower incidence of acute rejection compared with the basiliximab group (15.6% vs 25.5%; P = .02). However, there were no differences in incidence of allograft survival, delayed graft function, and death among the 2 groups. Although there may be no difference in allograft 5-year survival between patients treated with rATG versus basiliximab, it is our opinion that there may be a benefit in choosing rATG to reduce the incidence of acute rejection in living donor kidney transplants.
These results were corroborated by a study done by Goumard and colleagues7 that showed that biopsy-proven rate of acute rejection was significantly less with rATG induction than with basiliximab induction in sensitized kidney transplant patients without preexisting DSA. Specifically, the rate of acute rejection was 25% with basiliximab and 8.2% with rATG. In conclusion, they reported a higher incidence of T-cell-mediated rejection and antibody-mediated rejection in sensitized transplant recipients without preexisting DSA who received basiliximab versus rATG induction therapy.
One study conducted by Lee and colleagues8 analyzed rates of acute rejection in 46 patients with low immunologic risk who received induction with thymoglobulin versus basiliximab. Low immunologic risk was defined as having a calculated PRA value less than 30%. Results showed that, with thymoglobulin, the rate of acute rejection was 0%, whereas, with basiliximab, it was 23.8%. This study concluded that low-immunologic risk kidney transplant with induction of thymoglobulin instead of basiliximab significantly reduced the incidence of acute rejection. Furthermore, they also showed no significant difference in estimated glomerular filtration rate between the 2 groups at 6 months posttransplant.
A prior review by Hellemans and colleagues9 investigated prevailing data regarding induction therapy for kidney transplant recipients and concluded that the role of basiliximab in kidney transplantation had become questionable because it might no longer be beneficial in standard-risk transplantation and might be inferior to rATG in high-risk settings. Acute rejection also had a negative impact on long-term allograft outcomes.10 Furthermore, incidence of chronic allograft nephropathy was less than 1% in patients with no episodes of acute rejection. Incidence of chronic allograft nephropathy was more frequent in patients with a history of acute rejection. If acute rejection occurred less than 60 days posttransplant, incidence of chronic allograft nephropathy was 20% for living donor kidneys and 36% for deceased donor kidneys. If acute rejection occurred greater than 60 days posttransplant, incidence of chronic allograft nephropathy was 43% for living donor kidneys and 60% for deceased donor kidneys.11 Therefore, there may be prognostic importance of reducing incidence of acute rejection.
This case report poses the question of whether recipients with low immunologic risk should receive induction therapy with rATG as opposed to basiliximab. Although the patient in our case report had low immunologic risk for rejection, he did have multiple HLA mismatches, and he received a kidney from a donor who was older. Therefore, we believe that more intensive induction therapy should be considered in the presence of HLA mismatches and with a kidney from an older (age >65 years) donor. There has been no large randomized trial comparing the efficacy of rATG versus basiliximab in patients undergoing living donor kidney transplant, particularly between an old recipient and an old donor. In conclusion, the use of rATG in these patients should remain the first-line induction unless a prospective randomized clinical trial shows otherwise.
DOI : 10.6002/ect.2020.0446
From the 1Department of Nephrology, USC Transplant, University of Southern California, Los Angeles, California; and the 2Keck School of Medicine, Los Angeles, California, USA
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Author contributions: NS was involved in conception and design of the case report and provided critical revision of the manuscript. TC was involved in retrieval of pertinent data and history for case and co-wrote and drafted the manuscript. All authors participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript.
Corresponding author: Neeraj Sharma, 2020 Zonal Avenue IRD #806, Los Angeles, CA 90033, USA
Table 1. Donor and Recipient Tissue Typing Results
Figure 1. Doppler Ultrasonography Showing Reversal of Diastolic Flow
Figure 2. Kidney Graft Biopsy at Postoperative Day 2