Novel technology in transplant, specifically, the Molecular Microscope Diagnostic System, has made it possible to diagnose a new clinical phenotype of rejection called “early antibody-mediated rejection.” Here, we present 2 kidney transplant recipients who had normal serum creatinine levels but elevated donor-derived cell-free DNA. Allograft biopsies did not show antibody-mediated rejection, but the Molecular Microscope Diagnostic System reported early antibody-mediated rejection. Once considered as an isolated incident occurring after kidney transplant, antibody-mediated rejection is now recognized to be a progressive condition that waxes and wanes over time and may ultimately lead to chronic allograft damage and allograft loss. Hence, if it can be diagnosed early before causing allograft injury, the early diagnosis can represent a paradigm shift in the management of antibody-mediated rejection in kidney transplant recipients, with better treatment outcomes and prolonged allograft survival.
Key words : Donor-derived cell-free DNA, Kidney transplant, Molecular Microscope Diagnostic System, Rejection
Novel technology in transplant, specifically, the Molecular Microscope Diagnostic System (MMDx), has made it possible to diagnose a new clinical phenotype of rejection called “early antibody-mediated rejection” (EABMR). Here, we describe 2 kidney transplant recipients who had normal serum creatinine levels but elevated donor-derived cell-free DNA, which prompted an allograft biopsy. On biopsy, MMDx was able to show EABMR. Once considered as an isolated incident occurring after kidney transplant, antibody-mediated rejection (ABMR) is now recognized to be a progressive condition that waxes and wanes over time and may ultimately lead to chronic allograft damage and allograft loss.1 Hence, if it can be diagnosed early before causing allograft injury, this diagnosis can bring about a paradigm shift in the management of this condition, with better treatment outcomes and prolonged allograft survival.
Patient 1 was a 50-year-old woman who received a deceased donor renal transplant 1 year ago for end-stage renal disease secondary to polycystic kidney disease. Her past history was significant for cervical cancer, for which she had undergone radical hysterectomy with pelvic irradiation. She received induction immunosuppression with basiliximab and methylprednisolone and maintenance immunosup-pression with mycophenolate mofetil, tacrolimus, and prednisone. She had delayed graft function posttransplant but achieved a baseline serum creatinine of 1.1 mg/dL. Baseline donor-derived cell-free DNA was 0.41%. Her immunosuppression was reduced due to bacteremia secondary to a urinary tract infection. There was no donor-specific antibody; however, her tacrolimus levels were subtherapeutic off and on and ranged between 6 and 9 ng/dL. At 11 months posttransplant, serum creatinine was 1.28 mg/dL and donor-derived cell-free DNA was 1.3%, which prompted an allograft renal biopsy. The biopsy showed mild lymphocytic tubulitis limited to the areas of interstitial fibrosis and one glomerulus with focal mesangiolysis. Although the patient had no evidence of transplant rejection on the biopsy, the MMDx reported EABMR (Figure 1). This created a therapeutic dilemma for the transplant team since this was the first time we had encountered such a clinical situation. We discussed this with the patient and decided to treat her with intravenous immunog-lobulin. Her creatinine levels remained stable, and, 1 month following treatment completion, donor-derived cell-free DNA level was 0.63%.
Patient 2 was a 30-year-old woman who received a deceased donor renal transplant 1 year ago for end-stage renal disease secondary to chronic glomerulonephritis. Her posttransplant course was uncomplicated, and she achieved a baseline serum creatinine of 1.0 mg/dL. She received induction immunosuppression with basiliximab and methyl-prednisolone and maintenance immunosuppression with mycophenolate mofetil, tacrolimus, and prednisone. Her tacrolimus levels were therapeutic and ranged between 8 and 10 ng/dL. The first donor-derived cell-free DNA test was done at 11 months posttransplant and was 1.6%. Because the patient’s laboratory tests were stable with serum creatinine level of 1.1 mg/dL, we repeated the donor-derived cell-free DNA test at 12 months posttransplant, with results now showing 3.90%. This prompted an allograft biopsy, which demonstrated borderline acute T-cell-mediated rejection along with mild peritubular capillaritis. There was occasional, mild lymphocytic tubulitis, and the interstitium demonstrated mild lymphoplasmacytic inflammation in the unscarred cortex (Banff classification showing i1, t1, v0, g0, ptc1, c4d0, ci0, ct0, cv0, cg0, ptcml0, ti1, i-IFTA1, t-IFTA0, pvl0). However, the MMDx reported EABMR and no T-cell-mediated rejection (Figure 1). We treated the patient with methylprednisolone and intravenous immunoglobulin. The serum creatinine remained stable, and, 1 month following treatment completion, the donor-derived cell-free DNA level was 1.6%.
Antibody-mediated rejection is the predominant cause for late allograft loss after kidney transplant.2 There is no FDA-approved treatment for this condition. The standard of care treatment based on expert consensus3 includes glucocorticoids, intra-venous immunog-lobulin, and plasma exchange; however, the treatment failure rate is very high. The two commonly recognized clinical phenotypes are acute and chronic ABMR, where acute ABMR generally occurs early and is more responsive to treatment while chronic ABMR occurs late and is not very responsive to treatment. There is also the more complicated Banff classification, which has been constantly evolving since it was first introduced. The most recent changes to Banff classification were applied in 2019.4,5 Redfield and colleagues reported a 55% rate of 2-year graft survival for patients with chronic active ABMR treated with standard of care treatment and a 20% rate of 2-year graft survival for patients with chronic active ABMR without any treatment.6 The transplant community has focused more on the late or chronic ABMR since it is difficult to treat and results in allograft failure in a large proportion of patients.
Histologic assessment of biopsies has its limitations because of the subjective nature of reporting by pathologists and limited reproducibility between observers, whereas MMDx can assess T-cell-mediated rejection and ABMR in a reference set of biopsy samples using machine learning-derived classifier algorithms.7 Molecular interpretation offers an objective second opinion that adds to local histology findings, thereby increasing clinician confidence with diagnosis and treatment planning. Scheduled surveillance with donor-derived cell-free DNA and molecular assessment of biopsy with MMDx have made it possible to diagnose EABMR and could potentially revolutionize the kidney transplant landscape by enabling early diagnosis and successful treatment of the commonest cause of late kidney allograft failure, thereby prolonging allograft survival.
DOI : 10.6002/ect.2021.0489
From the 1Michael and Marian Ilitch Department of Surgery, Wayne Health, Detroit, Michigan; and the 2Transplant Surgery, DMC-Harper University Hospital, Detroit, Michigan, 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 conflictsof interest.
Corresponding author: Rajeev Sharma, Michael and Marian Ilitch Department of Surgery, Wayne Health, 4160 John R Street, Professional Building, Suite 400, Detroit, MI, USA
Phone: +1 3137458797
Figure 1. Molecular Microscope Diagnostic Systemand Allograft Biopsy Findings in Patient 1 and Patient 2