The Value of Protocol Biopsies to Identify Patients With De Novo Donor-Specific Antibody at High Risk for Allograft Loss

Abstract

De novo donor-specific antibody (dnDSA) is associated with antibody-mediated rejection (AMR) and allograft loss, yet the allograft histology associated with dnDSA remains unclear. The aim of this study was to examine the allograft histology associated with dnDSA in patients with serial surveillance biopsies. We retrospectively studied adult conventional solitary kidney transplant recipients from October 2007 to May 2014. The definition of dnDSA was new donor-specific antibody (DSA) with mean fluorescence intensity (MFI) >1000. The incidence of dnDSA was 7.0% (54 of 771) over mean follow-up of 4.2 ± 1.9 years. Patients with dnDSA had reduced death-censored allograft survival (87.0% vs. 97.0% no dnDSA, p < 0.01). Moreover, 94% of patients received a biopsy after dnDSA (mean of three biopsies per patient). AMR was present in 25.0% and 52.9% of patients at dnDSA detection and at 1 year, respectively. Patients with both class I and II dnDSA had the highest rate of allograft loss. The higher the sum MFI at dnDSA detection, the higher the incidence of AMR. In conclusion, patients with dnDSA without AMR at time of detection may benefit from a follow-up biopsy within 1 year because AMR can be missed initially. In addition, the dnDSA class and sum MFI at baseline appear to be prognostic. The higher the sum MFI of dnDSA at baseline, the higher the incidence of AMR.

Keywords: alloantibody; biopsy; clinical research/practice; immunosuppressive regimens; induction; kidney (allograft) function/dysfunction; kidney transplantation/nephrology; rejection: antibody-mediated (ABMR).

Figure 1

Patients Studied

Figure 2. Time to de novo DSA detection

The mean time to de novo DSA detection post-transplant was 1.8±1.6 years. At our center, surveillance testing for dn DSA is performed at 4 months post-transplant and yearly thereafter. Testing for dn DSA is also obtained for clinical indication (i.e. acute cellular rejection).

Figure 3. Patient and Allograft Survival

Patients with de novo DSA had reduced death-censored allograft survival, p= 0.01. At the end of follow-up, the actuarial death-censored allograft survival was 87.0% in the patients who developed dnDSA and 97.0% in patients who did not develop dnDSA, p=0.01. Cox regression with a time-dependent variable (dnDSA) was used to compare groups (Wald’s test at the 0.05 level).

Figure 4. Allograft rejection at De Novo DSA detection and in 1 year

The prevalence of acute cellular rejection remained similar at 1 year post dnDSA detection, but there was increased acute, active and chronic AMR. The definition of acute, active, AMR was Banff 1) ptc + g score >2 or 2) ptc >0 or g> 0 and C4d >1. Chronic AMR was present if Banff cg score was >0. All patients with chronic AMR had concomitant acute, active AMR. McNemar’s paired analysis was used to compare serial biopsies.

Figure 5. Allograft histology at De Novo DSA detection and in 1 year

The prevalence of chronic AMR increased in the year following the detection of dnDSA. McNemar’s paired analysis was used to compare serial biopsies.

Figure 6. Allograft function and proteinuria when De Novo DSA detected and at follow-up

At the time of dnDSA detection, the mean iothalamate clearance was 55.0± 20.4 ml/min/BSA and at one year post detection, it decreased to 52.5 ±18.6 ml/min/BSA, p<0.01 (paired t-test) During the entire follow-up following dnDSA detection (mean 3.2±2.0 years); the mean iothalamate GFR decreased to 44.5 ± 21.7 ml/min/BSA, p=0.01. During the same follow-up, the mean 24 hr. urine proteinuria increased from 391.4±865.5 to 603.6 ± 1035.8, but this did not reach statistical significance p=0.24.

Figure 7. Allograft failure, eGFR decline, and AMR in patients with and without De novo DSA

Graft failure, the composite end-point of graft failure and/or 50% reduction in GFR Acute, active AMR, and chronic AMR were higher in patients with dnDSA. Patients with both class I + II dnDSA had the highest rate of graft loss and 50% decline in eGFR. 94.4% (51/54) of patients received a biopsy. The mean follow-up post dn DSA was 3.2±2.0 years. * No patients with class I dnDSA only lost their allografts during follow-up. † All statistical comparisons were with the no dnDSA group.

Figure 8. Allograft function and histology stratified by de novo DSA mean fluorescence intensity (MFI)

The rates allograft loss; composite end-point; acute, active AMR; and chronic AMR; were similar in patients with transient de novo DSA as compared to patients without de novo DSA. A higher sum MFI of dnDSA at baseline was associated with higher rates of acute, active, AMR (p=0.03, Cochran test for trend). * Comparison between outcomes in patients with no dnDSA and patients with transient dnDSA. †Cochran test for trend comparison outcomes in patients with dnDSA MFI < 3000, 3000–6000, and >6000 at baseline.

Figure 9. Acute, active AMR and dnDSA associated with allograft failure and eGFR decline

* No dnDSA patients without AMR lost their allograft during follow-up. † All statistical comparisons were to the no dnDSA group.