PMC9875042_01
Histological features of subclinical chronic active AMR in Patient 1 before treatment and changes in DSA throughout treatment. (A) HLA phenotype results for the recipient and his donor. (B) Typical histological findings of chronic active AMR and their Banff 2017 Scores. (C) Changes in MFI values of the anti-DQ7 DSA (1:3 or 1:12-diluted serum) during the first round of treatment containing rituximab, PP/IVIG, and carfilzomib. (D) Changes in MFI values of the anti-DQ7 DSA (1:4/1:32/1:64-diluted serum and positive control serum) after the treatment with daratumumab-based therapy.
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The donor-recipient HLA-A, -B, -DR, -DQ mismatch grade was 6 ( Figure 1A ). Pathology examination revealed mild glomerulitis (Banff 2017 Schema: g1), mild-to-moderate peritubular capillaritis (ptc1-2), mild peritubular capillary C4d deposition (C4d1), focal glomerular basement membrane double contours (cg1), and peritubular capillary basement membrane multilayering (ptcml, electron microscopy), which were diagnosed as subclinical chronic active AMR ( Figure 1B ). AMR: rituximab (200 mg), carfilzomib (30 mg twice weekly), and 14 PP/IVIG (25g each time) sessions (three times weekly). After 4 weeks of treatment, the MFI level of anti-DQ7 DSA decreased significantly but was still >12,000 ( Figure 1C ). When we further diluted the serum samples to 1:32 and 1:64, the DSA-MFI values demonstrated a more obvious reduction (from 15,731 to 3,763 at 1:32 dilution; from 13,926 to 1,320 at 1:64 dilution) ( Figure 1D ). Seven months later, the DSA-MFI value eventually dropped to 1,572 ( Figure 1D ).
PMC9875042_02
Course of Patient 2's DSA and renal function after the diagnosis of late active AMR. (A) HLA phenotype results for the recipient and his donor. (B) Changes in MFI values of the anti-DQ7 DSA (1:4 or 1:64-diluted serum and positive control serum) during the treatment. (C) Changes in serum creatinine and eGFR levels after the diagnosis and treatment of late active AMR.
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The donor-recipient HLA-A, -B, -DR, -DQ mismatch grade was 4 ( Figure 2A ). After treatment, the DSA-MFI value had decreased by ~30% ( Figure 2B ). After 4 weeks of treatment, the MFI value of anti-DQ7 DSA was reduced by 12%, from 18,548 to 16,374, in the 1:4 diluted serum, and by 50%, from 8,827 to 4,249, in the 1:64 diluted serum ( Figure 2B ). The patient's renal graft function was simultaneously improved (SCr, 133 mumol/L; eGFR increased from 38 to 46 ml/min/1.73m2) ( Figure 2C ). After 5 weeks of combination therapy, the MFI value of anti-DQ7 DSA had decreased markedly, to 3,760 at a serum dilution of 1:4 ( Figure 2B ). During the first 4 months of the maintenance treatment, the DSA-MFI value of the 1:4-diluted serum remained low, at around 5,000 ( Figure 2B ). At the follow-up on day 346 of treatment, a sudden increase in SCr (235 mumol/L) and a low trough level of tacrolimus (3.7 ng/ml) suggested the possibility of acute rejection ( Figure 2C ). However, during the 11 weeks of combination therapy, the patient's DSA-MFI value did not decline as before but continued to rise (to 19,442) ( Figure 2B ). In addition, the patient's SCr level returned ( Figure 2C ).
Histological features of late active AMR in Patient 2 before and after treatment. (A) Typical histological findings of active AMR in Patient 2 before the treatment and their Banff 2019 Scores. (B) The pathology results of a second renal biopsy performed on day 137 after the initiation of treatment and their Banff 2019 Scores. (C) The pathology results of a third renal biopsy performed on day 350 after the initiation of treatment (when acute rejection was clinically suspected) and their Banff 2019 Scores. (D) The pathology results of a fourth renal biopsy performed on day 422 after the initiation of treatment (when poor response was observed to daratumumab intensive therapy) and their Banff 2019 Scores.
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After admission, a biopsy of the renal graft was performed, and pathological findings confirmed active AMR (Banff 2019 Schema: g1, ptc2, C4d3, cg0;  Figure 3A ). The results showed that the acute tissue injury was alleviated (g0, ptc1, and C4d0) when compared with the first biopsy, and chronic tissue lesions remained minimal (cg0) ( Figure 3B ). AMR reappeared (g1, ptc1, C4d3) ( Figure 3C ). After rescue therapy with pulse MP (400 mg/day for 3 days), his SCr decreased to 148 mumol/L.