Purpose: Recurrence of proteinuric diseases is a dreaded complication post kidney transplantation (PKTx). Even though >50% of these recurrences are amenable to pre/post-Tx plasmapheresis, anti-CD20 monoclonal antibodies, LDL apheresis, or a combination of these measures, a subset of patients continues to have nephrotic range proteinuria, which may be due to inadequate suppression of plasma cells. Daratumumab (Dara), a human monoclonal antibody targets CD38 and depletes plasma cells, NK cells and monocytes, is approved for multiple myeloma. Here, we describe our experience with Dara to treat refractory proteinuria PKTx in pediatric patients.
Methods: 3 patients (mean age at Dara use 16.3 years; 2 male) with ESRD secondary to FSGS (#1 and #3) and Lupus (#2), were found to have nephrotic range proteinuria with a urine protein to creatinine ratio (UPC, mg/mg) of 10.3, 7.01 and 13.4 (normal <0.2) PKTx, despite being treated with plasmapheresis, +/- CD20 monoclonal antibodies, and LDL apheresis (#1). Patient #2 with lupus underwent a renal biopsy which showed secondary FSGS. All patients underwent treatment with Dara: 1800mg subcutaneously weekly for 4 weeks. They were monitored for UPC, renal function, serum IgG and infections including viral PCRs monthly. Peripheral blood flow cytometry immunophenotyping for T and B cell surface markers was performed pre-Dara and 3-9 months post-Dara in 2 patients.
Results: All 3 patients had significant reductions in proteinuria within 1 month of completion of Dara (UPC of 3.06, 1.9, 3.77 respectively). Renal function remained stable throughout the course of Dara and during follow up (mean 6 months). Patient #1 had persistent decrease in serum IgG levels (<400mg/dl) requiring monthly IVIg infusions for 6 months. Patient #3 developed low grade BK viremia one month post Dara necessitating decrease in immunosuppression. There was no increase in other infections. Immunophenotyping showed CD38 (a marker for immune cell types including monocytes, NK cells and activated T and B lymphocytes) was present in pre-Dara samples and absent/significantly diminished 1-2 months post completion of Dara. CD38 expression increased to pre-Dara levels at 8 months and 4 months post-Dara, but proteinuria continued to remain low (UPC: 0.86 and 0.38 respectively).
Conclusions: Daratumumab is emerging as an important therapeutic for antibody mediated rejection with benefits likely due to depletion of NK-cells and Antibody-Dependent Cell-mediated Cytotoxicity (ADCC). Importantly, we now see improvements in treatment of recurrent proteinuric renal diseases. Although the depletion of pathogenic antibody producing plasma cells is likely the most important target, we cannot rule out depletion of ADCC effectors such as monocytes and NK cells.