P-314: Daratumumab for refractory proliferative glomerulonephritis with monoclonal immunoglobulin G deposits and severe chronic kidney disease

Introduction:


Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a rare immune-mediated kidney disorder most often associated with IgG3 kappa deposition in glomeruli. PGNMID poses major challenges to clinicians as it frequently progresses towards kidney failure and recurs after transplantation. In addition, there is no consensus about the appropriate treatment in patients with PGNMID, especially in the absence of a plasma or B cell clone.

Methods:
Here we report the presentation and outcome of a patient with PGNMID refractory to rituximab and complicated by severe chronic kidney disease treated with daratumumab.

Results:
A 54-year-old White patient with no relevant medical history was referred for nephrotic syndrome, heavy proteinuria (urine protein to creatinine ratio 9 g/g), hematuria and progressive decline in glomerular filtration rate (GFR). A kidney biopsy showed mesangioproliferative glomerulonephritis, with bright (3+) IgG3 kappa and complement C3 deposition on immunofluorescence, and the absence of organized deposits on ultrastructural analysis, consistent with the diagnosis of PGNMID. Interstitial fibrosis and tubular atrophy score was 2, involving 25-50% of the renal cortex. A complete workup, including serum and electrophoresis and immunofixation, serum free light chains assay, bone marrow aspiration, positron emission tomography and flow cytometry showed no evidence of plasma or B cell clone.

Despite renin angiotensin system inhibition, dapagliflozin, and four weekly doses of rituximab (375 mg/m²), proteinuria and hematuria persisted and the CKD-EPI estimated GFR declined from 55 mL/min to 16 mL/min/1.73 m² over a 12-month period. The patient was then referred to discuss alternative treatment options. Based on a recent case series from the Mayo Clinic, suggesting that daratumumab may lead to remission in cases of PGNMID refractory to rituximab (Zand, JASN 2021), the patient was treated with subcutaneous daratumumab (1800 mg) weekly for 8 weeks, then every other week for 8 additional doses. Daratumumab was well tolerated, i.e. with no infection. After 6 months, proteinuria decreased to 4 g/g, serum albumin increased from 29 to 37 g/L and eGFR stabilized at 19-21 mL/min/1.73 m², in contrast to the >35 ml/min decline over the 12 months preceding initiation of the anti-CD38 monoclonal antibody (see graph). Because of the risk of relapse and the low eGFR, daratumumab was further continued once a month for at least 6 additional consolidation cycles.

Conclusions:
Daratumumab may delay progression to kidney failure in patients with PGNMID refractory to rituximab and severe chronic kidney disease. Daratumumab appears to be effective and well tolerated, and deserves further evaluation in both treatment-naïve and treatment-resistant PGNMID.