Obinutuzumab in Rituximab-resistant and recurrent membranous nephropathy: a case-series

Abstract

Background: Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults, with high risk of progression to end-stage kidney disease when untreated. Rituximab is commonly used in its treatment however many patients do not respond. Obinutuzumab is a novel anti-CD20 monoclonal antibody for which there is increasing observational evidence in treatment-resistant membranous nephropathy. The majority of evidence for its use relates to anti-phospholipase A2 receptor-(PLA2R) associated membranous nephropathy.

Methods: This was a single-centre case-series of all patients at a tertiary nephrology centre in Melbourne, Australia, treated with Obinutuzumab for membranous nephropathy, between January 2023 and June 2024. All patients who received Obinutuzumab were included in this case-series, irrespective of PLA2R status.

Results: Out of 5 patients with treatment-resistant membranous nephropathy, 3 had PLA2R-associated membranous nephropathy which had previously been refractory to, or relapsed on Rituximab therapy. All 3 patients with PLA2R-positive membranous nephropathy achieved complete immunological and clinical remission after receiving Obinutuzumab. The case of secondary PLA2R-negative membranous nephropathy only achieved partial remission after Obinutuzumab before unexpectedly dying from another cause. The case of recurrent PLA2R-associated membranous nephropathy in a renal allograft did not respond to Obinutuzumab.

Conclusion: This case-series supports the existing evidence in favour of Obinutuzumab for treatment-resistant PLA2R-associated membranous nephropathy. To our knowledge it is the first reported use of Obinutuzumab in sarcoidosis-associated membranous nephropathy.

Keywords: Membranous nephropathy; Obinutuzumab; Treatment-resistant.

Fig. 1

Graph of trend in serum albumin and urine protein-creatinine ratio, Case 1. Graph of serum albumin (g/L) and urine protein-creatinine ratio (mg/mmol) for Case 1. Studies in July 2022 demonstrated heavy proteinuria and hypoalbuminaemia. Subsequently, the patient received treatment with Rituximab. Repeat investigations in February 2023 demonstrated worsening proteinuria and hypoalbuminaemia. Subsequent treatment with Obinutuzumab. Significant increase in serum albumin and reduction in urine protein-creatinine ratio with most recent studies demonstrating complete remission

Fig. 2

Graph of trend in serum albumin and urine albumin/protein-creatinine ratio, Case 2. Graph of serum albumin (g/L) and urine protein-creatinine ratio and albumin-creatinine ratio (mg/mmol) for Case 2. Studies in September, November and December 2023 demonstrated heavy proteinuria and hypoalbuminaemia. Subsequently the patient received treatment with Obinutuzumab. Repeat investigations in January 2024 demonstrated gradually improving serum albumin and proteinuria with normalisation of serum albumin despite ongoing nephrotic range protenuria. Complete remission of proteinuria (uPCR < 30mg/mmol) was achieved by month 9 after Obinutuzumab

Fig. 3

Kidney biopsy images, Case 1 and Case 5. Case 1(a): diffuse thickening of the glomerular basement membrane (H&E × 400), 9 Jun 2022. Case 1(b): glomerular basement membrane spiking with subepithelial deposits (periodic acid silver methenamine × 1000), 9 Jun 2022. Case 1(c): granular glomerular basement membrane immunoperoxidase staining with IgG, 9 June 2022. Case 5(a): diffuse thickening of the glomerular basement membrane (H&E × 400), 5 Apr 2023. Case 5(b): glomerular basement membrane encircling deposits with “split” appearance (periodic acid silver methenamine × 1000), 5 Apr 2023. Case 5(c): positive immunoperoxidase staining for PLA2R