Obinutuzumab appears useful in treatment-resistant or recurrent membranous nephropathy, according to a small Australian case series.
The series supports the existing evidence in favour of the anti-CD20 monoclonal antibody for treatment-resistant PLA2R-associated membranous nephropathy and includes the first report of obinutuzumab in sarcoidosis-associated membranous nephropathy and one of only a few reports in a renal allograft.
The five cases, published together in the Journal of Nephrology [link here], were treated with obinutuzumab for membranous nephropathy between January 2023 and June 2024 at a single nephrology unit in Melbourne.
Three patients had PLA2R-associated membranous nephropathy which had previously been refractory to, or relapsed on rituximab. All achieved complete immunological and clinical remission after receiving obinutuzumab.
Two cases were a man and a woman in their early-70s with relatively short histories of nephrotic syndrome and treatment with renin–angiotensin–aldosterone blockade and modified Ponticelli regimen then rituximab or antiproteinuric therapy then rituximab and tacrolimus. Both cases responded to obinutuzumab within a few months.
In the third case of PLA2R-associated membranous nephropathy, a 43 year-old woman had a 20-year history of nephrotic syndrome.
Antiproteinuric therapy as well as prednisolone and azathioprine were initially successful however rituximab was introduced after multiple relapses over about 15 years. She continued to relapse and received tacrolimus but relapsed again until obinutuzumab was also introduced.
“One month following obinutuzumab, she attained complete remission with uACR 16 mg/mmol and negative serum PLA2R, and remains in complete remission 4 months after obinutuzumab with a plan to wean tacrolimus,” the study said.
In the case of a 42 year-old man with sarcoidosis-associated membranous nephropathy, he was variously managed with antiproteinuric therapy, tacrolimus and rituximab to achieve a partial response.
“Given persistent proteinuria, in February 2023 a kidney biopsy was repeated, demonstrating ongoing active membranous nephropathy with 40% interstitial fibrosis and tubular atrophy,” the study said.
“B-cell reconstitution was noted, and the decision was made to trial obinutuzumab for ongoing active membranous nephropathy, particularly due to poor tolerance of ongoing steroid therapy.”
He achieved partial remission through to a 9-month follow-up but died suddenly and unexpectedly from a suspected cardiac event.
In the final case of recurrent primary membranous nephropathy, a 37 year-old man was initially managed with a modified Ponticelli regimen. The patient progressed to end stage kidney failure requiring peritoneal dialysis then a kidney transplant.
Graft function was excellent in the first couple of years post-transplant with no rejection episodes.
However on evidence of recurrent membranous nephropathy, he was started on rituximab and antiproteinuric therapy maximised to achieve a partial response. He was later started on obinutuzumab without response at 14 months follow-up.
Agent well tolerated
Obinutuzumab was well-tolerated with none of the patients reporting adverse effects or infusion reactions attributable to the monoclonal antibody.
The investigators, including Dr Basu Gopal, Dr Scott Wilson and Dr Holly Hutton from Alfred Health, said obinutuzumab was “reasonable to consider in disease refractory to existing agents”.
“The improved response to obinutuzumab in rituximab-refractory membranous nephropathy is thought to relate to more profound and sustained CD19+ B cell depletion compared to rituximab,” they said.
“One theory regarding rituximab-resistant disease in the setting of peripheral B cell depletion is that pathogenic B cells are hidden in sanctuary sites such as tissue or bone marrow.”
“Obinutuzumab is likely more efficacious in depleting bone marrow and tissue-resident B cells compared with rituximab, which may help explain its benefits.”
A phase 3 RCT is currently underway assessing the efficacy and safety of obinutuzumab compared to tacrolimus in primary membranous nephropathy [link here].