Of 5 cases reported, 3 achieved complete clinical and immunological remission after Obinutuzumab, all of whom have maintained remission through to the end of the study period. All 3 patients had PLA2R-associated membranous nephropathy. One case of secondary membranous nephropathy associated with sarcoidosis only attained partial clinical remission before dying unexpectedly from another cause. One case of refractory membranous nephropathy in a renal allograft did not respond to Obinutuzumab; this patient was tissue-PLA2R-positive but serum PLA2R-negative. All patients had full CD19+ suppression after Obinutuzumab. Time to complete remission ranged from 1 to 9 months (Table 1).

Table 1 Results pre and post-ObinutuzumabCase 1—PLA2R-associated membranous nephropathy

A 72-year-old woman presented in July 2022 with a 4-month history of nephrotic syndrome with preserved renal function, uPCR 458 mg/mmol, and serum albumin 21 g/L. There were no relevant comorbidities. Serum PLA2R antibody was positive with titre 1270 RU/mL. Investigations for secondary causes of membranous nephropathy demonstrated positive hepatitis B core antibody, with negative surface antigen, and were otherwise negative. Kidney biopsy confirmed membranous nephropathy, with no fibrosis.

Antiproteinuric therapy was initiated. Nevertheless, proteinuria worsened, with uPCR 1134 mg/mmol at one-month follow-up. Due to doubling of proteinuria and high initial PLA2R, Rituximab was given, 1 g two weeks apart. She was covered with entecavir for hepatitis B reactivation prophylaxis.

Six months after Rituximab, PLA2R titre was still elevated at 111 RU/mL and heavy proteinuria persisted with uPCR 1700 mg/mmol and serum albumin 23 g/L. Tacrolimus was commenced, with a trough target of 5–7 ng/mL, and a decision was made to proceed to Obinutuzumab in March 2023. Four months after Obinutuzumab administration serological remission was attained with negative serum PLA2R and full CD19 suppression (< 0.1%), with improvement in uPCR to 483 mg/mmol and serum albumin to 36 g/L (Fig. 1). Complete clinical remission was attained by month-6 post Obinutuzumab with uPCR 25 mg/mmol. At latest follow-up, 13 months post Obinutuzumab, there is ongoing complete remission, with uPCR 22 mg/mmol and serum albumin 41 g/L, despite B-cell reconstitution (Fig. 1).

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

Tacrolimus is being weaned to cessation given the excellent response to Obinutuzumab.

Case 2—PLA2R-associated membranous nephropathy

A 74-year-old man presented with recurrent primary membranous nephropathy in September 2023. He was diagnosed with primary membranous nephropathy in 2017, after presenting with nephrotic syndrome with uPCR 803 mg/mmol, serum albumin 26 g/L and renal impairment with sCr 129 mmol/L, with positive serum PLA2R.

His relevant past medical history included hypertension and hyperlipidaemia, and he had no secondary cause for membranous nephropathy.

He was initially treated with renin–angiotensin–aldosterone (RAAS) blockade and modified Ponticelli regimen (cyclical corticosteroids and cyclophosphamide), after which he achieved partial remission.

He relapsed with nephrotic syndrome in May 2019 with uPCR 1400 mg/mmol, serum albumin 19 g/L and PLA2R-positive at 41 RU/mL. He was then treated with Rituximab, 1 g two weeks apart, and he attained complete immunological remission and partial clinical remission. From 2020 to 2022 he had ongoing sub-nephrotic proteinuria, with undetectable PLA2R, and stable kidney function.

His nephrotic syndrome relapsed in September 2023 with uPCR 800 mg/mmol and serum albumin 29 g/L with positive PLA2R titre 19 RU/mL. Repeat kidney biopsy demonstrated features of membranous nephropathy with mild fibrosis. He was given Obinutuzumab in December 2023. In February 2024 he had normalisation of PLA2R titre and serum albumin, improvement in uPCR to 518 mg/mmol and suppression of B cells (CD19 < 0.1%). As of his most recent follow up, in September 2024, he remains in immunological remission and is, for the first time since initial diagnosis, in full clinical remission with urine ACR 10 mg/mmol and serum albumin 44 g/L (Fig. 2).

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

Case 3—PLA2R-associated membranous nephropathy

A 43-year-old woman was seen in our clinic with frequently relapsing primary membranous nephropathy. She had initially been diagnosed in 2002 after presenting with nephrotic syndrome with proteinuria 13 g/day with preserved renal function. Renal biopsy confirmed primary membranous nephropathy with positive serum PLA2R. She had no relevant past medical history nor any secondary cause for membranous nephropathy.

She was treated with antiproteinuric therapy as well as prednisolone and azathioprine, achieving remission.

She subsequently went on to have multiple relapses, in 2003, 2012, and 2016; treated with azathioprine and prednisolone in 2003, then cyclosporin and prednisolone followed by partial remission. In June 2017 she had another nephrotic relapse, serum PLA2R 84 RU/mL; repeat kidney biopsy confirmed ongoing membranous nephropathy, with mild fibrosis. She was treated with Rituximab with partial remission. She had two further nephrotic relapses between 2018 and 2019, both treated with further Rituximab. After a relapse in 2021 she was commenced on tacrolimus with a target range of 4–6 ng/mL. She achieved partial clinical and full immunological remission with this, and improved to full clinical remission in 2023.

In March 2024, tacrolimus was weaned. Two months after cessation she relapsed with urine PCR 438 mg/mmol, serum albumin 32 g/L and PLA2R- positive at 50 RU/mL. Tacrolimus was restarted and Obinutuzumab was given. 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.

Case 4—secondary membranous nephropathy

A 42-year-old man was diagnosed with membranous nephropathy in July 2021 after presenting with nephrotic syndrome with preserved renal function. Urine PCR was 1393 mg/mmol, serum albumin 18 g/L. Serum PLA2R antibody was negative. Kidney biopsy confirmed membranous nephropathy, with minimal fibrosis. PLA2R staining on biopsy was not performed. Antiproteinuric therapy was initiated.

Relevant past medical history included Hodgkin’s lymphoma treated in 2000 with chemotherapy (doxorubicin, bleomycin, vinblastine and dacarbazine), now in remission.

Screening for secondary causes of membranous nephropathy revealed mediastinal and hilar lymphadenopathy and multiple lung nodules. Lymph node core biopsy demonstrated non-caseating granulomas, consistent with a diagnosis of sarcoidosis.He was commenced on high dose prednisolone for the sarcoidosis. Due to ongoing nephrotic syndrome, he was then given tacrolimus with a target trough level 6-8 ng/mL and Rituximab 1 g two weeks apart for the membranous nephropathy. Therapy was complicated by steroid-induced diabetes.

His membranous nephropathy partially responded to this therapy, with concurrent response of sarcoidosis.

Tacrolimus was discontinued in month 10 due to acute kidney injury (AKI), with peak creatinine 315 µmol/L resolving to a new baseline of 130–150 µmol/L. Due to increasing nephrotic range proteinuria following this, tacrolimus was recommenced with a lower trough target (3–6 ng/mL) and further Rituximab given. There was no response, despite B-cell suppression.

Given persistent proteinuria, in February 2023 a kidney biopsy was repeated, demonstrating ongoing active membranous nephropathy with 40% interstitial fibrosis and tubular atrophy. There was also evidence of pulmonary sarcoid recurrence. The prednisolone dose was increased for sarcoidosis treatment. 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. The patient received Obinutuzumab in May 2023. At follow-up 9 months post, there was partial remission with uPCR reduced to 215 mg/mmol (see Table 1), sCr 145 µmol/L, and full CD19 suppression (< 0.1%).

Unfortunately, in March 2024, the patient died suddenly and unexpectedly at home. Post-mortem was not performed due to cultural reasons. Discussion at a multidisciplinary meeting revealed a consensus opinion of the likely cause of death to be an acute cardiac event, in view of significant cardiovascular risk factors. Cardiac sarcoid was thought to be unlikely in view of a negative PET scan.

Case 5—recurrent primary membranous nephropathy in renal allograft

A patient was diagnosed with primary membranous nephropathy in 2009 at the age of 37 years, which was managed with the modified Ponticelli regimen. Serum PLA2R was negative, kidney biopsy PLA2R stain was not performed. He progressed to ESKD in 2014 and commenced peritoneal dialysis.

In 2016, he received a deceased donor (after brain death) kidney transplant and was maintained on conventional tacrolimus, prednisolone, and mycophenolate mofetil immunosuppression. Graft function was excellent in the early years post-transplant with no rejection episodes.

In May 2018, the patient developed rising proteinuria with uPCR 289 mg/mmol and new hypoalbuminaemia (serum albumin 27 g/L), with relatively preserved renal function. Transplant kidney biopsy demonstrated global thickening of the glomerular basement membrane (GBM) with diffuse IgG and IgG4 staining and weak granular IgM staining, consistent with recurrent membranous nephropathy. There was no evidence of rejection. Serum PLA2R antibody was negative, and staining for PLA2R on biopsy was not performed. Rituximab, 1 g, two weeks apart was given for recurrent membranous nephropathy, and antiproteinuric therapy was maximised. There was partial response with improvement to < 1 g/day proteinuria.

In 2021, the patient’s membranous nephropathy relapsed. uPCR was 420 mg/mmol and weak de novo donor-specific antibodies (DSAs) to two class II antigens were detected. Biopsy demonstrated advanced membranous nephropathy with sclerosis. Immuno-peroxidase stain for PLA2R showed strong diffuse GBM staining. C4d stain was negative on peritubular capillaries but strongly positive on peripheral glomerular capillary loop walls. Serum PLA2R remained negative. Further Rituximab was given, as well as intravenous immunoglobulin to offset DSA production and any contribution to the proteinuria from possible antibody-mediated rejection.

Nephrotic range proteinuria persisted, with urine PCR > 300–400 mg/mmol, despite partial CD19 suppression (0.2%). Renal function worsened, with sCr 153 µmol/L in January 2023. Repeat biopsy one year following the second course of Rituximab demonstrated ongoing active primary membranous nephropathy with strong PLA2R staining in peripheral capillary loops, with 20% interstitial fibrosis and tubular atrophy (IFTA). C4d staining was again present in glomeruli but not in the peritubular capillaries (Fig. 3).

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

In view of ongoing membranous nephropathy with inadequate response to Rituximab, he proceeded to Obinutuzumab in May 2023.

As yet, there has been no response to Obinutuzumab. A follow-up biopsy 6 months post-Obinutuzumab demonstrated ongoing active membranous nephropathy with PLA2R staining of unchanged intensity and 20–25% IFTA. At his most recent follow up, 14 months post Obinutuzumab, there is ongoing proteinuria, with most recent uPCR of 466 mg/mmol, serum albumin of 31 g/L, despite full CD19 suppression. Renal function has deteriorated, with recent sCr in the range of 250–300 µmol/L.

The patient remains on transplant immunosuppression, as well as monthly intravenous immunoglobulin. He developed central serous chorioretinopathy from steroids, therefore his prednisolone dose has been weaned to 1 mg/day, with tacrolimus trough levels maintained between 7 and 9 ng/mL. Given his deteriorating renal function, he is being worked up for dialysis initiation.