Obinutuzumab in Refractory Phospholipase A2 receptor-Associated Membranous Nephropathy With Severe CKD

To the Editor:

Currently, there are limited options for managing M-Type antiphospholipase A2 receptor antibody-associated membranous nephropathy (MN) with severe chronic kidney disease (CKD) (stage 4 or stage 5).^1,2 Obinutuzumab, a humanized type II anti-CD20 receptor antibody, induces more profound and long-lasting B-lymphocyte depletion, culminating in superior clinical response in patients with chronic lymphocytic leukemia.³ In the present manuscript, we report 2 cases of refractory (cyclical cyclophosphamide and corticosteroids, and rituximab) MN with severe CKD managed successfully with obinutuzumab.

Both patients had antiphospholipase A2 receptor-related MN refractory to rituximab and cyclical cyclical cyclophosphamide and corticosteroids therapy (patient 1 was also resistant to cyclosporine A therapy). The clinical details, kidney biopsy, and follow-up are shown in Table 1. The details of previous therapies are shown in Supplementary Table S1 and Supplementary Figures S1, S2, and S3. Both patients received 1 g of obinutuzumab on day 0 and day 15, and B-lymphocyte depletion (absolute CD19 count < 5 cells/μl) was achieved. At the last follow-up, both patients had immunologic and proteinuric remission, and a reasonable improvement in kidney function (Table 1).

Table 1.

Clinical and biochemical characteristics of the patients

Patient characteristics	Patient 1	Patient 2
Age	67 yr	33 yr
Sex	Female	Male
Duration of disease	5 yr	7 yr
Diabetes mellitus	Yes	No
Hypertension	Yes	No
Serum albumin at presentation	1.89 g/dl	1.8 g/dl
Proteinuria at presentation	12 g/dl	10.5 g/dl
Creatinine at presentation	0.9 mg/dl	0.83 mg/dl
Serum anti-PLA2R titer at presentation	100 RU/ml	194.59 RU/ml
Kidney biopsy findings	16G, diffuse GBM thickening, IFTA–60%, PLA2R positive	7 G, 5/6 show GBM thickening, Collapse in glomeruli, IFTA–5%, PLA2R positive
Therapies received	rituximab-resistant cyclosporine-resistant cyclical CYC/CS-resistant	rituximab-resistant cyclical CYC/CS-resistant
Serum albumin at administration	2.55 g/dl	2.70 g/dl
Proteinuria at administration	12.03 g/dl	9.71 g/dl
Serum creatinine at administration	2.41 mg/dl	4.8 mg/dl
eGFR at administration (MDRD equation)	27 ml/min per 1.73 m2	14.1 ml/min per 1.73 m2
Anti-PLA2R levels at administration	200.71 RU/ml	125.13 RU/ml
Time from biopsy to obinutuzumab administration	24 mo	48 moa
Treatment	Obinutuzumab 1g d 0 and 15	Obinutuzumab 1g d 0 and 15
Post treatment serum albumin	3.99 g/dl	4.13 g/dl
Post treatment proteinuria	2.05 g/d	3.39 g/d
Post treatment serum creatinine	1.62 mg/dl	2.53 mg/dl
Post treatment eGFR (MDRD Equation)	43 ml/min per 1.72 m2	30 ml/min per 1.72 m2
Post treatment anti-PLA2R antibody levels	2.55 RU/ml	0.6 RU/ml
Untoward events	CAD with PTCAb	Nil
Follow-up duration	18 mo	10 mo
Immunologic response	Remission	Remission
Clinical response	Partial remission	Partial remission
B-lymphocyte (absolute CD19 count) at last follow-up	<5 cells/μl	<5 cells/μl

CAD, coronary artery disease; CYC/CS, cyclophosphamide/corticosteroids; eGFR, estimated glomerular filtration rate; G, glomeruli; GBM, glomerular basement membrane; IFTA, interstitial fibrosis and tubular atrophy; MDRD, modification of diet in renal disease; PLA2R, M-type phospholipase A2 receptor; PTCA, percutaneous transluminal coronary angioplasty.

^aFrom the second biopsy.

^bLikely unrelated to obinutuzumab therapy.

Recent reports (Supplementary Table S2) suggest an emerging role of obinutuzumab in refractory MN, mostly with normal kidney functions.S1^,S2^,S3 MN with severe CKD is rare. The Kidney Disease: Improving Global Outcomes 2021 guidelines recommend only cyclical cyclical cyclophosphamide and corticosteroids for managing MN with rapid deterioration of kidney function. Despite the routine use of rituximab in managing MN, there is limited enthusiasm for managing MN patients with severe CKD. The present manuscript is the first report on the utility of obinutuzumab in refractory phospholipase A2 receptor-related MN with severe CKD. Despite advanced chronicity and/or severe kidney dysfunction, the patients responded favorably to obinutuzumab therapy. Another aspect that deserves due deliberation is the legacy effect of immunosuppressive therapies in achieving remission. However, a prolonged interval between the previous immunosuppressive therapies and obinutuzumab rules out the legacy effect (for patients 1 and 2, the interval between previous therapy and obinutuzumab was 18 and 30 months, respectively). To conclude, the current report highlights obinutuzumab as a promising agent in refractory phospholipase A2 receptor-related MN with severe CKD.

Supplementary Material

Table S1. Previous therapy details

Table S2. Published cases of Anti PLA2R associated membranous nephropathy in native kidney receiving Obinutuzumab.

Supplementary References.

Figure S1. Line graph showing trends in proteinuria, serum albumin, serum creatinine, and response to various therapies in patient 1.

Figure S2. Line graph showing trends in proteinuria, serum albumin, serum creatinine, and response to various therapies in patient 2.

Figure S3. Line graph showing trends in anti-PLA2R levels and response to various therapies in both patients.