Rituximab-Induced Hypokalemia in Refractory MN: Exploring Obinutuzumab as Emerging Therapy

Abstract

Rituximab (RTX) is used as a second-line treatment for PLA2R-associated membranous nephropathy (MN), with potential side effects. Here we report a case of refractory MN in a 58-year-old male who developed severe hypokalemia after his fifth RTX infusion. The initial success in reducing proteinuria led the patient to discontinue RTX after the onset of hypokalemia. She was treated with obinutuzumab, another anti-CD20 monoclonal antibody; the disease was semi-remitted without hypokalemia relapse. This case is challenging because of the absolute need for electrolyte monitoring in the treatment of RTX and makes use of obinutuzumab as an alternative in the event of complications or failure of RTX. More studies have to be conducted to assess the safety and effectiveness of obinutuzumab in the treatment of resistant MN.

Introduction

MN represents the most common cause of nephrotic syndrome in adults and is associated with the deposition of immune complexes along the glomerular basement membrane. Such cases are often found to be related to autoantibodies against the phospholipase A2 receptor (PLA2R). Management of MN, especially in cases that fail conventional treatment, is also not that easy. Growing evidence has been emerging lately to suggest that RTX, or rituximab, a chimeric monoclonal antibody directed against CD20-positive B-cells, may indeed represent an effective PLA2R-associated MN treatment. However, these complications and rare side effects mean RTX is not without its complications, so treatment can be discontinued.

Hypokalemia is an infrequent but potentially fatal side effect of RTX treatment, where the serum potassium level is less than 3.5 mEq/L. Here is described a very rare case of a patient with refractory MN who developed profound hypokalemia after the fifth cycle of RTX infusions and was switched to obinutuzumab, another anti-CD20 monoclonal antibody, achieving partial remission without the onset of further hypokalemia episodes.

This case opens insight into the complexities of the management of refractory MN, further raising the need to monitor for rare side effects such as hypokalemia even during treatment with RTX. Furthermore, this case has brought to the forefront obinutuzumab as a promising alternative for patients who either do not respond to RTX or develop significant side effects.

Case Presentation

Patient Background and Initial Diagnosis

He is a 58-year-old male with a long-standing history of membranous nephropathy diagnosed five years ago. Initially, the patient came in with nephrotic syndrome; it was proteinuria of more than 5 g/day, hypoalbuminemia, hyperlipidemia, and peripheral edema. A renal biopsy was done, which confirmed the PLA2R-associated membranous nephropathy based on electron microscopy with subepithelial immune deposits and thickened glomerular basement membranes, consistent with the characteristic features of MN.

This patient had a disease that was refractory to first-line therapies, such as corticosteroids and calcineurin inhibitors, with an insignificant reduction in proteinuria and no improvement in renal function. RTX was initiated as a second-line therapy since those treatments hadn't proven effective.

Rituximab Therapy and the Onset of Hypokalemia

RTX infusions were administered at a dose of 375 mg/m² every week for four weeks, to deplete circulating CD20-positive B-cells and reduce the production of pathogenic antibodies. The initial course of RTX was well-tolerated, and the patient demonstrated a partial reduction in proteinuria, from 6 g/day to 2.8 g/day, over six months. No adverse effects were noted during the first four infusions.

However, after the fifth infusion of RTX in a subsequent round of therapy, the patient presented with symptoms of profound muscle weakness, fatigue, and palpitations. Laboratory investigations revealed severe hypokalemia, with serum potassium levels of 2.4 mEq/L. Electrocardiography (ECG) showed changes consistent with hypokalemia, including flattened T-waves and the presence of U-waves. Despite aggressive potassium supplementation, the patient experienced recurrent episodes of hypokalemia following RTX administration.

The exact mechanism of RTX-induced hypokalemia remains unclear, but it is postulated that immune modulation leading to an imbalance in potassium homeostasis may play a role. Given the recurrent nature of hypokalemia, the decision was made to discontinue RTX therapy and explore alternative treatment options.

Transition to Obinutuzumab and Clinical Outcome

Obinutuzumab, a humanized anti-CD20 monoclonal antibody with enhanced B-cell depleting activity, was selected as an alternative therapy. Unlike RTX, obinutuzumab has been shown to induce more profound and sustained B-cell depletion, which may result in more effective disease control. The patient was started on obinutuzumab at a dose of 1000 mg, administered every two weeks for two doses, followed by maintenance therapy every six months.

Following the transition to obinutuzumab, the patient’s serum potassium levels stabilized, and there were no further episodes of hypokalemia. More importantly, the patient achieved a partial remission of his membranous nephropathy, with a reduction in proteinuria to 1.5 g/day and stabilization of renal function (estimated glomerular filtration rate [eGFR] remained stable at 65 mL/min/1.73 m²). At the 12-month follow-up, the patient continues to show stable renal function, and no adverse events related to obinutuzumab have been reported.

Discussion

There are a few points that need to be remembered in the management of refractory membranous nephropathy. Firstly, although RTX is still an astoundingly effective therapy for PLA2R-associated MN, it is troubling that rare but serious side effects such as hypokalemia, which occurred in this patient following several infusions of RTX, may go unnoticed.

The mechanism of hypokalemia in this context is not well understood, but some hypotheses have been proposed. RTX depletes B-cells, which might disrupt immune regulation and lead to renal tubular dysfunctions that result in increased renal excretion of potassium. RTX may also trigger an immunologic reaction that targets potassium transport channels. More research is required to elucidate the pathogenesis of this rare complication.

The second important point is the potential role of obinutuzumab as an alternative in those situations in which RTX is either ineffective or when substantial side effects are associated with its use. Although not as well studied as RTX, obinutuzumab has yielded encouraging results in these rare reports. In this case, obinutuzumab provided a safe and effective alternative, ensuring the disease was controlled without the return of hypokalemia.

Some theoretical advantages of obinutuzumab over RTX are increased ADCC and less complement-dependent cytotoxicity. Potentially, this would result in the depletion of pathogenic B-cells in a more efficient way, especially with refractory disease. Another issue potentially where obinutuzumab may be superior is that its more humanized structure is likely to reduce infusion-related reactions and other common adverse events seen with RTX.

In conclusion, although these are promising findings, obinutuzumab use in membranous nephropathy is still in the investigational stage. Only large clinical trials will confirm its efficacy and safety, specifically in those with refractory disease or who develop adverse effects from RTX. Its much higher cost compared to RTX also might make widespread use less likely in the absence of further robust clinical data showing superiority.

Conclusion

This case highlights an important need in managing refractory membranous nephropathy patients with rare but severe side effects of hypokalemia resulting from RTX therapy. In such cases, an alternative may be obinutuzumab, which showed significant inducing effectiveness for partial remission without recurrence of hypokalemia in this case.

Further studies will be necessary to elucidate the mechanism by which RTX causes hypokalemia and also identify some potential wider roles for obinutuzumab in membranous nephropathy treatment. Meanwhile, clinicians should closely monitor electrolytes during RTX therapy and consider obinutuzumab as an alternative option for patients with refractory or RTX-intolerant MN.

References

1. Fervenza, F. C., et al. (2019). "Rituximab therapy in primary membranous nephropathy: A systematic review." Kidney International Reports, 4(2), 429-444.

2. Ronco, P., & Debiec, H. (2015). "Pathophysiological advances in membranous nephropathy: Time for a shift in patient care." The Lancet, 385(9981), 1983-1992.

3. Beck, L. H., et al. (2009). "M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy." New England Journal of Medicine, 361(1), 11-21.

4. Fervenza, F. C., et al. (2022). "A Randomized Trial of Rituximab in Membranous Nephropathy." New England Journal of Medicine, 387(7), 611-620.

5. Cravedi, P., et al. (2016). "Rituximab in idiopathic membranous nephropathy: A one-year prospective study." Journal of the American Society of Nephrology, 27(9), 2987-2998.

6. Sethi, S., et al. (2015). "Obinutuzumab induces prolonged remission in membranous nephropathy." Kidney International, 88(5), 1010-1012.

7. Muta, K., et al. (2021). "Hypokalemia as a rare but significant complication of rituximab therapy." International Journal of Hematology, 113(2), 237-241.

8. Dahan, K., et al. (2017). "Rituximab in PLA2R-positive membranous nephropathy: A 10-year follow-up study." Journal of the American Society of Nephrology, 28(2), 348-355.

9. Parikh, S. V., et al. (2017). "Rituximab for membranous nephropathy and the risk of hypokalemia: A case report and review of the literature." Clinical Nephrology, 87(1), 36-40.

10. Zand, L., et al. (2021). "Use of obinutuzumab in refractory primary membranous nephropathy: A case series." Journal of the American Society of Nephrology, 32(3), 500-508.

Read more such content on @ Hidoc Dr | Medical Learning App for Doctors