Nephrotic syndrome (NS) is a common renal disorder characterized by heavy proteinuria (defined as ≥40 mg/m²/hour or a urine protein/creatinine ratio ≥200 mg/mL or urine dipstick protein 3+), hypoalbuminemia (<25 g/L), edema, and hyperlipidemia (Downie et al., 2017). The pathophysiology is complex and involves injury to the glomerular filtration barrier. The incidence of NS varies across regions and populations.

Traditional immunotherapies for NS include glucocorticoids, cyclophosphamide, and calcineurin inhibitors, among others (Boyer et al., 2017; Robinson et al., 2025; Wang et al., 2012). In recent years, biologic agents such as rituximab have been increasingly used in NS, often with favorable efficacy and safety profiles in various settings (Larkins et al., 2024; Rojas-Rivera et al., 2019). Rituximab is a chimeric anti-CD20 monoclonal antibody. CD20 is primarily expressed on pre-B cells and mature B cells; rituximab binds CD20 and activates a cascade of immune effector mechanisms that culminate in B-cell lysis, thereby exerting therapeutic effects (Bergantini et al., 2020). Rituximab is now widely employed in the treatment of autoimmune diseases and malignancies. According to KDIGO 2021 Clinical Practice Guideline for Glomerular Diseases, rituximab is recommended as a first-line therapy for membranous nephropathy (MN) and for minimal change disease (MCD) with frequent relapses or steroid dependence (Teisseyre et al., 2022; Ronco et al., 2021; Rovin et al., 2021). Although there is extensive literature documenting acute and chronic adverse events associated with rituximab, reports of hypokalemia as an adverse event remain scarce.

This study reports two patients with neuroskeletal (NS) involvement who developed hypokalemia following rituximab therapy. The objective is to describe the clinical features of this rare adverse event and to discuss a broad differential diagnosis—not to establish causality—in order to provide safety references that can guide the clinical use of rituximab and enhance pharmacovigilance in this patient population.

We report two cases of nephrotic syndrome in which severe hypokalemia occurred shortly after rituximab infusion. The first patient had steroid-dependent minimal change disease and developed hypokalemia during his fifth infusion after four prior, well-tolerated courses. The second patient had membranous nephropathy and experienced hypokalemia during his sixth infusion, following five uneventful administrations. The purpose of this report is not to establish causality but to document the temporal association between rituximab infusion and severe hypokalemia and to highlight the broad differential diagnosis required in such scenarios. Rituximab-associated hypokalemia is rare but potentially serious, and its nonspecific presentation may lead to under-recognition. We recommend pre- and post-infusion potassium monitoring to facilitate early detection. Clinicians should remain vigilant for this electrolyte disturbance even in patients who have previously tolerated rituximab without incident.

A review of the existing literature shows that rituximab’s major adverse events include infusion-related reactions (IRRs) (Paul and Cartron, 2019), allergic reactions (Fouda and Bavbek, 2020), infections (McAtee et al., 2021), and posterior reversible encephalopathy syndrome (PRES) (Wardrope et al., 2016). IRRs are the most common events, typically occurring during the first infusion and presenting with fever, chills, fatigue, rash, urticaria, edema, or pruritus (Basu et al., 2018; Levin et al., 2017). Less common manifestations include hypotension, hypertension, myocardial infarction, and hypoalbuminemia (Iijima et al., 2014). While most IRRs are mild to moderate, reports of severe or even life-threatening reactions do exist (Miyabe et al., 2016).

Hypokalemia is a rare but potentially serious adverse effect of rituximab, capable of precipitating arrhythmias or respiratory compromise and is often overlooked. Only a few case reports exist (Table 2). One study described a young woman with steroid-dependent idiopathic nephrotic syndrome who developed acute hypokalemia with dizziness and palpitations after rituximab infusion; intravenous potassium replenishment rapidly resolved symptoms (Guzzi et al., 2020). Another report described two nephrotic syndrome patients who developed symptomatic hypokalemia after rituximab infusion; one patient experienced marked fatigue and myalgias with a substantial drop in potassium, which normalized after aggressive potassium repletion (Song et al., 2023). A case report described successful management with obinutuzumab in a patient who developed acute hypokalemia after rituximab for refractory membranous nephropathy. Switching to obinutuzumab yielded partial renal remission without recurrent hypokalemia, suggesting obinutuzumab as a safe and effective alternative in rituximab-induced electrolyte disturbances (Zhang et al., 2024). Sherwani et al. (2025) reported a case of an autoimmune disease patient without nephrotic syndrome who developed severe hypokalemia (1.3 mmol/L) leading to paralysis after infusion. Miks and Mussarat (2023) described a membranous nephropathy patient who experienced a sudden, severe hypokalemia (2.1 mmol/L) after the second infusion, necessitating ICU admission, highlighting that even patients with prior tolerance may experience life-threatening electrolyte disturbances with subsequent infusions. Collectively, reported cases demonstrate that acute hypokalemia may occur after rituximab infusion in patients with nephrotic syndrome and other autoimmune conditions. Common symptoms include muscle weakness, paralysis, dizziness, palpitations, and fatigue. Hypokalemia was consistently corrected with potassium supplementation. In one patient, switching to obinutuzumab achieved partial renal remission without recurrent hypokalemia, suggesting it as a potential alternative. Recent reports also highlight that severe, life-threatening hypokalemia can occur even after previously tolerated infusions, warranting close clinical monitoring.

The pathophysiology of rituximab-associated hypokalemia is not fully understood, but likely involves multiple factors. On one hand, rituximab may disrupt immune regulation after therapy, affecting renal handling of potassium in a way that increases renal potassium loss. The kidney plays a central role in maintaining potassium balance, and transporter and regulatory mechanisms along the nephron are complex. Immune modulation within the renal microenvironment may interfere with epithelial ion transport proteins in the tubular segments, leading to increased potassium excretion and hypokalemia (Abbas et al., 2015). On the other hand, rituximab-induced hypokalemia may be linked to immune-system changes, such as treatment-associated hypogammaglobulinemia, which can elevate infection risk and potentially disturb electrolyte homeostasis (Labrosse et al., 2021; Barmettler et al., 2018). Additionally, rituximab-related inflammatory responses could alter renal ion transport through inflammatory mediators, contributing to potassium distribution and metabolic disturbances that culminate in hypokalemia (Boleto et al., 2018). These mechanisms require further study with larger datasets to be clarified. Studies indicate that rituximab can trigger immune-mediated responses that lead to tubulointerstitial inflammation. This inflammatory process may cause tubular dysfunction and electrolyte disturbances (Boyer-Suavet et al., 2020). Some reports link rituximab-associated hypokalemia to proximal renal tubular dysfunction, suggesting a potential role for tubulointerstitial impairment in this context (Koithara and Makashir, 2025).

Because key laboratory data are missing, the precise mechanism of hypokalemia cannot be determined. Based on available clinical information, several possibilities warrant consideration: intracellular potassium shift (although no typical precipitants were identified, glucocorticoids administered during infusion could contribute); gastrointestinal losses (patients denied vomiting or diarrhea, making this unlikely); medication effects, particularly pre-infusion dexamethasone, whose mineralocorticoid-like activity may confound interpretation; infusion-related dilution (total IV fluid volume was approximately 1,100 mL, but fluid-balance data are unavailable); hormonal causes (hyperaldosteronism cannot be excluded due to missing renin–aldosterone measurements); renal tubular dysfunction (would require urinary electrolytes and acid–base data, which were not obtained); hypomagnesemia (serum magnesium was at the lower limit of normal, making it unlikely as the primary driver); and covert diuretic use (not supported by history). In summary, there is no evidence for common extrarenal potassium losses, severe hypomagnesemia, or undisclosed diuretic use. However, without critical data—acid–base status, fractional excretion of potassium, renin–aldosterone levels, and glucose/insulin measurements—we cannot distinguish among potential mechanisms such as intracellular shift, medication-induced renal potassium wasting, dilution, or tubular dysfunction. Consequently, all mechanistic interpretations remain speculative, and the observed association with rituximab is temporal.

This case series has several important limitations that must be acknowledged. First and foremost, its retrospective design led to the absence of systematically collected, mechanism-defining laboratory data. Critical parameters—such as acid-base status (pH, bicarbonate, anion gap), urinary electrolytes (including potassium and chloride for TTKG calculation), renin and aldosterone levels, serum insulin, and creatine kinase—were not available. This fundamental lack of data prevents any definitive distinction between potential causes of hypokalemia, such as intracellular shift, renal wasting, extrarenal losses, or medication effects, and therefore precludes supporting mechanistic conclusions. Second, the small sample size (two cases) limits the generalizability of the observations. Third, for Case 2, specific details of the earlier rituximab infusions (e.g., exact infusion rates, premedication) were obtained from external records and could not be independently verified. Given these constraints, particularly the missing biochemical data, the association between rituximab infusion and hypokalemia in these cases remains strictly temporal. Any discussion of pathophysiology is necessarily hypothetical and speculative, and no causal inference can be made.

In summary, we report two cases of nephrotic syndrome in which episodes of acute, severe hypokalemia could not be explained by common causes after multiple rituximab infusions. Both cases demonstrated a clear temporal association, yet the absence of key laboratory data leaves the underlying mechanism speculative. These cases underscore the importance of vigilance for electrolyte disturbances during rituximab therapy. Prospective studies should systematically collect relevant biochemical parameters to elucidate potential mechanisms.