Five-year follow-up sustained remission with rituximab in a patient with focal segmental glomerulosclerosis: A case report

Abstract

BACKGROUND

Focal segmental glomerulosclerosis (FSGS) represents a major cause of nephrotic syndrome, with glucocorticoids constituting first-line therapy. When patients develop steroid dependence or resistance, calcineurin inhibitors (CNIs) serve as effective alternatives. However, CNI dependence or resistance may emerge, and prolonged use of either steroid or CNI therapy carries substantial toxicity risks. These limitations create an unmet need for safer treatments capable of maintaining durable remission.

CASE SUMMARY

The patient initially presented with acute anasarca, nephrotic-range proteinuria (5.6 g/24 hours), hypoalbuminemia (2.1 g/dL), and preserved renal function. She experienced repeated relapses after corticosteroid and cyclosporine tapering, ultimately exhibiting a steroid- and CNI-dependent disease course. Rituximab was administered as two 1 g infusions 14 days apart, resulting in complete remission sustained for five years.

CONCLUSION

This case contributes to the growing evidence supporting rituximab’s therapeutic potential in adult FSGS, while highlighting the need for randomized controlled trials to establish its efficacy and optimal use in this challenging patient population.

Key Words: Glomerulonephritis; Glomerulosclerosis; Focal segmental glomerulosclerosis; Proteinuria; Rituximab; Case report

Core Tip: This case report describes a patient with steroid- and calcineurin inhibitor-dependent primary focal segmental glomerulosclerosis (FSGS) who achieved complete and sustained remission for five years following a two-dose regimen of rituximab (RTX). The case highlights the potential of RTX as a steroid- and calcineurin inhibitor-sparing agent in adult FSGS, particularly in patients with significant toxicity or dependence on standard immunosuppressive therapy. The extended follow-up adds valuable insight into the long-term efficacy and safety of RTX in this challenging population.

INTRODUCTION

Focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome, histologically characterized by segmental areas of sclerosis affecting at least one glomerulus in a kidney biopsy specimen[1]. Although its global prevalence is not well established, FSGS is estimated to account for approximately 35% of nephrotic syndrome cases in adults[2]. The prevalence of FSGS has increased over the past few decades, rising from 0.2% to 2.3% between 1980 and 2000[3,4]. Distinguishing between primary, secondary, and genetic forms of FSGS is essential for guiding both therapeutic decisions and prognostic evaluation. Current data suggest that approximately 50% to 60% of patients with primary FSGS respond to treatment with glucocorticoids or calcineurin inhibitors (CNIs)[5,6].

In patients with primary FSGS, an additional classification based on therapeutic response has been proposed[1]: (1) Steroid-resistant primary FSGS; (2) Steroid-dependent primary FSGS; (3) CNI-resistant primary FSGS; and (4) CNI-dependent primary FSGS. Steroid resistance is defined as persistent nephrotic-range proteinuria (> 3.5 g/day) with ≤ 50% reduction from baseline after 16 weeks of high-dose oral glucocorticoid therapy[1]. Steroid dependence refers to a relapse occurring during glucocorticoid treatment or within two weeks of its discontinuation[1]. CNI resistance is defined by persistent nephrotic-range proteinuria with ≤ 50% reduction from baseline despite four to six months of treatment with cyclosporine A (CyA) (trough level 100-175 ng/mL) or tacrolimus (trough level 5-10 ng/mL)[1]. CNI dependence is characterized by a relapse during treatment or within two weeks of stopping cyclosporine or tacrolimus after more than 12 months of therapy[1].

A deeper understanding of FSGS pathophysiology is likely essential for the development of new therapeutic strategies. Rituximab (RTX) may also exert direct podocyte-protective effects by interacting with SMPDL-3b and stabilizing the actin cytoskeleton, as demonstrated in experimental models[7]. This mechanistic hypothesis provides additional biological plausibility for its use in FSGS beyond simple B-cell depletion. To date, the most extensively studied treatments remain glucocorticoid-based regimens and CyA[6,8,9]. However, options are limited for patients with contraindications to glucocorticoids. Although agents such as mycophenolate, tacrolimus, and RTX have been investigated, existing studies are mostly small, observational, and of limited duration. Moreover, these alternative therapies are not universally accessible.

RTX, an anti-CD20 monoclonal antibody, has been increasingly used as a steroid-sparing agent in nephrotic syndrome[10]. Although its efficacy is well established in pediatric steroid-dependent forms, data in adults with FSGS remain limited. Observational studies suggest remission rates between 35%-55% in adults with steroid-dependent or frequently relapsing FSGS treated with RTX[10,11]. Thus, reporting both treatment failures and successes with such agents may support clinical decision-making and help broaden access to effective treatments for FSGS.

CASE PRESENTATION

Chief complaints

A 34-year-old woman presented with progressive lower limb edema evolving into anasarca and foamy urine, consistent with nephrotic syndrome.

History of present illness

The symptoms began acutely in February 2017. Despite initial medical evaluation and a recommendation for kidney biopsy, the patient chose to postpone further investigations and follow-up. Over the subsequent three months, she self-treated with herbal remedies without clinical improvement.

In July 2017, due to persistent edema and worsening symptoms, she was admitted for empirical therapy with intravenous methylprednisolone (500 mg/day for 3 days), followed by high-dose oral prednisone (60 mg/day). Shortly after initiating corticosteroid therapy, the patient developed upper gastrointestinal bleeding, prompting discontinuation of glucocorticoids and initiation of CyA at 3 mg/kg/day. Remission was achieved within weeks and maintained for six months, with CyA trough levels between 100-150 ng/mL.

Following discontinuation of CyA, the patient relapsed two weeks later with nephrotic-range proteinuria (5587.7 mg/24 hours) and edema. Remission was again induced with CyA and low-dose prednisone (15 mg/day), which were continued for 12 months and tapered over 6 months (totaling 18 months of therapy). A second relapse occurred 10 days after therapy cessation. She was re-treated with prednisone 60 mg/day, achieving remission within 10 days, but relapsed one week after tapering. This confirmed a steroid- and CNI-dependent pattern. The patient declined cyclophosphamide and opted for RTX, receiving two 1 g infusions 14 days apart in 2019. Prednisone was tapered over 8 weeks. Sustained complete remission has been maintained for five years. A detailed timeline of relapses, treatments, and remission periods is provided in Figure 1. Quantitative biochemical trends - including serum albumin, creatinine, lipids, CyA trough levels, and urinary protein excretion - are summarized in Table 1 to facilitate interpretation of the clinical course.

Figure 1  Medical history timeline of patient remissions and relapses.

Table 1 Serial laboratory data from 2017-2025.

	March 2017	July 2017	August 2017	September 2017	January 2018	March 2018	April 2018	June 2018	July 2018	May 2019	November 2019	December 2019	January 2020	May 2020	June 2, 2020	June 11, 2020	September 2020	July 2021	May 2022	May 2025
LDL-C (mg/dL)	228	245	237.6	75.6	79.3	123.7	154.1	101	78	112	105	168	285	107	129.4	120.8	121.2	106	108.4	107
Triglycerides (mg/dL)	69	127	212.2	106.1	99.3	137.9	121	55	74	39	66	116	130	97	141.7	175.9	62.1	39	88	73
Serum albumin (g/dL)	2.6	2.1	3.3		4.7	3.9	2.4	4.5	4.6	4.7	4.4	2.6		4.2	4.1	3.9	4.4	4.7		4.4
Urea (mg/dL)	15	31	17.6	16.4	21.3	13.5		24	23	26	24	26	19	17	19.1	22.8	21.9	13	19.3	24
Creatinine (mg/dL)	0.5	0.5	0.6	0.7	0.7	0.5	0.6	0.7	0.8	0.8	0.7	0.7	0.7	0.7	0.8	0.8	0.8	0.6	0.7	0.7
UACR (mg/g)		4100		4.8	2.9	15.1	60	2.0	6.2	1.4	5.0	1240	430				2	5	24	1.7
24-hour proteinuria			5757 mg/24 hours			5581.7 mg/24 hours						1524 mg/24 hours		1272 mg/24 hours	6645 mg/24 hours	112.2 mg/24 hours
Urine analysis	Protein 1+; hemoglobin 3+					Protein 1+; hemoglobin 3+	Protein neg; hemoglobin neg		Protein neg; hemoglobin neg		Protein neg; hemoglobin neg		Protein 2+; hemoglobin neg						Protein neg; hemoglobin neg	Protein neg; hemoglobin neg
Cyclosporine serum level (ng/mL)			104	111	91			126

LDL-C: Low-density lipoprotein cholesterol; UACR: Urine albumin-to-creatinine ratio.

History of past illness

The patient had no known prior chronic illnesses, comorbidities, or relevant previous hospitalizations before the onset of nephrotic syndrome.

Personal and family history

No personal history of smoking, alcohol or drug use. No known family history of kidney disease, autoimmune disorders, or hereditary conditions.

Physical examination

At the time of initial hospital admission in July 2017, the patient presented with significant anasarca, including periorbital and lower limb edema. Blood pressure and heart rate were within normal limits. No signs of systemic infection or organomegaly were observed. Cardiopulmonary and neurologic examinations were unremarkable.

Laboratory examinations

Initial workup revealed nephrotic-range proteinuria, hypoalbuminemia, and hypercholesterolemia with preserved renal function (Table 1). Serologies for viral hepatitis and human immunodeficiency virus were negative. Autoimmune screening was non-reactive. Urinalysis: Proteinuria 5587.7 mg/24 hours; serum albumin: 2.1 g/dL; lipid profile: Elevated; renal function: Normal serum creatinine; other immunologic and infectious markers: Within normal limits or negative.

Imaging examinations

Renal ultrasound showed normal-sized kidneys with preserved corticomedullary differentiation and no structural abnormalities. No other imaging studies were deemed necessary during the initial evaluation.

MULTIDISCIPLINARY EXPERT CONSULTATION

Kidney biopsy performed during hospitalization revealed segmental sclerosis and podocyte hypertrophy in a subset of glomeruli, consistent with a diagnosis of FSGS. Light microscopy demonstrated a glomerulus with flocculocapsular adhesion at the hilar pole and podocyte hypertrophy, suggestive of tip lesion variant, as seen with Grocott-Methenamine-Silver staining and hematoxylin-eosin staining at 400× magnification (Figure 2). No significant interstitial fibrosis or tubular atrophy was noted. While electron microscopy and immunofluorescence were not available due to logistical limitations, the histological features, clinical context, and nephrotic-range proteinuria supported a diagnosis of primary FSGS, likely in the tip lesion spectrum.

Figure 2 Kidney histology by light microscopy of patient with primary focal segmental glomerulosclerosis. A: Grocott-Methenamine-Silver staining 400×. Glomerulus with probable tubular pole adhesion and area of podocyte turgescence, suggesting a tip lesion variant; B: Hematoxylin-eosin staining 400×. Glomerulus with flocculocapsular adhesion at the hilar pole and area of podocyte turgor.

FINAL DIAGNOSIS

Primary FSGS, likely tip lesion variant, steroid- and CNI-dependent.

TREATMENT

The patient was initially treated with high-dose steroids, then switched to CyA due to gastrointestinal complications. After several relapses under steroid and CNI therapy, the patient received two 1 g infusions of RTX 14 days apart in 2019. No maintenance immunosuppression was used after that. Prednisone was tapered over 8 weeks following RTX infusion.

OUTCOME AND FOLLOW-UP

The patient achieved complete remission after RTX administration and has maintained sustained remission without relapse or additional immunosuppressive therapy for five years.

DISCUSSION

This case provides an uncommon and informative contribution due to several distinguishing features. The patient is a young adult woman with no comorbidities, who presented with severe nephrotic syndrome, experienced life-threatening corticosteroid-associated gastrointestinal bleeding, and demonstrated both steroid- and CNI-dependence. Notably, complete remission was achieved and sustained for five years after a single course of RTX without additional immunosuppressive therapy. Unlike most published cases, this patient was treated in a private outpatient setting, without access to electron microscopy or genetic testing-highlighting the pragmatic clinical applicability of RTX in real-world, resource-constrained environments. This long-term remission also adds rare evidence supporting the potential durability of RTX effects in adult primary FSGS.

Glucocorticoids are the cornerstone of initial FSGS therapy, supported by observational studies demonstrating their efficacy in inducing proteinuria remission and a relatively low incidence of severe adverse effects, even at high doses[1,6,8]. However, high-dose steroids may cause serious complications, precluding their use in some patients. Similarly, prolonged glucocorticoid therapy is unsustainable for patients with steroid-resistant or steroid-dependent primary FSGS[9,12-14]. For these groups, CNIs (CyA or tacrolimus) are recommended for at least six months[1]. Due to their potential nephrotoxicity, therapeutic drug monitoring is essential, which can be burdensome and increases treatment costs[1,9,12-14].

Most studies on CNIs in FSGS are observational, primarily focusing on glucocorticoid-dependent or glucocorticoid-resistant primary FSGS[9,12-14]. The evidence supporting CyA as an alternative therapy remains of low quality. Although remission is often achieved, relapse rates are high[1]. Approximately 25%-35% of patients with complete remission and over 50% of those with partial remission relapse within 20-36 months post-treatment[6].

Prolonged use of immunosuppressive agents, even with therapeutic drug monitoring, carries significant risks, including severe infections and medication-related adverse effects[9,12-14]. Long-term CNI use is associated with nephrotoxicity, neurotoxicity, new onset diabetes, hypertension, malignancies, and other complications[1,9,12-14]. Immunosuppressive regimens that induce sustained remission without requiring chronic exposure could therefore offer substantial benefits for patients.

For patients with previously steroid-sensitive primary FSGS, such as the case reported here, KDIGO recommends management similar to minimal change disease (MCD)[1]. RTX is a therapeutic option, showing acceptable efficacy in pediatric nephrotic syndrome, with remission rates of 44%-80%[15,16]. Studies in children also suggest RTX reduces relapse frequency and enables decreased use of other immunosuppressive agents[15].

The efficacy of RTX in adults with nephrotic syndrome remains uncertain. A meta-analysis of 14 observational studies involving patients ≥ 18 years with FSGS or MCD reported a 53.6% remission rate among those with FSGS receiving RTX[10].

An Italian study of 31 patients with steroid-resistant or steroid-dependent primary FSGS treated with RTX and followed for a mean of 17 months reported remission rates of 39%, 52%, and 42% at 3 months, 6 months, and 12 months, respectively, with higher remission rates at 6 months in steroid-dependent patients[11]. Another study of 14 FSGS patients found that RTX reduced relapse risk and facilitated corticosteroid dose reduction or discontinuation[17]. Similarly, a Chinese study of 81 patients with steroid-dependent or frequently relapsing FSGS over two years reported significantly reduced relapse frequency after RTX treatment[18].

The mechanism by which RTX induces remission in FSGS and MCD remains unclear. RTX, a monoclonal antibody targeting CD20-positive B lymphocytes, is approved for B cell-mediated malignancies and connective tissue diseases but lacks formal approval for nephrotic syndrome. Its high cost further limits global access. While the mechanism of RTX-induced remission in our patient remains unclear, several hypotheses may explain the sustained response. RTX’s depletion of CD20-positive B cells likely reduced pathogenic autoantibodies or immune complexes contributing to podocyte injury. Beyond B-cell depletion, RTX may modulate podocyte signaling pathways. Experimental evidence demonstrates that RTX binds to SMPDL-3b on podocytes, restoring acid sphingomyelinase activity and preventing cytoskeletal disorganization. Additionally, alterations in memory and regulatory B-cell subsets have been associated with relapse risk in idiopathic nephrotic syndrome[7,19]. The prolonged remission could reflect immune reprogramming or reduced pro-inflammatory cytokine production, though further research is needed to elucidate these mechanisms in adult FSGS.

Emerging data suggest that the therapeutic effects of RTX in FSGS may extend beyond B-cell depletion. In experimental models, RTX has been shown to interact directly with podocytes through SMPDL-3b and acid sphingomyelinase signaling pathways, stabilizing the actin cytoskeleton and promoting podocyte survival[7]. Moreover, a subset of patients may harbor circulating permeability factors or autoantibodies that are neutralized or modulated by RTX, indirectly preventing podocyte injury. Recent immunophenotyping studies have proposed that certain B-cell subtypes, such as memory B cells and regulatory B cells, may correlate with treatment response in nephrotic syndrome[19]. Ongoing clinical trials-such as NCT04716231-are exploring the broader immunologic effects and clinical efficacy of RTX in glomerular diseases, including adult FSGS[20]. These evolving hypotheses underscore the need to better define immunologic biomarkers and predictors of response in RTX-treated patients.

Emerging reports support the safe use of RTX[10,14,16]; however, robust studies specifically evaluating RTX in FSGS are lacking, with most data derived from MCD. Randomized controlled trials are needed to confirm RTX’s efficacy in adult FSGS patients, potentially supporting its inclusion in standard treatment protocols. Case reports with extended follow-up, like this study, provide valuable evidence of RTX’s therapeutic success and may advocate for its approval in FSGS treatment.

Despite its strengths, this report is subject to the inherent limitations of a single-case observation, including limited generalizability and the inability to infer causality. The absence of genetic testing and electron microscopy further restricts the phenotypic characterization of the disease. Additionally, spontaneous remission-though unlikely in this clinical context-cannot be definitively ruled out. While our findings support the potential role of RTX in inducing durable remission in adult primary FSGS, robust conclusions can only be drawn through well-designed randomized controlled trials. Several ongoing studies are currently investigating the safety and efficacy of RTX and related B-cell targeting agents in adult nephrotic syndrome, which will provide much-needed clarity on its therapeutic utility.

CONCLUSION

Primary FSGS is a leading cause of nephrotic syndrome, typically managed with glucocorticoids due to their efficacy in achieving proteinuria remission and favorable safety profile. However, steroid- and CNI-dependent cases, like the one reported here, pose significant therapeutic challenges. This case demonstrates the successful use of two 1 g doses of RTX in a patient with steroid- and CNI-dependent primary FSGS, achieving complete remission sustained for five years. While RTX shows promise in reducing relapses in pediatric nephrotic syndrome, its efficacy in adults remains uncertain. Well-designed clinical trials are needed to validate RTX’s role in adult FSGS and expand therapeutic options for managing complex cases.