Delayed-Release Budesonide in a Patient With Progressive IgA Nephropathy and Stage 4 Chronic Kidney Disease: A Case Report

Abstract

Delayed-release (DR) budesonide received expedited approval from the US Food and Drug Administration (FDA) as a treatment for reducing proteinuria in individuals with primary IgA nephropathy (IgAN) who are at significant risk of disease progression. The approval was based on clinical trials primarily involving patients with an estimated glomerular filtration rate (eGFR) greater than 30 mL/min/1.73 m². However, the efficacy of DR budesonide in reducing kidney function decline, especially in patients with an eGFR less than 30 mL/min/1.73 m² and proteinuria less than 1 g/d, remains unclear. We report the case of a 43-year-old man with a long-term history of hypertension and biopsy-proven IgAN who experienced a progressive increase in proteinuria and serum creatinine, along with a decline in eGFR to 28 mL/min/1.73 m² despite maximal supportive management. Following therapy with DR budesonide, a decreasing trend in proteinuria and a stabilization of eGFR were observed in the recent measurements. While initial data suggested the effectiveness of DR budesonide primarily in patients with an eGFR over 30 mL/min/1.73 m², our case demonstrates the potential of DR budesonide for use in scenarios beyond its currently approved indications. This underscores the need for additional research on patients with advanced stages of chronic kidney disease.

Introduction

IgA nephropathy (IgAN) is the most prevalent form of primary glomerulonephritis worldwide. ¹ This disease is characterized by the accumulation of pathogenic IgA immune complexes within glomeruli, manifesting as proteinuria, hematuria, hypertension, and reduced kidney function. ² While the rates of kidney function decline vary across individuals, the majority of adults diagnosed with IgAN develop end-stage kidney disease (ESKD) during their lifetime.^3,4

In the absence of rapidly progressive glomerulonephritis, the management of IgAN has traditionally focused on supportive care, including blood pressure control, renin-angiotensin system (RAS) blockade, and more recently sodium-glucose cotransporter-2 inhibitors.^5,6 Per the most recent 2021 KDIGO guidelines, patients should be optimized on supportive care. Patients with >1 g/d proteinuria and at a high risk of disease progression despite 3 months of optimal supportive care should be evaluated for potential enrollment in a clinical trial. Per current guidelines, corticosteroids are suggested for patients at risk of disease progression despite maximal supportive care on an individual basis. ⁵

Delayed-release budesonide (DR budesonide) emerged as a novel therapeutic option for IgAN, specifically designed for targeted delivery to Peyer’s patches in the distal ileum.^7,8 This agent was recently approved by the US Food and Drug Administration (FDA) for reducing proteinuria in adults with primary IgAN at risk of rapid progression. The efficacy and safety of DR budesonide were evaluated in the NefIgArd trial in patients with biopsy-proven primary IgAN, an estimated glomerular filtration rate (eGFR) of ≥35 mL/min and significant proteinuria.^8-10 However, the effectiveness and safety of this medication in patients with lower glomerular filtration rates (GFR) have not yet been thoroughly investigated. In this report, we present the first documented case of DR budesonide use for an individual with IgAN and chronic kidney disease (CKD) stage G4 with 1 year of follow-up.

Case Report

We present the case of a 43-year-old Hispanic male with a history of hypertension, biopsy-proven IgAN, and CKD stage 3, all diagnosed at an outside institution approximately 10 years prior to the prescription of DR budesonide. Histological grading according to the Oxford classification was M1E0S1T0. Immunofluorescence microscopy showed IgA (4+), IgM (1-2+), C3 (trace-1+), and kappa, lambda (3+ each) in the mesangial region.

Upon diagnosis, the patient was prescribed benazepril 20 mg and hydrochlorothiazide 12.5 mg daily. Five years prior to initiating treatment with DR budesonide, hydrochlorothiazide was discontinued, and the dosage of benazepril was increased to 40 mg daily. In October 2022, dapagliflozin was prescribed; however, due to insurance issues, the patient ended up starting the medication in January 2023. Despite maximal supportive care, he experienced a progressive decline in eGFR. In October 2022, his eGFR was recorded at 28 mL/min/1.73 m², gradually having decreased from 41 mL/min/1.73 m² in 2015, when it was first documented at our center. His proteinuria also increased gradually despite treatment, reaching its highest level of 1100 mg/g by October 2022, up from 551 mg/g in 2015 (Figure 1).

Figure 1.

Longitudinal trends in kidney function and proteinuria before and after initiation of delayed-release budesonide. The blue and red lines represent the estimated glomerular filtration rate (eGFR, calculated by the 2021 CKD-EPI equation) and the urine protein/creatinine ratio, respectively. The graph displays the changes from 2015 to 2023. The green line marks the start of delayed-release (DR) budesonide treatment, and the orange line indicates the initiation of SGLT-2 Inhibitor therapy.

Due to his increasing proteinuria and declining eGFR, treatment with DR budesonide 16 mg daily was initiated in November 2022. This was done after a detailed discussion of risks and benefits due to individuals with his degree of kidney impairment having been excluded from the NefIgArd trial. ¹⁰

After 12 months of therapy with DR budesonide, his eGFR remained stable, and his proteinuria decreased from 1339 mg/g in December 2022 to 452 mg/g in November 2023 (Figure 1). Importantly, as of his most recent appointment in January 2024, the patient had not experienced any significant drug-related side effects, such as headaches, nausea, weight gain, lower extremity edema, uncontrolled blood pressure, or dyspepsia.

Discussion

In this case report, we describe the successful 12-month outcome of using DR budesonide in an individual with progressive IgAN who had an eGFR below the 35 mL/min/1.73 m² inclusion criteria for the NefIgArd trial. ¹⁰

IgAN represents a notable health issue globally, with an estimated annual incidence rate of 2.5 cases per 100 000 people. ¹¹ Studies indicate that approximately half of IgAN patients progress to ESKD within 20 years, underscoring the disease’s chronic nature and need for long-term targeted therapeutics.^1,4 Mucosal B lymphocytes, especially those in Peyer’s patches, are thought to be involved in the production of galactose-deficient IgA1(Gd-IgA1), which is thought to be an important part of the pathogenesis for IgAN.^12-14 Therefore, suppressing mucosal B-lymphocyte activity could reduce GdIgA1 production and, consequently, mitigate kidney damage. ¹²

Delayed-release budesonide is a novel approach in this context, acting locally in the ileocecal region. It is theorized to modulate the quantity and function of mucosal B cells producing pathogenic Gd-IgA1 antibodies.^8,12

Initial investigations into the efficacy and safety of DR budesonide for IgAN showed promising results. In a 2011 pilot study, DR budesonide led to significant reductions in urinary albumin excretion with modest improvement in eGFR. ⁸ The follow-up phase 2b study confirmed these findings, showing that DR budesonide, alongside optimized RAS blockade, decreased proteinuria, and maintained eGFR in patients with IgAN at risk for CKD progression. ⁹ This effect persisted over the study period, emphasizing the potential of DR budesonide as a disease-modifying treatment. ⁹ Most recently, the phase 3 NefIgArd trial further solidified these findings. ¹⁰ The trial demonstrated a significant improvement in eGFR and a sustained reduction in proteinuria with DR budesonide compared to placebo, confirming its efficacy and tolerability in managing IgAN. ¹⁰ While no head-to-head trials comparing DR budesonide to systemic steroids have been conducted, the TESTING trial did show a signal for more infectious complications with systemic methylprednisolone.^10,15

While the NefIgArd trial specifically included individuals with an eGFR of at least 35 mL/min/1.73 m², it does not provide data on the treatment effects in patients with Stage 4 CKD, where a notable gap in the literature remains. ¹⁰ Our case might suggest that DR budesonide could be effective in patients with CKD stage 4, a group previously unstudied in this context. However, given the absence of a control group and the single-patient case, definitive conclusions about the treatment’s effectiveness and safety in this population cannot be drawn. Furthermore, the impact of concurrent medications, such as dapagliflozin, and their timing relative to budesonide administration complicate interpretations of clinical outcomes. This report suggests that further study in this patient population may be of clinical utility.

Conclusion

In individuals with IgAN who are at high risk for progression despite optimal medical therapy, DR budesonide may be a safe and effective option even with an eGFR below 35 mL/min/1.73 m². This demographic is under-represented in the available literature and may benefit from additional targeted therapeutics to mitigate the risk of disease progression. Further studies are needed to address this issue.