Rituximab as Rescue Therapy for Atezolizumab-Induced IgA Vasculitis

Abstract

Immune checkpoint inhibitors have transformed cancer therapy but are associated with immune-related adverse events, including kidney injury. Although acute interstitial nephritis is the most common renal immune-related adverse events, glomerular diseases such as immunoglobulin A (IgA) vasculitis remain rare and poorly characterized. We report the first biopsy-confirmed case of IgA vasculitis with crescentic glomerulonephritis associated with the programmed death-ligand 1 inhibitor atezolizumab. A 75-year-old man with metastatic small-cell neuroendocrine prostate carcinoma developed a skin palpable purpuric rash after atezolizumab exposure treated with topical corticosteroids, with subsequent development of acute kidney injury. Kidney biopsy demonstrated IgA-dominant necrotizing and crescentic glomerulonephritis, consistent with IgA vasculitis. High-dose oral and intravenous corticosteroids resulted in only partial renal improvement and persistent systemic inflammation. Subsequent treatment with rituximab (RTX) led to sustained stabilization of kidney function, normalization of previously elevated inflammatory cytokines (tumor necrosis factor-α, interleukin 18, soluble interleukin-2 receptor), and complete peripheral B-cell depletion. Although the malignancy later progressed, kidney function remained stable following RTX therapy. This case highlights IgA vasculitis as a rare but serious renal complication of programmed death-ligand 1 inhibition and supports RTX as a potential rescue therapy in corticosteroid-refractory cases. Careful biomarker monitoring and multidisciplinary management are essential to balance renal protection with oncologic outcomes.

Introduction

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block inhibitory receptors on T cells, thereby enhancing antitumor immunity and significantly improving survival across a wide range of malignancies. Since their first Food and Drug Administration approval in 2011, 10 ICIs targeting cytotoxic T lymphocyte--associated antigen 4, programmed cell death protein 1, programmed cell death ligand 1 (PD-L1), and lymphocyte activation gene-3 have transformed oncology and are now approved for more than 20 cancer types.^1,2

The clinical success of ICIs, however, comes with the price of immune dysregulation. By unleashing T-cell activity, these therapies can trigger autoimmune toxicities, collectively referred to as immune-related adverse events. Virtually every organ system may be affected, including the kidneys.^1,3 Renal immune-related adverse events are relatively uncommon, occurring in ∼3%-5% of patients, and in nearly 90% of biopsy-proven cases, the underlying lesion is acute interstitial nephritis.^1,3, 4, 5, 6

Although less frequent, ICIs have also been associated with glomerular diseases.⁷ These include pauci-immune glomerulonephritis, podocytopathies, and C3 glomerulopathy, and more rarely, immunoglobulin (Ig)A vasculitis.7, 8, 9 Published cases of ICI-associated IgA vasculitis are scarce and have largely involved pembrolizumab or nivolumab, either alone or in combination with ipilimumab, underscoring both the rarity of this complication and the lack of standardized treatment strategies.^7,9,10 To date, no biopsy-confirmed cases have been linked to PD-L1 blockade with atezolizumab (ATZ).

Management of ICI-induced kidney injury centers on corticosteroids.^1,11 Yet, in glomerular disease, response to steroids is often incomplete, relapses may occur, and prolonged therapy carries significant risks.^1,8,11 Rituximab (RTX), a B cell--depleting monoclonal antibody, has shown promise in refractory vasculitic syndromes and is increasingly considered in select ICI-related vasculitis.^9,12 By depleting B cells and reducing inflammatory cytokine production, RTX offers a mechanism to dampen immune amplification while potentially preserving antitumor efficacy.^1,12, 13, 14

In this study, we present what we believe to be the first biopsy-confirmed case of ATZ-associated IgA vasculitis with crescentic glomerulonephritis successfully treated with RTX. This case illustrates both the therapeutic potential of RTX and the clinical challenge of balancing renal protection with cancer control.

Case Description

A 75-year-old man with hypertension and metastatic small-cell neuroendocrine carcinoma of the prostate presented with widespread disease involving the liver, lungs, and vasculature, as well as a 16-cm pelvic mass causing obstructive nephropathy. Bilateral nephrostomy tubes were placed, and he developed stage 3 chronic kidney disease with a baseline serum creatinine (Scr) level of 1.5-1.8 mg/d.

He was started on carboplatin and etoposide, to which ATZ was later added as part of a clinical trial protocol. Before cancer-directed therapy, urinalysis showed no hematuria, only low-grade proteinuria, and there was no history of known glomerular disease. The patient initially tolerated therapy well and completed 4 doses of ATZ; however, his treatment course was later complicated by recurrent urinary tract infections, requiring hospitalization and temporary interruption of ATZ.

Following resolution of the infections, ATZ was resumed for 2 additional doses. Shortly thereafter, the patient developed a palpable purpuric rash on the lower extremities, prompting discontinuation of ATZ. Skin biopsy confirmed IgA leukocytoclastic vasculitis, which improved with topical corticosteroids. Concurrent cytokine profiling revealed elevated inflammatory markers, including serum tumor necrosis factor-α (TNF-α) at 22.8 pg/mL, interleukin (IL) 18 at 1,267 pg/mL, and soluble IL-2 receptor (sIL-2R) at 2,843 pg/mL.

Given resolution of the rash and clinical stability, ATZ was rechallenged. Soon thereafter, the patient developed acute kidney injury (AKI), with Scr rising to 2.73 mg/dL, an elevated urine retinol-binding protein-to-creatinine ratio of 13,206 mcg/g, and an increased C-reactive protein (CRP) level of 35.5 mg/L. ATZ was again discontinued, and prednisone 80 mg daily was initiated for presumed ICI-related nephrotoxicity.

Kidney function partially improved, with Scr decreasing to 2.23 mg/dL, allowing cautious steroid tapering. Despite supportive measures, systemic inflammation persisted, with elevated TNF-α (23.0 pg/mL), sIL-2R (3,189 pg/mL), and CRP (15.5 mg/L). The urine retinol-binding protein-to-creatinine ratio decreased to 7,867 mcg/g, although interpretation of urinalysis was limited by the presence of nephrostomy tubes. Serum IgA was elevated at 494 mg/dL, with normal complement levels (C3 114 mg/dL and C4 32 mg/dL), and serologies were negative for anti-proteinase 3 and myeloperoxidase antibodies.

Given failure of kidney function to return to baseline, a kidney biopsy was performed, revealing IgA nephropathy with focal necrotizing and crescentic glomerulonephritis, consistent with IgA vasculitis, along with acute tubular injury and interstitial fibrosis. Four of the 35 glomeruli contained cellular crescents, and immunofluorescence demonstrated 2+ mesangial staining for IgA (Fig 1). In view of these findings, elevated Scr, and persistent biomarker abnormalities despite high-dose corticosteroids, ATZ was discontinued, intravenous RTX (1,000 mg) was initiated, and corticosteroid therapy was adjusted. Following the first RTX infusion, Scr improved to 2.05 mg/dL, and CRP decreased to <3 mg/L.

Figure 1.

Kidney biopsy findings. The biopsy contained 35 glomeruli, of which 4 showed extracapillary proliferation with cellular crescent formation. One glomerulus showed fibrinoid necrosis, consistent with necrotizing glomerulonephritis. The tubulointerstitial compartment demonstrated acute tubular injury, characterized by tubular epithelial flattening and luminal dilatation, with mild interstitial inflammation. Tubular atrophy and interstitial fibrosis involved ∼20% of the cortical area. The vasculature showed mild intimal sclerosis without evidence of thrombosis or arteritis. Electron-dense deposits were not identified along the glomerular capillary walls, and there was no evidence of subepithelial deposits. The mesangium contained electron dense deposits. According to the Oxford classification, the findings were M1, E1, S1, T0, and C1. (A and B) Hematoxylin and eosin--stained sections demonstrating glomeruli with large cellular crescents. (C) Masson’s trichrome staining highlighting a glomerulus with a smaller cellular crescent. (D) Immunofluorescence microscopy demonstrating mesangial immunoglobulin A deposition (2+ intensity). Additional immunofluorescence staining revealed mesangial C3 (2+) and lambda light chain (2+) deposition.

Given tumor progression and stable kidney function, a second dose of RTX (1,000 mg) was administered to consolidate immunologic control while corticosteroids were continued at a reduced dose. After confirmation of renal stability, a second ATZ rechallenge was attempted following multidisciplinary discussion. This resulted in recurrent AKI, with Scr rising to 2.86 mg/dL accompanied by elevated inflammatory biomarkers, including CRP 58 mg/L, TNF-α 30.3 pg/mL, sIL-2R 2,536 pg/mL, and IL-18 1,014 pg/mL. Corticosteroids were intensified, and ATZ was permanently discontinued.

Following definitive cessation of immunotherapy and adjustment of immunosuppressive therapy, with continuation of low-dose prednisone, kidney function stabilized with an Scr level of 2.3 mg/dL and normalization of inflammatory markers (TNF-α < 10 pg/mL, sIL-2R 1,680 pg/mL, IL-18 710 pg/mL). No additional RTX was administered after confirmation of complete B-cell depletion. Although renal recovery was achieved, the malignancy subsequently progressed, necessitating transition to alternative systemic therapy and later radiation for brain metastases. At the last follow-up, kidney function had returned to baseline (Scr 1.86 mg/dL), CRP was <3 mg/L, and inflammatory biomarkers were undetectable (Fig 2). The temporal relationship between immunotherapy exposure, renal and cutaneous manifestations, biopsy findings, and therapeutic interventions is summarized in Fig 3.

Figure 2.

Trends in kidney function and serum inflammatory markers following rituximab (RTX) therapy. Gray bars indicate timing of RTX infusions. Following RTX administration, serum creatinine progressively improved and stabilized at a baseline of 1.8 mg/dL, paralleled by marked declines in serum TNF-α, sIL-2R, IL-18, and urinary RBP/Cr ratios. Peripheral CD19 cell counts decreased to 2 cells/μL after the first RTX dose and reached 0 cells/μL after the second, confirming complete B-cell depletion. Once CD19 counts were undetectable, kidney function remained stable and no further RTX doses were administered. Abbreviations: IL-18, interleukin 18; RBP/Cr, retinol-binding protein-to-creatinine; sIL-2R, soluble interleukin-2 receptor; TNF-α, tumor necrosis factor-α.

Figure 3.

Clinical timeline of atezolizumab-associated immunoglobulin A (IgA) vasculitis with renal involvement. The timeline illustrates the temporal association between atezolizumab (ATZ; PD-L1 inhibitor) exposure, development of cutaneous IgA leukocytoclastic vasculitis, subsequent acute kidney injury, biopsy-confirmed IgA vasculitis with crescentic glomerulonephritis, and response to immunosuppressive therapy. Initial and recurrent ATZ rechallenges were associated with increases in serum creatinine and inflammatory markers, whereas rituximab led to stabilization of kidney function and biomarker normalization. Permanent ATZ discontinuation resulted in sustained renal recovery on low-dose corticosteroids. Abbreviations: CRP, c-reactive protein; GN, glomerulonephritis; IL-18, interleukin 18; MPO, myeloperoxidase; PR3, proteinase 3; Scr, serum creatinine; TNF-α, tumor necrosis factor-α; UA, urinalysis; UTI, urinary tract infection; sIL-2R, soluble interleukin-2 receptor.

Discussion

This case represents, to our knowledge, the first biopsy-confirmed report of IgA vasculitis with crescentic glomerulonephritis associated with ATZ, a PD-L1 inhibitor. Although IgA vasculitis has been described in association with other ICIs, most previously described cases have involved programmed cell death protein 1 blockade, primarily nivolumab or pembrolizumab, either alone or in combination with ipilimumab.^5,7,9,10,12 As summarized in Table S1, IgA vasculitis with renal involvement remains distinctly uncommon compared with IgA nephropathy, and reports involving PD-L1 inhibitors are particularly rare. These findings expand the spectrum of ICIs implicated in IgA-mediated kidney disease and highlight the importance of considering ICI-related IgA vasculitis in patients with unexplained AKI during immunotherapy.

The pathogenesis of ICI-associated IgA vasculitis is not fully understood. Proposed mechanisms include upregulation of chemokines such as CXCL9 and CXCL10, which enhance T-cell recruitment and drive immune complex--mediated injury.^15,16 In our patient, elevations in systemic inflammatory markers—including TNF-α and CRP, both previously linked to ICI use and ICI-induced AKI,^17,18 as well as IL-18 and sIL-2R—paralleled deterioration in kidney function and improved following RTX therapy. Peripheral B-cell monitoring showed complete depletion of CD19 cells after the second RTX infusion, at which point additional doses were withheld. This temporal association between cytokine normalization, B-cell depletion, and renal stabilization supports a B cell--driven mechanism of immune amplification and suggests a potential role for cytokine profiling and B-cell monitoring as adjunctive tools in assessing disease activity in ICI-associated kidney injury.¹³

Importantly, kidney injury in this patient was multifactorial, with contributions from obstructive uropathy, recurrent urinary tract infections, and biopsy-documented acute tubular injury. Obstructive uropathy and urinary tract infections were limited to the early clinical course and were appropriately managed with nephrostomy tube placement and antibiotic therapy, respectively. However, several findings support a predominant immune-mediated contribution to the peaks of AKI—biopsy-proven IgA vasculitis with necrotizing and crescentic glomerulonephritis; a close temporal relationship between ATZ rechallenge and recurrent AKI; parallel elevations in systemic inflammatory biomarkers during AKI episodes; and improvement in kidney function and inflammatory markers following immunotherapy discontinuation and RTX administration. In addition, normal complement levels and the absence of subepithelial deposits on electron microscopy argued against infection-related glomerulonephritis. Taken together, these findings suggest that, within a background of chronic and intercurrent renal insults, the most severe episodes of AKI were most consistent with ICI-associated immune-mediated injury.

Corticosteroids remain the standard first-line therapy for ICI-related kidney injury; however, their efficacy in glomerular disease is often incomplete, and prolonged exposure carries substantial risk.^1,2,11 RTX was selected in this case based on its ability to deplete B cells and reduce proinflammatory cytokine production, providing a rational therapeutic alternative in corticosteroid-refractory cases.^12,13,19 Importantly, prior case series suggest that RTX treatment for ICI-induced vasculitis can achieve partial to complete renal recovery, shorten corticosteroid exposure, and reduce relapse risk without major safety concerns.^7,12 Our patient’s clinical course reflected the following observations: despite persistently elevated inflammatory biomarkers while on high-dose corticosteroids, kidney function stabilized, and biomarkers normalized following RTX therapy.

Nonetheless, the oncologic outcome underscores the clinical dilemma inherent in managing ICI nephrotoxicity.¹ Although RTX preserved kidney function in this case, the malignancy ultimately progressed, necessitating alternative oncologic therapies. Importantly, evidence remains limited regarding the optimal timing of ICI reinitiation after B-cell depletion and its impact on tumor control. These observations highlight the delicate balance between mitigating immune-mediated organ injury and preserving effective cancer treatment, emphasizing the need for individualized, multidisciplinary decision making.^1,2,18,20

In conclusion, IgA vasculitis with crescentic glomerulonephritis represents a rare but serious renal complication of PD-L1 inhibition. RTX may serve as an effective rescue therapy in corticosteroid-refractory cases, with improvement reflected both in kidney outcomes and serum inflammatory markers. Prospective studies and multicenter registries are needed to better define the safety, oncologic implications, and optimal timing of ICI rechallenge following B cell--direct therapy, and to establish standardized management strategies for ICI-associated IgA-mediated glomerular disease.

Supplementary Materials

Supplementary File (PDF)

Table S1.