Immune checkpoint inhibitors associated granulomatous small vessel vasculitis accompanied with tubulointerstitial nephritis: a case report

Abstract

Background: Immune checkpoint inhibitors (ICIs) have provided significant benefits in cancer treatment, but they could develop immune-related adverse events (irAE). ICI-associated renal adverse effects are rare and tubulointerstitial nephritis (TIN) is the most common in the renal irAE. However, only a few case reports of renal vasculitis associated with ICI have been reported. In addition, the characteristics of infiltrating inflammatory cells of ICI-associated TIN and renal vasculitis have been uncertain.

Case presentation: A 65-year-old man received immune checkpoint inhibitors (ICIs), anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and anti-PD-1 (programmed cell death 1) antibodies for aggravated metastatic malignant melanoma. About 1 week after the second administration of nivolumab and ipilimumab, acute kidney injury developed. A renal biopsy was performed that showed TIN and non-necrotizing granulomatous vasculitis in interlobular arteries. Massive CD3⁺ T cells and CD163⁺ macrophages infiltrated both tubulointerstitium and interlobular arteries. Many infiltrating cells tested positive for Ki-67 and PD-1 ligand (PD-L1), but negative for PD-1. In CD3⁺ T cells, CD8⁺ T cells were predominantly infiltrated, and these cells were positive for Granzyme B (GrB) and cytotoxic granule TIA-1, but negative for CD25, indicating antigen-independent activated CD8⁺ T cells. Infiltration of CD4⁺ T cells was noted without obvious CD4⁺ CD25⁺ regulatory T (Treg) cells. His renal dysfunction recovered within 2 months of treatment with prednisolone in addition to discontinuation of nivolumab and ipilimumab.

Conclusions: We herein reported a case of ICI-related TIN and renal granulomatous vasculitis with infiltration of massive antigen-independent activated CD8⁺ T cells and CD163⁺ macrophages, and none or few CD4⁺ CD25⁺ Treg cells. These infiltrating cells might be a characteristic of the development of renal irAE.

Keywords: Acute kidney injury; Granulomatous vasculitis; Immune checkpoint inhibitor; Immune-related adverse event; Tubulointerstitial nephritis.

Fig. 1

Tubulointerstitial nephritis and granulomatous vasculitis. (A) Tubulointerstitial nephritis developed with focal but extensive infiltration of inflammatory cells in the tubulointerstitium. (B) Tubulointerstitial nephritis was noted, but glomerular lesions could not be seen. (C) Mononuclear cells including eosinophils (arrowhead) infiltrated the interstitium with mild tubulitis (arrow). (D, E) Non-necrotizing and granulomatous vasculitis developed in interlobular arteries. (F) Infiltration of mononuclear inflammatory cells were found in arterial intima, arterial media (arrowhead), and the arterial adventitia to the perivascular area without fibrinoid necrosis, indicating non-necrotizing and granulomatous arteritis. (A-C) HE stain; (D-F) PAM stain; (A) × 100, (B) × 200; (C, F) × 1,000; (D, E) × 400

Fig. 2

Characteristics of inflammatory cells in the granulomatous arteritis and tubulointerstitial nephritis. In renal granulomatous vasculitis (A-J), many CD3⁺ T cells (A) and CD163⁺ macrophages (B) infiltrated the arterial intima, media, and adventitia up to around the interlobular artery. Many infiltrative inflammatory cells were positive for Ki67 (C), indicating that infiltrating cells were proliferating in the vasculitis lesion. (D, E) Inflammatory cells were PD-1 negative and PD-L1 positive. (F, G) In CD3⁺ cells, abundant CD8⁺ T cells and less predominantly CD4⁺ T cells were noted. (H) Only a few CD25⁺ cells (arrowhead) were detected, however almost all cells were negative for CD25. Infiltrating cells were positive for granzyme B (GrB) (arrow in I) and cytotoxic granule T cell intracellular antigen 1 (TIA-1) (J), indicating effector and cytotoxic T cells. In tubulointerstitial nephritis (K-O), a similar phenotype of infiltrating cells, such as CD3⁺ T cells (K), predominantly CD8⁺ T cells (L), without CD25 expression (M), but positive for TIA-1 (N) were noted in interstitium. (O) Many CD163⁺ macrophages were also evident in intersitium. (A-G, K-M, O) × 200; (H-J, N) × 400