The mechanisms of acute interstitial nephritis in the era of immune checkpoint inhibitors in melanoma

Abstract

Treatment with immune checkpoint inhibitors (ICIs) has improved the prognosis of patients with a number of types of cancer, but the frequent development of immune-related adverse effects (irAEs) can worsen the outcome. The most common irAEs involve the gastrointestinal, cutaneous, and endocrine systems, but nephrotoxicity, resulting from damage to the tubule-interstitial compartment, may occur in some patients. The early phases of acute interstitial nephritis (AIN) are characterized by systemic symptoms that indicate a poor clinical state as well as a mild deterioration of renal function. Tubular injury is due to a direct effect mediated by cytotoxic CD8⁺ T cells, which sustain the local production of pro-inflammatory cytokines that progressively impair renal function. The treatment of AIN is mainly based on high-dose steroids, which in most instances leads to the recovery of renal function. However, the premature discontinuation of ICI therapy may prevent the impact of treatment on the clinical progression of the malignancy. Adequately addressing irAEs requires a standardized therapy that is based on the results of large clinical trials.

Keywords: acute interstitial nephritis; immunotherapy; melanoma; nephrotoxicity.

Figure 1.

The hallmark of acute interstitial nephritis induced by an anti-PD-1 monoclonal antibody. (a) A representative renal biopsy from a patient treated with anti-PD-1 who developed severe tubulitis (*). The diffuse infiltrate mostly consists of lymphocytes and plasma cells. The glomerular morphology (**) is almost normal but a mild to moderate intimal fibrosis is seen in an interlobular artery. (b) and (c) Diffuse severe tubular inflammation (*) without findings associated with atrophy, including lymphocyte infiltration and interstitial edema (**). (d) Mild-moderate capillary congestion in a glomerulus surrounded by an interstitial infiltrate but without any other significant abnormalities. Silver methenamine staining of renal tissues visualized by optical microscopy (50× and 400× magnification).

Figure 2.

Mechanisms of renal damage induced by PD-1 inhibitors. (a) shows the mechanisms regulating the immune surveillance in melanoma and the basic events activated during the T cell interplay with DCs. This crosstalk is the consequence of antigen/drug processing and mostly occurs via TCR-MHC engagement. (b) The resulting T cell activation is followed by migration toward lymphoid and nonlymphoid tissues, including the kidney. T cells expressing PD-1 may bind PD-L1 expressed on renal cells, which generates inhibitory signals driving T cell exhaustion (left). In contrast, T cells in which PD-1 is blocked by ICIs (right) migrate toward the kidney, where they may cause cytotoxicity by the local over production of nephritogenic cytokines. This event may result in irreversible damage to the tubules and the progressive deterioration of kidney function.