The Use of Immune Checkpoint Inhibitors in Oncology and the Occurrence of AKI: Where Do We Stand?

Abstract

Immune checkpoint inhibitors (ICIs) are a novel class of immunotherapy drugs that have improved the treatment of a broad spectrum of cancers as metastatic melanoma, non-small lung cancer or renal cell carcinoma. These humanized monoclonal antibodies target inhibitory receptors (e.g. CTLA-4, PD-1, LAG-3, TIM-3) and ligands (PD-L1) expressed on T lymphocytes, antigen presenting cells and tumor cells and elicit an anti-tumor response by stimulating immune system. Nevertheless, the improved overall survival is complicated by the manifestation of Immune-related Adverse Effects (irAEs). During treatment with ICIs, the most common adverse kidney effect is represented by the development of acute kidney injury (AKI) with the acute tubulointerstitial nephritis as recurrent histological feature. The mechanisms involved in ICIs-induced AKI include the re-activation of effector T cells previously stimulated by nephrotoxic drugs (i.e. by antibiotics), the loss of tolerance versus self-renal antigens, the increased PD-L1 expression by tubular cells or the establishment of a pro-inflammatory milieu with the release of self-reactive antibodies. For renal transplant recipient treated with ICIs, the increased incidence of rejection is a serious concern. Therefore, the combination of ICIs with mTOR inhibitors represents an emerging strategy. Finally, it is relevant to anticipate which patients under ICIs would experience severe irAEs and from a kidney perspective, to predict patients with higher risk of AKI. Here, we provide a detailed overview of ICIs-related nephrotoxicity and the recently described multicenter studies. Several factors have been reported as biomarkers of ICIs-irAEs, in this review we speculate on potential biomarkers for ICIs-associated AKI.

The Mechanism of Drug Nephrotoxicity and the Methods for Preventing Kidney Damage

“…This strategy has proven extremely effective in some types of cancer and revolutionized the immunotherapy methods used to date. This group of drugs includes anti-CTLA-4 antibodies (ipilimumab, tremelimumab), anti-programmed cell death protein 1 antibodies (nivolumab, pembrolizumab) and anti-programmed cell death ligand 1 antibodies (atezolizumab) [ 74 , 75 , 76 ]. These medications initiate different mechanisms of kidney injury, although ATIN is the main one.…”

“…They induce the development of T-cells designed against tumor cells, although there is most likely cross-reaction with renal tissue there, as well. When using these drugs, our system is deprived of the ability to regulate the immune system, which causes it to lose tolerance to its own tissues, including renal [ 30 , 31 , 69 , 74 , 76 ]. Another mechanism involves the formation of antibodies against tubular epithelial cells, mesangial cells, and podocytes [ 32 ].…”

Kidney injury associated with antitumor therapy: focus on the adverse events of modern immuno-oncological drugs

“…Необходимо также учитывать, что у онкологических пациентов в силу разных причин может быть снижена мышечная масса, соответственно, исходные уровни сывороточного Кр (сКр) будут ниже и даже при выраженном нарушении функции почек могут оставаться в пределах нормальных значений. В такой ситуации критерий нефротоксичности «повышение Кр», сравнивающий изменение уровней этого показателя с верхней границей нормы (ВГН), будет неприменим [38]. Кроме того, необходимо исключать другие причины ОПП, в том числе вклад предшествовавшей или сопутствующей терапии (комбинированные режимы с химиотерапией или таргетными препаратами, применение нестероидных противовоспалительных препаратов -НПВП, ингибиторов протонной помпы -ИПП, антибиотиков и т.п.…”

Nephrotoxicity of Immune Checkpoint Inhibitors: Acute Kidney Injury and Beyond

“…Patients were treated with ICIs for 13-40 weeks before ICI-AKI was diagnosed. The latency of AKI is probably due to the prolonged longevity of activated T-cells, rather than the direct toxicity of ICIs [ 14 ].…”