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

Immune checkpoint inhibitors (ICIs), including cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed death protein 1 (PD-1) or its ligand (PD-L1), are a new generation of immuno-oncological drugs that to date have demonstrated efficacy in a number of malignancies. The mechanism of ICT inhibitors action consist in the potentiation of the immune response by eliminating the tumor cells inhibitory effect on the T-lymphocytes activation. However, excessive immune system activation can cause the development of a special class of immune-related adverse events (irAEs) involved a wide variety of organs and systems, including the kidneys. Despite the fact that immuno-mediated kidney injury caused by ICI therapy develops quite rarely, it can be serious and determine the patient's prognosis, which necessitates early diagnosis and timely start of treatment. In this regard, awareness of the manifestations of ICI-associated renal irAEs is particularly relevant not only for oncologists and for nephrologists, but for doctors of other specialties. In this review, we elucidated the main variants of immuno-mediated kidney injury caused by ICI therapy, discussed possible predictors and mechanisms of their development, and considers the general principles of diagnosis and management of patients according to the severity of irAEs.

Download Full-text

Acute kidney injury from immune checkpoint inhibitor use

BMJ Case Reports ◽

10.1136/bcr-2019-231211 ◽

2019 ◽

Vol 12 (10) ◽

pp. e231211 ◽

Cited By ~ 1

Author(s):

Lexis Gordon ◽

Pouneh Dokouhaki ◽

Kimberly Hagel ◽

Bhanu Prasad

Keyword(s):

Acute Kidney Injury ◽

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Kidney Injury ◽

Acute Interstitial Nephritis ◽

Programmed Death ◽

Programmed Death 1

Immune checkpoint inhibitors are novel oncological medications, current classes of which include monoclonal antibodies that target inhibitory receptors cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed death 1 protein (PD-1) and programmed death-ligand 1. While they are novel in their ability to treat cancer, they also have a unique spectrum of immune-related adverse events. Renal-related immune adverse events, though rare, are an increasingly recognised clinical entity. We present the case of a 67-year-old man with acute kidney injury (AKI) after the second cycle of combination anti-CTLA-4 and anti-PD-1 antibodies for metastatic cutaneous melanoma. He presented with vomiting and diarrhoea, and AKI secondary to dehydration was treated with aggressive rehydration. After failing to recover biochemically, a renal biopsy was performed, which demonstrated severe acute interstitial nephritis. The culprit medications were held and he was treated with steroids. With immunosuppression, creatinine improved to pretreatment values.

Download Full-text

A case report of psoriasis flare following immunotherapy: Report of an important entity and literature review

SAGE Open Medical Case Reports ◽

10.1177/2050313x19897707 ◽

2020 ◽

Vol 8 ◽

pp. 2050313X1989770 ◽

Cited By ~ 2

Author(s):

Anastasia Politi ◽

Dimas Angelos ◽

Davide Mauri ◽

George Zarkavelis ◽

George Pentheroudakis

Keyword(s):

Adverse Events ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Skin Lesions ◽

Inflammatory Disorder ◽

Immune Mediated ◽

Programmed Death ◽

History Of ◽

Programmed Death 1 ◽

Cessation Of Treatment

Immune checkpoint inhibitors, such as anti-cytotoxic T-lymphocyte–associated antigen-4 and anti-programmed death-1, are a type of cancer immunotherapy approved for late-stage malignancy treatment. However, such therapies often induce immune-related adverse events. During anti-programmed death-1 blockade therapy, the most commonly reported adverse effects are skin toxicities, such as psoriasis—a chronic immune-mediated inflammatory disorder affecting the skin. We present the clinical characteristics of flared psoriasis in one patient under anti-programmed death-1 therapy who was diagnosed with T2N2M0/IIIB squamous lung carcinoma with a history of psoriasis for the past 5 years, exacerbated after the first cycle of nivolumab. After the third cycle, the extensive skin plaques necessitated treatment cessation. Following the discontinuation of anti-programmed death-1 treatment, skin lesions were treated locally. Possibly, anti-programmed death-1 immunotherapy can trigger immune-mediated diseases, such as psoriasis. Physicians should be alert to immune-related adverse events. Continuation or permanent cessation of treatment depends on the severity and reversibility of immune-related adverse events.

Download Full-text

T follicular helper cells: linking cancer immunotherapy and immune-related adverse events

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-002588 ◽

2021 ◽

Vol 9 (6) ◽

pp. e002588

Author(s):

Dirk Baumjohann ◽

Peter Brossart

Keyword(s):

Adverse Events ◽

Cancer Immunotherapy ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Underlying Mechanism ◽

Tfh Cells ◽

Follicular Helper ◽

Programmed Death ◽

Cancer Types ◽

Cell Death Protein

Cancer immunotherapy utilizing immune checkpoint inhibitors (ICIs) has revolutionized the treatment of numerous cancer types. As the underlying mechanism of these treatments lies in the interference with inhibitory signals that usually impair potent antitumor immunity, for example, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the programmed cell death protein 1 (PD-1):programmed death-ligand 1/2 (PD-L1/2) pathway, it is not surprising that this could also promote exaggerated adaptive immune responses to unrelated antigen specificities. One of the side effects of ICI-based cancer immunotherapy that is increasingly observed in the clinic is immune-related adverse events (irAEs), including various types of autoimmunity. However, the precise etiology is incompletely understood. T follicular helper (Tfh) cells provide essential help to B cells for potent antibody responses and their tumor tissue presence is often correlated with a better outcome in several solid tumor entities. Importantly, these CD4+ T cells express very high amounts of PD-1 and other co-stimulatory and inhibitory receptors. Here, we address the hypothesis that targeting CTLA-4 or PD-1 and its ligand PD-L1 critically impacts the function of Tfh cells in patients that receive these ICIs, thereby providing a link between ICI treatment and the development of secondary autoimmunity.

Download Full-text

How we treat neurological toxicity from immune checkpoint inhibitors

ESMO Open ◽

10.1136/esmoopen-2019-000540 ◽

2019 ◽

Vol 4 (Suppl 4) ◽

pp. e000540 ◽

Cited By ~ 4

Author(s):

Lavinia Spain ◽

Zayd Tippu ◽

James M Larkin ◽

Aisling Carr ◽

Samra Turajlic

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Death Receptor ◽

Treatment Strategies ◽

Presenting Symptoms ◽

Programmed Death ◽

Symptoms And Signs ◽

Substantial Morbidity

Neurological adverse events from immune checkpoint inhibition are increasingly recognised, especially with combination anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) and anti-programmed death receptor 1 (anti-PD-1) therapies. Their presenting symptoms and signs are often subacute and highly variable, reflecting the numerous components of the nervous system. Given the risk of substantial morbidity and mortality, it is important to inform patients of symptoms that may be of concern, and to assess any suspected toxicity promptly. As with other immune-related adverse events, the cornerstone of management is administration of corticosteroids. Specialist neurology input is vital in this group of patients to guide appropriate investigations and tailor treatment strategies.

Download Full-text

Management of Immune Checkpoint Inhibitor-Related Rheumatological Toxicities

Journal of Clinical Rheumatology and Immunology ◽

10.1142/s2661341720300013 ◽

2020 ◽

Vol 20 (01) ◽

pp. 25-34

Author(s):

Pak Yui Fong ◽

Shing Chuen Chow ◽

Bernard Ming Hong Kwong ◽

Charlene Cheuk Lam Lau ◽

Christy Yik Ching Lau ◽

...

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Eosinophilic Fasciitis ◽

Low Grade ◽

Programmed Death ◽

Rheumatological Diseases ◽

Cell Death Protein

Immune checkpoint inhibitors (ICIs) have forged a new direction for the treatment of cancer. However, ICIs – programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors – are also known to cause immune-related adverse events (irAEs). Rheumatological adverse events are uncommon and often low grade, but flares of underlying rheumatological diseases may be triggered. Guidelines are available for the effective management of the rheumatological adverse events that more frequently arise from the use of ICIs, such as inflammatory arthritis, inflammatory myopathies, Sjogren syndrome, scleroderma, and polymyalgia rheumatica and eosinophilic fasciitis.

Download Full-text

Mechanisms and clinical manifestations of cardiovascular toxicities associated with immune checkpoint inhibitors

Clinical Science ◽

10.1042/cs20200331 ◽

2021 ◽

Vol 135 (5) ◽

pp. 703-724

Author(s):

Alan H. Baik ◽

Katy K. Tsai ◽

David Y. Oh ◽

Mandar A. Aras

Keyword(s):

Immune System ◽

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Clinical Manifestations ◽

Immune System Activation ◽

Wide Range ◽

Anti Cancer

Abstract Immunotherapies have greatly expanded the armamentarium of cancer-directed therapies in the past decade, allowing the immune system to recognize and fight cancer. Immune checkpoint inhibitors (ICIs), in particular, have revolutionized cancer treatment and have demonstrated survival benefit in numerous types of cancer. These monoclonal antibodies increase anti-cancer immunity by blocking down-regulators of adaptive immunity, including cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand (PD-L1), resulting in anti-tumor activity. As ICIs increase immune system activation, they can cause a wide range of inflammatory side effects, termed immune-released adverse events. Though these toxicities can affect nearly any organ, the most fatal toxicity is myocarditis. Here, we discuss the diverse spectrum of cardiovascular toxicities associated with ICI use. In addition, we provide insight and future directions on mechanisms and treatments for immune-related adverse events (irAEs) involving the myocardium, pericardium, vasculature, and conduction system.

Download Full-text

Ipilimumab-induced renal granulomatous arteritis: a case report

BMC Nephrology ◽

10.1186/s12882-019-1552-2 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 3

Author(s):

Mathilde Lemoine ◽

Baptiste Dilly ◽

Alexandre Curie ◽

Vivien Hébert ◽

Charlotte Laurent ◽

...

Keyword(s):

Acute Kidney Injury ◽

Adverse Events ◽

Kidney Biopsy ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Oral Prednisone ◽

Kidney Injury ◽

New Drugs ◽

Case Presentation ◽

Cell Death Protein

Abstract Background Immune Checkpoint Inhibitors (ICPIs) are promising new drugs in treatment of advanced tumours targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD1) or its ligand (PDL-1). Ipilimumab is a monoclonal antibody targeting the CTLA-4 receptor used in treatment of metastatic melanoma. By increasing activity of the immune system, ICPIs lead to immune-related adverse events, such as dermatitis, colitis or hepatitis. ICPIs-related kidney adverse events are rare and acute tubulointerstitial nephritis with or without granuloma have mainly been reported. Case presentation We report a case of acute kidney injury in a patient with melanoma treated by ipilimumab. Kidney biopsy revealed acute interlobular and juxtaglomerular granulomatous arteritis, which has not yet been reported in patients treated by ICPIs. Kidney function partially recovered after ipilimumab discontinuation and oral prednisone. Unfortunately, the patient died a few months later from progression of his melanoma. Conclusion This case highlights a new mechanism of acute kidney injury related to ICPIs and supports the interest of kidney biopsy in case of ICPIs related acute renal failure.

Download Full-text

The Price of Success: Immune-Related Adverse Events from Immunotherapy in Lung Cancer

Current Oncology ◽

10.3390/curroncol28060373 ◽

2021 ◽

Vol 28 (6) ◽

pp. 4392-4407

Author(s):

Courtney H. Coschi ◽

Rosalyn A. Juergens

Keyword(s):

Immune Response ◽

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Low Grade ◽

Cancer Type ◽

Immune System Activation ◽

Cancer Types ◽

System Activation

Cancer immunotherapy has the goal of enhancing a patient’s intrinsic immune processes in order to mount a successful immune response against tumor cells. Cancer cells actively employ tactics to evade, delay, alter, or attenuate the anti-tumor immune response. Immune checkpoint inhibitors (ICIs) modulate endogenous regulatory immune mechanisms to enhance immune system activation, and have become the mainstay of therapy in many cancer types. This activation occurs broadly and as a result, activation is supraphysiologic and relatively non-specific, which can lead to immune-related adverse events (irAEs), the frequency of which depends on the patient, the cancer type, and the specific ICI antibody. Careful assessment of patients for irAEs through history taking, physical exam, and routine laboratory assessments are key to identifying irAEs at early stages, when they can potentially be managed more easily and before progressing to higher grades or more serious effects. Generally, most patients with low grade irAEs are eligible for re-challenge with ICIs, and the use of corticosteroids to address an irAE is not associated with poorer patient outcomes. This paper reviews immune checkpoint inhibitors (ICIs) including their mechanisms of action, usage, associated irAEs, and their management.

Download Full-text

Immune-Related Pancytopenia Induced by Anti-PD-1 Therapy – Interrupt or Continue Treatment – The Role of Immunohistochemical Examination

Case Reports in Oncology ◽

10.1159/000504130 ◽

2019 ◽

Vol 12 (3) ◽

pp. 820-828 ◽

Cited By ~ 1

Author(s):

Bożena Cybulska-Stopa ◽

Andrzej Gruchała ◽

Maciej Niemiec

Keyword(s):

Bone Marrow ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Death Receptor ◽

Positive Outcomes ◽

Hematological Disorders ◽

Therapeutic Outcomes ◽

Appropriate Treatment ◽

Programmed Death

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) and anti-programmed death receptor-1/ligand-1 (anti-PD-1/anti-PD-L1) caused a breakthrough in oncology and significantly improved therapeutic outcomes in cancer patients. ICIs generate a specific reaction in T cells, directed against antigens on cancer cells, leading to their damage and death. Through similar or the same antigens, activated lymphocytes may also have a cytotoxic effect on healthy cells, causing development of specific adverse effects – so-called immune-related adverse events (irAEs). We present the case report of a 56 year old patient with disseminated melanoma. During treatment with immunotherapy (anti PD-1), neutropenic fever and pancytopenia occurred. Trepanobiopsy of the bone marrow was performed to determine the cause of pancytopenia. Histopathological assessment of bone marrow combined with immunophenotype investigations may explain the cause of hematological disorders occurring in the course of treatment with ICIs, and support the choice of an appropriate treatment, directly translated into positive outcomes.

Download Full-text

Development of preclinical and clinical models for immune-related adverse events following checkpoint immunotherapy: a perspective from SITC and AACR

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-002627 ◽

2021 ◽

Vol 9 (9) ◽

pp. e002627

Author(s):

Nicholas L Bayless ◽

Jeffrey A Bluestone ◽

Samantha Bucktrout ◽

Lisa H Butterfield ◽

Elizabeth M Jaffee ◽

...

Keyword(s):

Adverse Events ◽

Cancer Immunotherapy ◽

Immune Cell ◽

Cytotoxic T Lymphocyte ◽

Action Plan ◽

Treatment Strategies ◽

Model Systems ◽

Preclinical Model ◽

Programmed Death ◽

Organ Systems

Recent advances in cancer immunotherapy have completely revolutionized cancer treatment strategies. Nonetheless, the increasing incidence of immune-related adverse events (irAEs) is now limiting the overall benefits of these treatments. irAEs are well-recognized side effects of some of the most effective cancer immunotherapy agents, including antibody blockade of the cytotoxic T-lymphocyte-associated protein 4 and programmed death protein 1/programmed-death ligand 1 pathways. To develop an action plan on the key elements needed to unravel and understand the key mechanisms driving irAEs, the Society for Immunotherapy for Cancer and the American Association for Cancer Research partnered to bring together research and clinical experts in cancer immunotherapy, autoimmunity, immune regulation, genetics and informatics who are investigating irAEs using animal models, clinical data and patient specimens to discuss current strategies and identify the critical next steps needed to create breakthroughs in our understanding of these toxicities. The genetic and environmental risk factors, immune cell subsets and other key immunological mediators and the unique clinical presentations of irAEs across the different organ systems were the foundation for identifying key opportunities and future directions described in this report. These include the pressing need for significantly improved preclinical model systems, broader collection of biospecimens with standardized collection and clinical annotation made available for research and integration of electronic health record and multiomic data with harmonized and standardized methods, definitions and terminologies to further our understanding of irAE pathogenesis. Based on these needs, this report makes a set of recommendations to advance our understanding of irAE mechanisms, which will be crucial to prevent their occurrence and improve their treatment.

Download Full-text