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Cardiorenal complications of immune checkpoint inhibitors

Nature Reviews Nephrology volume 14, pages 571–588 (2018)Cite this article

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Abstract

The development of immune checkpoint inhibitors (ICIs) has driven a revolutionary change in cancer treatment. Although traditional chemotherapeutic agents remain the first-line option for most cancers, targeted immune therapies are emerging as standard treatments for advanced-stage cancers. These agents target cell surface checkpoint proteins to stimulate the recognition and destruction of cancer cells by the immune system. Clinical studies have demonstrated these immunotherapeutics to elicit favourable antitumour responses in a variety of chemotherapy-refractory malignancies. However, use of these agents can also induce immune-related adverse events (irAEs) in off-target organs, including the heart and kidney. The most common manifestations of heart and kidney damage are myocarditis and acute interstitial nephritis, respectively, but other manifestations have been reported and, although rare, these off-target effects can be life threatening. Available data suggest that ICIs induce their off-target effects through several mechanisms, including direct binding to cell surface proteins expressed in healthy tissue, activation of T cells that cross-react with off-target tissues, generation of autoantibodies or by increasing levels of pro-inflammatory cytokines. Greater understanding of the adverse effects of cancer immunotherapies and the underlying mechanisms will facilitate the development of biomarkers to identify at-risk patients and approaches to prevent these irAEs.

Key points

  • Tumours use immune checkpoint pathways including programmed cell death protein 1 (PD-1)-mediated and cytotoxic T lymphocyte antigen 4 (CTLA4)-mediated pathways to evade recognition and destruction by the host immune system.

  • Immune checkpoint inhibitors (ICIs) target these checkpoint pathways and re-programme the host immune system to activate an antitumour immune response.

  • The use of ICIs is rapidly expanding for a variety of cancers owing to their established clinical efficacy; however, they are associated with a variety of immune-mediated injuries in different organs, including the kidney and heart.

  • Immune-mediated kidney injury with ICIs most commonly manifests as acute interstitial nephritis, although other patterns of renal injury have also been described; early treatment with corticosteroids typically reverses kidney injury.

  • Cardiac effects of ICIs are highly variable, but myocarditis is the most reported form of ICI-associated cardiotoxicity; this cardiotoxicity is generally reversible with corticosteroids, but fatal steroid-resistant cases have been reported.

  • Biomarker development and improved understanding of the mechanisms of immune-related adverse events will be crucial to aid early diagnosis and develop targeted treatment.

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Fig. 1: Mechanisms of cancer immunoediting.
Fig. 2: Cell surface ligands involved in T cell activation and inhibition.
Fig. 3: The immune checkpoint molecules CTLA4 and PD-1 regulate different immune compartments.
Fig. 4: Acute interstitial nephritis in the setting of immune checkpoint inhibitor therapy.
Fig. 5: Post-mortem analysis of the heart of a patient who developed cardiogenic shock while on nivolumab monotherapy.

All images courtesy of Douglas Rottmann, Yale University, USA.

Fig. 6: Potential mechanisms of immune-related adverse events.

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Reviewer information

Nature Reviews Nephrology thanks I. Glezerman, D. Leaf and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Section of Nephrology, Yale University School of Medicine, New Haven, CT, USA

    Krishna Sury, Mark A. Perazella & Anushree C. Shirali

  2. VA Medical Center, West Haven, CT, USA

    Mark A. Perazella

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  1. Krishna Sury
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  2. Mark A. Perazella
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All authors researched data for the article and contributed to writing the review and editing the manuscript before submission.

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Correspondence to Anushree C. Shirali.

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Glossary

T helper 1 (TH1) cells

Differentiated population of T cells that provide antibacterial and antiviral immunity. They are characterized by expression of the transcription factors signal transducer and activator of transcription 4 (STAT4)–T-box transcription factor TBX21 (also known as TBET) and production of IFNγ, IL-2 and tumour necrosis factor (TNF).

TH2 cells

Differentiated population of T cells that provide antiparasitic immunity and tissue repair and mediate allergic diseases such as asthma. They are characterized by expression of the transcription factors signal transducer and activator of transcription 6 (STAT6)–trans-acting T cell-specific transcription factor GATA3 and by the production of IL-4, IL-5, IL-9, IL-10, IL-13 and IL-25.

Regulatory T (Treg) cells

Specialized subset of T lymphocytes characterized by the expression of CD4 and CD25 as well as the transcription factor forkhead box protein P3. These cells suppress the activation, proliferation and cytokine production of CD4+ and CD8+ T cells via cytokines such as IL-10 and transforming growth factor-β (TGFβ).

Langerhans cells

DCs found specifically in the epidermis.

Microclusters

Complex structure of the T cell receptor and antigen-presenting cell with major histocompatibility complex-bound antigen along with co-stimulatory and signalling molecules. This structure is thought to promote T cell activation by providing sustained signalling.

Tumour-draining DCs

Dendritic cells (DCs) found in the draining lymph nodes of tumours. These DCs can process tumour antigen and subsequently activate T cells that are specific for these antigens.

Acute interstitial nephritis

(AIN). The pathologic description given to the influx of mononuclear immune cells including lymphocytes, macrophages and eosinophils into the interstitium and peritubular regions of the kidney. Clinically, AIN results in acute kidney injury and can result from an inflammatory reaction to drugs or to infections including viruses and bacteria.

Granuloma

Aggregate of histiocytes, lymphocytes, plasma cells and eosinophils that form in tissues including the kidney in response to viral infection or autoimmune disease.

Hypophysitis

Inflammation of the pituitary gland.

Sterile pyuria

Appearance of white blood cells in the urine without growth of microorganisms in urine culture to suggest an infectious aetiology.

White blood cell casts

Microscopic cylindrical structures formed by the accumulation of white blood cells and protein within the lumen of kidney tubules. These casts can slough off into urine and may be detected on microscopy of urine sediment.

Bland urine sediment

Absence of cells or cellular casts in the urine.

Ileitis

Inflammation of the ileum, the terminal component of the small intestine, due to drugs, infection or autoimmune disease.

Sialadenitis

Inflammation of the salivary glands.

Iritis

Form of anterior uveitis characterized by inflammation of the iris, the middle part of the uvea, which surrounds the pupil.

Pyuria

Presence of white blood cells in urine.

Myocarditis

Inflammation of the myocardium due to infection, drug reaction or ischaemia.

Myositis

Inflammation of muscle due to infection, injury or drugs.

Troponin I

Inhibitory subunit of the myocardial troponin complex that is released from the myocardium following myocardial infarction or other injury. Troponin I serves as a specific biomarker for cardiac injury.

P–R interval

Time period between atrial repolarization and ventricular repolarization, measured on an electrocardiogram between the beginning of the P wave until the beginning of the QRS complex.

ST-segment depression

Electrocardiogram pattern seen in myocardial ischaemia that represents a defect in ventricular depolarization and repolarization. It is characterized by a down-sloping segment instead of the usual flat line between the S and T waves.

Right bundle branch block

Pattern on electrocardiogram characterized by delayed depolarization of the right ventricle, resulting in aberrant waves such as a widened QRS complex and terminal R wave in lead V1. Right bundle branch block may indicate the presence of underlying cardiac ischaemia.

Creatine kinase-muscle/brain

(CK-MB). Isozyme of creatine kinase that is abundantly found in the heart and to a lesser degree in skeletal muscle. Similar to troponin I, CK-MB is released into the systemic circulation within hours of myocardial injury but decreases to normal levels within 24–48 hours.

Hypokinesis

Decreased wall motion on transthoracic electrocardiogram reflecting weakened myocardial muscle.

Akinesis

Failure of the ventricles of the heart to fully contract, which is seen as localized or global lack of wall motion on transthoracic electrocardiogram.

T1-weighted

Type of MRI in which only longitudinal movement of protons is measured. Images are characterized by fat appearing white, which is ideal for anatomical analysis.

T2-weighted

Type of MRI in which only transverse movement of protons is measured. Images are characterized by fat and water appearing white, which detects pathology such as infection or tumour.

Type II hypersensitivity

Immune reaction caused by antigen–antibody complexes that activate the complement system and cause cell lysis.

Type IV hypersensitivity

Immune reaction caused by activation of antigen-specific T cells by dendritic cells. The effector function of these cells includes direct cytotoxicity or cytokine release, which mediates cell or tissue injury.

Drug-specific T cells

T cells that become activated when they recognize a specific peptide in drugs, either directly or via cross reactivity. These T cells can circulate and infiltrate various tissues, causing inflammatory injury.

Drug-specific lymphocyte proliferation tests

Also known as the lymphocyte tolerance test; an in vitro assay that examines T cell proliferation and/or cytokine release in response to stimulation with specific drugs.

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Sury, K., Perazella, M.A. & Shirali, A.C. Cardiorenal complications of immune checkpoint inhibitors. Nat Rev Nephrol 14, 571–588 (2018). https://doi.org/10.1038/s41581-018-0035-1

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