In Practice
Kidney Complications of Immune Checkpoint Inhibitors: A Review

https://doi.org/10.1053/j.ajkd.2019.03.433Get rights and content

Immunologic control of malignancy has long been recognized as an important determinant of disease progression. Recent advances in immunology have led to the focus on several mechanisms that can be targeted to achieve tumor suppression. In particular, checkpoint inhibition has evolved in less than a decade to become one of the most important strategies in cancer therapy, with a meaningful improvement in patient survival. Six agents have been approved for clinical use to date and many more are in the industry pipeline. The spectrum of malignancies responsive to immunotherapy ranges from advanced melanoma, for which the first immune checkpoint inhibitor ipilimumab was approved, to Hodgkin lymphoma, non–small cell lung cancer, renal cell carcinoma, and others. Notwithstanding its clinical benefits, checkpoint inhibition carries a risk for significant off-target toxicity stemming from the immune system activation. In this review, we discuss general principles of checkpoint inhibition, mechanisms of toxicity, and kidney complications of the treatment and propose diagnostic and treatment strategies when kidney injury occurs.

Section snippets

Clinical Vignette

A 68-year-old man with stage IV non–small cell lung cancer presented to the hospital with dysphagia to liquids and acute kidney injury (AKI). Before presentation, the patient received 2 doses of cisplatin (75 mg/m2), 3 doses of pemetrexed (500 mg/m2), and 3 doses of nivolumab (10 mg/kg). Baseline serum creatinine (Scr) level 2 weeks after the last dose of cisplatin was 0.8 mg/dL. The last doses of nivolumab and pemetrexed were given 15 days before admission.

On presentation, Scr level was 4.1 mg/dL.

Background

Onconephrology is a rapidly growing subspecialty focusing on kidney complications of cancer and cancer treatment. Its growth is spurred by several factors, including the evolution of understanding of complex interaction between cancer cells and the kidney; the development of novel cancer therapies that can be nephrotoxic and lead to AKI, proteinuria, or electrolyte derangement1, 2, 3; and greater efficacy of cancer treatment, resulting in considerably longer survival of patients with cancer,

Antitumor Activity of Immune Checkpoint Inhibitors

Cancer immunotherapy is based on the principle of modulating the immune system to enhance the recognition and elimination of tumor cells. This process is dependent on the complex interplay between multiple immune system components, including cytotoxic, helper, and regulatory T cells; macrophages; natural killer cells; and myeloid-derived suppressor cells. The balance between a hyperactive immune response resulting in immune-mediated damage to healthy tissues and a hypoactive immune response

Immune-Related Adverse Effects

Off-target inflammatory responses to checkpoint inhibitors are commonly referred to as immune-related adverse effects (irAEs). These adverse effects can affect almost every organ system and their manifestations closely resemble autoimmune diseases. More than 50 checkpoint inhibitors have been discovered and their respective adverse effects have been demonstrated in animal models. For example, inhibition of PD-1 and the FCγRIIB inhibitory receptor on B cells leads to the development of

Epidemiology and Clinical Features

The reporting and communication of irAEs involving kidneys are limited by the use of Common Terminology Criteria for Adverse Effects (CTCAE) to classify and grade the severity of adverse effects of cancer therapy, including AKI (Table 2).37 Notwithstanding the many limitations of the KDIGO AKI classification system,38 applying CTCAE criteria fails to capture lower grade kidney complications as defined by KDIGO that have been validated in high-quality studies.39, 40, 41 For example, a 1.5-fold

Treatment Strategy

In general, the American Society of Clinical Oncology (ASCO) recommends withholding checkpoint inhibitor therapy for patients developing grade 2 CTCAE complications until at least partial symptom improvement.60 Oral corticosteroids are given for patients whose symptoms persist more than 1 week. For those developing grades 3 and 4 complications, checkpoint inhibitor therapy is discontinued and a more intensive corticosteroid regimen is administered. Objective response rate, overall survival, and

Special Considerations for Patients With Kidney Allografts

Data are limited on the outcomes of solid-organ transplant recipients because of the presumed high risk for organ rejection. De Bruyn et al69 reported rejection rates of 45% in patients with kidney allografts undergoing cancer treatment with checkpoint inhibition coupled with reduction of immunosuppression. It must be noted that tumor control was achieved in 30% of these patients. Provided that the patients are well informed, use of checkpoint inhibitors for cancer treatment may represent a

Sequelae of AKI

Publications have reported the long-term sequelae of immunotherapy-associated AKI. Among a series of 24 patients and 6 individual case reports with biopsy-confirmed AIN with follow-up of up to 12 months, 8 patients recovered kidney function completely, and all but 1 patient received corticosteroid therapy of various intensity and duration for the treatment of AIN.44, 46, 47, 54 Eleven other patients exhibited partial improvement of AIN and 3 patients required long-term renal replacement

Case Review

Treatment with the PD-1 checkpoint inhibitor was permanently discontinued in our patient. His Scr level declined to 1.3 mg/dL with initiation of corticosteroid treatment. However, 8 weeks after the biopsy was performed, Scr level increased to 2.7 mg/dL when the prednisone dose was reduced to 20 mg daily. To address this increase in Scr level, the sulfamethoxazole/trimethoprim therapy was discontinued and the prednisone dose was increased to 60 mg daily. Scr level declined again, but the patient

Conclusion

The present case demonstrates the challenges of AKI diagnosis and treatment in patients treated with checkpoint inhibitors and highlights the importance of kidney biopsy in diagnosing AIN, as opposed to cisplatin- or ifosfamide-induced acute tubular necrosis. With the growth of immunotherapy treatment choices and applications, nephrologists should be aware of the kidney effects of these agents and the potential treatment strategies and kidney prognosis in cancer survivors.

Article Information

Authors’ Full Names and Academic Degrees

Roman Shingarev, MD, and Ilya G. Glezerman, MD.

Support

This article was supported in part through the National Institutes of Health/National Cancer Institute Cancer Center support grant P30 CA008748.

Financial Disclosure

Dr Glezerman owns Pfizer Inc stock. Dr Shingarev declares that he has no relevant financial interests.

Acknowledgements

We thank Mr Ricardo Cano for help with formatting Figures 1 and 2.

Peer Review

Received October 11, 2018, in response to an invitation from the journal. Evaluated by 2 external peer reviewers and a member of the Feature

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