In PracticeKidney Complications of Immune Checkpoint Inhibitors: A Review
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
References (71)
- et al.
Drug-induced Fanconi's syndrome
Am J Kidney Dis
(2003) - et al.
VEGF signalling inhibition-induced proteinuria: mechanisms, significance and management
Eur J Cancer
(2010) - et al.
Signal transduction by the TCR for antigen
Curr Opin Immunol
(2000) - et al.
Patient-reported outcomes in KEYNOTE-006, a randomised study of pembrolizumab versus ipilimumab in patients with advanced melanoma
Eur J Cancer
(2017) - et al.
Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial
Lancet
(2016) - et al.
Spontaneous autoimmune disease in Fc(gamma)RIIB-deficient mice results from strain-specific epistasis
Immunity
(2000) - et al.
Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor
Immunity
(1999) - et al.
Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab
Ann Oncol
(2017) - et al.
Immune-related adverse events with immune checkpoint blockade: a comprehensive review
Eur J Cancer
(2016) - et al.
The duration of postoperative acute kidney injury is an additional parameter predicting long-term survival in diabetic veterans
Kidney Int
(2010)
Association of acute interstitial nephritis with programmed cell death 1 inhibitor therapy in lung cancer patients
Am J Kidney Dis
Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors
Kidney Int
Nephrotic syndrome with cancer immunotherapies: a report of 2 cases
Am J Kidney Dis
Ipilimumab-associated minimal-change disease
Kidney Int
Goodpasture's disease in a patient with advanced lung cancer treated with nivolumab: an autopsy case report
Lung Cancer
Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy
Cancer Treat Rev
Methotrexate-induced renal impairment: clinical studies and rescue from systemic toxicity with high-dose leucovorin and thymidine
J Clin Oncol
Long-term effects on renal function and blood pressure of treatment with cisplatin, vinblastine, and bleomycin in patients with germ cell cancer
J Clin Oncol
Chronic kidney disease in long-term survivors of hematopoietic cell transplant
Bone Marrow Transplant
The immunological synapse: a molecular machine controlling T cell activation
Science
Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/ B7 family
Immunol Rev
Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma
J Clin Oncol
The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection
Nat Immunol
Nivolumab and ipilimumab in advanced melanoma
N Engl J Med
PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma
N Engl J Med
Nivolumab versus everolimus in advanced renal-cell carcinoma
N Engl J Med
Nivolumab for recurrent squamous-cell carcinoma of the head and neck
N Engl J Med
Abnormal CTLA-4 function in T cells from patients with systemic lupus erythematosus
Eur J Immunol
Soluble PD-1 aggravates progression of collagen-induced arthritis through Th1 and Th17 pathways
Arthritis Res Ther
CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics
J Exp Med
Abatacept in the treatment of patients with psoriatic arthritis: results of a six-month, multicenter, randomized, double-blind, placebo-controlled, phase II trial
Arthritis Rheum
Review of recent genome-wide association scans in lupus
J Intern Med
A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans
Nat Genet
FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity
Nat Genet
Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders
JAMA Oncol
Cited by (51)
Acute kidney injury associated with immune checkpoint inhibitors: A pharmacovigilance study
2022, International ImmunopharmacologyHypersensitivity Reactions and Immune-Related Adverse Events to Immune Checkpoint Inhibitors: Approaches, Mechanisms, and Models
2022, Immunology and Allergy Clinics of North AmericaPD-1 inhibitor causes pathological injury to multiple organs in a Lewis lung cancer mouse model
2022, International ImmunopharmacologyImmune checkpoint inhibitors: An emergency medicine focused review
2021, American Journal of Emergency Medicine
Complete author and article information provided before references.