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    Immune checkpoint inhibitor-associated acute kidney injury

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    Common electrolyte disorders associated with immune checkpoint inhibitors

  • 1.

    Gupta S, et al. Acute kidney injury in patients treated with immune checkpoint inhibitors. J Immunother Cancer 2021; 9:e003467. doi: 10.1136/jitc-2021-003467

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Gupta S, et al. Immune checkpoint inhibitor nephrotoxicity: Update 2020. Kidney360 2020; 1:130140. https://kidney360.asnjournals.org/content/1/2/130

  • 3.

    Brahmer JR, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer 2021; 9:e002435. doi: 10.1136/jitc-2021-002435

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Kitchlu A, et al. A systematic review of immune checkpoint inhibitor-associated glomerular disease. Kidney Int Rep 2021; 6:6677. doi: 10.1016/j.ekir.2020.10.002

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Uppal NN, et al. Electrolyte and acid-base disorders associated with cancer immunotherapy. Clin J Am Soc Nephrol [Published online ahead of print January 21, 2022]. doi: 10.2215/CJN.14671121; https://cjasn.asnjournals.org/content/early/2022/02/06/CJN.14671121

    • Search Google Scholar
    • Export Citation
  • 6.

    Wanchoo R, et al. Immune checkpoint inhibitor-associated electrolyte disorders: Query of the Food and Drug Administration Adverse Event Reporting System. Kidney Int 2021; 100:945947. doi: 10.1016/j.kint.2021.06.001

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Seethapathy H, et al. Hyponatremia and other electrolyte abnormalities in patients receiving immune checkpoint inhibitors. Nephrol Dial Transplant 2021; 36:22412247. doi: 10.1093/ndt/gfaa272

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Manohar S, et al. Programmed cell death protein 1 inhibitor treatment is associated with acute kidney injury and hypocalcemia: Meta-analysis. Nephrol Dial Transplant 2019; 34:108117. doi: 10.1093/ndt/gfy105

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Vogel WV., et al. Ipilimumab-induced sarcoidosis in a patient with metastatic melanoma undergoing complete remission. J Clin Oncol 2012; 30:e7e10. doi: 10.1200/JCO.2011.37.9693

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Mills TA, et al. Parathyroid hormone-related peptide-linked hypercalcemia in a melanoma patient treated with ipilimumab: Hormone source and clinical and metabolic correlates. Semin Oncol 2015; 42:909914. doi: 10.1053/j.seminoncol.2015.09.006

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Chalan P, et al. Thyroid dysfunctions secondary to cancer immunotherapy. J Endocrinol Invest 2018; 41:625638. doi: 10.1007/s40618-017-0778-8

  • 12.

    Ferris RL, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016; 375:18561867. doi: 10.1056/nejmoa1602252

Immune Checkpoint Inhibitors and the Kidney: An Update

  • 1 Shruti Gupta, MD, MPH, is Director of Onco-Nephrology at Brigham and Women's Hospital (BWH) and Dana-Farber Cancer Institute and an Associate Physician in the Division of Renal Medicine, BWH, Boston, MA. Paul E. Hanna, MD, MSc, is a clinical research fellow at Massachusetts General Hospital, Boston.
Full access

Immune checkpoint inhibitors (ICPis) have transformed the landscape of oncology, and they are now approved for the treatment of over one dozen different types of cancer. ICPis block immune checkpoints—the “brakes” of the immune system—and therefore activate cytotoxic T-cells to eliminate cancer cells. However, enhancement of T-cell activity also leads to autoimmune toxicities or immune-related adverse events (irAEs), which can affect multiple organ systems, including the kidneys. ICPi-associated acute kidney injury (ICPi-AKI) can have major repercussions, including discontinuation from therapy and prolonged courses of immunosuppression.

Recently, Gupta et al. (1) conducted a multicenter study of 429 cases of clinically adjudicated and/or biopsy-proven ICPi-AKI from 30 sites across 10 countries, highlighting key risk factors, clinical features, and outcomes of ICPi-AKI. Compared with contemporaneous controls who received ICPis but did not develop ICPi-AKI, patients with ICPi-AKI were more likely to have lower baseline kidney function, receive proton pump inhibitors, and have a history of extrarenal irAEs (e.g., rash or hepatitis). ICPi-AKI occurred at a median of 16 weeks (interquartile range [IQR] 8−32) after ICPi initiation. Urinalysis findings were neither sensitive nor specific for ICPi-AKI. The most common lesion on biopsy was acute tubulointerstitial nephritis (ATIN); however, other lesions were present in up to 20% of patients. The majority of patients (82%) were treated with corticosteroids, and early initiation of corticosteroids (e.g., within 3 days of ICPi-AKI) was associated with a higher odds of kidney recovery (Figure 1).

Figure 1
Figure 1

Immune checkpoint inhibitor-associated acute kidney injury

Citation: Kidney News 14, 5

AKI, acute kidney injury; ATIN, acute tubulointerstitial nephritis, eGFR, estimated glomerular filtration rate; ICPi-AKI, immune checkpoint inhibitor-associated AKI; irAEs, immune-related adverse events; PPI, proton pump inhibitor; UA, urinalysis.

Some of the most compelling findings were outcomes after rechallenge. A total of 121 of the 429 patients (28.2%) were rechallenged with an ICPi after ICPi-AKI. Of these, only 20 (16.5%) developed recurrent ICPi-AKI, of whom 60% had kidney recovery at a median of 34 days (IQR 27−38) following recurrent ICPi-AKI. These findings collectively show that rechallenge should be strongly considered after ICPi-AKI.

There is considerable debate about the utility of a kidney biopsy in patients with ICPi-AKI. Biopsy may be relatively contraindicated in patients with a history of nephrectomy or in those for whom anticoagulation cannot be safely discontinued (2). However, biopsy should be strongly considered in patients with a plausible alternative etiology for AKI and/or atypical features (e.g., hematuria or heavy proteinuria) (2, 3). ATIN is the most common lesion on kidney biopsy, although other lesions have been reported. One meta-analysis found that pauci-immune glomerulonephritis (GN), podocytopathies, and C3 GN are the most frequently observed lesions, although immunoglobulin A nephropathy and amyloidosis have also been reported (4). The pathophysiology behind these lesions is not well understood but may be related to both T-cell hyperactivity and B-cell-driven, autoantibody-mediated disease.

In addition to AKI, ICPis are also associated with a number of electrolyte disturbances, most commonly, hyponatremia, hypokalemia, and hypercalcemia (57). The incidence of hyponatremia varies from 1.2% in clinical trials to 62% in real-world studies (7, 8). Risk factors for hyponatremia include use of ipilimumab, diuretics, and non-White race (7). Hyponatremia may occur in the setting of endocrinopathies, such as hypophysitis, adrenalitis, and thyroid dysfunction; however, volume shifts and the syndrome of inappropriate diuretic hormone secretion are likely more common causes. Hypokalemia may occur from gastrointestinal losses in the setting of ICPi-mediated colitis or renal losses in patients with renal tubular acidosis. Hypercalcemia has been observed in patients with elevated parathyroid hormone-related peptide, sarcoid-like granulomas, and hyperprogression of disease (912) (Figure 2).

Figure 2
Figure 2

Common electrolyte disorders associated with immune checkpoint inhibitors

Citation: Kidney News 14, 5

GI, gastrointestinal; HyperCa+, hypercalcemia; HypoCa+, hypocalcemia; HypoK+, hypokalemia; HypoNa+, hyponatremia; HypoPhos, hypophosphatemia; PTHrP, parathyroid hormone-related peptide; RTA, renal tubular acidosis; SIADH, syndrome of inappropriate anti-diuretic hormone release.

Given the rapid and dramatic growth in ICPi therapy, there is considerable interest in understanding mechanisms behind ICPi-AKI and electrolyte abnormalities, as well as addressing challenges related to diagnosis and management of ICPi-AKI. Biomarkers with anatomic specificity are needed to distinguish ICPi-AKI from other causes and to identify potential therapeutic targets. Additionally, prospective studies measuring hormone levels and fractional excretion of electrolytes may help shed further light on the mechanisms behind electrolyte abnormalities.

References

  • 1.

    Gupta S, et al. Acute kidney injury in patients treated with immune checkpoint inhibitors. J Immunother Cancer 2021; 9:e003467. doi: 10.1136/jitc-2021-003467

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Gupta S, et al. Immune checkpoint inhibitor nephrotoxicity: Update 2020. Kidney360 2020; 1:130140. https://kidney360.asnjournals.org/content/1/2/130

  • 3.

    Brahmer JR, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer 2021; 9:e002435. doi: 10.1136/jitc-2021-002435

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Kitchlu A, et al. A systematic review of immune checkpoint inhibitor-associated glomerular disease. Kidney Int Rep 2021; 6:6677. doi: 10.1016/j.ekir.2020.10.002

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Uppal NN, et al. Electrolyte and acid-base disorders associated with cancer immunotherapy. Clin J Am Soc Nephrol [Published online ahead of print January 21, 2022]. doi: 10.2215/CJN.14671121; https://cjasn.asnjournals.org/content/early/2022/02/06/CJN.14671121

    • Search Google Scholar
    • Export Citation
  • 6.

    Wanchoo R, et al. Immune checkpoint inhibitor-associated electrolyte disorders: Query of the Food and Drug Administration Adverse Event Reporting System. Kidney Int 2021; 100:945947. doi: 10.1016/j.kint.2021.06.001

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Seethapathy H, et al. Hyponatremia and other electrolyte abnormalities in patients receiving immune checkpoint inhibitors. Nephrol Dial Transplant 2021; 36:22412247. doi: 10.1093/ndt/gfaa272

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Manohar S, et al. Programmed cell death protein 1 inhibitor treatment is associated with acute kidney injury and hypocalcemia: Meta-analysis. Nephrol Dial Transplant 2019; 34:108117. doi: 10.1093/ndt/gfy105

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Vogel WV., et al. Ipilimumab-induced sarcoidosis in a patient with metastatic melanoma undergoing complete remission. J Clin Oncol 2012; 30:e7e10. doi: 10.1200/JCO.2011.37.9693

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Mills TA, et al. Parathyroid hormone-related peptide-linked hypercalcemia in a melanoma patient treated with ipilimumab: Hormone source and clinical and metabolic correlates. Semin Oncol 2015; 42:909914. doi: 10.1053/j.seminoncol.2015.09.006

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Chalan P, et al. Thyroid dysfunctions secondary to cancer immunotherapy. J Endocrinol Invest 2018; 41:625638. doi: 10.1007/s40618-017-0778-8

  • 12.

    Ferris RL, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016; 375:18561867. doi: 10.1056/nejmoa1602252

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