Acute interstitial nephritis associated with immune checkpoint inhibitor therapy

Case presentation

A 66-year-old man presents with a history significant for coronary artery disease, peripheral vascular disease, hypertension, diabetes, and stage 3B chronic kidney disease (CKD). His oncologic history is significant for stage IVB non-small-cell lung cancer, diagnosed two years ago. He was initially treated with carboplatin and four cycles of pemetrexed pembrolizumab, then eight cycles of pemetrexed pembrolizumab consolidation, and has been on pembrolizumab maintenance for the last year. His current medications include pregabalin, duloxetine, vitamin C, vitamin D, aspirin, oxycodone, omeprazole, and lisinopril.

During an outpatient routine blood investigation, he was noted to have worsening renal function. At baseline, his creatinine level was 2 mg/dL, and his estimated glomerular filtration rate (eGFR) was 30 to 35 mL/min/1.73 m². On this presentation, the patient had an eGFR of 19 mL/min/1.73 m², a creatinine level of 3.3 mg/dL, a blood urea nitrogen (BUN) level of 36 mg/dL, and a potassium level of 5.8 mmol/L. The patient was advised to go to the ED for further investigation.

On presentation at the ED, his vital signs are stable, and he does not report any specific problems. The review of systems is negative, and he is admitted for further investigation and diagnosis.

Complete blood count at admission shows a total leukocyte count of 8.6 cells/mm³, a hemoglobin level of 11.1 mg/dL, and a platelet count of 253 cells/mm³. Differential count shows 17.6% eosinophils, 7.9% monocytes, 18.6% lymphocytes, 54.7% neutrophils, 0.9% basophils, and an eosinophil absolute count of 1.51 cells/mm³. Urinalysis is positive for eosinophils. Ultrasound of the kidneys shows no evidence of obstruction, and findings are compatible with chronic medical renal disease.

Nephrology is consulted due to worsening renal function and concern for acute interstitial nephritis (AIN). No other etiology for acute kidney injury (AKI), including any prerenal cause, infection, or obstruction, is identified, and pembrolizumab-induced AIN is suspected given that omeprazole, the other potential cause, is used only intermittently.

Background

Immune checkpoint inhibitors (ICIs) are a novel class of oncologic therapy that has gained popularity in the treatment of various kinds of cancers due to promising results. They are used in melanoma, lung cancer, urothelial cancer, renal cell carcinoma, and other types. ICIs are humanized monoclonal antibodies that inhibit cytotoxic lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand (PD-L1) signaling pathways, which act as negative immunologic regulators on T-cells and other immune cells (11. Osipov A, Murphy A, Zheng L. From immune checkpoints to vaccines: The past, present and future of cancer immunotherapy. Adv Cancer Res. 2019;143:63-144. [PMID: 31202363]). Inhibition of these pathways leads to anti-tumor immune responses by engaging the innate and adaptive immune system against tumor cells. However, this mechanism is not selective, and precipitation of immune response can lead to immune-related adverse events. The most frequently affected organs are the skin, gastrointestinal tract, liver, and endocrine system, with an incidence that ranges between 15% and 90% (22. Champiat S, Lambotte O, Barreau E, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol. 2016;27:559-74. [PMID: 26715621], 33. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378:158-168. [PMID: 29320654]). Kidney involvement is less frequent, with an estimated incidence of 3% to 5% (44. Cortazar FB, Kibbelaar ZA, Glezerman IG, et al. Clinical features and outcomes of immune checkpoint inhibitor-associated AKI: A multicenter study. J Am Soc Nephrol. 2020;31:435-446. [PMID: 31896554]).

Etiology and pathogenesis

AIN is the most frequently encountered pathology for ICI-related AKI. However, cases of glomerular nephritis, vasculitis, and minimal change disease have also been reported (55. Mamlouk O, Selamet U, Machado S, et al. Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: single-center experience. J Immunother Cancer. 2019;7:2. [PMID: 30612580]). The underlying mechanism for ICI-related AIN is assumed to involve cell-mediated immunity, similar to other drug-induced AIN. ICI therapy may promote the migration of T-cells into the kidneys and initiate an inflammatory response (66. Perazella MA. Checkmate: kidney injury associated with targeted cancer immunotherapy. Kidney Int. 2016;90:474-6. [PMID: 27521108]). The risk factors for ICI-related AKI include 1) use of other AIN-causing drugs, mainly proton-pump inhibitors; 2) concomitant use of multiple ICI agents; 3) prior or concomitant extrarenal immune-related symptoms such as rash and hepatitis; 4) hypertension; and 5) chronic kidney disease (77. Gupta S, Short SAP, Sise ME, et al; ICPi-AKI Consortium Investigators. Acute kidney injury in patients treated with immune checkpoint inhibitors. J Immunother Cancer. 2021;9. [PMID: 34625513]). Whether patients on ICI therapy should avoid concomitant long-term use of proton-pump inhibitors remains an open question.

Diagnosis

The median time for AKI to occur after initiation of ICI has been reported to be three months, with a range of 21 to 245 days (44. Cortazar FB, Kibbelaar ZA, Glezerman IG, et al. Clinical features and outcomes of immune checkpoint inhibitor-associated AKI: A multicenter study. J Am Soc Nephrol. 2020;31:435-446. [PMID: 31896554]). Common clinical findings include rising serum creatinine levels, hematuria, pyuria, proteinuria, and increased blood eosinophil count. Based on the serum creatinine elevation from baseline, AKI can be classified as grade I to IV, per guidelines from the American Society of Clinical Oncology (ASCO) (88. Brahmer JR, Lacchetti C, Schneider BJ, et al; National Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: american society of clinical oncology clinical practice guideline. J Clin Oncol. 2018;36:1714-1768. [PMID: 29442540]). Diagnostic workup should include a complete blood count, complete metabolic panel, urinalysis, and renal imaging. Other diagnostic etiologies, including urinary tract infection, nephrotoxic medications, volume depletion, contrast exposure, and obstruction, should be excluded.

Kidney biopsy should be avoided until corticosteroid treatment has been attempted. Per ASCO guidelines, kidney biopsy should be performed in patients undergoing ICI treatment if there is proteinuria greater than 3 g, oliguria, dysmorphic hematuria, and suboptimal response to empirical treatment with a corticosteroid. However, kidney biopsy should be considered strongly and maybe even early if an alternative etiology of AKI is suspected, since it can prevent unnecessary interruption of immunotherapy and use of corticosteroids.

There is no clear consensus on the timing of referral to a nephrologist, but given the complexity of the diagnosis and the possibility of poor outcomes, nephrology consultation should be pursued if the creatinine level increases to more than 1.5 times the baseline level.

Treatment

The current guidelines from ASCO recommend a clinical decision-making process based on the rising serum creatinine level and renal function deterioration. If creatinine is 1.5 to 2 times the baseline, ICI therapy should be stopped, with discontinuation of other nephrotoxic medications and monitoring of renal function. If renal function deteriorates further, with an increase in serum creatinine level to two or three times the baseline, the recommendation is to treat with prednisone equivalents at 0.5 to 1 mg/kg per day (which can be increased up to 1 to 2 mg/kg per day if no improvement), in addition to holding ICIs (88. Brahmer JR, Lacchetti C, Schneider BJ, et al; National Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: american society of clinical oncology clinical practice guideline. J Clin Oncol. 2018;36:1714-1768. [PMID: 29442540]). Additional immunosuppressants, e.g., mycophenolate, can be considered in cases of worsening renal function. Renal replacement therapy is indicated for refractory cases or other life-threatening consequences. Once renal function returns to baseline, corticosteroids can be tapered over four to six weeks. ICI therapy should be permanently discontinued in patients whose serum creatinine levels rise to three times above baseline or 4 mg/dL. The resumption of ICI therapy can be considered for other patients after a review of the risks and benefits.

An important point of consideration is patients who are recipients of kidney transplant and at risk of allograft rejection. Anti-PD-1/PDL-1 therapies are associated with a higher risk of allograft rejection compared to anti-CTLA-4 agents. In such patient populations, management with mTOR inhibitors is recommended in addition to corticosteroids (99. Murakami N, Mulvaney P, Danesh M, et al; Immune Checkpoint Inhibitors in Solid Organ Transplant Consortium. A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant. Kidney Int. 2021;100:196-205. [PMID: 33359528]).

There has been a lot of emphasis on identifying early biomarkers to diagnose renal failure associated with ICIs, which could also be of prognostic significance. The role of IL-17, sCD163 (soluble receptor expressed from M2 macrophages), and IL-6 is currently under investigation (1010. Gupta S, Cortazar FB, Riella LV, et al. Immune checkpoint inhibitor nephrotoxicity: update 2020. Kidney360. 2020;1:130-140. [PMID: 35372904]). Urinary-level tumor necrosis factor-alpha and IL-9 have been found to be higher in patients with AIN compared to others with biopsied kidney pathology, such as acute tubular necrosis, diabetic nephropathy, or glomerulonephritis (1111. Moledina DG, Wilson FP, Pober JS, et al. Urine TNF-α and IL-9 for clinical diagnosis of acute interstitial nephritis. JCI Insight. 2019;4. [PMID: 31092735]).

Back to the case

The patient was diagnosed with AIN, grade I, and did not undergo kidney biopsy. He was treated with prednisone, 1 mg/kg, with plans to decrease by 10 mg every three days after two weeks of treatment. Lisinopril, omeprazole, and pembrolizumab were discontinued. Three days later, at discharge, his creatinine level was 2.22 mg/dL, his BUN level was 18.4 mg/dL, and his eGFR was 36 L/min/1.73 m². The complete blood count showed a reduction in absolute eosinophil count to 0.8 cells/mm³. Repeat urinalysis did not find any eosinophils. The patient was advised to follow up with oncology to discuss resuming pembrolizumab or trying an alternative agent.

Conclusion

With the increasing use of ICIs for the treatment of various cancers, clinicians should be vigilant for potential renal immunotoxicity, such as AIN. Early detection, differentiation from other etiologies of AKI, and guided treatment are the keys to better survival and outcome. Discontinuation of ICI agents and corticosteroid use remains the mainstay of treatment. Kidney biopsy is not always recommended. Inpatient management and nephrology consultation may be necessary based on the severity of renal injury.