Dotted lines represent baseline of creatinine and sodium, respectively

Dotted lines represent baseline of creatinine and sodium, respectively. Discussion Immune checkpoint blockade produces potentially durable responses in a subset of patients with metastatic melanoma [1] and may be associated with a myriad of irAEs, including colitis, hepatitis, pneumonitis, hypophysitis, and rash, among others [1,2]. blockade (ICB) Elobixibat can lead to deep responses in a significant subset of melanoma patients [1], and associated immune related adverse events (irAEs) and their management have become increasingly well characterized [2,3]. Efforts to combine ICB with targeted RAF/MEK inhibitors aim to leverage the frequently rapid responses to RAF/MEK inhibitors with potentially durable responses to ICB in the hope of achieving long-term responses in more patients. However, how these combination therapies change the landscape of adverse Tlr2 effects remains poorly understood. Here, we describe the emergence of rapid onset acute kidney injury as a sentinel irAE, an otherwise infrequent irAE, in a patient with metastatic melanoma concurrently treated with ICB and RAF/MEK inhibitors. This case highlights the need to consider the potentiation of toxicity when combining ICB and targeted therapies as a shifting therapeutic landscape moves towards using combination regimens. Case presentation A 67-year-old woman with a remote history of a resected dysplastic nevus of the chest wall presented with Elobixibat a painless axillary lump. An ultrasound demonstrated a mass measuring about 6 cm. A fine-needle aspiration was performed, and pathological examination and immunohistochemistry were consistent with melanoma; targeted sequencing of BRAF revealed a typical BRAFV600E mutation. A CT Elobixibat of the chest, abdomen, and pelvis demonstrated numerous metastatic lesions in the lung, liver, and spleen. An MRI of the brain was negative for brain metastases. She was initially treated on a clinical protocol with ipilimumab and bevacizumab but progressed 2 months later with a pathologic humerus Elobixibat fracture. She was, therefore, switched to RAF/MEK inhibitor (RMi) therapy with dabrafenib and trametinib. Interval imaging at 4 and 12 months of treatment demonstrated a significant partial response in all lesions. After 16 months of treatment, a CT of the torso showed persistent disease involving the spleen and liver. Following several discussions about the potential benefits and adverse effects of adding concurrent immune checkpoint blockade prior to the clinical development of RMi resistance, which may be associated with reduced sensitivity to anti-CTLA-4/anti-PD-1 therapy, we initiated therapy with pembrolizumab. About 10 days after the first infusion of pembrolizumab, she presented to the clinic with exertional dyspnea, bilateral lower extremity edema, and a 15-pound weight gain. Laboratory workup was significant for acute kidney injury with a serum creatinine of 3.0 mg/dl (from baseline of 1 1.0 mg/dl), blood urea nitrogen of 41 mg/dl, and new hyponatremia with a sodium of 125 mEq/L. Her volume overload was thought to be secondary to her acute kidney injury; she had a newly elevated NT-pro-BNP to 4198, an albumin of 2.6 mg/dl which was consistent with her baseline, trans-thoracic echocardiography was significant for a normal left ventricular ejection fraction of 55% and no evidence of diastolic dysfunction, and her liver function tests were normal. Urine electrolytes demonstrated a fractional excretion of sodium of Elobixibat 5.3%, and urinalysis and urine sediment showed only trace granular casts. Serum osmolarity was 278 mOsm/kg, urine sodium 64 mEq/L, and urine osmolarity 307 mOsm/kg. A workup for endocrinological etiologies, including thyroid stimulating hormone and free T4, and fasting AM cortisol was unrevealing. Hence, her hyponatremia was thought to be secondary to syndrome of inappropriate antidiuretic hormone, with possible additional contribution of intrinsic renal failure. She was admitted to the hospital and received one dose of IV furosemide (20 mg) and was placed on a 2 L free water restriction. RMi therapy was held. However, her creatinine continued to rise to a maximum of 4.8 mg/dl, raising concern for progressive renal failure. On day 6 of admission, an empiric trial of prednisone 50 mg twice daily was initiated.