Abstract Introduction Renal cell carcinoma (RCC) is the most common kidney cancer in adults, originating from the renal tubular epithelium and accounting for approximately 85% of all kidney malignancies. Up to 90% of clear cell RCC cases involve mutations in the von Hippel-Lindau (VHL) gene. VHL acts as a tumor suppressor by targeting hypoxia-inducible factors (HIFs) for degradation under normoxia. Loss of VHL leads to accumulation of HIF-2α, which promotes angiogenesis, tumor growth, and cell survival. Belzutifan, a selective HIF-2α inhibitor, was developed to block this dysregulated pathway and has demonstrated efficacy in both hereditary and sporadic RCC. Description A 55-year-old man with metastatic RCC, partial nephrectomy, asthma, hx of multi-organism pneumonia infections (pseudomonas, Rhizopus, and mycobacterium avium complex), and bronchiectasis presented for elective liver biopsy. Although he experienced chronic resting hypoxia (SpO2 84-88%), he declined home oxygen therapy to maintain eligibility for clinical trials and was still able to perform daily activities. He had no history of febrile illness, chest pain, cough, airway obstruction or volume overload. On arrival, SpO2 was 84%. He was intubated for biopsy, but after extubation, desaturated to the 60s. He was placed on high-flow nasal cannula (60% FiO2/40 LPM), improving saturation to 87-91%. Workup included chest CT, sputum cultures, and viral panel was negative. Empiric Zosyn was started for possible pneumonia. In the absence of a clear infectious or structural cause, Belzutifan was held in coordination with oncology. The patient was discharged on 4L/min home oxygen with outpatient follow-up and consideration for therapy resumption. Discussion Belzutifan, a HIF-2α inhibitor, can cause hypoxia by impairing the body’s adaptive response to low oxygen levels, including suppression of erythropoietin production and blunting of cellular hypoxia signaling. This may lead to anemia and reduced tissue oxygenation, particularly in patients with pre-existing pulmonary or metastatic disease. This case highlights the diagnostic complexity of hypoxia in patients with extensive oncologic and pulmonary history. Belzutifan-induced hypoxia, although rare, should be considered in the differential, particularly after exclusion of infectious or structural causes. This abstract is funded by: None
Mehdi et al. (Fri,) studied this question.