A Case Report of Severe Type B Lactic Acidosis Following First Dose of Nivolumab in a VHL-Mutated Metastatic Renal Cell Carcinoma

Abstract

We report a case of severe type B lactic acidosis (LA) in a 51-year-old male, 12 days after he received his first dose of nivolumab for metastatic Von Hippel Lindau (VHL)-mutated, clear cell renal cell carcinoma. Throughout his hospital course, infection, hypoperfusion, and tissue necrosis were not identified. We propose that his LA may have resulted from either inherent tumor glycolysis or immune activation and enhanced metabolism. The patient's course was complicated by acute renal failure, and his LA rose progressively, eventually necessitating daily hemodialysis (HD). After receiving five consecutive days of HD, the patient started everolimus daily with the intent of reducing glycolytic metabolism. Subsequently, the rate of lactic acid production slowed, and HD was no longer required after two doses of everolimus. To our knowledge, this is the first reported case of type B LA following nivolumab administration, and the use of everolimus to treat type B LA in a patient with renal cancer.

Keywords: Renal cell carcinoma; acidosis; everolimus.

Fig.1

Axial, coronal, and sagittal CT images of the patient’s abdomen and pelvis revealing metastatic disease at different time points during his therapy. A. Prior to sunitinib and gemcitabine therapy. B. After sunitinib and gemcitabine therapy, prior to nivolumab therapy and one month prior to admission. C. 47 days after admission. Image shown after nivolumab and during everolimus therapy. Overall response was mixed as compared to prior to everolimus therapy.

Fig.2

Lactic acid and bicarbonate levels during hospitalization. Lactic acid trend is shown in red, while bicarbonate levels are shown in black. Time zero represents time of admission. * represents a four-hour hemodialysis session. + represents administration of daily everolimus 10 mg.

Fig.3

Potentials sources of lactic acid production. A. Activated T-cells, such as those stimulated an anti-PD-1 antibody such as nivolumab, are known to have increased glycolysis, leading to lactic acid production via lactate dehydrogenase (LDH). Lactic acid is exported from the cell via a monocarboxylase transporter (MCT) B. Alternatively, in clear cell RCC cells, Von Hippel Lindau (VHL) mutated tumor cells lose their ability to degrade hypoxia induced factor (HIF). The accumulation of HIF promotes anaerobic glycolysis, which produces lactic acid as an end product. mTOR signaling enhances anaerobic glycolysis further, increasing the localization of glucose transporters (Glut1) to the cell membrane for more efficient glucose uptake. Everolimus, the mammalian target of rapamycin (mTOR) inhibitor, blocks HIF translation, promotes the degradation of HIF via the proteasome, and limits glucose importation from glucose transporters, culminating in decreased glycolysis.