A Single-Center Retrospective Study of Acute Kidney Injury Incidence in Patients With Advanced Malignancies Treated With Antimitochondrial Targeted Drug

Abstract

Introduction: Mitochondrial dysfunction plays an important role in the pathophysiology of kidney disease. Inhibitors of mitochondrial metabolism are being developed for the treatment of solid organ and hematologic malignancies. We describe the incidence and clinical features of acute kidney injury (AKI) in patients treated with the antimitochondrial drug CPI-613.

Methods: We identified 33 patients with relapsed or refractory malignancy, previously enrolled in 3 open-label phase II studies, who received single-agent CPI-613 chemotherapy. AKI was defined by the Kidney Disease Improving Global Outcomes serum creatinine criteria. Participants were followed for a median (25th-75th percentile) of 120.0 (74.0-301.0) days. Risk factors for AKI were assessed by proportional hazards regression using univariate and multivariate analyses.

Results: Participants had baseline mean (SD) age of 63.8 (11.6) years and serum creatinine 0.9 (0.3) mg/dl. AKI developed in 9 (27%) patients; chart review failed to identify a potential cause of AKI other than CPI-613 administration in 5 (15%) patients, of whom 1 had AKI stage 1, 1 had AKI stage 2, and 3 experienced AKI stage 3. Time from initiation of CPI-613 treatment to AKI was 51.0 (16.0-58.0) days. Age, per 5-year increase, was associated with higher risk of AKI (adjusted hazard ratio 2.01, 95% confidence interval 1.06-3.79, P = 0.03). Follow-up serum creatinine was available in 4 participants 174.8 (139.6) days after the episode of AKI; 3 patients had complete recovery in kidney function and 1 had partial recovery.

Conclusion: AKI is a possible complication during treatment with mitochondria-targeted chemotherapy.

Keywords: CPI-613; acute kidney injury; antimitochondrial therapy; chemotherapy; mitochondria.

Graphical abstract

Figure 1

Serum creatinine trend over time in 4 patients who developed unexplained acute kidney injury (AKI). Urine studies obtained at the time of AKI were available in 3 patients. Urine microscopy red blood cell count per high power field (RBC/hpf), white blood cell count per high power field (WBC/hpf), and dipstick urine albumin (albumin mg/dl) or spot urine protein-to-creatinine ratio (UPCR mg/g) were as follows: 4 to 8 RBC/hpf, 0 to 5 WBC/hpf, UPCR 1046 mg/g (red line); 0 to 3 RBC/hpf, 0 to 5 WBC/hpf, albumin 300 mg/dl with specific gravity 1024 (green line); and 0 to 3 RBC/hpf, 0 to 5 WBC/hpf, albumin negative (orange line).

Figure 2

Schematic of hypothetical mechanism for CPI-613–induced kidney injury. Under physiologic conditions, the tricarboxylic acid (TCA) cycle is coupled with oxidative phosphorylation in the mitochondria to generate adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and inorganic phosphate. Most fuel molecules enter the TCA cycle as acetyl coenzyme A (Acetyl-CoA); glutamine may also enter the TCA cycle by converting into α-ketoglutarate. Reactive oxygen species (ROS) form as a byproduct of mitochondrial cellular respiration. At low levels, mitochondrial ROS have physiological functions by regulating cellular proliferation and cellular survival in response to stress conditions. We hypothesize 2 synergistic mechanisms through which CPI-613 can lead to kidney injury: increased ROS and ammonia (NH₄⁺) production. Inhibition of α-ketoglutarate dehydrogenase (KGDH) by CPI-613 leads to excess ROS production, which in turn causes cellular damage by inducing nuclear and mitochondrial DNA damage and promoting cell apoptosis. These effects are desirable within neoplastic cells, but are deleterious for the surviving nephrons. Furthermore, TCA cycle inhibition with CPI-613 may increase glutamine flux through the mitochondrial pathway and promotes ammoniagenesis. The process of ammoniagenesis occurs throughout most tubular epithelial cells from glutamine metabolism, which produces 2 NH₄⁺ for each glutamine metabolized. Excess NH₄⁺ production can lead to tubulointerstitial injury via alternative complement pathway activation and increased endothelin-1 levels in the kidneys. Increased NH₄⁺ levels within renal tubular epithelial cells may increase the susceptibility to ROS-mediated cellular damage, creating an amplification loop of cellular toxicity. FAD, flavin adenine dinucleotide; FADH₂, flavin adenine dinucleotide high-energy electron carrier; NAD, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide high-energy electron carrier; PDH, pyruvate dehydrogenase; SDH, succinate dehydrogenase.