Understanding the Risk Factors and Long-Term Consequences of Cisplatin-Associated Acute Kidney Injury: An Observational Cohort Study.

Acute kidney injury (AKI) is a well-known complication of cisplatin-based chemotherapy; however, its impact on long-term patient survival is unclear. We sought to determine the incidence and risk factors for development of cisplatin-associated AKI and its impact on long-term renal function and patient survival. We identified 233 patients who received 629 cycles of high-dose cisplatin (99±9mg/m2) for treatment of head and neck cancer between 2005 and 2011. These subjects were reviewed for development of AKI. Cisplatin nephrotoxicity (CN) was defined as persistent rise in serum creatinine, with a concomitant decline in serum magnesium and potassium, in absence of use of nephrotoxic agents and not reversed with hydration. All patients were hydrated per protocol and none had baseline glomerular filtration rate (GFR) via CKD-EPI<60mL/min/1.73m2. The patients were grouped based on development of AKI and were staged for levels of injury, per KDIGO-AKI definition. Renal function was assessed via serum creatinine and estimated glomerular filtration rate (eGFR) via CKD-EPI at baseline, 6- and 12-months. Patients with AKI were screened for the absence of nephrotoxic medication use and a temporal decline in serum potassium and magnesium levels. Logistic regression models were constructed to determine risk factors for cisplatin-associated AKI. Twelve-month renal function was compared among groups using ANOVA. Kaplan-Maier curves and Cox proportional hazard models were constructed to study its impact on patient survival. Of 233 patients, 158(68%) developed AKI; 77 (49%) developed stage I, 55 (35%) developed stage II, and 26 (16%) developed stage III AKI. Their serum potassium and magnesium levels correlated negatively with level of injury (p<0.05). African American race was a significant risk factor for cisplatin-associated AKI, OR 2.8 (95% CI 1.3 to 6.3) and 2.8 (95% CI 1.2 to 6.7) patients with stage III AKI had the lowest eGFR value at 12 months (p = 0.05) and long-term patient survival (HR 2.1; p<0.01) than patients with no or lower grades of AKI. Most common causes of death were recurrent cancer (44%) or secondary malignancy elsewhere (40%). Cisplatin-associated severe AKI occurs in 20% of the patients and has a negative impact on long-term renal function and patient survival. PEG tube placement may be protective and should be considered in high risk-patients.

Magnetic resonance assessment of pulmonary (QP) to systemic (QS) flows using 4D phase-contrast imaging: pilot study comparison with standard through-plane 2D phase-contrast imaging.

RATIONALE AND OBJECTIVES: To investigate four-dimensional (4D) phase-contrast (PC) magnetic resonance (MR) in the evaluation of intracardiac shunts by simultaneous assessment of pulmonary (QP) and systemic (QS) flows in a pilot study and to compare results to through-plane two-dimensional (2D) PC MR. MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained. Nineteen patients with suspected intracardiac shunts underwent cardiac MR at 1.5T. Assessments of QP and QS were performed using free-breathing retrospectively gated 2D PC gradient recalled echo (GRE; 1.6 × 1.6 × 5 mm(3)) imaging with one-dimensional through-plane velocity encoding gradient (venc = 150 cm/s) in consecutive measurements for the main pulmonary artery (MPA) and ascending aorta (AA), respectively. A prospectively triggered 4D PC GRE technique (2.4 × 1.8 × 3 mm(3)) with three orthogonal venc directions was also used with volume coverage of both MPA and AA. RESULTS: QP and QS assessed by 4D PC correlated with 2D PC acquisitions (r = 0.92 and r = 0.67 respectively; P < .0001 for both) but demonstrated significant underestimation of individual flow volumes (-21.9 ± 12.2 mL; P < .0001 and -10.7 ± 13.1 mL; P = .0023, respectively). Calculated QP:QS ratios demonstrated high correlation (r = 0.78; P < .0001) and no significant differences between 4D PC and 2D PC acquisitions (-0.09 ± 0.24, P = .14). Image acquisition times for 2D PC assessment of QP and QS were 2.98 ± 0.52 and 2.84 ± 0.50 minutes, respectively (P = .038), whereas time to acquire 4D PC images was significantly longer, 18.75 ± 4.58 minutes (P < .001). CONCLUSIONS: Four-dimensional PC MR imaging allows for accurate assessment of QP:QS ratios in the evaluation of intracardiac shunts while absolute flow volumes demonstrate offsets. Further refinement of the technique with improvement in acquisition times may be required before widespread clinical implementation.

Cytotoxic effects of polychlorinated biphenyl hydroquinone metabolites in rat hepatocytes.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that exhibit various toxic effects in animals and exposed human populations. The molecular mechanisms of PCB toxicity have been attributed to the toxicological properties of its metabolites, such as hydroquinones, formed by cytochrome-P-450 oxidation. The effects of PCB hydroquinone metabolites towards freshly isolated rat hepatocytes were investigated. Hydroquinones can be oxidized to semiquinones and/or quinone metabolites. These metabolites can conjugate glutathione or can oxidize glutathione as a result of redox cycling. This depletes hepatocyte glutathione, which can inhibit cellular defence mechanisms, causing cell death and an increased susceptibility to oxidative stress. However in the following, glutathione-depleted hepatocytes became more resistant to the hydroquinone metabolites of PCBs. This suggested that their glutathione conjugates were toxic and that there was a third type of quinone toxicity mechanism which involved a hydrogen peroxide-accelerated autoxidation of the hydroquinones to form toxic electrophilic quinone and semiquinone-glutathione conjugates.