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We sought to examine the relation between sodium bicarbonate prophylaxis for contrast-associated nephropathy (CAN) and mortality. We conducted an individual patient data meta-analysis from multiple randomized controlled trials. We obtained individual patient data sets for 7 of 10 eligible trials (2,292 of 2,764 participants). For the remaining 3 trials, time-to-event data were imputed based on follow-up periods described in their original reports. We included all trials that compared periprocedural intravenous sodium bicarbonate to periprocedural intravenous sodium chloride in patients undergoing coronary angiography or other intra-arterial interventions. Included trials were determined by consensus according to predefined eligibility criteria. The primary outcome was all-cause mortality hazard, defined as time from randomization to death. In 10 trials with a total of 2,764 participants, sodium bicarbonate was associated with lower mortality hazard than sodium chloride at 1 year (hazard ratio 0.61, 95% confidence interval [CI] 0.41 to 0.89, p = 0.011). Although periprocedural sodium bicarbonate was associated with a reduction in the incidence of CAN (relative risk 0.75, 95% CI 0.62 to 0.91, p = 0.003), there exists a statistically significant interaction between the effect on mortality and the occurrence of CAN (hazard ratio 5.65, 95% CI 3.58 to 8.92, p

Background: Blocking the mechanistic target of rapamycin complex-1 (mTORC1) with chemical inhibitors such as rapamycin has shown limited clinical efficacy in cancer. The tumor microenvironment is characterized by an acidic pH which interferes with cancer therapies. The consequences of acidity on the anti-cancer efficacy of mTORC1 inhibitors have not been characterized and are thus the focus of our study. Methods: Cancer cell lines were treated with rapamycin in acidic or physiological conditions and cell proliferation was investigated. The effect of acidity on mTORC1 activity was determined by Western blot. The anticancer efficacy of rapamycin in combination with sodium bicarbonate to increase the intratumoral pH was tested in two different mouse models and compared to rapamycin treatment alone. Histological analysis was performed on tumor samples to evaluate proliferation, apoptosis and necrosis. Results: Exposing cancer cells to acidic pH in vitro significantly reduced the anti-proliferative effect of rapamycin. At the molecular level, acidity significantly decreased mTORC1 activity, suggesting that cancer cell proliferation is independent of mTORC1 in acidic conditions. In contrast, the activation of mitogen-activated protein kinase (MAPK) or AKT were not affected by acidity, and blocking MAPK or AKT with a chemical inhibitor maintained an anti-proliferative effect at low pH. In tumor mouse models, the use of sodium bicarbonate increased mTORC1 activity in cancer cells and potentiated the anti-cancer efficacy of rapamycin. Combining sodium bicarbonate with rapamycin resulted in increased tumor necrosis, increased cancer cell apoptosis and decreased cancer cell proliferation as compared to single treatment. Conclusions: Taken together, these results emphasize the inefficacy of mTORC1 inhibitors in acidic conditions. They further highlight the potential of combining sodium bicarbonate with mTORC1 inhibitors to improve their anti-tumoral efficacy.