Urate is a potent antioxidant at high concentrations but it has also been associated with a wide variety of health risks. Plasma urate concentration is determined by ingestion, production, and urinary excretion; however, factors that regulate urate excretion remain uncertain. The objective of this study was to determine whether cellular stress, which has been shown to affect other renal transport properties, modulates urate secretion in the avian renal proximal tubule. Chick kidney proximal tubule epithelial cell primary culture monolayers were used to study the transepithelial transport of radiolabeled urate. This model allowed examination of the processes, such as multidrug resistance protein 4 (Mrp4, Abcc4), which subserve urate secretion in a functional, intact, homologous system. Our results show that the recently implicated urate efflux transporter, breast cancer resistance protein (ABCG2), does not significantly contribute to urate secretion in this system. Exposure to a high concentration of zinc for 6 h induced a cellular stress response and a striking decrease in transepithelial urate secretion. Acute exposure to zinc had no effect on transepithelial urate secretion or isolated membrane vesicle urate transport, suggesting involvement of a cellular stress adaptation. Activation of AMP-activated protein kinase (AMPK), a candidate modulator of ATP-dependent urate efflux, by 5'-aminoimidazole-4-carboxamide 1-β-d-ribo-furanoside caused a decrease in urate secretion similar to that seen with zinc-induced cellular stress. This effect was prevented with the AMPK inhibitor compound C. Notably, the decrease in urate secretion seen with zinc-induced cellular stress was also prevented by compound C, implicating AMPK in regulation of renal uric acid excretion.
BackgroundSugammadex rapidly reverses deep neuromuscular blockade, but owing to cost,
questions remain about its optimal utilization. After the unrestricted
introduction of sugammadex at Emory University Hospital, we hypothesized
that reductions would be demonstrated in the primary outcome of
post-anesthesia care unit (PACU) mechanical ventilation (MV) and secondary
outcomes of PACU length of stay (LOS) and emergence time (surgery end to
anesthesia end time in the PACU).MethodsThis retrospective observational study included patients undergoing general
anesthesia over a 12-month period. Using multiple variable penalized
logistic regression in a one-group before-and-after design, we compared the
categorized rates of PACU MV to examine the effect of sugammadex
introduction following a post-hoc chart review to ascertain the reason for
postoperative MV. Additionally, multiple variable linear regression was used
to assess for differences in PACU LOS and emergence time within a
propensity-matched set of patients receiving neostigmine or sugammadex.ResultsIn total, 7,217 surgical cases met the inclusion criteria: 3,798 before and
3,419 after sugammadex introduction. The incidence of PACU MV was 2.3%
before and 1.8% after (P = 0.118) sugammadex introduction. PACU MV
due to residual neuromuscular blockade (rNMB) decreased from 0.63% to 0.20%
(P = 0.005). Ventilation because of other causes was unchanged. PACU
LOS and emergence time were unchanged in the propensity-matched set of 1,444
patients.ConclusionsrNMB was an important contributor to PACU MV utilization and its incidence
significantly decreased after sugammadex introduction. The selected
efficiency measures may not have been sufficiently granular to identify
improvements following introduction.
Plasma urate level is primarily regulated by urinary excretion, and ~70% of urate excretion is due to tubular secretion. Birds, which only secrete urate, and humans, which secrete and reabsorb, maintain similar normal urate concentrations (~300 μM). Tubular secretion includes basolateral entry via Oat1/3‐like transport and apical membrane exit via Mrp4 transport, but regulating factors in the pathway remain uncertain. In other systems, cellular stress has been shown to affect transport properties by altering both stress protein levels and transporter expression or activity. We have shown that prolonged zinc‐induced cell stress inhibited active transepithelial urate secretion by chicken renal proximal tubule epithelial cell monolayers (cPTCs) with no change in Mrp4 expression, glucose transport, or transepithelial resistance. Acute exposure of cPTCs to zinc had no effect, nor was there an effect of zinc on urate uptake by isolated brush border membrane vesicles, suggesting involvement of a cellular stress adaptation. AMPK, which responds to cellular stress by shutting down non‐vital ATP‐utilizing processes, may be linked to this stress adaptation. Activation of AMPK by AICAR decreased urate secretion by cPTCs similar to the effect seen with zinc. The AMPK inhibitor, Compound C, prevented both AICAR and zinc inhibition of urate secretion. Supported by NSF.
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