Acute Kidney Injury (AKI) is an independent risk factor for mortality in hospitalized patients. AKI syndrome leads to fluid overload, electrolyte and acid-base disturbances, immunoparalysis, and propagates multiple organ dysfunction through organ “crosstalk”. Preclinical models suggest AKI causes acute lung injury (ALI), and conversely, mechanical ventilation and ALI cause AKI. In the clinical setting, respiratory complications are a key driver of increased mortality in patients with AKI, highlighting the bidirectional relationship. This article highlights the challenging and complex interactions between the lung and kidney in critically ill patients with AKI and acute respiratory distress syndrome (ARDS) and global implications of AKI. We discuss disease-specific molecular mediators and inflammatory pathways involved in organ crosstalk in the AKI-ARDS construct, and highlight the reciprocal hemodynamic effects of elevated pulmonary vascular resistance and central venous pressure (CVP) leading to renal hypoperfusion and pulmonary edema associated with fluid overload and increased right ventricular afterload. Finally, we discuss the notion of different ARDS “phenotypes” and the response to fluid overload, suggesting differential organ crosstalk in specific pathological states. While the directionality of effect remains challenging to distinguish at the bedside due to lag in diagnosis with conventional renal function markers and lack of tangible damage markers, this review provides a paradigm for understanding kidney-lung interactions in the critically ill patient.
Significant ingestion of anticholinergic substances is often fatal. This case describes a favorable outcome after ECPR and aggressive supportive management following a large intentional overdose of diphenhydramine.
Clearance (CL) prediction remains a significant challenge in drug discovery, especially when complex processes such as drug transporters are involved. The present work explores various in vitro to in vivo extrapolation (IVIVE) approaches to predict hepatic CL driven by uptake transporters in rat. Broadly, two different IVIVE methods using suspended rat hepatocytes were compared: initial uptake CL (PS u,inf ) and intrinsic metabolic CL (CL int,met ) corrected by unbound hepatocytes to media partition coefficient (Kp uu ). Kp uu was determined by temperature method (Temp Kp uu,ss ), homogenization method (Hom Kp uu,ss ), and initial rate method (Kp uu,V0 ). In addition, impact of albumin (BSA) on each of these methods was investigated. Twelve compounds, which are known substrates of organic anion-transporting polypeptides (OATP) representing diverse chemical matter, were selected for these studies. As expected, CL int,met alone significantly underestimated hepatic CL for all the test compounds. Overall, predicted hepatic CL using PS u,inf with BSA, Hom Kp uu,ss with BSA and Temp Kp uu,ss showed the most robust correlation with in vivo rat hepatic CL. Adding BSA improved hepatic CL prediction for selected compounds when using PS u,inf and Hom Kp uu,ss methods, with minimal impact on Temp Kp uu,ss and Kp uu,V0 methods. None of the IVIVE approaches required empirical scaling factor. These results suggest that supplementing rat hepatocyte suspension with BSA may be essential in discovery research for novel chemical matters to improve CL prediction.
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