Multiscale Mathematical Model of Drug-Induced Proximal Tubule Injury: Linking Urinary Biomarkers to Epithelial Cell Injury and Renal Dysfunction.

Drug-induced nephrotoxicity is a major cause of acute kidney injury, and thus detecting the potential for nephrotoxicity early in the drug development process is critical. Various urinary biomarkers exhibit different patterns following drug-induced injury, which may provide greater information than traditional biomarkers like serum creatinine. In this study, we developed a multiscale quantitative systems pharmacology model relating drug exposure to proximal tubule (PT) epithelial cell injury and subsequently to expression of multiple urinary biomarkers and organ-level functional changes. We utilized urinary kidney injury molecule-1 (Kim-1), alpha glutathione S-transferase, albumin (αGST), glucose, and urine volume time profiles as well as serum creatinine and histopathology data obtained from rats treated with the nephrotoxicant cisplatin to develop the model. Although the model was developed using single-dose response to cisplatin, the model predicted the serum creatinine response to multidose cisplatin regimens. Further, using only the urinary Kim-1 response to gentamicin (a nephrotoxicant with a distinctly different injury time course than cisplatin), the model detected and predicted mild to moderate PT injury, as confirmed with histopathology, even when serum creatinine was unchanged. Thus, the model is generalizable, and can be used to deconvolute the underlying degree and time course of drug-induced PT injury and renal dysfunction from a small number of urinary biomarkers, and may provide a tool to determine optimal dosing regimens that minimize renal injury.

Babesiosis and blood transfusion: flying under the radar.

Infectious agents of disease continue to plague transfusion medicine as an increasing number of pathogens are described that pose a potential blood safety risk. While the recent focus has been on newly emerged agents, several well-established pathogens provide timely reminders that other agents continue to pose threats, but invariably 'fly under the radar', thereby failing to elicit adequate measures to prevent their transmission by blood transfusion. Perhaps foremost among this group of agents are the Babesia spp., which have been known to cause human disease, in the USA, for close to 40 years. B. microti, B. divergens and several Babesia-like agents are responsible for a growing number of human babesiosis infections. Concomitantly, in the USA, there has been a sharp rise in the number of transfusion-transmitted infections of Babesia spp., attributable almost exclusively to B. microti. Despite the obvious public health issues posed by Babesia spp., options for preventing their transmission by blood transfusion remain limited. However, recognition that the Babesia spp. are indeed an ongoing and expanding blood safety threat will probably prove instrumental in the development of viable interventions to limit transmission of these agents.