A Boolean Model of Microvascular Rarefaction to Predict Treatment Outcomes in Renal Disease

Erika Williams,Alejandro R Chade

doi:10.1038/s41598-019-57386-8

Erika Williams, Alejandro R Chade

Open Access

https://doi.org/10.1038/s41598-019-57386-8

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Abstract

Despite advances in renovascular disease (RVD) research, gaps remain between experimental and clinical outcomes, translation of results, and the understanding of pathophysiological mechanisms. A predictive tool to indicate support (or lack of) for biological findings may aid clinical translation of therapies. We created a Boolean model of RVD and hypothesized that it would predict outcomes observed in our previous studies using a translational swine model of RVD. Our studies have focused on developing treatments to halt renal microvascular (MV) rarefaction in RVD, a major feature of renal injury. A network topology of 20 factors involved in renal MV rarefaction that allowed simulation of 5 previously tested treatments was created. Each factor was assigned a function based upon its interactions with other variables and assumed to be “on” or “off”. Simulations of interventions were performed until outcomes reached a steady state and analyzed to determine pathological processes that were activated, inactivated, or unchanged vs. RVD with no intervention. Boolean simulations mimicked the results of our previous studies, confirming the importance of MV integrity on treatment outcomes in RVD. Furthermore, our study supports the potential application of a mathematical tool to predict therapeutic feasibility, which may guide the design of future studies for RVD.

Highlights

Major advances in nephrology research have been achieved thanks to numerous experimental studies that have elucidated underlying mechanisms of deteriorating renal function and identified therapeutic targets with potential for clinical translation
Such findings support the importance of the renal MV integrity for renal function in renovascular disease (RVD), and suggest a network of numerous factors that are part of a vicious cycle driving progressive MV rarefaction that may contribute to the declining renal function
It should be noted that, for this Boolean model of MV rarefaction in RVD, we are interested in simulating the outcomes of therapies previously tested only in our experimental swine model of RVD

Summary

Introduction

Major advances in nephrology research have been achieved thanks to numerous experimental studies that have elucidated underlying mechanisms of deteriorating renal function and identified therapeutic targets with potential for clinical translation. We showed that inhibition of factors involved in oxidative stress, inflammation, and vasoconstriction, and stimulation of angiogenic signaling in RVD improved stenotic kidney hemodynamics, fibrosis, and associates with preserved MV architecture (Fig. 1)[7,8,12,13,14,15,16,17,18,19,20] Such findings support the importance of the renal MV integrity for renal function in RVD, and suggest a network of numerous factors that are part of a vicious cycle driving progressive MV rarefaction that may contribute to the declining renal function.

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