Hemodynamic Consequences of Cisplatin‐Induced Acute Proximal Tubular Injury: A Mathematical Modeling Analysis
Authors: Gebremichael Yeshitila , Lu James , Shankaran Harish , Helmlinger Gabriel , Mettetal Jerome , Hallow Melissa 
Published: November 2023

In the kidney, proximal tubule (PT) epithelial cells (EpCs) are highly exposed to drugs and chemicals filtered through the glomerulus, making them vulnerable to drug‐induced toxicity and acute kidney injury (AKI). In AKI, PT EpCs suffer damage ranging from mild sub‐lethal changes such as loss of brush borders to catastrophic necrotic death. Rapid decline in glomerular filtration rate (GFR) is the hallmark of AKI. The pathophysiologic mechanisms by which drug‐ induced PT EpC injury ultimately leads to impaired filtration are complex and incompletely understood, but likely involve hemodynamic, intrinsic, and neurohumoral feedback mechanisms.Given the multiple feedbacks involved in AKI, mathematical modeling of renal function and feedback mechanisms can be a useful tool for understanding this complexity. In addition, newer biomarkers such as Kim‐1 and αGST provide greater information and temporal precision for measuring the extent and type of drug‐induced PT injury as compared to serum creatinine, a traditional biomarker of renal function. The aim of this study was to utilize mathematical modeling, coupled with time course data from multiple biomarkers, to gain insights on the intermediate pathophysiologic mechanisms linking PT EpC injury to impaired GFR. To this end, we developed a multi‐scale model of drug‐induced PT EpC injury and renal systemic hemodynamics. At the cellular level, structural and functional integrity was linked to PT EpC capacity for reabsorbing sodium, glucose, and albumin; cell injury or death impairs these functions. At the organ and systems level, processes of renal filtration, reabsorption and excretion were modeled dynamically, which ultimately impact body sodium and water balance and blood pressure; furthermore, key intrinsic and neurohumoral feedback mechanisms such as tubuloglomerular feedback (TGF) and the renin‐angiotensin‐aldosterone‐system (RAAS) were included. This model structure allowed simulation of consequences of PT EpC injury on renal and systemic hemodynamics.To inform the model parameters, we utilized time profiles of multiple urinary biomarkers (KIM‐1, αGST, albumin, glucose, and urine volume), from rats treated with cisplatin. At the cellular level, urinary KIM‐1 and αGST signals were used to inform the magnitude and time‐course of cell injury and necrosis following cisplatin exposure, and the model was able to reproduce observed changes in urinary water, albumin, and glucose excretion. The model also captured the suppression in GFR resulting from impaired PT EpC function. The model demonstrated that the reduction in GFR occurs as a result of: a) increased Bowman's pressure; b) renal vascular effects of the RAAS and TGF leading to suppressed intraglomerular pressure; c) systemic consequences of excess sodium and water excretion leading to suppressed renal perfusion pressure. This work increases our understanding and ability to quantitatively relate kidney function with biomarker changes. Going forward, the model can be used to evaluate AKI in humans and explore consequences of patient characteristics (e.g., preexisting renal impairment) on the renal hemodynamic response to drug‐induced PT injury.Support or Funding InformationAstraZeneca Pharmaceuticals