Early Detection of Drug-Induced Renal Hemodynamic Dysfunction Using Sonographic Technology in Rats

Abstract

The kidney normally functions to maintain hemodynamic homeostasis and is a major site of damage caused by drug toxicity. Drug-induced nephrotoxicity is estimated to contribute to 19-25% of all clinical cases of acute kidney injury (AKI) in critically ill patients. AKI detection has historically relied on metrics such as serum creatinine (sCr) or blood urea nitrogen (BUN) which are demonstrably inadequate in full assessment of nephrotoxicity in the early phase of renal dysfunction. Currently, there is no robust diagnostic method to accurately detect hemodynamic alteration in the early phase of AKI while such alterations might actually precede the rise in serum biomarker levels. Such early detection can help clinicians make an accurate diagnosis and help in in decision making for therapeutic strategy. Rats were treated with Cisplatin to induce AKI. Nephrotoxicity was assessed for six days using high-frequency sonography, sCr measurement and upon histopathology of kidney. Hemodynamic evaluation using 2D and Color-Doppler images were used to serially study nephrotoxicity in rats, using the sonography. Our data showed successful drug-induced kidney injury in adult rats by histological examination. Color-Doppler based sonographic assessment of AKI indicated that resistive-index (RI) and pulsatile-index (PI) were increased in the treatment group; and peak-systolic velocity (mm/s), end-diastolic velocity (mm/s) and velocity-time integral (VTI, mm) were decreased in renal arteries in the same group. Importantly, these hemodynamic changes evaluated by sonography preceded the rise of sCr levels. Sonography-based indices such as RI or PI can thus be useful predictive markers of declining renal function in rodents. From our sonography-based observations in the kidneys of rats that underwent AKI, we showed that these noninvasive hemodynamic measurements may consider as an accurate, sensitive and robust method in detecting early stage kidney dysfunction. This study also underscores the importance of ethical issues associated with animal use in research.

An Activatable Near-Infrared Fluorescence Probe for in Vivo Imaging of Acute Kidney Injury by Targeting Phosphatidylserine and Caspase-3

“…Current clinical diagnostic methods mainly rely on the measurement of serum creatinine (CR) and blood urea nitrogen (BUN), which are insensitive and incapable of accurately diagnosing AKI at the early stage as obvious changes in the levels of CR and BUN can only occur at the loss of about 75% of functional nephrons. 10 Though traditional imaging methods such as computed tomography, 11 magnetic resonance imaging, 12 and ultrasound imaging 13 have been useful for AIK diagnosis mainly via noninvasive in vivo imaging of the changes in anatomy and histology of the kidneys, the lack of detecting AKI-associated biomarkers at the molecular level has impeded the ability for the early diagnosis of AKI. Recently, molecular optical imaging 14−18 that allows high sensitivity, low cost, and facile operation has shown promise for AKI diagnosis.…”

Biomarkers Versus Duplex Ultrasonography for Early Detection of Acute Kidney Injury in Dogs: An Experimental Study

“…In the present study, the increase of RI was parallel with the increase of serum creatinine after the third day of infusion. In another study on mice, the renal RI precedes the serum creatinine in a diagnosis of AKI after cisplatin infusion (12). However, there are some limitations for using RI in the diagnosis of all kidney diseases because it is affected by other hemodynamic disorders rather than in kidney as well as the difficulty of measuring RI without sedation of dogs which affected on its measurement (10,12).…”

“…Moreover, it can differentiate transient from persistent AKI in critically ill patients (10,11). Recently, it was reported that an increase in the renal RI is an accurate and sensitive tool for early prediction of AKI in rats (12).…”

Sex-specific differences in endoplasmic reticulum aminopeptidase 1 modulation influence blood pressure and renin-angiotensin system responses

“…Renal blood flow measurement with noninvasive Doppler ultrasound. Pulse-wave Doppler ultrasound was performed at the Cardiovascular Physiology Core at Brigham and Women's Hospital as previously described (40). Briefly, all animals were acclimatized overnight before experimental procedures were performed.…”