A Uremic Goat Model Created by Subtotal Renal Artery Embolization and Gentamicin

Abstract

A large animal model of (end-stage) kidney disease (ESKD) is needed for the preclinical testing of novel renal replacement therapies. This study aimed to create stable uremia via subtotal renal artery embolization in goats and induce a temporary further decline in kidney function by administration of gentamicin. Renal artery embolization was performed in five Dutch white goats by infusing polyvinyl alcohol particles in branches of the renal artery, aiming for the embolization of ~80% of one kidney and complete embolization of the contralateral kidney. Gentamicin was administered to temporarily further increase the plasma concentrations of uremic toxins. After initial acute kidney injury, urea and creatinine plasma concentrations stabilized 1.5 ± 0.7 months post-embolization and remained elevated (12 ± 1.4 vs. 5.6 ± 0.8 mmol/L and 174 ± 45 vs. 65 ± 5.6 µmol/L, resp.) during follow-up (16 ± 6 months). Gentamicin induced temporary acute-on-chronic kidney injury with a variable increase in plasma concentrations of small solutes (urea 29 ± 15 mmol/L, creatinine 841 ± 584 µmol/L, phosphate 2.2 ± 0.3 mmol/L and potassium 5.0 ± 0.6 mmol/L) and protein-bound uremic toxins representative of patients with ESKD. A uremic goat model characterized by stable moderate uremia was established via subtotal renal artery embolization with the induction of temporary severe acute-on-chronic kidney injury by the administration of gentamicin, allowing preclinical in vivo validation of novel renal replacement technologies.

A robust, accurate, sensitive LC–MS/MS method to measure indoxyl sulfate, validated for plasma and kidney cells

“…We observed a distinct baseline level of plasma IS concentration among different species, but these levels are comparable to previously reported studies with human (Imazu et al, 2020 ; Poesen et al, 2015 ), goat (van Gelder et al, 2021 ), rat (Aoyama et al, 2002 ; Kikuchi et al, 2010 ), and mouse (Hung et al, 2016 ; Mishima et al, 2018 ). IS concentration in pig plasma has not been reported earlier.…”

Renal Embolization-Induced Uremic Swine Model for Assessment of Next-Generation Implantable Hemodialyzers

“…Recently, a similar endovascular nephrectomy protocol has been used to induce uremia in swine for the study of novel peritoneal dialysis therapies [ 22 ]. The same group has also developed an acute-on-chronic goat model of kidney injury using a combination of endovascular nephrectomy and gentamicin-induced kidney injury with animals surviving for 10 months; a procedure which may be advantageous for studying chronic dialysis therapies [ 23 ]. In our protocol, we found that a staged approach results in a state of renal failure manageable with initial daily hemodialysis for one week, followed by hemodialysis every 2–3 days, and allows the animals to stay healthy for at least one month (see Table 1 for detailed comparison of the surgical approaches).…”

“…An ideal model should replicate human renal physiology and anatomy, induce stable renal failure while remaining compatible with standard hemodialysis techniques, and preserve surgical anatomy for implantation of experimental RRT devices. Animal models with some of these characteristics have been established in swine, sheep, and goats [ 21 , 22 , 23 , 24 ]. Specifically in swine, several models have been developed to induce acute and chronic renal failure via surgery, ischemia-reperfusion (IR) injury, sepsis, nephrotoxic drugs, and combinations these modalities.…”