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

SIMPLE SUMMARY: To improve the treatment of patients with kidney disease, new renal replacement therapies are being developed. Prior to their use in humans with end-stage kidney disease (ESKD), these therapies need to be tested in animals with kidney disease. Goats seem particularly suitable because they are docile, have bodyweights comparable to humans and easily accessible neck veins to obtain blood access and tolerate frequent blood sampling, allowing for repeated monitoring. To obtain high blood concentrations of waste solutes that accumulate in patients with kidney disease and allow for the evaluation of solute removal by the new renal replacement therapies, we established kidney failure in five goats by partially blocking the blood supply of the kidneys via radiographic embolization. This resulted in stable moderate kidney disease. The administration of high-dose gentamicin caused a temporary further decline in kidney function. Although the response varied with animal, blood concentrations of waste solutes were representative of those found in ESKD patients. These animals can survive for more than ten months in good condition, allowing for the repetitive testing of new therapies in one animal, and therefore limiting the use of laboratory animals. 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.