Translational Traits of a Swine Model of CKD: Inflammation

Abstract

The cardiovascular and renal anatomy and physiology of the pig are virtually identical to humans. We recently developed a model of CKD induced by dietary dyslipidemia and bilateral renal artery stenosis in pigs that develops a sustained decrease in renal function (comparable to CKD stage 2) and progressive parenchymal injury. Inflammation plays a role in the increased cardiovascular and all‐cause mortality in CKD and may precede renal fibrosis. Thus, we aim to characterize inflammation in CKD using markers shared by human and pigs to support the translational traits of the model.Ten pigs were divided into either normal or CKD (n=5 each). CKD/sham was induced and pigs observed for 14 weeks. Blood pressure was continuously measured by telemetry. Total RBF and GFR were quantified in vivo using multi‐detector CT. Blood and urine were collected, then pigs were euthanized and ex vivo studies performed to quantify plasma creatinine, blood urea nitrogen (BUN), renal injury markers kidney injury molecule 1 (KIM‐1) and neutrophil gelatinase associated lipocalin (NGAL) (urine, ELISA), renal inflammation (total macrophages, pro‐inflammatory M1‐IDO‐ and anti‐inflammatory M2‐MRC1‐subpopulations) and fibrosis (trichrome)Following fourteen weeks of CKD, pigs showed reduced RBF, GFR, hypertension, elevated plasma creatinine and BUN. These were associated with elevated urinary KIM‐1 and NGAL, inflammation (indicated by significant M1‐IDO+ macrophage infiltration over M2‐MRC1), and fibrosis (Figure).The decline in renal function associated with significant macrophage infiltration and increased markers of renal injury. KIM‐1 and NGAL have been suggested to initially attenuate inflammation and promote a pro‐repair M2 macrophage phenotype. However, they may have been insufficient to prevent the shift towards pro‐inflammatory M1s in our model, suggesting prolonged imbalance between inflammation and repair beyond the acute phase of renal injury. The use of markers shared by pigs and humans underscored the translational potential of this model for CKD research as a feasible platform to study and possibly target inflammation.Support or Funding InformationSupport: AHA‐18490005 and intramural grant UMMC to ARC.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.