Files
Abstract
Chronic kidney disease (CKD), a prevalent metabolic disorder in aged companion animals, is irreversible and progressive. Proteinuria, chronic renal hypoxia, and maladaptive stimulation of the renin-angiotensin-aldosterone system (RAAS) are among the most widely cited mechanisms for the intrinsic progression of CKD. Nevertheless, significant knowledge gaps exist in the role of these factors in canine and feline CKD.Glomerular disease, a common cause of canine CKD, is classically associated with proteinuria, the magnitude of which is positively correlated with hastened progression of CKD, increased risk for uremic crises, and renal and all-cause mortality. Antagonism of the RAAS is a crucial part of antiproteinuric therapy; however, angiotensin-converting enzyme inhibitors (ACEi) are not universally efficacious. In a prospective, double-masked, randomized clinical trial that evaluated dogs with persistent renal proteinuria, we showed that compared to an ACEi, the angiotensin receptor blocker telmisartan led to greater reduction of proteinuria, offering promise as a first-line therapy.In contrast to dogs, the majority of cats with CKD are affected by primary lesions of the tubulointerstitial compartment, with fibrosis and inflammation developing from the early stages. Chronic renal hypoxia is a described cause and consequence of tubulointerstitial fibrosis, activating numerous pro-inflammatory and pro-fibrotic pathways. Our work demonstrates upregulation in the transcription of specific fibrosis mediators, including members of the matrix metalloproteinase family, hypoxia-inducible factor and transforming growth factor, in both ischemia-induced and naturally-occurring feline CKD.While inappropriate activation of the RAAS is well-defined in CKD of many non-feline species, data from cats offer conflicting results. Here, we not only document upregulation of intrarenal renin-angiotensin system (RAS) components in experimentally-induced and naturally-occurring feline CKD, but also show that markers of the circulating RAAS are inconsistently correlated with those of the intrarenal RAS in feline CKD models and healthy cats. Therefore, as in other mammals, regulation of tissular RAS appears to be independent of that of its circulating counterpart.Collectively, our studies provide valuable evidence to guide refinement of antiproteinuric therapy in dogs, and advance our knowledge of the pathophysiology underlying feline CKD progression, identifying new candidate biomarkers and therapeutic targets for renal disease in cats.