Abstract
Objective
To compare urinary angiotensinogen, a proposed biomarker for intrarenal renin-angiotensinogen system (RAS) activity, between cats with surgically induced chronic kidney disease (CKD) and healthy cats and explore its correlation with select clinical and circulating renin-angiotensin-aldosterone system (RAAS) markers.
Methods
Urine was banked from September 2022 through April 2023 during a study comparing circulating RAAS markers between cats with induced CKD and sex- and life stage–matched healthy cats. Urinary angiotensinogen concentration was measured from October 2025 through July 2026 using a validated in-house ELISA. Urinary concentration of angiotensinogen was indexed to that of creatinine or protein to account for urine concentration or indiscriminate urinary protein loss, respectively.
Results
28 cats (n = 14/group) were included. The median (IQR) indexed urinary angiotensinogen was higher in cats with CKD than in healthy cats (urinary angiotensinogen-to-protein ratio, 9.80 [5.47, 17.22] vs 3.38 [1.09, 5.52]; urinary angiotensinogen-to-creatinine ratio, 0.99 [0.40, 2.34] vs 0.31 [0.21, 0.60]). In cats with CKD, indexed urinary angiotensinogen correlated positively with serum creatinine concentration (urinary angiotensinogen-to-protein ratio, ρ = 0.573; urine angiotensinogen-to-creatinine ratio, ρ = 0.642). In healthy cats, urinary angiotensinogen-to-creatinine ratio correlated negatively with several circulating RAAS markers, including serum angiotensin II (ρ = −0.547) and angiotensin 1-7 (ρ = −0.631) equilibrium concentrations.
Conclusions
The intrarenal RAS, assessed by urinary angiotensinogen, is activated in cats with induced CKD, and its activity is inversely related to that of the circulating RAAS in healthy cats but not those with CKD.
Clinical Relevance
Concurrent evaluation of circulating RAAS and intrarenal RAS markers is required for complete assessment of this system.
Keywords: intrarenal renin-angiotensin system; circulating renin-angiotensin-aldosterone system; enzyme-linked immunosorbent assay (ELISA); amlodipine; urinary biomarker
Chronic kidney disease (CKD) is among the most common conditions affecting senior cats, impacting quality of life and survival.1,2 Overactivation of the renin-angiotensin-aldosterone system (RAAS), a key regulator of vascular tone and extracellular fluid volume and composition, contributes to CKD progression and development of systemic arterial hypertension.3–6 In addition to the important physiologic and pathophysiologic roles of the historically described circulating RAAS, recent studies7–9 increasingly highlight the roles of an intrarenal, paracrine/autocrine renin-angiotensin system (RAS) regulated at the tissular level; this is now widely known as the intrarenal RAS.
Direct evaluation of the intrarenal RAS requires renal tissue, sampling of which relies on renal biopsy or postmortem sample collection, which has been a major obstacle for relevant research. In the field of human medicine, the urinary concentration of angiotensinogen, the only known precursor protein of angiotensin and possibly the rate-limiting factor of the intrarenal RAS,7 has been proposed as the most promising noninvasive biomarker for intrarenal RAS.7,10 In humans, urinary angiotensinogen is positively correlated with intrarenal angiotensin II immunostaining11–16 and inversely correlated with kidney function.17,18 Further, urinary angiotensinogen predicts the risk of kidney function deterioration in patients with immunoglobulin A (IgA) nephropathy19 or CKD of various etiologies.12 These data have enabled researchers to use urinary angiotensinogen as a surrogate for intrarenal RAS activity in humans, although debate remains over whether the urinary angiotensinogen elevation observed in patients merely reflects an overall increase in urinary protein loss.20,21
Information on the intrarenal RAS in cats remains limited and restrained by the need for tissue samples. Two earlier studies22,23 assessing RAS components in kidney tissue using immunohistochemistry staining reported mixed results on intrarenal RAS activation in cats with impaired kidney function. However, relevant medical history, including diet, systemic arterial blood pressure, and whether the cats were administered RAAS-modifying drugs, was not described. Two more recent studies24,25 assessed the intrarenal RAS through kidney tissue mRNA levels of relevant genes (eg, angiotensinogen and renin). Both studies identified a higher angiotensinogen mRNA level in cats with kidney disease compared to healthy cats. Further, post hoc analysis from one of these studies25 found a positive association between angiotensinogen mRNA level and the equilibrium concentration of angiotensin II in the kidneys of cats.26 Notably, the corresponding urinary angiotensinogen concentration was not determined as the methodology to measure urinary angiotensinogen was not available when these studies were conducted.
An in-house ELISA that quantifies feline angiotensinogen in urine was recently developed and validated.26 This study aimed to compare urinary angiotensinogen in cats with surgically induced CKD and in sex- and life stage–matched healthy cats. Given its proposed role as an indicator of intrarenal RAS, we also investigated correlations between urinary angiotensinogen and select clinical and circulating RAAS markers.
Methods
Study design
This was a retrospective study using data and urine samples banked from a previous study27 that aimed to characterize the circulating RAAS in cats with surgically induced CKD. In that study, the circulating RAAS was evaluated via measurement of serum equilibrium concentrations of various angiotensin peptides (ie, angiotensin I, II, III, IV, 1-5, and 1-7) and aldosterone using LC-MS-MS. Urine samples collected during that study were banked at −80 °C for future analyses. Clinical, clinicopathologic, and circulating RAAS data generated in the previous study were reviewed, and banked urine samples were used for urinary angiotensinogen, protein, and creatinine analyses.
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