Changes in urinary angiotensinogen posttreatment in pediatric IgA nephropathy patients

Abstract

Background Recently, we demonstrated that urinary angiotensinogen (AGT) levels are increased and reflect intrarenal renin–angiotensin system (RAS) status in pediatric patients with chronic glomerulonephritis. Therefore, this study was performed to test the hypothesis that urinary AGT (UAGT) levels provide a specific index of intrarenal RAS status associated with RAS blockade treatment in pediatric IgA nephropathy (IgAN) patients. Methods We measured plasma and UAGT levels and urinary transforming growth factor beta (TGF-β) levels, after which we performed immunohistochemical analysis of AGT, angiotensin II (Ang II), and TGF-β in 24 pediatric IgAN patients treated with RAS blockades for 2 years. Paired tests were used to analyze the changes from baseline to study end. Results Although there was no change in plasma AGT levels, UAGT and TGF-β levels were significantly decreased after RAS blockade, which was accompanied by the expression levels of AGT, Ang II, and TGF-β, as well as the magnitude of glomerular injury. Baseline UAGT levels positively correlated with diastolic blood pressure, urinary protein levels, scores for mesangial hypercellularity, and the expression levels of AGT, Ang II, and TGF-β in renal tissues. Conclusions These data indicate that UAGT is a useful biomarker of intrarenal RAS activation, which is associated with glomerular injury during RAS blockade in pediatric IgAN patients.

Role of the intrarenal renin–angiotensin system in the progression of renal disease

“…Furthermore, a paired test analyzing the changes from baseline to the values obtained at the end of the study demonstrated that urinary AGT levels were statistically decreased after RAS blockade, accompanied by a reduction in the mesangial hypercellularity score, and renal AGT, Ang II, and TGF-β levels. Urushihara et al further reported that the urinary AGT levels were correlated with these parameters [66]. Taken together, these data suggest that the efficacy of RAS blockade in the reduction of intrarenal RAS activity can be confirmed by measurements of urinary AGT in chronic GN.…”

“…These data indicate that urinary AGT levels are increased in patients with chronic GN and that treatment with RAS blockers suppresses urinary AGT secretion [57]. Observational studies have been performed to test the hypothesis that urinary AGT provides a specific index of intrarenal RAS status in patients with immunoglobulin A nephropathy (IgAN) [58,66]. In the study by Nishiyama et al, urinary AGT levels did not differ between healthy volunteers and patients with minor glomerular abnormalities; however, urinary AGT levels, renal tissue AGT expression, and Ang II immunoreactivity were significantly higher in patients with IgAN than in patients with minor glomerular abnormalities.…”

Longer duration of obesity is associated with a reduction in urinary angiotensinogen in prepubertal children

“…Previous studies have shown an increase in U-AGT in children with renal disease of different etiologies [16,38,39], namely in adolescents with type 1 diabetes [15] or with primary hypertension [14], and in children with very low birth weight [40]. Based on these published data and on the negative impact that obesity has on the kidney [2], we would expect that overweight/obese children had higher U-AGT than age-matched controls of normal weight.…”

“…Childhood obesity is also associated with renal injury, and the kidney is particularly vulnerable to the effects of the RAAS, both through the hemodynamic impact of systemic RAAS activation and by local intrarenal activation, mostly derived from AGT produced in the proximal tubule [7,13]. Urinary excretion of AGT (U-AGT) has been validated as a noninvasive biomarker of intrarenal RAAS activity [13] and increased U-AGT has been found in human hypertension, diabetes, and renal disease [13] even in adolescents [14,15] and children [16]. The rise in U-AGT precedes the onset of microalbuminuria, suggesting that U-AGT might be an early marker of nephropathy [15].…”

Urinary angiotensin converting enzyme 2 and disease activity in pediatric IgA nephropathy

“…Recently, we demonstrated that ACE2 expression in the kidney was increased in pediatric IgA nephropathy and was accompanied by mesangial hypercellularity (11). Furthermore, we clarified that intrarenal RAS activation was suppressed in pediatric IgA nephropathy patients treated with RAS blockade (12). In the present study, we measured urinary ACE2 levels following treatment with RAS blockade and evaluated the expression of ACE2 in the kidney tissue to test the hypothesis that ACE2 is associated with kidney damage in pediatric IgA nephropathy.…”