Urinary angiotensinogen level is associated with potassium homeostasis and clinical outcome in patients with polycystic kidney disease: a prospective cohort study

Abstract

Background: Guidelines for general hypertension treatment do not recommend the combined use of reninangiotensin-aldosterone system (RAAS) inhibitors due to the risk of hyperkalemia. However, a recent clinical trial showed that polycystic kidney disease (PKD) patients had infrequent episodes of hyperkalemia despite receiving combined RAAS inhibitors. Because intrarenal RAAS is a main component for renal potassium handling, we further investigated the association between intrarenal RAAS activity and serum potassium level in patients with chronic kidney disease, particularly in PKD patients, and examined whether intrarenal RAAS activity has a prognostic role in patients with PKD. Methods: A total of 1788 subjects from the KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD) were enrolled in this study. Intrarenal RAAS activity was assessed by the measurement of urinary angiotensinogen (AGT). The primary outcome was the composite of all-cause mortality and renal function decline. Results: Patients with PKD had a significantly lower serum potassium level in chronic kidney disease stages 1 to 3b than non-PKD patients. In logistic regression analysis, after adjusting for multiple confounders, PKD patients had a significantly lower risk of hyperkalemia than non-PKD patients. In multivariable linear regression analysis, the urinary AGT/creatinine (Cr) ratio was negatively correlated with the serum potassium level (β = − 0.058, P = 0.017) and positively correlated with the transtubular potassium gradient (TTKG, β = 0.087, P = 0.001). In propensity score matching analysis, after matching factors associated with serum potassium and TTKG, PKD patients had a significantly higher TTKG (P = 0.021) despite a lower serum potassium level (P = 0.004). Additionally, the urinary AGT/Cr ratio was significantly higher in PKD patients than in non-PKD patients (P = 0.011). In 293 patients with PKD, high urinary AGT/Cr ratio was associated with increased risk of the composite outcome (hazard ratio 1.29; 95% confidence interval, 1.07-1.55; P = 0.007). Conclusions: High activity of intrarenal RAAS is associated with increased urinary potassium excretion and low serum potassium level in patients with PKD. In addition, intrarenal RAAS activity can be a prognostic marker for mortality and renal function decline in these patients.

Insights Into the Molecular Mechanisms of Polycystic Kidney Diseases

“…Besides increased blood pressure, there is a possibility that dysregulation of RAAS can potentially contribute to disease progression by activating signaling cascades that promote cyst growth and especially affect epithelial transport. Kim et al (2019) revealed that high activity of intrarenal RAAS (assessed by urinary angiotensinogen) is associated with increased excretion of K + in patients with PKD, and suggested intrarenal RAAS activity as a prognostic marker for mortality and renal function decline [data obtained from the KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD; Kim et al, 2019 )]. However, reports regarding the effects of RAAS blockade in ADPKD are controversial.…”

The KNOW-CKD Study: What we have learned about chronic kidney diseases

“…Candidate biomarkers of CKD outcomes are cystatin C [21], albuminuria [52], adiponectin [53][54][55][56][57][58], FGF23 [31,59], high density lipoprotein cholesterol [60], troponin T [61] (Fig. 4), hepcidin [26,30], Klotho [28,62], OPG [63], and various urinary markers [46,47,[64][65][66]. The main results of the biomarker studies are described in Table 5 [28,[53][54][55][56][57][58][59][60][61][62][63][64][65][66].…”

“…4), hepcidin [26,30], Klotho [28,62], OPG [63], and various urinary markers [46,47,[64][65][66]. The main results of the biomarker studies are described in Table 5 [28,[53][54][55][56][57][58][59][60][61][62][63][64][65][66].…”

Urinary Angiotensinogen and Progression of Chronic Kidney Disease: Results from KNOW-CKD Study

“…Second, we excluded the subjects with eGFR < 15 mL/min/1.73 m 2 (CKD stage 5), because the subjects with eGFR < 15 mL/min/1.73 m 2 are relatively small in number, and may exaggerate the association between serum TG level and study outcomes due to far-advanced CKD. Third, we excluded the subjects with DM or PKD as a primary cause of CKD, as the association of UAGT/Cr with renal outcomes among the subjects with DM or PKD was previously demonstrated [ 21 , 22 , 23 , 24 , 25 ]. Fourth, we assessed cause-specific HRs for the primary study outcome by UAGT/Cr levels, where death before reaching the composite renal event was considered a competing risk and treated as censoring.…”

“…A translational study also reported that UAGT may be a marker of intrarenal AngII activity in patients with CKD [ 20 ]. Accordingly, it has been reported that UAGT is associated with adverse renal outcomes in specific subsets of patients with CKD, such as those with type 2 diabetes mellitus (DM) [ 21 , 22 , 23 ] and polycystic kidney disease (PKD) [ 24 , 25 ]. Yet, the prognostic value of UAGT in patients with CKD of various etiologies has not been completely evaluated.…”