angiotensinogen and Hyperkalemia

Guidelines for general hypertension treatment do not recommend the combined use of renin-angiotensin-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.. 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.. 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).. 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.

Topics: Adult; Aged; Angiotensinogen; Biomarkers; Cohort Studies; Female; Homeostasis; Humans; Hyperkalemia; Male; Middle Aged; Polycystic Kidney Diseases; Potassium; Prospective Studies; Treatment Outcome; Young Adult

Sudden cardiac death (SCD) is the leading global cause of mortality, exhibiting increased incidence in patients with diabetes mellitus. Ion channel gene perturbations provide a well-established ventricular arrhythmogenic substrate for SCD. However, most arrhythmia-susceptibility genes, including the KCNE2 K(+) channel β subunit, are expressed in multiple tissues, suggesting potential multiplex SCD substrates.. Using whole-transcript transcriptomics, we uncovered cardiac angiotensinogen upregulation and remodeling of cardiac angiotensinogen interaction networks in P21 Kcne2(-/-) mouse pups and adrenal remodeling consistent with metabolic syndrome in adult Kcne2(-/-) mice. This led to the discovery that Kcne2 disruption causes multiple acknowledged SCD substrates of extracardiac origin: diabetes mellitus, hypercholesterolemia, hyperkalemia, anemia, and elevated angiotensin II. Kcne2 deletion was also a prerequisite for aging-dependent QT prolongation, ventricular fibrillation and SCD immediately after transient ischemia, and fasting-dependent hypoglycemia, myocardial ischemia, and AV block.. Disruption of a single, widely expressed arrhythmia-susceptibility gene can generate a multisystem syndrome comprising manifold electric and systemic substrates and triggers of SCD. This paradigm is expected to apply to other arrhythmia-susceptibility genes, the majority of which encode ubiquitously expressed ion channel subunits or regulatory proteins.

Topics: Anemia; Angiotensin II; Angiotensinogen; Animals; Arrhythmias, Cardiac; Death, Sudden, Cardiac; Diabetes Mellitus; Dyslipidemias; Gene Regulatory Networks; Genotype; Heterozygote; Hyperkalemia; Ischemia; Long QT Syndrome; Mice; Mice, Knockout; Potassium Channels, Voltage-Gated

To identify patient-specific factors associated with spironolactone-induced potassium level elevation in patients with heart failure.. Prospective cohort study.. Two adult heart failure clinics.. Sixty-two adult (mean +/- SD age 54 +/- 16 yrs) aldosterone antagonist-naïve patients with heart failure.. Patients received spironolactone 12.5 mg/day, titrated to 25 mg/day if tolerated.. Blood samples were obtained at baseline, 1 week after spironolactone initiation, and 1 week after spironolactone dose titration for assessment of baseline aldosterone level, serum chemistry, and angiotensinogen (AGT) c.-6G>A and p.M268T and mineralocorticoid receptor (NR3C2) c.215C>G and p.I180V genotypes. Patient characteristics, laboratory values, and genotypes were compared between those whose potassium levels increased by more than 0.5 mEq/L (15 patients) and those with lower potassium level elevations (47 patients) after spironolactone initiation and dose titration. Patients with a greater potassium level elevation had a higher mean +/- SD aldosterone concentration (178 +/- 92 vs 102 +/- 57 pg/ml, p=0.007) and NR3C2 215G allele frequency (50% vs 22%, p<0.01). Aldosterone concentrations positively correlated with diuretic dose (r=0.313, p=0.014) and negatively correlated with serum potassium level (r= -0.319, p=0.012). On regression analysis, factors predictive of potassium level increases greater than 0.5 mEq/L with spironolactone were aldosterone level greater than 150 pg/ml (odds ratio [OR] 30, 95% confidence interval [CI] 3.2-287] and NR3C2 215G carrier status (OR 17, 95% CI 1.6-167).. Our data suggest that potassium should be monitored with particular caution when spironolactone is started in patients with heart failure who have evidence of elevated aldosterone levels, such as high diuretic requirements, or the NR3C2 215G allele.

Topics: Adult; Aged; Aldosterone; Angiotensinogen; Black or African American; Cohort Studies; Diuretics; Female; Genotype; Heart Failure; Humans; Hyperkalemia; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Potassium; Receptors, Mineralocorticoid; Spironolactone; Statistics as Topic; White People

The renin-angotensin system was studied in rats suffering from hereditary hydronephrosis in which normal blood pressure, hyperkalemia, and damage to the renal medulla and distal tubules were found. An increased serum creatinine level, decreased creatinine clearance and increased 24 hrs urine volume were observed in rats with bilateral hydronephrosis. When compared to rats with normal kidneys, bilaterally hydronephrotic animals exhibited elevated plasma renin activity (9.9 +/- 1.3/S.E./ng AI/ml/hr vs. 2.4 +/- 0.4 in rats with normal kidneys), and decreased renal renin concentration (78 +/- 4 mug AII/g vs. 132 +/- 5). No correlation between the extent of kidney damage and renal renic concentration was found. After the hyperkalemia of the hydronephrotic rats was corrected, there were significant increases in both plasma renin activity and renal renin concentration, but the renal renin concentration remained significantly lower than that observed in animals with normal kidneys. The results suggest that renin production and/or storage capacity are diminished in hydronephrotic kidneys.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Female; Hydronephrosis; Hyperkalemia; Kidney; Male; Organ Size; Rats; Renin; Sodium