Intrarenal Renin-angiotensin-aldosterone System Research Articles

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

BackgroundGuidelines 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.MethodsA 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.ResultsPatients 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).ConclusionsHigh 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.

Responses of the renin-angiotensin-aldosterone system in pregnant chronic kidney disease patients with and without superimposed pre-eclampsia.

BackgroundWomen with chronic kidney disease (CKD) are at increased risk of superimposed pre-eclampsia (SPE). Accurate identification of SPE is challenging. We hypothesized that specific components of the renin–angiotensin–aldosterone system (RAAS) would discriminate between CKD and SPE. The aim of the study was to establish differences in circulating and intrarenal RAAS in women with CKD with and without SPE and compare these to normotensive controls (NCs) and women with pre-eclampsia (PE).MethodsWhite European NC women (n = 20), women with PE (n = 9), normotensive CKD without SPE (n = 8) and with SPE (n = 11) were recruited in the third trimester. Plasma renin, plasma and urine total angiotensinogen (AGT) concentrations were quantified by enzyme-linked immunosorbent assay, urinary tetrahydroaldosterone (TH-aldo) concentration by gas chromatography-mass spectrometry and placental growth factor (PlGF) by immunoassay.ResultsUrinary TH-aldo:creatinine ratios were lower in women with PE or SPE compared with NC or women with CKD (P < 0.05 for all). The same group differences were observed for plasma active renin and PlGF concentrations (P < 0.05 for all). Urine total AGT was higher in women with PE compared with NC (P < 0.05) and urine TH-aldo:urine AGT was lower (P < 0.05). However, women with SPE had lower urinary AGT concentrations compared with women with PE (P < 0.05). No differences in plasma total AGT were observed between groups.ConclusionsWomen with SPE have a lower urinary TH-aldo:creatinine ratio, lower plasma active renin and lower PlGF concentrations than women with CKD, comparable to women with PE without pre-existing disease, suggestive of similar pathophysiology. These data suggest disruption of the RAAS pathway in SPE similar to PE. Exploration of the predictive value of RAAS components for adverse pregnancy events in women with CKD is required.

Abstract P109: Collecting Duct Renin and Aldosterone Regulate Potassium Homeostasis

The kalliuric action of the renin-angiotensin-aldosterone system (RAAS) is well established as highlighted by hyperkaliemia side effect of RAAS inhibitors but such action is usually ascribed to systemic RAAS. The present study attempted to address the involvement of intrarenal RAAS in K + homeostasis with emphasis on locally generated renin and aldosterone (Aldo) within the collecting duct (CD). In normal C57BL/6 mice, a 1-wk high K + (HK) intake (5% KCl in diet) induced parallel increases in renal prorenin (cortex: 298.8%; medulla: 323.8%) assessed by immunoblotting, and urinary prorenin/renin content (URC) (2.5-fold) assessed by ELISA, and urinary renin activity (URA) (1.5-fold), contrasting to suppressed plasma prorenin/renin concentration (by 25.6%) and renin activity (by 61.6%). Following 1-wk HK loading, mice lacking renin in the CD (CD renin KO) had decreased urinary K + excretion (by 20.2%) and elevated plasma K + level (KO+HK: 4.35 ± 0.14 vs. Floxed+HK: 3.89 ± 0.04 mM, P &lt;0.01), accompanied with a reduction of URC (by 40%), URA (by 58.5%), urinary free and total Aldo excretion (by 50.6% and 36.6%, respectively), and kidney cortical and medullary Aldo (by 33.5% and 49.9%, respectively), without affecting plasma Aldo or renin levels. HK upregulated renal protein expression of Aldo synthase CYP11B2 (cortical: 133.4%, medullary: 221.5%), renal outer medullary K + channel (ROMK) (146.4%), calcium-activated potassium channel subunit alpha-1 (α-BK) (160.9%), α-Na + -K + -ATPase (155.8%), β-ENaC (165.1%), and cleaved-γ-ENaC (1800%), all of which were significantly blunted in CD renin KO mice (by 25-75%). We have developed an inducible renal tubule-wide CYP11B2 KO using the Pax8/LC1 transgenes (termed as RT CYP11B2 KO). While the homozygous deletion is lethal, the heterozygous mice exhibited normal development and were subjected to 3-day HK. K + -loaded RT CYP11B2 KO mice had decreased urinary K + excretion (by 30.5%) and hyperkalemia (KO+HK: 4.63 ± 0.05 vs . Floxed+HK: 3.98 ± 0.09 mM, P &lt;0.01), accompanied with a reduction of urinary free and total Aldo excretion (by 20.4% and 34.4%, respectively) without affecting plasma Aldo levels. Taken together, these results support a local action of CD renin and Aldo in regulation of K + homeostasis.

NSAIDs and heart failure: A dangerous relationship.

One of the potential cardiotoxic action of anti-inflammatory drugs is the occurrence of heart failure (HF), due to their effects on fluid retention and blood pressure. The risk of hospitalization for HF is roughly doubled for both Coxibs, cyclooxygenase-1 (COX-1) and cyclooxygenase- 2 (COX-2) inhibitors, and all the conventional nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs are also associated with a risk of vascular thrombosis, which for NSAIDs is different in relation to their different ability to inhibit COX-1 and COX-2. The cardiovascular toxicity of these drugs in the direction of HF follow different pathways respect to their related vascular thrombosis toxicity and involves, in particular, the renal prostaglandins, PGE2 and prostacyclin, mostly synthesized by COX-2. In the kidneys the PGs perform a direct vasodilatory action, e.g. by means of non-contrasting angiotensin mechanisms, and for this reason nimesulide effects on renal microcirculation are independent from the prevalence of intrarenal renin angiotensin aldosterone system (RAAS) activity. Conversely, nimesulide reduces sodium tubular urinary flow only in presence of intrarenal RAAS.

Renin-angiotensin-aldosterone system activation in long-standing type 1 diabetes

In type 1 diabetes (T1D), adjuvant treatment with inhibitors of the renin-angiotensin-aldosterone system (RAAS), which dilate the efferent arteriole, is associated with prevention of progressive albuminuria and renal dysfunction. Uncertainty still exists as to why some individuals with long-standing T1D develop diabetic kidney disease (DKD) while others do not (DKD resistors). We hypothesized that those with DKD would be distinguished from DKD resistors by the presence of RAAS activation. Renal and systemic hemodynamic function was measured before and after exogenous RAAS stimulation by intravenous infusion of angiotensin II (ANGII) in 75 patients with prolonged T1D durations and in equal numbers of nondiabetic controls. The primary outcome was change in renal vascular resistance (RVR) in response to RAAS stimulation, a measure of endogenous RAAS activation. Those with DKD had less change in RVR following exogenous RAAS stimulation compared with DKD resistors or controls (19%, 29%, 31%, P = 0.008, DKD vs. DKD resistors), reflecting exaggerated endogenous renal RAAS activation. All T1D participants had similar changes in renal efferent arteroilar resistance (9% vs. 13%, P = 0.37) irrespective of DKD status, which reflected less change versus controls (20%, P = 0.03). In contrast, those with DKD exhibited comparatively less change in afferent arteriolar vascular resistance compared with DKD resistors or controls (33%, 48%, 48%, P = 0.031, DKD vs. DKD resistors), indicating higher endogenous RAAS activity. In long-standing T1D, the intrarenal RAAS is exaggerated in DKD, which unexpectedly predominates at the afferent rather than the efferent arteriole, stimulating vasoconstriction. JDRF operating grant 17-2013-312.

Intrarenal Angiotensin-Converting Enzyme: the Old and the New.

The intrarenal renin-angiotensin-aldosterone system (RAS) is an independent paracrine hormonal system with an increasingly prominent role in hypertension and renal disease. Two enzyme components of this system are angiotensin-converting enzyme (ACE) and more recently discovered ACE2. The purpose of this review is to describe recent discoveries regarding the roles of intrarenal ACE and ACE2 and their interaction. Renal tubular ACE contributes to salt-sensitive hypertension. Additionally, the relative expression and activity of intrarenal ACE and ACE2 are central to promoting or inhibiting different renal pathologies including renovascular hypertension, diabetic nephropathy, and renal fibrosis. Renal ACE and ACE2 represent two opposing axes within the intrarenal RAS system whose interaction determines the progression of several common disease processes. While this relationship remains complex and incompletely understood, further investigations hold the potential for creating novel approaches to treating hypertension and kidney disease.

Roles of the circulating renin-angiotensin-aldosterone system in human pregnancy

This review describes the changes that occur in circulating renin-angiotensin-aldosterone system (RAAS) components in human pregnancy. These changes depend on endocrine secretions from the ovary and possibly the placenta and decidua. Not only do these hormonal secretions directly contribute to the increase in RAAS levels, they also cause physiological changes within the cardiovascular system and the kidney, which, in turn, induce reflex release of renal renin. High levels of ANG II play a critical role in maintaining circulating blood volume, blood pressure, and uteroplacental blood flow through interactions with the ANG II type I receptor and through increased production of downstream peptides acting on a changing ANG receptor phenotype. The increase in ANG II early in gestation is driven by estrogen-induced increments in angiotensinogen (AGT) levels, so there cannot be negative feedback leading to reduced ANG II production. AGT can exist in various forms in terms of redox state or complexed with other proteins as polymers; these affect the ability of renin to cleave ANG I from AGT. Thus, during pregnancy the rate of ANG I production varies not only because levels of renin change in response to homeostatic demand but also because AGT changes not only in concentration but in form. Activation of the circulating and intrarenal RAASs is essential for normal pregnancy outcome subserving the increased demand for salt and, hence, water during pregnancy. Thus, the complex integration of the secretions and actions of the circulating maternal renin-angiotensin system in pregnancy plays a key role in pregnancy outcome.

Time course of antiproteinuric effect of aliskiren in arterial hypertension associated with type 2 diabetes and microalbuminuria

Objective: The aim was to compare the antiproteinuric effect of aliskiren and ramipril in hypertensive patients with type 2 diabetes and microalbuminuria.Research design and methods: A total of 138 patients were treated with aliskiren 300 mg/day or ramipril 10 mg/day for 12 weeks and checked after 1, 2, 4, 8 and 12 weeks and 2 and 4 weeks after treatment withdrawal.Main outcome measures: Clinic and ambulatory BP, urinary albumin excretion rate (UAER) and plasma aldosterone were measured.Results: Both aliskiren and ramipril induced a similar lowering in clinic and ambulatory BP (p < 0.001 vs baseline). However, such a lowering persisted longer after stopping aliskiren than after stopping ramipril regimen. Both treatments reduced UAER, but the decrease in UAER associated with aliskiren was more pronounced, the difference vs ramipril being maximal at week 12 (−42 vs −15%, p < 0.01). Two weeks after stopping therapy, UAER remained below baseline values with aliskiren, but not in the ramipril group. Plasma aldosterone decreased in the aliskiren group, whereas in the ramipril group it decreased until week 8 and thereafter increased toward baseline values.Conclusions: Aliskiren has a greater and more prolonged antiproteinuric effect than R; it might partly be related to a higher degree of intrarenal renin–angiotensin–aldosterone system blockade.

The atrial peptide system in cardiac disease.

Atrial natriuretic factor (ANF) is a peptide hormone of cardiac origin, released in response to atrial distention, that increases sodium excretion, inhibits the renin-angiotensin-aldosterone (RAA) system, and decreases arterial pressure. Congestive heart failure (CHF) is a clinical syndrome that is characterized by chronic atrial distention, sodium retention with edema, and activation of the RAA system. The role of ANF in the pathophysiology of CHF remains to be defined. Circulating ANF is greatly increased in congestive heart failure. The mechanism of this elevation of ANF is explained by increased synthesis and release of ANF from the atria with atrial depletion of ANF in response to chronic atrial overload. Recent work also suggests the presence of ANF in ventricular myocardium in heart failure in which the ventricle is recruited to synthesize and release this peptide hormone. Despite increased circulating ANF in heart failure, the kidney retains sodium and is hyporesponsive to exogenous administration of ANF. The mechanism of this hyporesponsiveness is multifactorial but may be explained in part by activation of the intrarenal RAA system as well as by a reduction in renal perfusion pressure. A therapeutic role for ANF remains unclear. To date, studies conflict, but some investigations of ANF infusions in man support a unique and selective renal vasodilator action in association with an ability to inhibit the RAA system.