Heightened Cardiovascular Risk in Hypertension Associated With Renin‐Independent Aldosteronism Versus Renin‐Dependent Aldosteronism: A Collaborative Study

Background While both renin‐dependent and renin‐independent aldosterone secretion contribute to aldosteronism, their relative associations with cardiovascular disease (CVD) risk has not been investigated. Methods and Results A total of 2909 participants from the FOS (Framingham Offspring Study) with baseline, serum aldosterone concentration, and plasma renin concentration who attended the sixth examination cycle and were followed up until 2014 and who were free of CVD were included. We further recruited 2612 hypertensive participants from the CONPASS (Chongqing Primary Aldosteronism Study). Captopril challenge test was performed to confirm renin‐dependent or ‐independent aldosteronism in CONPASS. Among 1433 hypertensive subjects of FOS, when compared with those with serum aldosterone concentration <10 ng dL −1 (normal aldosterone), participants who had serum aldosterone concentration ≥10 ng dL −1 and plasma renin concentration ≤15 mIU L −1 (identified as renin‐independent aldosteronism) showed a higher risk of CVD (hazard ratio, 1.40 [95% CI, 1.08–1.82]), while those who had serum aldosterone concentration ≥10 ng dL −1 and plasma renin concentration >15 mIU L −1 (identified as renin‐dependent aldosteronism) showed an unchanged CVD risk. In CONPASS, renin‐independent aldosteronism carried a significantly higher risk of CVD than normal aldosterone (odds ratio, 2.57 [95% CI, 1.13–5.86]), while the CVD risk remained unchanged in renin‐dependent aldosteronism. Elevation of the urinary potassium‐to‐sodium excretion ratio, reflective of mineralocorticoid receptor activity, was only observed in participants with renin‐independent aldosteronism. Conclusions Among patients with hypertension, renin‐independent aldosteronism is more closely associated with CVD risk than renin‐dependent aldosteronism.

Plasma Renin Concentration in Critically Ill COVID-19 Patients

Investigations of plasma renin concentration as a marker of organ perfusion in several intensive care settings have shown a significant correlation between its increase and a lack of perfusion in critical tissues, especially in septic patients. Castillo et al. proposed that activation of the non-canonical pathway of the renin–angiotensin–aldosterone system could improve cardiovascular homeostasis under COVID-19. During the first wave of COVID-19, we preliminarily enrolled a small cohort of subjects admitted to the Intensive Care Unit with a diagnosis of COVID-19 and acute respiratory distress syndrome. Their plasma renin value was measured in the first 24 h (T0), in the following 72 h (T1), and after one week (T2). In eight patients, we observed a higher plasma renin concentration—patients with difficulty weaning and in non-survivors. This is a preliminary observation. The variation of plasma renin levels in a septic condition is known, but settings such as COVID-19 infection have recently been investigated, showing a correlation with angiotensin-converting enzyme 2 receptor expression and functionality; in the near future, it will be interesting to have more data about its variation and value in COVID-19 patients.

Preoperative Renin Status Indicate the Clinical Outcome of Aldosterone-Producing Adenoma

Primary aldosteronism is widely recognized as renin-independent hypersecretion of aldosterone and aldosterone-producing adenoma(APA) represents the typical clinical subtype. Plasma renin below detection levels was considered as an important indicator for PA, and the suppressed renin level after confirmatory tests was considered to be a prerequisite when interpreting the results of confirmatory tests, before making the diagnosis of PA. Strictly, there is no specific definition of suppressed renin level in patients with PA. Clinically, the renin level of patients with APA varied greatly within the low to normal range. However, the clinical characteristics and outcomes in patients with APA having different renin status remain unclear. This retrospective study included 274 patients with APA who underwent unilateral laparoscopic adrenalectomy with at least a 12-month follow-up postoperatively. Patients were classified into the following 2 groups: low renin and non-low renin groups measured at 8.2 mU/L, according to the widely used criteria(defined as plasma renin activity&lt;1ng/ml/h≈PRC 8.2 mU/L). Only patients with two consecutive PRC less than 8.2 mU/L could be classified into the low renin group. For the screening test and the confirmatory tests, antihypertensive medication was withheld or changed according to the guideline. Chemiluminescence immunoassays showed the range of the plasma renin concentration as 0.4–41.5mU/L. Non-low renin APA patients (n=26) had higher presurgical SBP(p=0.028), DBP(p=0.001) and PRC post confirmatory tests(p&lt;0.001), compared with low renin APA patients(n=248). There was no significant difference in baseline PAC(p=0.507) and serum potassium(p=0.348) between the two groups. Intriguingly, non-low renin APA patients had higher PAC(p&lt;0.001) and PRC(p&lt;0.001) and lower serum potassium(p&lt;0.001) at follow-up. For non-low renin APA patients, the rate of complete clinical success after surgery was 42.3%, 25% lower than that of low renin APA patients. APA patients with PRC&lt;0.5mU/L had the highest rate of complete clinical success(75%), followed by PRC 0.5~8.2 mU/L(65%) and 8.2~20 mU/L(50%), with the lowest rate in patients with PRC&gt;20 mU/L(33%). Multivariable logistic regression showed that the presence of baseline PRC&gt;8.2 mU/L was a strong independent predictor for the lack of complete clinical success[OR 3.7(1.5–8.9),p=0.004]. Plasma renin concentration is closely related to the clinical outcome of APA patients postoperatively. APA patients with higher baseline renin status are at high likelihood of persistent hypertension after surgery, in whom strengthened monitoring of blood pressure is necessary.

Abstract 308: Nephron Specific Deletion Of Angiotensinogen Modulates Blood Pressure

It is unknown if intrarenal generation of angiotensinogen (AGT) is important in blood pressure (BP) regulation. Previous studies showed that proximal tubule-specific overexpression of AGT increases BP, while proximal tubule-specific deletion of AGT using the KAP promoter-Cre transgene did not alter BP. The latter study may not have completely eliminated nephron AGT production; in addition, BP was only assessed on a normal salt diet. To evaluate this issue in greater detail, we developed mice with inducible nephron-wide AGT deletion. Mice were generated which were hemizygous for the Pax8-rtTA and LC-1 transgenes and homozygous for loxP flanked AGT alleles to achieve nephron-specific AGT disruption after doxycycline induction. Adult Pax8-rtTA/LC-1/floxed AGT mice at 3 months of age were treated with doxycycline 2 mg/ml in drinking water for 11 days and studied 4 weeks after treatment. Blood pressure (recorded via telemetry) and metabolic balance studies were determined during 5 days of normal, high and low Na diets. Compared to controls, AGT knockout (KO) mice demonstrated significantly lower systolic, diastolic, and mean BPs on all three diets (N=4 each group). The BP reduction was most evident on a low Na diet (mean BP 107 ± 2 mmHg in controls and 88 ± 13 mmHg in AGT KO). Plasma renin concentration was higher in the AGT KO mice as compared to controls on all three diets. There were no detectable differences in weight, urine volume, urine osmolality or urine Na excretion between the controls and KO mice on all three diets, however due to variability, small differences in these parameters may not have been detected. Taken together, these data suggest that nephron AGT may contribute to BP regulation and this is most evident during low Na intake.