IL-18 (Interleukin-18) Produced by Renal Tubular Epithelial Cells Promotes Renal Inflammation and Injury During Deoxycorticosterone/Salt-Induced Hypertension in Mice

IL-18 (interleukin-18) is elevated in hypertensive patients, but its contribution to high blood pressure and end-organ damage is unknown. We examined the role of IL-18 in the development of renal inflammation and injury in a mouse model of low-renin hypertension. Hypertension was induced in male C57BL6/J (WT) and IL-18 −/− mice by uninephrectomy, deoxycorticosterone acetate (2.4 mg/d, s.c.) and 0.9% drinking saline (1K/DOCA/salt). Normotensive controls received uninephrectomy and placebo (1K/placebo). Blood pressure was measured via tail cuff or radiotelemetry. After 21 days, kidneys were harvested for (immuno)histochemical, quantitative-PCR and flow cytometric analyses of fibrosis, inflammation, and immune cell infiltration. 1K/DOCA/salt-treated WT mice developed hypertension, renal fibrosis, upregulation of proinflammatory genes, and accumulation of CD3 + T cells in the kidneys. They also displayed increased expression of IL-18 on tubular epithelial cells. IL-18 −/− mice were profoundly protected from hypertension, renal fibrosis, and inflammation. Bone marrow transplantation between WT and IL-18 −/− mice revealed that IL-18-deficiency in non-bone marrow-derived cells alone afforded equivalent protection against hypertension and renal injury as global IL-18 deficiency. IL-18 receptor subunits—interleukin-18 receptor 1 and IL-18R accessory protein—were upregulated in kidneys of 1K/DOCA/salt-treated WT mice and localized to T cells and tubular epithelial cells. T cells from kidneys of 1K/DOCA/salt-treated mice produced interferon-γ upon ex vivo stimulation with IL-18, whereas those from 1K/placebo mice did not. In conclusion, IL-18 production by tubular epithelial cells contributes to elevated blood pressure, renal inflammation, and fibrosis in 1K/DOCA/salt-treated mice, highlighting it as a promising therapeutic target for hypertension and kidney disease.

Real-World Effectiveness of Mineralocorticoid Receptor Antagonists in Primary Aldosteronism

ObjectiveTo investigate how often target renin is pursued and achieved in patients with primary aldosteronism (PA) and other low renin hypertension (LRH) treated with mineralocorticoid receptor antagonists (MRAs), as reversal of renin suppression was shown to circumvent the enhanced cardiovascular and renal morbidity and mortality in these patients.Patients and MethodsWe conducted a retrospective cohort study of patients with PA and LRH treated with MRAs in an academic outpatient practice from January 1, 2000, through May 31, 2020.ResultsOf 30,777 patients with hypertension treated with MRAs, only 7.3% were evaluated for PA. 163 patients (123 with PA) had renin followed after MRA initiation. After a median follow-up of 124 [interquartile range, 65-335] days, 70 patients (43%) no longer had renin suppression at the last visit. The proportion of those who achieved target renin was higher in LRH than in PA (53% vs. 40%). Lower baseline serum potassium, lower MRA doses, and beta-blocker use were independently associated with lower odds of achieving target renin in PA, while male sex was associated with target renin in LRH. Overall, 50 patients (30.7%) had 55 adverse events, all from spironolactone, and 26 patients (52%) were switched to eplerenone or had a spironolactone dose reduction.ConclusionDespite evidence that reversal of renin suppression confers cardio-renal protection in patients with PA and LRH, renin targets are followed in very few and are achieved in under half of such patients seen in an academic setting, with possibly even lower rates in community practices.

PECULIARITIES OF HEMODYNAMIC AND METABOLIC INDICATORS IN PATIENTS WITH ARTERIAL HYPERTENSION AND CONCOMITANT OBESITY DEPENDING ON PLASMA RENIN ACTIVITY

The aim of the research: to evaluate the effect of plasma renin activity on the state of hemodynamic and neurohumoral parameters in obese hypertensive patients. Anthropometric, biochemical, automated methods of immune analysis, spectrophotometric, instrumental, statistical methods were used to examine 200 hypertensive patients with class I–II obesity aged 45–55 years. Patients were divided into two groups depending on plasma renin activity: the first group included 21 patients with low-renin hypertension, the second – 179 patients with high-renin hypertension. Patients with HRAH had higher blood pressure BP (DBP, p = 0.004, SBP and mean blood pressure, p<0.001 for both indicators), higher CIMT bifurcation (p = 0.003) and cPWV (p = 0.023), larger size of the left ventricle and its MM (p = 0.039) compared with patients with LRAH. The HRAH was associated with a more pronounced imbalance of the oxidative stress system – antioxidant protection, higher levels of leptin, total cholesterol and LDL cholesterol. In the absence of differences in glycemic levels, patients with HRAH had significantly higher insulin levels and more pronounced IR, as assessed by the HOMA index. Patients with low plasma renin activity had significantly lower serum aldosterone levels with significantly higher ARR levels than patients with high plasma renin activity. Features of cardiovascular remodeling and neurohumoral status depending on the phenotype of hypertension in patients with concomitant obesity have been established.

SAT-564 Effectiveness of Treatment with Mineralocorticoid Receptor Antagonistsin Primary Aldosteronism

Background: Medical treatment with mineralocorticoid receptor antagonists (MRAs) is preferred for patients with primary aldosteronism (PA) who are not surgical candidates. Adequate mineralocorticoid receptor blockade, as suggested by renin elevation above suppression levels, has been associated with lower rates of cardiovascular and renal complications as compared with PA with sustained renin suppression. Objectives: To assess the timeline and rates of achieving target renin levels in patients with PA and low renin hypertension treated with MRAs. Patients and Methods: We conducted a retrospective cohort study of adult patients with hypertension who were treated with MRAs in an academic center between 2003-2019. Of these, we included patients who had suppressed renin at baseline, and repeated renin measurement(s) during MRAs therapy. Renin suppression was defined as plasma renin activity (PRA) 1.0 ng/mL/h or direct renin concentration (DRC) 8.0 pg/mL. We excluded patients with adrenal cancer, end-stage renal disease, exogenous glucocorticoids, and critically ill. Mann-Whitney test, Wilcoxon signed rank test, Chi-Square test and multiple logistic regression analysis were employed, as appropriate. Results: So far, 89 patients (45 men), median age 56 (range, 19-84), have been included. Of these, 46% had confirmed PA; 25% had positive PA screening, but no confirmatory tests; and 29% had other forms of low-renin hypertension. On average, patients were on 2.9 1.6 antihypertensive agents; 62% of patients were prescribed beta blockers, and 38% were on K+ supplements. Overall, renin (PRA in 69 cases, and DRC in 20 cases) increased after MRA treatment (from 0.40 [0.10, 0.60] ng/mL/h to 1.10 [0.60, 2.23] ng/mL/h; and from 2.1 [2.1, 3.7] pg/mL to 5.7 [2.9, 16.7] pg/mL, respectively, p&lt;0.0001 for both). The cumulative proportions of patients in whom renin reached target levels during MRA treatment were: 25% at 2 weeks; 38.9% at 1 month; 34.2% at 3 months; 39.5% at 6 months; and 47.2% at 1 year. Age, sex, race, blood pressure, use of beta blockers, renal function, serum K+ and aldosterone concentrations were similar between patients with target vs. suppressed renin. Multiple logistic regression analysis suggested that after adjusting for age and sex, higher MRA dose and higher BMI were associated with higher likelihood of achieving target renin during MRA therapy (odds ratio (95%CI): 1.021 (1.001-1.041) and 1.097 (1.008-1.193), respectively, p&lt;0.05 for both); conversely, beta blockers use tended to be less often associated with target renin (odds ratio, 0.37 (0.13-1.008), p=0.052). Conclusion: Although raising renin above suppression levels is important for reducing the cardiovascular risk associated with PA, this goal is achieved in less than half of patients, even after one year of treatment with MRAs, in an academic setting. Strategies for optimizing PA treatment are critically needed.

Genetics of Hypertension in African Americans and Others of African Descent

Hypertension is the leading cause of cardiovascular disease in the United States, affecting up to one-third of adults. When compared to other ethnic or racial groups in the United States, African Americans and other people of African descent show a higher incidence of hypertension and its related comorbidities; however, the genetics of hypertension in these populations has not been studied adequately. Several genes have been identified to play a role in the genetics of hypertension. They include genes regulating the renin-aldosterone-angiotensin system (RAAS), such as Sodium Channel Epithelial 1 Beta Subunit (SCNN1B), Armadillo Repeat Containing 5 (ARMC5), G Protein-Coupled Receptor Kinase 4 (GRK4), and Calcium Voltage-Gated Channel Subunit Alpha1 D (CACNA1D). In this review, we focus on recent genetic findings available in the public domain for potential differences between African Americans and other populations. We also cover some recent and relevant discoveries in the field of low-renin hypertension from our laboratory at the National Institutes of Health. Understanding the different genetics of hypertension among various groups is essential for effective precision-guided medical therapy of high blood pressure.