Somatic Mutations in MCOLN3 in Aldosterone-Producing Adenomas cause Primary Aldosteronism.

Primary aldosteronism is characterized by renin-independent hyperaldosteronism that originates from aldosterone-producing lesions in the adrenal glands. Under physiological conditions, aldosterone synthase ( CYP11B2 ) expression is confined to the adrenal zona glomerulosa where it catalyzes the final reaction yielding aldosterone. The regulation of CYP11B2 transcription depends on the control of cellular membrane potential and cytosolic calcium activity. In primary aldosteronism, aldosterone-producing adenomas (APAs) are characterized by disrupted regulation of CYP11B2 expression resulting in autonomous biosynthesis of aldosterone. These lesions often harbor aldosterone-driver somatic mutations in genes encoding ion transporters/channels/pumps that increase cytosolic calcium activity causing increased CYP11B2 expression and aldosterone biosynthesis. We investigated APAs devoid of known somatic mutations and detected a missense mutation and a deletion-insertion variant in MCOLN3 which encodes for mucolipin-3 (TRPML3) - a highly conserved inwardly-rectifying, cation-permeable channel. These MCOLN3 mutations were identified in three APAs derived from male patients with primary aldosteronism: p. Y391D and p.N411_V412delinsI. Both mutations are located near the ion pore and selectivity filter of TRPML3. This is the first report of disease-causing MCOLN3 mutations in humans. Functional studies suggest MCOLN3 Y391D might directly or indirectly via membrane depolarization alter calcium influx of transfected adrenocortical cells, resulting in increased CYP11B2 transcription and aldosterone production. This study implicates mutated MCOLN3 as a driver of aldosterone excess in primary aldosteronism. Significance Statement: Primary aldosteronism is a common but under-diagnosed endocrine disease that contributes to global hypertension burden and cardiovascular mortality and morbidity. Hyperaldosteronism in primary aldosteronism is mainly caused by adrenal lesions harboring somatic mutations that disrupt intracellular calcium levels and consequently aldosterone synthase expression and aldosterone production. Majority of these mutations have been identified in genes encoding ion transporters/channels/pumps. Herein, we report the first disease-causing somatic mutations in human MCOLN3 in aldosterone-producing adenomas (APAs) devoid of known mutations. In vitro investigations showed the MCOLN3 variant (p.Y391D) caused an influx of cytosolic calcium in adrenocortical cells and the subsequent increase in aldosterone synthase and aldosterone biosynthesis.

Pulse Pressure and Cardiovascular and Kidney Outcomes by Age in the Chronic Renal Insufficiency Cohort (CRIC).

BACKGROUND: Wide pulse pressure (PP) is associated with cardiovascular events and the progression of chronic kidney disease (CKD) to kidney failure. PP naturally widens with age, but it is unclear whether the risks associated with greater PP are the same across all ages. METHODS: We used Cox proportional hazards models to investigate the association of PP with (i) atherosclerotic cardiovascular disease (ASCVD) events or death and (ii) a 50% reduction in estimated glomerular filtration rate or kidney failure in the chronic renal insufficiency cohort (CRIC). We evaluated the association of time-updated PP with these outcomes, accounting for time-updated confounders using inverse probability weighting. RESULTS: Among 5,621 participants with CKD, every 10-mmHg greater PP was associated with a 6% higher risk of an ASCVD event or death (hazard ratio [HR] = 1.06, 95% CI 1.04, 1.08) and 17% higher risk of the composite kidney outcome (HR = 1.17, 95% CI 1.16, 1.18). Greater PP was associated with a higher risk of ASCVD events or death among participants in the lowest age tertile (21-61 years), but a higher risk of the composite kidney outcome in the oldest age tertile (71-79 years). While wide PP in participants that experienced the primary outcomes was predominantly driven by elevated SBP, PP remained significantly associated with the composite kidney outcome across all ages and with ASCVD events or death in the first age tertile when SBP was added to the Cox regression model. CONCLUSIONS: Our findings suggest that the mechanism by which PP is associated with adverse outcomes may differ by age.

Immediate-Release versus Extended-Release Tacrolimus: Comparing Blood Pressure Control in Kidney Transplant Recipients - A Retrospective Cohort Study.

BACKGROUND: Hypertension (HTN) is a common side effect of tacrolimus (Tac), the first-line antirejection medication for kidney transplant recipients. The impact of immediate-release tacrolimus (Tac IR) dosed twice daily versus extended-release tacrolimus (Tac ER) dosed once daily on long-term blood pressure control in kidney transplant recipients remains understudied. This study aims to compare the use of Tac IR versus Tac ER in kidney transplant recipients and evaluate the effects of the different formulations on systolic blood pressure (SBP), diastolic blood pressure (DBP), and HTN crisis. METHODS: This retrospective cohort study at a single institution collected baseline characteristics, time-varying exposure to Tac IR versus Tac ER, SBP, DBP, HTN crisis, and confounders at each posttransplant visit. A marginal structural linear mixed-effects model was employed to analyze the longitudinal blood pressure control in kidney transplant recipients receiving Tac IR and Tac ER. RESULTS: The final analysis included 654 patients, with mean ages of 52.0 years for Tac IR and 50.3 years for Tac ER. Males constituted 56.7% in Tac IR and 55.0% in Tac ER. Notably, the black population had 2.44 times higher odds of receiving Tac ER after adjusting for the rest of the baseline characteristics. No difference was found between longitudinal SBP (p = 0.386, 95% CI: -1.00, 2.57) or DBP (p = 0.797, 95% CI: -1.38, 1.06). CONCLUSION: Our study indicates that posttransplant patients taking Tac ER exhibit no difference in chronic SBP and DBP controls compared to Tac IR.

Adrenal Vein Sampling Results and Surgical Outcomes in Patients with Nonsuppressed Plasma Renin Activity.

PURPOSE: To determine adrenal vein sampling (AVS) and postadrenalectomy outcomes in patients with a nonsuppressed plasma renin activity (PRA) and elevated aldosterone-to-renin ratio (ARR). MATERIALS AND METHODS: The study sample included 23 patients with an ARR of >20 and PRA of >1 ng/mL/h (nonsuppressed group) and 69 patients with an ARR of >20 and PRA of <0.6 ng/mL/h (suppressed group) who underwent AVS from 2006 to 2023. Data regarding baseline clinical characteristics, AVS results, and outcomes after adrenalectomy were analyzed. RESULTS: The proportion of patients in the nonsuppressed group who had a lateralization index of >4 was lower than that in the suppressed group, although this was nonsignificant (43% vs 62%; P = .15). The mean lateralization index in the nonsuppressed group was lower compared with that in the suppressed group (8.7 vs 17.4; P = .05). The proportion of patients in the nonsuppressed group with improved or cured hypertension following adrenalectomy was similar to that of patients in the suppressed group who also underwent surgery (6/8, 75%, vs 25/32, 78%; P = .71). All hypokalemic patients (32/32) who underwent adrenalectomy had normalization of their potassium levels following procedure. CONCLUSIONS: Nearly half of patients with nonsuppressed PRA lateralized with AVS. The patients who did lateralize had similar blood pressure response and correction of hypokalemia following adrenalectomy, regardless of PRA. Therefore, patients with a nonsuppressed PRA (>1 ng/mL/h) should still be considered for AVS provided the ARR is elevated.

Randomized Trials of Renal Denervation for Uncontrolled Hypertension: An Updated Meta-Analysis.

BACKGROUND: Despite optimal medical therapy, a significant proportion of patients' blood pressure remains uncontrolled. Catheter-based renal denervation (RDN) has been proposed as a potential intervention for uncontrolled hypertension. We conducted an updated meta-analysis to assess the efficacy and safety of RDN in patients with uncontrolled hypertension, with emphasis on the differential effect of RDN in patients on and off antihypertensive medications. METHODS AND RESULTS: Online databases were searched to identify randomized clinical trials comparing efficacy and safety of RDN versus control in patients with uncontrolled hypertension. Subgroup analyses were conducted for sham-controlled trials and studies that used RDN devices that have gained or are currently seeking US Food and Drug Administration approval. Fifteen trials with 2581 patients (RDN, 1723; sham, 858) were included. In patients off antihypertensive medications undergoing RDN, a significant reduction in 24-hour ambulatory (-3.70 [95% CI, -5.41 to -2.00] mm Hg), office (-4.76 [95% CI, -7.57 to -1.94] mm Hg), and home (-3.28 [95% CI, -5.96 to -0.61] mm Hg) systolic blood pressures was noted. In patients on antihypertensive medications, a significant reduction was observed in 24-hour ambulatory (-2.23 [95% CI, -3.56 to -0.90] mm Hg), office (-6.39 [95% CI, -11.49 to -1.30]), home (-6.08 [95% CI, -11.54 to -0.61] mm Hg), daytime (-2.62 [95% CI, -4.14 to -1.11]), and nighttime (-2.70 [95% CI, -5.13 to -0.27]) systolic blood pressures, as well as 24-hour ambulatory (-1.16 [95% CI, -1.96 to -0.35]), office (-3.17 [95% CI, -5.54 to -0.80]), and daytime (-1.47 [95% CI, -2.50 to -0.27]) diastolic blood pressures. CONCLUSIONS: RDN significantly lowers blood pressure in patients with uncontrolled hypertension, in patients off and on antihypertensive medications, with a favorable safety profile. The efficacy of RDN was consistent in sham-controlled trials and contemporary trials using US Food and Drug Administration-approved devices.

Cardiac Effects of Renin-Angiotensin System Inhibitors in Nonproteinuric CKD.

BACKGROUND: In contrast to proteinuric chronic kidney disease (CKD), the relative cardioprotective benefits of antihypertensive medications in nonproteinuric CKD are unknown. We examined long-term cardiovascular outcomes and mortality in patients with nonproteinuric CKD treated with renin-angiotensin system inhibitors (RASIs) versus other antihypertensive medications. METHODS: Among participants of the CRIC study (Chronic Renal Insufficiency Cohort) without proteinuria, we used intention-to-treat analyses with inverse probability of treatment weighting and Cox proportional hazards modeling to determine the association of RASIs versus other antihypertensive medications with a composite cardiovascular outcome (myocardial infarction, stroke, heart failure hospitalization, and death) and mortality. Secondary analyses included per-protocol analyses accounting for continuous adherence and time-updated analyses accounting for the proportion of time using RASIs during follow-up. RESULTS: A total of 2806 participants met the inclusion criteria. In the intention-to-treat analyses, RASIs versus other antihypertensive medications were not associated with an appreciable difference in cardiovascular events (adjusted hazard ratio [aHR], 0.94 [95% CI, 0.80-1.11]) or mortality (aHR, 1.06 [95% CI, 0.88-1.28]). In the per-protocol analyses, RASIs were associated with a lower risk of adverse cardiovascular events (aHR, 0.78 [95% CI, 0.63-0.97]) and mortality (aHR, 0.64 [95% CI, 0.48-0.85]). Similarly, in the time-updated analyses, a higher proportion of RASI use over time was associated with a lower mortality risk (aHR, 0.33 [95% CI, 0.14-0.86]). CONCLUSIONS: Among individuals with nonproteinuric CKD, after accounting for time-updated use, RASIs are associated with fewer cardiovascular events and a lower mortality risk compared with other antihypertensive medications. Patients with nonproteinuric CKD may benefit from prioritizing RASIs for hypertension management.

Cardiovascular and Kidney Outcomes of Non-Diabetic CKD by Albuminuria Severity: Findings From the CRIC Study.

RATIONALE & OBJECTIVE: The clinical trajectory of normoalbuminuric chronic kidney disease (CKD), particularly in the absence of diabetes, has not yet been well-studied. This study evaluated the association of kidney and cardiovascular outcomes with levels of albuminuria in a cohort of patients with nondiabetic CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 1,463 adults with nondiabetic CKD without known glomerulonephritis and diagnosed with hypertensive nephrosclerosis or unknown cause of CKD participating in the Chronic Renal Insufficiency Cohort (CRIC) Study. EXPOSURE: Albuminuria stage at study entry. OUTCOME: Primary outcome: Composite kidney (halving of estimated glomerular filtration rate [eGFR], kidney transplantation, or dialysis), Secondary outcomes: (1) eGFR slope, (2) composite cardiovascular disease events (hospitalization for heart failure, myocardial infarction, stroke, or all-cause death), (3) all-cause death. ANALYTICAL APPROACH: Linear mixed effects and Cox proportional hazards regression analyses. RESULTS: Lower levels of albuminuria were associated with female sex and older age. For the primary outcome, compared with normoalbuminuria, those with moderate and severe albuminuria had higher rates of kidney outcomes (adjusted hazard ratio [AHR], 3.3 [95% CI, 2.4-4.6], and AHR, 8.6 [95% CI, 6.0-12.0], respectively) and cardiovascular outcomes (AHR, 1.5 [95% CI, 1.2-1.9], and AHR, 1.5 [95% CI, 1.1-2.0], respectively). Those with normoalbuminuria (<30µg/mg; n=863) had a slower decline in eGFR (-0.46mL/min/1.73m2 per year) compared with those with moderate (30-300µg/mg, n=372; 1.41mL/min/1.73m2 per year) or severe albuminuria (>300µg/mg, n=274; 2.63mL/min/1.73m2 per year). In adjusted analyses, kidney outcomes occurred, on average, sooner among those with moderate (8.6 years) and severe (7.3 years) albuminuria compared with those with normoalbuminuria (9.3 years) whereas the average times to cardiovascular outcomes were similar across albuminuria groups (8.2, 8.1, and 8.6 years, respectively). LIMITATIONS: Self-report of CKD etiology without confirmatory kidney biopsies; residual confounding. CONCLUSIONS: Participants with normoalbuminuric nondiabetic CKD experienced substantially slower CKD progression but only modestly lower cardiovascular risk than those with high levels of albuminuria. These findings inform the design of future studies investigating interventions among individuals with lower levels of albuminuria. PLAIN-LANGUAGE SUMMARY: Diabetes and hypertension are the leading causes of chronic kidney disease (CKD). Urine albumin levels are associated with cardiovascular and kidney disease outcomes among individuals with CKD. However, previous studies of long-term clinical outcomes in CKD largely included patients with diabetes. As well, few studies have evaluated long-term outcomes across different levels of urine albumin among people without diabetes. In this study, we found individuals with nondiabetic CKD and low urine albumin had much slower decline of kidney function but only a modestly lower risk of a cardiovascular events compared with those with high levels of urine albumin. Individuals with low urine albumin were much more likely to have a cardiovascular event than progression of their kidney disease. These findings inform the design of future studies investigating treatments among individuals with lower levels of albuminuria.

Clonal hematopoiesis of indeterminate potential contributes to accelerated chronic kidney disease progression.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a common inflammatory condition of aging that causes myriad end-organ damage. We have recently shown associations for CHIP with acute kidney injury and with kidney function decline in the general population, with stronger associations for CHIP driven by mutations in genes other than DNMT3A (non- DNMT3A CHIP). Longitudinal kidney function endpoints in individuals with pre-existing chronic kidney disease (CKD) and CHIP have been examined in two previous studies, which reported conflicting findings and were limited by small sample sizes. Methods: In this study, we examined the prospective associations between CHIP and CKD progression events in four cohorts of CKD patients (total N = 5,772). The primary outcome was a composite of 50% kidney function decline or kidney failure. The slope of eGFR decline was examined as a secondary outcome. Mendelian randomization techniques were then used to investigate potential causal effects of CHIP on eGFR decline. Finally, kidney function was assessed in adenine-fed CKD model mice having received a bone marrow transplant recapitulating Tet2 -CHIP compared to controls transplanted wild-type bone marrow. Results: Across all cohorts, the average age was 66.4 years, the average baseline eGFR was 42.6 ml/min/1.73m 2 , and 24% had CHIP. Upon meta-analysis, non- DNMT3A CHIP was associated with a 59% higher relative risk of incident CKD progression (HR 1.59, 95% CI: 1.02-2.47). This association was more pronounced among individuals with diabetes (HR 1.29, 95% CI: 1.03-1.62) and with baseline eGFR ≥ 30 ml/min/1.73m (HR 1.80, 95% CI: 1.11-2.90). Additionally, the annualized slope of eGFR decline was steeper among non- DNMT3A CHIP carriers, relative to non-carriers (ß -0.61 ± 0.31 ml/min/1.73m 2 , p = 0.04). Mendelian randomization analyses suggested a causal role for CHIP in eGFR decline among individuals with diabetes. In a dietary adenine mouse model of CKD, Tet2 -CHIP was associated with lower GFR as well as greater kidney inflammation, tubular injury, and tubulointerstitial fibrosis. Conclusion: Non- DNMT3A CHIP is a potentially targetable novel risk factor for CKD progression.

Renal Denervation for Hypertension: The Current Landscape and Future Directions.

Hypertension (HTN) is one of the largest contributors to cardiovascular (CV) morbidity and mortality in the USA and is estimated to affect 47% of the US population; however, recent estimates suggest that over 40% continue to have uncontrolled HTN. In the past decade, multiple placebo-controlled randomized studies have shown the safety and efficacy of renal denervation as an adjunctive therapy, culminating in the recent approval of two devices by the US Food and Drug Administration (FDA). These devices use either radiofrequency or ultrasound energies to ablate the perivascular sympathetic nerves in the renal arteries and have been shown to reduce blood pressure. In this immediate post-FDA approval era, there are still multiple issues regarding the future of the technology in its applications and reimbursement landscapes.

Head and Neck Paragangliomas: Overview of Institutional Experience.

Head and neck paragangliomas (HNPGLs) are rare and have high rates of genetic mutations. We conducted a retrospective review of 187 patients with 296 PGLs diagnosed between 1974 and 2023. The mean age of diagnosis was 48.8 years (range 10 to 82) with 69.0% female and 26.5% patients with multiple PGLs. Among 119 patients undergoing genetic testing, 70 (58.8%) patients had mutations, with SDHB (30) and SDHD (26) being the most common. The rates of metastasis and recurrence were higher among patients with SDHB mutations or SDHD mutations associated with multiple PGLs. Metabolic evaluation showed elevated plasma dopamine levels were the most common derangements in HNPGL. MRI and CT were the most common anatomic imaging modalities and DOTATATE was the most common functional scan used in this cohort. Most patients (81.5%) received surgery as the primary definitive treatment, while 22.5% patients received radiation treatment, mostly as an adjuvant therapy or for surgically challenging or inoperable cases. Systemic treatment was rarely used in our cohort. Our single-center experience highlights the need for referral for genetic testing and metabolic evaluation and for a team-based approach to improve the clinical outcomes of patients with HNPGLs.

Multifocal, Asymmetric Bilateral Primary Aldosteronism Cannot be Excluded by Strong Adrenal Vein Sampling Lateralization: An International Retrospective Cohort Study.

BACKGROUND: Primary aldosteronism (PA) has been broadly dichotomized into unilateral and bilateral forms. Adrenal vein sampling (AVS) lateralization indices (LI) ≥2 to 4 are the standard-of-care to recommend unilateral adrenalectomy for presumed unilateral PA. We aimed to assess the rates and characteristics of residual PA after AVS-guided adrenalectomy. METHODS: We conducted an international, retrospective, cohort study of patients with PA from 7 referral centers who underwent unilateral adrenalectomy based on LI≥4 on baseline and/or cosyntropin-stimulated AVS. Aldosterone synthase (CYP11B2) immunohistochemistry and next generation sequencing were performed on available formalin-fixed paraffin-embedded adrenal tissue. RESULTS: The cohort included 283 patients who underwent AVS-guided adrenalectomy, followed for a median of 326 days postoperatively. Lack of PA cure was observed in 16% of consecutive patients, and in 22 patients with lateralized PA on both baseline and cosyntropin-stimulated AVS. Among patients with residual PA postoperatively, 73% had multiple CYP11B2 positive areas within the resected adrenal tissue (versus 23% in those cured), wherein CACNA1D mutations were most prevalent (63% versus 33% in those cured). In adjusted regression models, independent predictors of postoperative residual PA included Black versus White race (odds ratio, 5.10 [95% CI, 1.45-17.86]), AVS lateralization only at baseline (odds ratio, 8.93 [95% CI 3.00-26.32] versus both at baseline and after cosyntropin stimulation), and CT-AVS disagreement (odds ratio, 2.75 [95% CI, 1.20-6.31]). CONCLUSIONS: Multifocal, asymmetrical bilateral PA is relatively common, and it cannot be excluded by robust AVS lateralization. Long-term postoperative monitoring should be routinely pursued, to identify residual PA and afford timely initiation of targeted medical therapy.

Orthostatic hypotension, orthostatic hypertension, and ambulatory blood pressure in patients with chronic kidney disease in CRIC.

BACKGROUND: Orthostatic changes in blood pressure (BP), either orthostatic hypotension or orthostatic hypertension (OHTN), are common among patients with chronic kidney disease. Whether they are associated with unique out-of-office BP phenotypes is unknown. METHODS: CRIC is a prospective, multicenter, observational cohort study of participants with CKD. BP measured at 2 min after standing and ambulatory BP monitoring (ABPM) were obtained on 1386 participants. Orthostatic hypotension was defined as a 20 mmHg drop in SBP or 10 mmHg drop in DBP when changing from seated to standing positions. Systolic and diastolic night-to-day ratio was also calculated. OHTN was defined as a 20 or 10 mmHg rise in SBP or DBP when changing from a seated to a standing position. White-coat effect (WCE) was defined as seated minus daytime ambulatory BP. RESULTS: Of the 1386 participants (age: 58 ±â€Š10 years, 44% female, 39% black), 68 had orthostatic hypotension and 153 had OHTN. Postural reduction in SBP or DBP was positively associated with greater systolic and diastolic WCE and systolic and diastolic night-to-day ratio. Orthostatic hypotension was positively associated with diastolic WCE (ß = 3 [0.2, 5.9]). Diastolic OHTN was negatively associated with systolic WCE (ß = -4 [-7.2, -0.5]) and diastolic WCE (ß = -6 [-8.1, -4.2]). CONCLUSION: Postural change in BP was associated with WCE and night-to-day-ratio. Orthostatic hypotension was positively associated with WCE and OHTN was negatively associated with WCE. These findings strengthen observations that postural changes in BP may associate with distinct BP patterns throughout the day. These observations are informative for subsequent research tailoring orthostatic hypotension and OHTN treatment to specific BP phenotypes.

Development of a risk-prediction model for primary aldosteronism in veterans with hypertension.

BACKGROUND: Rates of screening for primary aldosteronism in patients who meet the criteria are exceedingly low (1%-3%). To help clinicians prioritize screening in patients most likely to benefit, we developed a risk-prediction model. METHODS: Using national Veterans Health Administration data, we identified patients who met the criteria for primary aldosteronism screening between 2000 and 2019. We performed multivariable logistic regression to identify characteristics associated with positive primary aldosteronism testing before generating a risk-scoring system based on the coefficients (0< ß < 0.5 = 1 pt, 0.5 ≤ ß < 1 = 2 pts, 1 ≤ ß < 1.5 = 3 pts) and then tested the system performance using an internal validation cohort. RESULTS: We identified 502,190 patients who met primary aldosteronism screening criteria, of whom 1.6% were screened and 15% tested positive. Based on the regression model, we generated a risk-scoring system based on a total of 9 possible points in which age under 50, absence of smoking history, and resistant hypertension each scored 1 point; elevated serum sodium 2 points; and hypokalemia 3 points. Rates of positive screening increased with risk score, with 5.6% to 6.7% of those scoring 0 points testing positive; 7.9% to 9.0% 1 point; 8.6% to 10% 2 points; 13% to 14% 3 points; 21% 4 points; 22% to 38% 5 points; 27% to 38% 6 points; 42% to 49% 7 points; and 50% to 51% ≥8 points. CONCLUSION: In hypertensive patients who meet the criteria for primary aldosteronism screening, rates of positive screening range from 5.6% to 51%. Use of our risk-predication model incorporating these factors can identify patients most likely to benefit from testing.

Safety and Efficacy of Renal Denervation in Patients Taking Antihypertensive Medications.

BACKGROUND: Renal denervation (RDN) reduces blood pressure (BP) in patients with uncontrolled hypertension in the absence of antihypertensive medications. OBJECTIVES: This trial assessed the safety and efficacy of RDN in the presence of antihypertensive medications. METHODS: SPYRAL HTN-ON MED is a prospective, randomized, sham-controlled, patient- and assessor-blinded trial enrolling patients from 56 clinical centers worldwide. Patients were prescribed 1 to 3 antihypertensive medications. Patients were randomized to radiofrequency RDN or sham control procedure. The primary efficacy endpoint was the baseline-adjusted change in mean 24-hour ambulatory systolic BP at 6 months between groups using a Bayesian trial design and analysis. RESULTS: The treatment difference in the mean 24-hour ambulatory systolic BP from baseline to 6 months between the RDN group (n = 206; -6.5 ± 10.7 mm Hg) and sham control group (n = 131; -4.5 ± 10.3 mm Hg) was -1.9 mm Hg (95% CI: -4.4 to 0.5 mm Hg; P = 0.12). There was no significant difference between groups in the primary efficacy analysis with a posterior probability of superiority of 0.51 (Bayesian treatment difference: -0.03 mm Hg [95% CI: -2.82 to 2.77 mm Hg]). However, there were changes and increases in medication intensity among sham control patients. RDN was associated with a reduction in office systolic BP compared with sham control at 6 months (adjusted treatment difference: -4.9 mm Hg; P = 0.0015). Night-time BP reductions and win ratio analysis also favored RDN. There was 1 adverse safety event among 253 assessed patients. CONCLUSIONS: There was no significant difference between groups in the primary analysis. However, multiple secondary endpoint analyses favored RDN over sham control. (SPYRAL HTN-ON MED Study [Global Clinical Study of Renal Denervation With the Symplicity Spyral Multi-electrode Renal Denervation System in Patients With Uncontrolled Hypertension in the Absence of Antihypertensive Medications]; NCT02439775).

Approach to Diagnosis and Management of Hypertension: A Comprehensive and Combined Pediatric and Adult Perspective.

The global prevalence of primary hypertension has been increasing both in children and in the adolescent and adult populations and can be attributed to changes in lifestyle factors with an obesity epidemic, increased salt consumption, and sedentary lifestyles. Childhood blood pressure is the strongest predictor of adult hypertension. Although hypertension in adults is associated strongly with an increased risk for cardiovascular disease, chronic kidney disease, and mortality, outcomes in children are defined less clearly. In adults, major guidelines agree on a threshold of less than 120/80 mm Hg as the optimal blood pressure (BP) and recommend a target of less than 130/80 mm Hg for treatment in most cases. In children, international pediatric guidelines recommend using thresholds based on the normative distribution of BP in healthy normal-weight children. Out-of-office BP assessment is extremely useful for confirming the diagnosis of hypertension and monitoring response to treatment. Lifestyle modifications are instrumental whether coupled or not with pharmacologic management. New agents such as nonsteroidal mineralocorticoid-receptor antagonists, aminopeptidase A inhibitors, aldosterone synthase inhibitors, and dual endothelin antagonists hold significant promise for resistant hypertension. The transition from pediatric to adult care can be challenging and requires careful planning and effective coordination within a multidisciplinary team that includes patients and their families, and pediatric and adult providers.

Congenital Cyanotic Heart Disease and the Association with Pheochromocytomas and Paragangliomas.

PURPOSE OF REVIEW: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that commonly produce excess catecholamines causing significant morbidity and mortality. Patients with cyanotic congenital heart disease (CCHD) develop PPGLs at a higher frequency than the general population. This review will summarize recent research in the association of PPGL and CCHD. RECENT FINDINGS: Advances in molecular genetics have provided new insights into a variety of germline mutations and somatic mutations related to PPGLs. In the CCHD population, mutations can occur in the hypoxia signaling pathway with gain-of-function somatic mutations in EPAS1, which prevent degradation of hypoxia-inducible factor-2 alpha. These mutations are implicated in oncogenesis. PPGLs associated with CCHD develop as early as age 15 years and have predominantly noradrenergic secretion. Surgical removal is considered the first line of therapy, although belzutifan, a HIF-2α inhibitor, is currently being tested as a potential therapy. Early screening with plasma metanephrines may assist in identifying PPGLs in patients with CCHD.

New Potential Treatments for Resistant Hypertension.

PURPOSE OF REVIEW: To provide an update and review approaches to the treatment of resistant hypertension (RH) with a focus on emerging potential therapies. RECENT FINDINGS: Resistant hypertension is defined as a blood pressure that remains elevated above a patient's individualized target despite the concurrent use of 3 antihypertensive agents of different classes including a diuretic or use of 4 or more antihypertensive agents. Patients with RH have an increased risk of adverse cardiovascular and renal outcomes. Most RH is attributed to apparent RH and is not true RH. True RH is a diagnosis of exclusion after apparent RH has been excluded. Treatment of RH is challenging, and blood pressure goal is often difficult to achieve. Currently several new therapies have emerged with forthcoming data that provide promise for improved blood pressure control in those with resistant hypertension. Once RH has been diagnosed, patients should be on standardized therapy that includes agents from three different classes including a diuretic with addition in most cases of a mineralocorticoid as a fourth line agent. There are newer agents in development currently being studied in clinical trials including dual endothelin receptor antagonists and aldosterone synthase inhibitors that appear to be efficacious. Other approved medications including SGLT2 inhibitors and non-steroidal mineralocorticoids such as finerenone also need to be incorporated into treatment paradigms. Renal denervation with catheter based devices is another potential promising treatment option in this population.

Primary Aldosteronism in Chronic Kidney Disease: Blood Pressure Control and Kidney and Cardiovascular Outcomes After Surgical Versus Medical Management.

BACKGROUND: Diagnosis and treatment of primary aldosteronism (PA) in chronic kidney disease (CKD) may be deferred due to limited evidence supporting safety and efficacy of treatment. Our goal was to assess clinical outcomes in patients with PA and CKD who received surgical or medical management. METHODS: We conducted a multicenter, retrospective cohort study of patients with PA and CKD who underwent adrenal vein sampling from 2009-2019. We characterized clinical outcomes and evaluated differences by surgical versus medical management. Primary outcomes were systolic blood pressure and number of antihypertensive medications. Secondary outcomes were diastolic blood pressure, serum potassium, estimated glomerular filtration rate (eGFR), and kidney and cardiovascular events. Analyses were adjusted for age, sex, race, cardiovascular disease, diabetes, and eGFR. RESULTS: Of 239 participants with PA and CKD, 158 (66%) underwent adrenalectomy, and 81 (34%) were treated medically. Mean age was 57±10 years, 67% were female, mean eGFR was 45±12 mL/min per 1.73 m2, and 49% were on potassium supplementation. At 5 years, mean blood pressure decreased from 149±22/85±14 to 131±28/78±16 mm Hg and mean number of antihypertensive medications decreased from 4.0±1.5 to 2.4±1.4. Adrenalectomy, compared to medical management, was associated with similar systolic blood pressure (-0.90 mm Hg [95% CI, -6.99 to 5.07]) but fewer medications (1.7 [95% CI, -2.24 to -1.10]), and no difference in potassium levels or kidney or cardiovascular outcomes. CONCLUSIONS: Patients with PA and CKD are likely to benefit from either surgical adrenalectomy or medical management. Detection and treatment of PA may help to reduce blood pressure and medication burden in patients with CKD.

Risk for Chronic Kidney Disease Progression After Acute Kidney Injury: Findings From the Chronic Renal Insufficiency Cohort Study.

BACKGROUND: Prior studies associating acute kidney injury (AKI) with more rapid subsequent loss of kidney function had methodological limitations, including inadequate control for differences between patients who had AKI and those who did not. OBJECTIVE: To determine whether AKI is independently associated with subsequent kidney function trajectory among patients with chronic kidney disease (CKD). DESIGN: Multicenter prospective cohort study. SETTING: United States. PARTICIPANTS: Patients with CKD (n = 3150). MEASUREMENTS: Hospitalized AKI was defined by a 50% or greater increase in inpatient serum creatinine (SCr) level from nadir to peak. Kidney function trajectory was assessed using estimated glomerular filtration rate (eGFR) based on SCr level (eGFRcr) or cystatin C level (eGFRcys) measured at annual study visits. RESULTS: During a median follow-up of 3.9 years, 433 participants had at least 1 AKI episode. Most episodes (92%) had stage 1 or 2 severity. There were decreases in eGFRcr (-2.30 [95% CI, -3.70 to -0.86] mL/min/1.73 m2) and eGFRcys (-3.61 [CI, -6.39 to -0.82] mL/min/1.73 m2) after AKI. However, in fully adjusted models, the decreases were attenuated to -0.38 (CI, -1.35 to 0.59) mL/min/1.73 m2 for eGFRcr and -0.15 (CI, -2.16 to 1.86) mL/min/1.73 m2 for eGFRcys, and the CI bounds included the possibility of no effect. Estimates of changes in eGFR slope after AKI determined by either SCr level (0.04 [CI, -0.30 to 0.38] mL/min/1.73 m2 per year) or cystatin C level (-0.56 [CI, -1.28 to 0.17] mL/min/1.73 m2 per year) also had CI bounds that included the possibility of no effect. LIMITATIONS: Few cases of severe AKI, no adjudication of AKI cause, and lack of information about nephrotoxic exposures after hospital discharge. CONCLUSION: After pre-AKI eGFR, proteinuria, and other covariables were accounted for, the association between mild to moderate AKI and worsening subsequent kidney function in patients with CKD was small. PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.