Publications by authors named "Vin-Cent Wu"

303 Publications

Cortisol-producing-adenoma Related Somatic Mutations in Unilateral Primary Aldosteronism with Concurrent Autonomous Cortisol Secretion - Their Prevalence and Clinical Characteristics.

Eur J Endocrinol 2022 Jul 1. Epub 2022 Jul 1.

V Wu, Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Objective: Concurrent autonomous cortisol secretion(ACS) in patients with primary aldosteronism(PA) was reported more frequently. Several somatic mutations including PRKACA, GNAS, and CTNNB1 were identified in cortisol-producing adenomas(CPAs). The presence of these mutations in unilateral PA(uPA) patients concurrent with ACS(uPA/ACS) is not well known. This study aimed to investigate the prevalence of these mutations and their clinical versus pathological characteristics in uPA/ACS.

Design: Retrospective cohort study.

Methods: 98 uPA patients among the TAIPAI registry having overnight 1-mg dexamethasone suppression test(DST) and adrenalectomy from 2016-2018 were enrolled. Their adrenal tumors were tested for PRKACA, GNAS, and CTNNB1 mutations.

Results: 11 patients had CPA-related mutations (7 PRKACA and 4 GNAS). The patients carrying these mutations had higher post-DST cortisol (5.6 versus. 2.6 μg/dL, p=0.003) and larger adenoma (2.2±0.3 vs. 1.9±0.7 cm, p=0.025). Adenomas with these mutations had a higher prevalence of non-classical uPA (72.7% vs. 26.3%, p=0.014). Numerically, slightly more complete clinical success of uPA patients with these mutations was noticed after adrenalectomy, although it was statistically non-significant. Post-DST cortisol levels, adenoma size >1.9cm, and the interaction of adenoma size >1.9cm with potassium level were found to be associated with the presence of these mutations.

Conclusion: Our study showed that CPA-related mutations were detected in 36.7% of uPA/ACS adenomas. The presence of these mutations was associated with higher post-DST cortisol levels, larger adenoma sizes, and a high percentage of non-classical uPA. However, these mutations did not significantly affect clinical and biochemical outcomes after adrenalectomy of uPA/ACS patients but they showed a better trend.
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http://dx.doi.org/10.1530/EJE-22-0286DOI Listing
July 2022

Distinct Subtyping of Successful Weaning from Acute Kidney Injury Requiring Renal Replacement Therapy by Consensus Clustering in Critically Ill Patients.

Biomedicines 2022 Jul 7;10(7). Epub 2022 Jul 7.

Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan.

Clinical decisions regarding the appropriate timing of weaning off renal replacement therapy (RRT) in critically ill patients are complex and multifactorial. The aim of the current study was to identify which critical patients with acute kidney injury (AKI) may be more likely to be successfully weaned off RRT using consensus cluster analysis. In this study, critically ill patients who received RRT at three multicenter referral hospitals at several timepoints from August 2016 to July 2018 were enrolled. An unsupervised consensus clustering algorithm was used to identify distinct phenotypes. The outcomes of interest were the ability to wean off RTT and 90-day mortality. A total of 124 patients with AKI requiring RRT (AKI-RRT) were enrolled. The 90-day mortality rate was 30.7% (38/124), and 49.2% (61/124) of the patients were successfully weaned off RRT for over 90 days. The consensus clustering algorithm identified three clusters from a total of 45 features. The three clusters had distinct features and could be separated according to the combination of urinary neutrophil gelatinase-associated lipocalin to creatinine ratio (uNGAL/Cr), Sequential Organ Failure Assessment (SOFA) score, and estimated glomerular filtration rate at the time of weaning off RRT. uNGAL/Cr (hazard ratio [HR] 2.43, 95% confidence interval [CI]: 1.36-4.33) and clustering phenotype (cluster 1 vs. 3, HR 2.7, 95% CI: 1.11-6.57; cluster 2 vs. 3, HR 44.5, 95% CI: 11.92-166.39) could predict 90-day mortality or re-dialysis. Almost half of the critical patients with AKI-RRT could wean off dialysis for over 90 days. Urinary NGAL/Cr and distinct clustering phenotypes could predict 90-day mortality or re-dialysis.
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http://dx.doi.org/10.3390/biomedicines10071628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9313082PMC
July 2022

A Novel Somatic Mutation of p.V1937M in Unilateral Primary Hyperaldosteronism.

Front Endocrinol (Lausanne) 2022 9;13:816476. Epub 2022 Jun 9.

Department of Urology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.

Background: Somatic mutations for excess aldosterone production have been frequently identified as important roles in the pathogenesis of unilateral primary hyperaldosteronism (uPA). Although mutation represents a minor etiology in primary aldosteronism, it plays a significant role in causing uPAs in sporadic cases.

Objective: To identify novel somatic mutation in patients with uPA and investigate the pathophysiological, immunohistological, and clinical characteristics of the variant.

Methods: We applied a customized and targeted gene panel next-generation sequencing approach to detect mutations from the uPA cohort in Taiwan Primary Aldosteronism Investigation study group. Information from pre-diagnostic to postoperative data was collected, including past history, medications, blood pressure readings, biochemical data, and image studies. The functional role of the variant was confirmed by studies, demonstrating aldosterone production in variant-transfected human adrenal cell lines.

Results: We identified a novel somatic mutation c.5809G>A (p.Val1937Met) in a uPA case. The gene encodes the pore-forming alpha-1H subunit of the voltage-dependent T-type calcium channel Cav3.2. This somatic p.V1937M variant showed excellent clinical and biochemical outcomes after ipsilateral adrenalectomy. The functional effect of somatic p.V1937M variant results in increased CYP11B2 expression and aldosterone biosynthesis in HAC15 cells. A distinct heterogeneous foamy pattern of CYP11B2 and CYP17A1 expression was identified in immunohistological staining, supporting the pathological evidence of aldosterone synthesis.

Conclusions: The somatic mutation of p.V1937M might be a pathogenic driver in aldosterone overproduction. This study provides new insight into the molecular mechanism and disease outcomes of uPA.
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http://dx.doi.org/10.3389/fendo.2022.816476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9218183PMC
June 2022

Aldosterone Suppresses Endothelial Mitochondria through Mineralocorticoid Receptor/Mitochondrial Reactive Oxygen Species Pathway.

Biomedicines 2022 May 12;10(5). Epub 2022 May 12.

Department of Internal Medicine, Division of Cardiology, College of Medicine, National Taiwan University Hospital, National Taiwan University, Taipei 100, Taiwan.

Excessive aldosterone secretion causes endothelial dysfunction, vascular inflammation, and vascular fibrosis in patients with primary aldosteronism (PA). Endothelial function is closely related to endothelial mitochondria. However, the effects of elevated aldosterone levels on endothelial mitochondria remain unclear. In this study, we used primary cultured human umbilical vein endothelial cells (HUVECs) to investigate the effects of aldosterone on endothelial mitochondria. Mineralocorticoid receptor (MR) small interfering (si)RNA or glucocorticoid receptor (GR) siRNA were used to confirm the pathway by which aldosterone exerts its effects on the mitochondria of HUVECs. The results showed that excess aldosterone suppressed mitochondrial DNA copy numbers, anti-mitochondrial protein, and SOD2 protein expression in a dose- and time-dependent manner. These effects were attenuated by treatment with MR siRNA, but not with GR siRNA. Furthermore, it was attenuated by treatment with a mitochondria-targeted antioxidant (Mito-TEMPO, associated with mitochondrial reactive oxygen species (ROS) production), but not N-acetyl-L-cysteine (associated with cytosolic ROS production), which suggests that the process was through the mitochondrial ROS pathway, but not the cytosolic ROS pathway. In conclusion, aldosterone excess suppressed endothelial mitochondria through the MR/mitochondrial ROS pathway.
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http://dx.doi.org/10.3390/biomedicines10051119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9138689PMC
May 2022

Divergent Characteristics of T-Cell Receptor Repertoire Between Essential Hypertension and Aldosterone-Producing Adenoma.

Front Immunol 2022 10;13:853403. Epub 2022 May 10.

Master Program in Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.

Aldosterone-producing adenoma (APA) is a benign adrenal tumor that results in persistent hyperaldosteronism. As one major subtype of primary aldosteronism, APA leads to secondary hypertension that is associated with immune dysregulation. However, how the adaptive immune system, particularly the T-cell population, is altered in APA patients remains largely unknown. Here, we performed TCR sequencing to characterize the TCR repertoire between two age-matched groups of patients: one with APA and the other one with essential hypertension (EH). Strikingly, we found a significant reduction of TCR repertoire diversity in the APA group. Analyses on TCR clustering and antigen annotation further showed that the APA group possessed lower diversity in TCR clonotypes with non-common antigen-specific features, compared with the EH group. In addition, our results indicated that the strength of correlation between generation probabilities and frequencies of TCR clonotypes was significantly higher in the APA group than that in the EH group. Finally, we observed that clinical features, including plasma aldosterone level, aldosterone-renin ratio, and blood sodium level, were positively associated with the strength of correlation between generation and abundance of TCR clonotypes in the APA group. Our findings unveiled the correlation between T-cell immune repertoire and APA, suggesting a critical role of such adrenal adenoma in the T-cell immunity of patients with hypertension.
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http://dx.doi.org/10.3389/fimmu.2022.853403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9127864PMC
May 2022

Radiomics utilization to differentiate nonfunctional adenoma in essential hypertension and functional adenoma in primary aldosteronism.

Sci Rep 2022 05 25;12(1):8892. Epub 2022 May 25.

Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.

We performed the present study to investigate the role of computed tomography (CT) radiomics in differentiating nonfunctional adenoma and aldosterone-producing adenoma (APA) and outcome prediction in patients with clinically suspected primary aldosteronism (PA). This study included 60 patients diagnosed with essential hypertension (EH) with nonfunctional adenoma on CT and 91 patients with unilateral surgically proven APA. Each whole nodule on unenhanced and venous phase CT images was segmented manually and randomly split into training and test sets at a ratio of 8:2. Radiomic models for nodule discrimination and outcome prediction of APA after adrenalectomy were established separately using the training set by least absolute shrinkage and selection operator (LASSO) logistic regression, and the performance was evaluated on test sets. The model can differentiate adrenal nodules in EH and PA with a sensitivity, specificity, and accuracy of 83.3%, 78.9% and 80.6% (AUC = 0.91 [0.72, 0.97]) in unenhanced CT and 81.2%, 100% and 87.5% (AUC = 0.98 [0.77, 1.00]) in venous phase CT, respectively. In the outcome after adrenalectomy, the models showed a favorable ability to predict biochemical success (Unenhanced/venous CT: AUC = 0.67 [0.52, 0.79]/0.62 [0.46, 0.76]) and clinical success (Unenhanced/venous CT: AUC = 0.59 [0.47, 0.70]/0.64 [0.51, 0.74]). The results showed that CT-based radiomic models hold promise to discriminate APA and nonfunctional adenoma when an adrenal incidentaloma was detected on CT images of hypertensive patients in clinical practice, while the role of radiomic analysis in outcome prediction after adrenalectomy needs further investigation.
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http://dx.doi.org/10.1038/s41598-022-12835-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9132956PMC
May 2022

RTL1/PEG11 imprinted in human and mouse brain mediates anxiety-like and social behaviors and regulates neuronal excitability in the locus coeruleus.

Hum Mol Genet 2022 May 14. Epub 2022 May 14.

Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan.

RTL1/PEG11 which has been associated with anxiety disorders is a retrotransposon-derived imprinted gene in the placenta. However, imprinting patterns and functions of RTL1 in the brain have not been well-investigated. We found Rtl1 was paternally, but not maternally, expressed in brain stem, thalamus, and hypothalamus of mice, and imprinting status of RTL1 was maintained in human brain. Paternal Rtl1 knockout (Rtl1m+/p-) mice had higher neonatal death rates due to impaired suckling, and low body weights beginning on embryonic day 16.5. High paternal expression of Rtl1 was detected in the locus coeruleus (LC) and Rtl1m+/p- mice showed an increased delay in time of onset for action potentials and inward currents with decreased neuronal excitability of LC neurons. Importantly, Rtl1m+/p- mice exhibited behaviors associated with anxiety, depression, fear-related learning and memory, social dominance, and low locomotor activity. Taken together, our findings demonstrate RTL1 is imprinted in brain, mediates emotional and social behaviors, and regulates excitability in LC neurons.
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http://dx.doi.org/10.1093/hmg/ddac110DOI Listing
May 2022

Autonomous cortisol secretion is associated with worse arterial stiffness and vascular fibrosis in primary aldosteronism: a cross-sectional study with follow-up data.

Eur J Endocrinol 2022 Jun 7;187(1):197-208. Epub 2022 Jun 7.

Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.

Objective: The presence of autonomous cortisol secretion (ACS) in patients with primary aldosteronism (PA) is common and potentially associated with poor outcomes. The aim of this study was to investigate the association between ACS and vascular remodeling in PA patients.

Design And Methods: We prospectively enrolled 436 PA patients from October 2006 to November 2019. ACS (defined as a cortisol level >1.8 μg/dL after a 1 mg dexamethasone suppression test) was detected in 23% of the PA patients. Propensity score matching (PSM) with age, sex, systolic and diastolic blood pressure was performed. The brachial-ankle pulse wave velocity (baPWV) was examined at baseline and 1 year after targeted treatment. Small arteries of periadrenal fat in 46 patients were stained with Picro Sirus red to quantify the severity of vascular fibrosis.

Results: After PSM, the PA patients with ACS had a significantly higher prevalence of diabetes mellitus, higher plasma aldosterone concentration and higher aldosterone-to-renin ratio. The baseline mean baPWV was also significantly higher in the PA patients with ACS. After multivariable regression analysis, the presence of ACS was a significant predictor of worse baseline mean baPWV (β: 235.745, 95% CI: 59.602-411.888, P = 0.010). In addition, the PA patients with ACS had worse vascular fibrosis (fibrosis area: 25.6 ± 8.4%) compared to those without ACS (fibrosis area: 19.8 ± 7.7%, P = 0.020). After 1 year of PA treatment, baPWV significantly improved in both groups.

Conclusion: The presence of ACS in PA patients is associated with worse arterial stiffness and vascular remodeling.
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http://dx.doi.org/10.1530/EJE-21-1157DOI Listing
June 2022

Angiotensin II Receptor Blocker Associated With Less Outcome Risk in Patients With Acute Kidney Disease.

Front Pharmacol 2022 20;13:714658. Epub 2022 Apr 20.

Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan.

The aim of this study was to explore the respective use of angiotensin-converting-enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) on the outcomes of patients who could be weaned from dialysis-requiring acute kidney injury (AKI-D). This case-control study enrolled 41,731 patients who were weaned from AKI-D for at least 7 days from Taiwan's National Health Insurance Administration. We further grouped AKI-D patients according to ACEi and ARB use to evaluate subsequent risks of all-cause mortality and re-dialysis. The outcomes included the all-cause mortality and new-onset of end-stage kidney disease (ESKD; re-dialysis) following withdraw from AKI-D. A total of 17,141 (41.1%) patients surviving AKI-D could be weaned from dialysis for at least 7 days. The overall events of mortality were 366 (48.9%) in ACEi users, 659 (52.1%) in ARB users, and 6,261 (41.3%) in ACEi/ARB nonusers, during a mean follow-up period of 1.01 years after weaning from AKI-D. In regard to all-cause of mortality, pre-dialysis ARB users had lower incidence than ACEi users [hazard ratio (HR 0.82), = 0.017]. Compared with ACEi/ARB nonusers, continuing ARB users had a significantly low risk of long-term all-cause mortality (adjusted hazard ratio 0.51, = 0.013) after propensity score matching. However, new users of ACEi at the acute kidney disease (AKD) period had a higher risk of re-dialysis after weaning than ACEi/ARB nonusers (aHR 1.82, < 0.001), whereas neither ACEi nor ARB users confronted significantly increased risks of hyperkalemia after weaning. Compared with patients without ACEi/ARB, those continuing to use ARB before the event and after weaning had low all-cause mortality, while new users of ACEi at AKD had increased risk of re-dialysis. AKI-D patients continuing to use ACEi or ARB did not have higher risk of hyperkalemia. Future prospective randomized trials are expected to confirm these findings.
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http://dx.doi.org/10.3389/fphar.2022.714658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065477PMC
April 2022

Accelerated versus watchful waiting strategy of kidney replacement therapy for acute kidney injury: a systematic review and meta-analysis of randomized clinical trials.

Clin Kidney J 2022 May 14;15(5):974-984. Epub 2022 Jan 14.

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Background: Critically ill patients with severe acute kidney injury (AKI) requiring kidney replacement therapy (KRT) have a grim prognosis. Recently, multiple studies focused on the impact of KRT initiation time [i.e., accelerated versus watchful waiting KRT initiation (WWS-KRT)] on patient outcomes. We aim to review the results of all related clinical trials.

Methods: In this systematic review, we searched all relevant randomized clinical trials from January 2000 to April 2021. We assessed the impacts of accelerated versus WWS-KRT on KRT dependence, KRT-free days, mortality and adverse events, including hypotension, infection, arrhythmia and bleeding. We rated the certainty of evidence according to Cochrane methods and the GRADE approach.

Results: A total of 4932 critically ill patients with AKI from 10 randomized clinical trials were included in this analysis. The overall 28-day mortality rate was 38.5%. The 28-day KRT-dependence rate was 13.0%. The overall incident of KRT in the accelerated group was 97.4% and 62.8% in the WWS-KRT group. KRT in the accelerated group started 36.7 h earlier than the WWS-KRT group. The two groups had similar risks of 28-day [pooled log odds ratio (OR) 1.001, = 0.982] and 90-day (OR 0.999, = 0.991) mortality rates. The accelerated group had a significantly higher risk of 90-day KRT dependence (OR 1.589, = 0.007), hypotension (OR 1.687, < 0.001) and infection (OR 1.38, = 0.04) compared with the WWS-KRT group.

Conclusions: This meta-analysis revealed that accelerated KRT leads to a higher probability of 90-day KRT dependence and dialysis-related complications without any impact on mortality rate when compared with WWS-KRT. Therefore, we suggest the WWS-KRT strategy for critically ill patients.
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http://dx.doi.org/10.1093/ckj/sfac011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9050527PMC
May 2022

Factors associated with renal function change after unilateral adrenalectomy in patients with primary aldosteronism.

Int J Urol 2022 Aug 26;29(8):831-837. Epub 2022 Apr 26.

Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.

Objectives: Decreased glomerular filtration rate has been reported in patients with primary aldosteronism after unilateral adrenalectomy. Glomerular hyperfiltration has been assumed to mask the preoperative subtle renal impairment. In this study, we investigated predictors for decreased estimated glomerular filtration rate after adrenalectomy in patients with primary aldosteronism.

Methods: From January 2006 through September 2018, 328 patients with confirmatory diagnoses of primary aldosteronism received unilateral laparoscopic adrenalectomy and subsequent follow-up for 12 months. We prospectively collected related parameters of the clinical outcomes and renal function to identify predictors of renal function impairment at 12 months after surgery.

Results: Patients were stratified into three groups by preoperative estimated glomerular filtration rate level: 144 (43.9%) with estimated glomerular filtration rate ≥90, 130 (39.6%) with estimated glomerular filtration rate within 60-89.9, and 54 (16.5%) with estimated glomerular filtration rate <60 mL/min/1.73 m . The estimated glomerular filtration rate decreased significantly at the 6th month and remained stable at the 12th month, postoperatively. Patients with estimated glomerular filtration rate ≥90 had better clinical outcome with 59.6% success rate (P = 0.006) among three groups. Multivariate logistic regression analysis indicated that preoperative estimated glomerular filtration rate (odds ratio 1.012, P = 0.02) and hypokalemia (odds ratio 2.018, P = 0.024) were associated with renal impairment at 12th month after adrenalectomy. Multivariate linear regression analysis revealed high preoperative estimated glomerular filtration rate (β = 0.261, P < 0.001), high preoperative systolic blood pressure (β = 0.168, P = 0.003), high level of microalbuminuria (β = 0.024, P = 0.001), and low level of serum potassium (β = -4.883, P = 0.007) were associated with estimated glomerular filtration rate percentage decline at 12th month after adrenalectomy.

Conclusions: Estimated glomerular filtration rate declined significantly after adrenalectomy in patients with estimated glomerular filtration rate ≥90. The study provided important information to identify primary aldosteronism patients with higher risk of estimated glomerular filtration rate decline after adrenalectomy and might help to adopt early interventions to improve the outcomes.
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http://dx.doi.org/10.1111/iju.14905DOI Listing
August 2022

Case Report: Primary Aldosteronism Due to Bilateral Aldosterone-Producing Micronodules With HISTALDO Classical and Contralateral Non-Classical Pathology.

Front Endocrinol (Lausanne) 2022 18;13:816754. Epub 2022 Mar 18.

Department of Urology, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan.

Background: Non-classical multiple aldosterone-producing micronodules/nodules (mAPM/mAPN) could be the pathogenesis of primary aldosteronism (PA). The co-existence of mAPM with adenomas harboring somatic mutations has not previously been reported.

Methods: We presented a PA patient with bilateral mAPM and concomitant autonomous cortisol secretion (ACS).

Results: A 46-year-old Taiwanese woman presented with hypertension, hypokalemia, and bilateral adrenal adenomas. A 1 mg low-dose dexamethasone suppression test showed elevated morning serum cortisol. An adrenal vein sampling (AVS) suggested a left-sided lateralization of hyperaldosteronism. A right partial adrenalectomy and a left total adrenalectomy were performed. The patient showed biochemical and hypertension remission after the operation. This patient had bilateral mAPM with concomitant ACS, a right histopathologically classical PA adenoma, and a left non-classical PA adenoma. The right adrenal adenoma showed CYP11B1-negative and CYP11B2-positive staining and harbored the -L168R mutation. The left adrenal adenoma showed CYP11B1-positive and CYP11B2-negative staining and harbored the L206R mutation.

Conclusion: In a PA patient with concomitant ACS, bilateral APM could coexist with both histopathologically classical and non-classical PA adenomas, each with different somatic mutations. The presence of ACS could lead to the misinterpretation of AVS results.
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http://dx.doi.org/10.3389/fendo.2022.816754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8989467PMC
April 2022

Urinary Biomarkers Can Predict Weaning From Acute Dialysis Therapy in Critically Ill Patients.

Arch Pathol Lab Med 2022 Mar 21. Epub 2022 Mar 21.

The Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan (T. T-M. Huang, Chen, Wu).

Context.—: Critically ill patients with acute kidney injury (AKI) requiring renal replacement therapy (RRT) have a poor prognosis. Several urinary AKI biomarkers have been proposed to predict renal recovery, but with limited discriminatory ability.

Objective.—: To validate the predictive performances of novel biomarkers to identify which critical patients with AKI may successfully wean from RRT.

Design.—: We prospectively recorded and analyzed clinical variables at several time points: (1) before starting RRT, (2) at the time of weaning off RRT, and (3) 24 hours after stopping RRT. A total of 140 critically ill patients who received RRT at a multicenter referral hospital from August 2016 to January 2019 were enrolled. The outcomes of interest were the ability to wean from RRT and 90-day mortality.

Results.—: The 90-day mortality rate was 13.6% (19 of 140), and 47.9% (67 of 140) of the patients were successfully weaned from RRT. Cluster analysis showed that the following biomarkers were correlated with estimated glomerular filtration rate at the time of weaning off RRT: urinary neutrophil gelatinase-associated lipocalin, kidney injury molecule 1, hemojuvelin, C-C motif chemokine ligand 14, interleukin 18, and liver-type fatty acid-binding protein (L-FABP). Among these, urinary L-FABP/creatinine (uL-FABP/Cr) at the time of weaning off RRT showed the best predictive performance for mortality (area under the receiver operating characteristic curve = 0.79). Taking mortality as a competing risk, Cox proportional hazards analysis indicated that a low uL-FABP/Cr (log) level was an independent prognostic factor for weaning from RRT (subdistribution hazard ratio, 0.35; P = .01).

Conclusions.—: uL-FABP/Cr at the time of weaning off RRT could predict weaning from RRT and 90-day mortality.
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http://dx.doi.org/10.5858/arpa.2021-0411-OADOI Listing
March 2022

KCNJ5 Somatic Mutation Is Associated With Higher Aortic Wall Thickness and Less Calcification in Patients With Aldosterone-Producing Adenoma.

Front Endocrinol (Lausanne) 2022 2;13:830130. Epub 2022 Mar 2.

Department of Business Administration and Graduate School of Service Management, Chihlee University of Technology, New Taipei City, Taiwan.

Objective: Primary aldosteronism (PA) is the most common type of secondary hypertension, and it is associated with a higher rate of cardiovascular complications. KCNJ5 somatic mutations have recently been identified in aldosterone-producing adenoma (APA), however their influence on vascular remodeling and injury is still unclear. The aim of this study was to investigate the association between KCNJ5 somatic mutation status and vascular status.

Methods: We enrolled 179 APA patients who had undergone adrenalectomy from a prospectively maintained database, of whom 99 had KCNJ5 somatic mutations. Preoperative clinical, biochemical and imaging data of abdominal CT, including abdominal aortic calcification (AAC) score, aortic diameter and wall thickness at levels of superior (SMA) and inferior (IMA) mesenteric arteries were analyzed.

Results: After propensity score matching for age, sex, body mass index, triglycerides and low-density lipoprotein, there were 48 patients in each KCNJ5 (+) and KCNJ5 (-) group. Mutation carriers had a lower AAC score (217.3 ± 562.2 vs. 605.6 ± 1359.1, P=0.018), higher aortic wall thickness (SMA level: 2.2 ± 0.6 mm vs. 1.8 ± 0.6 mm, P=0.006; IMA level: 2.4 ± 0.6 mm vs. 1.8 ± 0.7 mm, P<0.001) than non-carriers. In multivariate analysis, KCNJ5 mutations were independently associated with AAC score (P=0.014) and aortic wall thickness (SMA level: P<0.001; IMA level: P=0.004). After adrenalectomy, mutation carriers had less aortic wall thickness progression than non-carriers (Δthickness SMA: -0.1 ± 0.8 mm vs. 0.9 ± 0.6 mm, P=0.024; IMA: -0.1 ± 0.6 mm vs. 0.8 ± 0.7 mm, P=0.04).

Conclusion: KCNJ5 mutation carriers had less calcification burden of the aorta, thickened aortic wall, and less wall thickness progression than non-carriers.
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http://dx.doi.org/10.3389/fendo.2022.830130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8924484PMC
April 2022

The Relationship Between Renal Stones and Primary Aldosteronism.

Front Endocrinol (Lausanne) 2022 9;13:828839. Epub 2022 Feb 9.

Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

Introduction: The association between primary aldosteronism (PA) and nephrolithiasis is still unclear. The hypercalciuria and hypocitraturia of PA patients might be the reason leading to recurrent calcium nephrolithiasis. This study aimed to evaluate the relationship between PA and renal stones, including stone size and density.

Materials And Methods: From February 2010 to March 2021, we retrospectively collected 610 patients who presented to our medical center with hypertension history, and all these patients, suspicious of PA, had PA data survey. In total, 147 patients had kidney stone and were divided into 44 patients with essential hypertension as group 1 and 103 patients with PA as group 2. Pearson χ test and independent Student's t-test were performed to examine the differences among variables.

Results: The mean age was 54.4 ± 12.0 years in group 1 and 53.0 ± 11.1 years in group 2. The incidence rate of renal stones in the PA group was around 24%. No significant differences between the two groups were found for gender, systolic/diastolic blood pressure, duration of hypertension, diabetes mellitus history, and laterality of kidney stone; however, mean stone size was 4.0 ± 3.3 mm in group 1 and 6.5 ± 7.2 mm in group 2, with a significantly larger renal stone size noted in the PA group than that in the essential hypertension group (p = 0.004). Hounsfield unit (HU) density was higher in the PA group the essential hypertension cohort, although this did not reach a significant difference (p = 0.204).

Conclusions: Our study revealed that PA patients had a higher incidence rate of renal stones compared to that of the general population. Besides, the PA-related renal stones also presented as larger and harder than those of the essential hypertension group. Further investigation concerning the association between PA and renal stones is warranted.
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http://dx.doi.org/10.3389/fendo.2022.828839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8864315PMC
March 2022

Vancomycin-Associated Acute Kidney Injury: A Narrative Review from Pathophysiology to Clinical Application.

Int J Mol Sci 2022 Feb 12;23(4). Epub 2022 Feb 12.

Division of Nephrology, Department of Internal Medicine, Camillian Saint Mary's Hospital Luodong, Yilan 265, Taiwan.

Vancomycin is the most frequently used antibiotic, accounting for up to 35% of hospitalized patients with infection, because of its optimal bactericidal effectiveness and relatively low price. Vancomycin-associated AKI (VA-AKI) is a clinically relevant but not yet clearly understood entity in critically ill patients. The current review comprehensively summarizes the pathophysiological mechanisms of, biomarkers for, preventive strategies for, and some crucial issues with VA-AKI. The pathological manifestations of VA-AKI include acute tubular necrosis, acute tubulointerstitial nephritis (ATIN), and intratubular crystal obstruction. The proposed pathological mechanisms of VA-AKI include oxidative stress and allergic reactions induced by vancomycin and vancomycin-associated tubular casts. Concomitant administration with other nephrotoxic antibiotics, such as piperacillin-tazobactam, high vancomycin doses, and intermittent infusion strategies compared to the continuous infusion are associated with a higher risk of VA-AKI. Several biomarkers could be applied to predict and diagnose VA-AKI. To date, no promising therapy is available. Oral steroids could be considered for patients with ATIN, whereas hemodialysis might be applied to remove vancomycin from the patient. In the future, disclosing more promising biomarkers that could precisely identify populations susceptible to VA-AKI and detect VA-AKI occurrence early on, and developing pharmacological agents that could prevent or treat VA-AKI, are the keys to improve the prognoses of patients with severe infection who probably need vancomycin therapy.
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http://dx.doi.org/10.3390/ijms23042052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8877514PMC
February 2022

Trends in the incidence and prevalence of end-stage kidney disease requiring dialysis in Taiwan: 2010-2018.

J Formos Med Assoc 2022 Feb 22;121 Suppl 1:S5-S11. Epub 2022 Jan 22.

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address:

Background/purpose: Taiwan has the highest incidence and prevalence of end-stage kidney disease (ESKD) worldwide. However, the epidemiologic features of ESKD requiring dialysis in Taiwan are unclear.

Methods: Our study population included all patients undergoing chronic dialysis (i.e., receiving dialysis treatment for at least three successive months) from the National Health Insurance Research Database from 2010 to 2018. Dialysis was defined using ICD-9-CM order codes for dialysis treatment. The age-standardized incidence and prevalence rates were calculated based on the World Health Organization standard population.

Results: The mean age was 47.7 ± 15.4 years at dialysis initiation. The incidence of ESKD requiring dialysis increased steadily during the study period, whereas the age-standardized incidence rate remained constant. The increased rate was particularly prevalent in men aged 65-74 and 75+ years. Additionally, the percentage of patients with estimated glomerular filtration rates > 10 mL/min/1.73 m at dialysis inception increased during the study period, especially in persons aged 75+ years. Most patients chose hemodialysis as the initial dialysis modality, including 86.8% in 2010 and 90.6% in 2018. The prevalence of dialysis increased substantially between 2010 and 2018, whereas the age-standardized prevalence of dialysis remained stable. The increasing trend was especially prominent in men aged ≥ 65 years. Among the patients on dialysis, the proportion of patients with mean dialysis times of more than 10 years has been increasing.

Conclusion: The annual incidence and prevalence of dialysis increased steadily from 2010 to 2018, whereas the age-standardized incidence and prevalence of dialysis remained stable. The increased numbers of patients undergoing incident and prevalent dialysis were mostly elderly, especially men aged ≥65 years. Age-based prevention strategies and multidisciplinary care should be implemented to target the elderly population at risk of developing ESKD.
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http://dx.doi.org/10.1016/j.jfma.2021.12.013DOI Listing
February 2022

Diabetes mellitus is associated with worse baseline and less post-treatment recovery of arterial stiffness in patients with primary aldosteronism.

Ther Adv Chronic Dis 2022 13;13:20406223211066727. Epub 2022 Jan 13.

Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, No. 7, Chung-Shan South Road, Taipei 100 Cardiovascular Center, National Taiwan University Hospital, Taipei.

Background: Aldosterone excess in primary aldosteronism (PA) has been linked to insulin resistance, and diabetes mellitus has been associated with increased arterial stiffness and worse cardiovascular outcomes. However, the impact of diabetes on baseline and post-treatment arterial stiffness in patients with PA is unknown.

Methods: This study prospectively enrolled 1071 PA patients, of whom 177 had diabetes and 894 did not. Clinical, biochemical, and brachial-ankle pulse wave velocity (baPWV) data were analyzed at baseline and 1 year after PA-specific treatment. After propensity score matching of age, sex, body mass index, systolic and diastolic blood pressure, hypertension duration, and number of antihypertensive medications, 144 patients with diabetes and 320 without diabetes were included for further analysis.

Results: After propensity score matching, the baseline characteristics were balanced between the diabetes and nondiabetes groups except for fasting glucose, HbA1c, and lipid profiles. The patients with diabetes had significantly worse baseline baPWV compared with those without diabetes. After multivariable linear regression, the presence of diabetes mellitus remained a significant predictor of worse baseline mean baPWV (β: 46.3, 95% confidence interval: 2.9-89.7,  = 0.037). After 1 year of PA-specific treatment, only the nondiabetes group had significant recovery of mean baPWV (1661.8 ± 332.3 to 1565.0 ± 329.2 cm/s,  < 0.001; Δ = -96.8 ± 254.6 cm/s). In contrast, the diabetes group had less improvement (1771.2 ± 353.8 cm/s to 1742.0 ± 377.2 cm/s,  = 0.259; Δ = -29.2 ± 263.2 cm/s) even though the systolic and diastolic blood pressure significantly improved in both groups.

Conclusion: The presence of diabetes mellitus in PA patients was associated with worse baseline and less post-treatment recovery of arterial stiffness.
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http://dx.doi.org/10.1177/20406223211066727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8771743PMC
January 2022

Predialysis serum lactate levels could predict dialysis withdrawal in Type 1 cardiorenal syndrome patients.

EClinicalMedicine 2022 Feb 10;44:101232. Epub 2022 Jan 10.

Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Background: Renal replacement therapy (RRT) is an effective rescue therapy for Type 1 cardiorenal syndrome (CRS). Previous studies have demonstrated that type 1 CRS patients with severe renal dysfunction were susceptible to sepsis, and that serum lactate has been correlated with the risk of mortality in patients with sepsis. However, the association between serum lactate level and the prognosis of type 1 CRS patients requiring RRT is unknown.

Methods: An inception cohort of 500 type 1 CRS patients who received RRT in a tertiary-care referral hospital in Taiwan from August 2011 to January 2018 were enrolled. The outcomes of interest were dialysis withdrawal and 90-day mortality. The results were further externally validated using sampling data of type 1 CRS patients requiring dialysis from multiple tertiary-care centers.

Findings: The 90-day mortality rate was 52.8% and the incidence rate of dialysis withdrawal was 34.8%. Lower pre-dialysis lactate was correlated with a higher rate of dialysis withdrawal and lower rate of mortality. Generalized additive model showed that 4.2 mmol/L was an adequate cut-off value of lactate to predict mortality. Taking mortality as a competing risk, Fine-Gray subdistribution hazard analysis further indicated that a low lactate level (≦ 4.2 mmol/L) was an independent predictor for the possibility of dialysis withdrawal, as also shown in external validation. The interaction of quick Sequential Organ Failure Assessment score and lactate was associated with dialysis dependence in a disease severity-dependent manner. Furthermore, the associations between hyperlactatemia and dialysis dependence were consistent in the patients with and without sepsis.

Interpretation: Serum lactate level is accurate and capable of forecasting the prognosis along with qSOFA severity for clinical decision-making for treating type 1 CRS patients. Further studies are needed to validate our results.

Funding: This study was supported by grants from Taiwan National Science Council [104-2314-B-002-125-MY3,106-2314-B-002-166-MY3,107-2314-B-002-026-MY3], National Taiwan University Hospital [106-FTN20,106-P02,UN106-014,106-S3582,107-S3809,107-T02,PC1246,VN109-09,109-S4634,UN109-041], Ministry of Science and Technology of the Republic of China [MOST106-2321-B-182-002,106-2314-B-182A-064,MOST107-2321-B-182-004,MOST107-2314-B-182A-138, MOST108-2321-B-182-003,MOST109-2321-B-182-001, MOST108-2314-B-182A-027], Chang Gung Memorial Hospital [CMRPG-2G0361,CMRPG-2H0161,CMRPG-2J0261, CMRPG-2K0091], and Ministry of Health and Welfare of the Republic of China [PMRPG-2L0011].
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http://dx.doi.org/10.1016/j.eclinm.2021.101232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8760464PMC
February 2022

GRAde: a long-read sequencing approach to efficiently identifying the CYP11B1/CYP11B2 chimeric form in patients with glucocorticoid-remediable aldosteronism.

BMC Bioinformatics 2022 Jan 10;22(Suppl 10):613. Epub 2022 Jan 10.

Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.

Background: Glucocorticoid-remediable aldosteronism (GRA) is a form of heritable hypertension caused by a chimeric fusion resulting from unequal crossing over between 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2), which are two genes with similar sequences. Different crossover patterns of the CYP11B1 and CYP11B2 chimeric genes may be associated with a variety of clinical presentations. It is therefore necessary to develop an efficient approach for identifying the differences between the hybrid genes of a patient with GRA.

Results: We developed a long-read analysis pipeline named GRAde (GRA deciphering), which utilizes the nonidentical bases in the CYP11B1 and CYP11B2 genomic sequences to identify and visualize the chimeric form. We sequenced the polymerase chain reaction (PCR) products of the CYP11B1/CYP11B2 chimeric gene from 36 patients with GRA using the Nanopore MinION device and analyzed the sequences using GRAde. Crossover events were identified for 30 out of the 36 samples. The crossover sites appeared in the region exhibiting high sequence similarity between CYP11B1 and CYP11B2, and 53.3% of the cases were identified as having a gene conversion in intron 2. More importantly, there were six cases for whom the PCR products indicated a chimeric gene, but the GRAde results revealed no crossover pattern. The crossover regions were further verified by Sanger sequencing analysis.

Conclusions: PCR-based target enrichment followed by long-read sequencing is an efficient and precise approach to dissecting complex genomic regions, such as those involved in GRA mutations, which could be directly applied to clinical diagnosis. The scripts of GRAde are available at https://github.com/hsu-binfo/GRAde .
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http://dx.doi.org/10.1186/s12859-022-04561-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8750845PMC
January 2022

Characteristics and Outcomes in Primary Aldosteronism Patients Harboring Glucocorticoid-Remediable Aldosteronism.

Biomedicines 2021 Dec 2;9(12). Epub 2021 Dec 2.

Department of Internal Medicine, National Taiwan University Hospital, Room 1555, Clinical Research Building, 7 Chung-Suan South Road, Taipei 100, Taiwan.

The clinical characteristics and surgical prognosis of glucocorticoid-remediable aldosteronism (GRA, also known as familial hyperaldosteronism type 1, FH-I) have not been widely studied. Using data from the Taiwan Primary Aldosteronism Investigation (TAIPAI) registry retrospectively, we describe the associated clinical factors for GRA and clinical predictors of surgical outcomes among identified GRA patients. We found 79 GRA-positive (51.2 ± 13.8 years; women 39 (49.4%)) and 114 GRA-negative primary aldosteronism (PA) patients matched with age, gender, and body mass index. Lower plasma aldosterone concentrations (PACs) and aldosterone-renin ratios were found among GRA-positive individuals. Multivariable logistic regression demonstrated that a PAC ≤ 40 ng/dL could predict concealed GRA individuals (OR 0.523, = 0.037). Low serum potassium (OR 0.285, = 0.008), but not the presence of GRA, was associated with hypertension-remission. Of note, PRA (OR 11.645, = 0.045) and hypokalemia (OR 0.133, = 0.048) were associated with hypertension-remission in GRA patients. Unilateral primary aldosteronism patients harboring concomitant GRA were not associated with inferior hypertension-remission after an adrenalectomy. Low serum potassium and high PRA were positively associated with hypertension-remission in GRA patients.
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http://dx.doi.org/10.3390/biomedicines9121816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8698750PMC
December 2021

Editorial: Diagnosis and Treatment of Primary Aldosteronism: from Clinical Origin to Translational Research.

Front Endocrinol (Lausanne) 2021 30;12:781105. Epub 2021 Nov 30.

Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan.

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http://dx.doi.org/10.3389/fendo.2021.781105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8669742PMC
February 2022

Feasibility of Imaging-Guided Adrenalectomy in Young Patients With Primary Aldosteronism.

Hypertension 2022 01 17;79(1):187-195. Epub 2021 Nov 17.

3rd Department of Medicine, Charles University Prague, General Hospital, Czech Republic (J.W., Z.K.).

Many of the patients with primary aldosteronism (PA) are denied curative adrenalectomy because of limited availability or failure of adrenal vein sampling. It has been suggested that adrenal vein sampling can be omitted in young patients with a unilateral adrenal nodule, who show a florid biochemical PA phenotype. As this suggestion was based on a very low quality of evidence, we tested the applicability and accuracy of imaging, performed by computed tomography and/or magnetic resonance, for identification of unilateral PA, as determined by biochemical and/or clinical cure after unilateral adrenalectomy. Among 1625 patients with PA submitted to adrenal vein sampling in a multicenter multiethnic international study, 473 were ≤45 years of age; 231 of them had exhaustive imaging and follow-up data. Fifty-three percentage had a unilateral adrenal nodule, 43% had no nodules, and 4% bilateral nodules. Fifty-six percentage (n=131) received adrenalectomy and 128 were unambiguously diagnosed as unilateral PA. A unilateral adrenal nodule on imaging and hypokalemia were the strongest predictors of unilateral PA at regression analysis. Accordingly, imaging allowed correct identification of the responsible adrenal in 95% of the adrenalectomized patients with a unilateral nodule. The rate raised to 100% in the patients with hypokalemia, who comprised 29% of the total, but fell to 88% in those without hypokalemia. Therefore, a unilateral nodule and hypokalemia could be used to identify unilateral PA in patients ≤45 years of age if adrenal vein sampling is not easily available. However, adrenal vein sampling remains indispensable in 71% of the young patients, who showed no nodules/bilateral nodules at imaging and/or no hypokalemia. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01234220.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.121.18284DOI Listing
January 2022

Long-term mortality and cardiovascular events in patients with unilateral primary aldosteronism after targeted treatments.

Eur J Endocrinol 2021 Dec 20;186(2):195-205. Epub 2021 Dec 20.

Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.

Objective: Long-term outcomes (especially mortality and/or major cardiovascular events (MACE)) of the unilateral primary aldosteronism (uPA) patients who underwent medical or surgery-targeted treatment, relative to those with essential hypertension (EH), have been scarcely reported.

Design And Settings: Using the prospectively designed observational Taiwan Primary Aldosteronism Investigation cohort, we identified 858 uPA cases among 1220 primary aldosteronism patients and another 1210 EH controls.

Exposures: Operated uPA patients were grouped via their 1-year post-therapy statuses.

Results: Primary Aldosteronism Surgical Outcome clinical complete success (hypertension remission) was achieved in 272 (49.9%) of 545 surgically treated uPA patients. After follow-up for 6.3 ± 4.0 years, both hypertension-remissive (hazard ratio (HR): 0.54; P < 0.001) and not-cured (HR: 0.61; P < 0.001) uPA patients showed a lower risk of all-cause mortality than that of EH controls; whereas the not-cured group had a higher risk of incident MACE (sub-hazard ratio (sHR), 1.41; P = 0.037) but similar atrial fibrillation (Af) and congestive heart failure (CHF). Mineralocorticoid receptor antagonist (MRA)-treated uPA patients had higher risks of MACE (sHR: 1.38; P = 0.033), Af (sHR:1.62, P = 0.049), and CHF (sHR: 1.44; P = 0.048) than those of EH controls, with mortality as a competing risk. Using inverse probability of treatment-weighted matching and counting adrenalectomy as a time-varying factor, treatment with adrenalectomy was associated with lower risks of all-cause mortality (HR: 0.57; P = 0.035), MACE (HR: 0.67; P = 0.037), and CHF (HR: 0.49; P = 0.005) compared to those of MRA therapy.

Conclusions: Adrenalectomy, independent of post-surgical hypertension remission, was associated with lower all-cause mortality of uPA patients, compared to that of EH patients. We further documented a more beneficial effect of adrenalectomy over MRA treatment on long-term mortality, MACE, and CHF in uPA patients.
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http://dx.doi.org/10.1530/EJE-21-0836DOI Listing
December 2021

Aldosterone-producing nodules and CYP11B1 signaling correlate in primary aldosteronism.

Endocr Relat Cancer 2022 01 10;29(2):59-69. Epub 2022 Jan 10.

TAIPAI, Taiwan Primary Aldosteronism Investigation (TAIPAI) Study Group, Taipei, Taiwan.

Autonomous cortisol secretion (ACS) could be found in some patients with unilateral primary aldosteronism (uPA). However, the histopathological patterns of uPA with concurrent ACS have not been well elucidated. The adrenal gland with the adenoma from 61 uPA patients who underwent unilateral adrenalectomy were assessed by immunohistochemistry. Bioinformatics analysis, including the Cancer Genome Atlas (TCGA) and Kyoto Encyclopedia of Genes and Genomes, was applied. The prevalence of multiple aldosterone-producing nodules or micronodules (mAPN/mAPM) was 65.6% (40/61) among our uPA patients. Concurrent ACS was identified in 32% of this uPA cohort; they were associated with the interaction of larger tumor size (>1.98 cm) and mAPN/mAPM (odds ratio = 3.08, P = 0.004). Transcriptome analysis uncovered a dominant enrichment of HSD3B7 overexpression (P = 0.004) in the adenomas of the histopathologically classical adrenal uPA lesions with concomitant mAPN/mAPM, compared with those uPA adenomas without concurrent surrounding mAPN/mAPM. We identified a novel linkage of enhanced steroidogenic genes of HSD3B7 expression concurrent with the downstream higher CYP11B1 expression; further relationship was confirmed by immunohistochemical staining and validated by TCGA bioinformatics. The presence of mAPN/mAPM in uPA patients had lower rate for biochemical success after adrenalectomy (P = 0.047). In summary, two-thirds of uPA patients had concomitant mAPN/mAPM; 1/3 of uPA patients had concurrent ACS. Steroidogenic HSD3B7/CYP11B1 signaling was associated with uPA adenomas with surrounding mAPN/mAPM. Interaction of larger adenoma size with the presence of mAPN/mAPM was linked to co-existing ACS. Such uPA patients with concomitant mAPN/mAPM had lower rate of biochemical success.
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http://dx.doi.org/10.1530/ERC-21-0287DOI Listing
January 2022

Heart-Ankle Pulse Wave Velocity Is Superior to Brachial-Ankle Pulse Wave Velocity in Detecting Aldosterone-Induced Arterial Stiffness.

Biomedicines 2021 Sep 22;9(10). Epub 2021 Sep 22.

Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.

Primary aldosteronism (PA) is associated with higher arterial stiffness compared to essential hypertension (EH). However, few studies have compared different pulse wave velocity (PWV) parameters to detect aldosterone-induced arterial stiffness. In this study, we aimed to compare the sensitivity in detecting aldosterone-induced arterial stiffness between brachial-ankle PWV (baPWV) and heart-ankle PWV (haPWV). We prospectively enrolled 1006 PA patients and 983 EH patients. Detailed medical history, basic biochemistry data and two PWV measurements (baPWV and haPWV) were collected in both groups. We performed analysis on the original cohort and two propensity score matching (PSM) models (model 1 adjusted for age and sex; model 2 adjusted for age, sex, systolic and diastolic blood pressure). The DeLong test was used to compare areas under receiver operating characteristic curves (AUCs) between baPWV and haPWV to predict PA. In all models, the PA patients had significantly higher baPWV compared to the EH patients. The AUC of haPWV was greater than that of baPWV. In conclusion, haPWV seems to be a better PWV parameter than baPWV in detecting aldosterone-induced arterial stiffness.
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http://dx.doi.org/10.3390/biomedicines9101285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533381PMC
September 2021

Subtypes of Histopathologically Classical Aldosterone-Producing Adenomas Yield Various Transcriptomic Signaling and Outcomes.

Hypertension 2021 12 18;78(6):1791-1800. Epub 2021 Oct 18.

Department of Urology, College of Medicine (J.S.C.), National Taiwan University Hospital, Taipei.

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.121.18006DOI Listing
December 2021

Characteristics of a Novel K416_F418delinsN Mutation in a Classical Aldosterone-Producing Adenoma.

Cancers (Basel) 2021 Sep 21;13(18). Epub 2021 Sep 21.

Department of Urology, College of Medicine, National Taiwan University, National Taiwan University Hospital, Taipei 110, Taiwan.

In patients with primary aldosteronism (PA), the prevalence of mutation is rare. The aim of this study is to report a novel mutation in a PA patient. Based on our tissue bank of aldosterone-producing adenomas (APA), we identified a novel somatic K416_F418delinsN mutation. The affected individual was a 53 year-old man with a 4 year history of hypertension. Computed tomography (CT) showed bilateral adrenal masses of 1.6 (left) and 0.5 cm (right) in size. An adrenal venous sampling (AVS) showed a lateralization index (LI) of 2.2 and a contralateral suppression index (CLS) of 0.12; indicating left functional predominance. After a left unilateral adrenalectomy, he achieved partial biochemical and hypertension-remission. This classical adenoma harbored a novel K416_F418delinsN somatic mutation, which is a deletion from nucleotides 1248 to 1253. The translated amino acid sequence from 416 to 418, reading as lysine-phenylalanine-phenylalanine, was deleted; however, an asparagine was inserted due to merging of residual nucleotide sequences. The CYP11B2 immunohistochemistry staining demonstrated strong immunoreactivity in this classical adenoma. The K416_F418delinsN mutation is a functional mutation in APA, since HAC15 cells, a human adrenal cell line, transfected with the mutant gene showed increased CYP11B2 expression and aldosterone production.
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http://dx.doi.org/10.3390/cancers13184729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472399PMC
September 2021

Novel Mutations Detection with Next-Generation Sequencing and Its Association with Clinical Outcome in Unilateral Primary Aldosteronism.

Biomedicines 2021 Sep 6;9(9). Epub 2021 Sep 6.

Department of Urology, and College of Medicine, National Taiwan University Hospital, Taipei 100, Taiwan.

Somatic mutations have been identified in adrenal tissues of unilateral primary aldosteronism (uPA). The spectrum of somatic mutations in uPAs was investigated using a customized and targeted next-generation sequencing (cNGS) approach. We also assessed whether cNGS or Sanger sequencing-identified mutations have an association with clinical outcomes in uPA. Adrenal tumoral tissues of uPA patients who underwent adrenalectomy were obtained. Conventional somatic mutation hotspots in 240 extracted DNA samples were initially screened using Sanger sequencing. A total of 75 Sanger-negative samples were further investigated by sequencing the entire coding regions of the known aldosterone-driver genes by our cNGS gene panel. Somatic mutations in aldosterone-driver genes were detected in 21 (28%) of these samples (8.8% of all samples), with 9 samples, including mutations in gene (12%), 5 in (6.6%), 3 in (4%), 2 in (2.6%), 1 in (1.3%), and 1 in (1.3%). Via combined cNGS and Sanger sequencing aldosterone-driver gene mutations were detected in altogether 186 of our 240 (77.5%) uPA samples. The complete clinical success rate of patients containing cNGS-identified mutations was higher than those without mutations (odds ratio (OR) = 10.9; = 0.012). Identification of somatic mutations with cNGS or Sanger sequencing may facilitate the prediction of complete clinical success after adrenalectomy in uPA patients.
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http://dx.doi.org/10.3390/biomedicines9091167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471673PMC
September 2021
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