Jacques W M Lenders

Technische Universität Dresden, Dresden, Saxony, Germany

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Publications (313)1508.08 Total impact

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    DESCRIPTION: Psychosom Med 1992 May-Jun;54(3):344-53.
    Full-text · Research · Jan 2016
  • M. Moors · T.A. Williams · J. Deinum · G. Eisenhofer · M. Reincke · J. W. M. Lenders
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    ABSTRACT: Primary aldosteronism encompasses 2 major underlying causes: (1) aldosterone producing adenoma and (2) bilateral adrenal hyperplasia. In addition to the aldosterone excess, increased production of other compounds of the steroidogenic pathways may be involved. Until recently, most studies examined the production of steroids other than aldosterone in tumor tissue, urine, or peripheral plasma samples, but several new studies have also addressed steroid levels in adrenal venous blood samples using liquid chromatography tandem mass spectrometry. Plasma and tissue levels of several precursors of aldosterone with mineralocorticoid activity are higher in patients with aldosterone producing adenomas than in those with bilateral hyperplasia. These include corticosterone, deoxycorticosterone, and their 18-hydroxylated metabolites. Similarly, urinary, peripheral, and adrenal venous concentrations of the hybrid steroids 18-oxocortisol and 18-hydroxycortisol are higher in patients with aldosterone producing adenomas than in bilateral hyperplasia. Differences in the pathophysiology and in clinical and biochemical phenotypes caused by aldosterone producing adenomas and bilateral adrenal hyperplasia may be related to the differential expression of steroidogenic enzymes, and associated to specific underlying somatic mutations. Correct appreciation of differences in steroid profiling between aldosterone producing adenomas and bilateral adrenal hyperplasia may not only contribute to a better understanding of the pathogenesis of primary aldosteronism but may also be helpful for future subtyping of primary aldosteronism.
    No preview · Article · Dec 2015 · Hormone and Metabolic Research
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    ABSTRACT: Primary aldosteronism comprises 2 main subtypes: unilateral aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia. Somatic KCNJ5 mutations are found in APA at a prevalence of around 40% that drive and sustain aldosterone excess. Somatic APA mutations have been described in other genes (CACNA1D, ATP1A1, and ATP2B3) albeit at a lower frequency. Our objective was to identify genotype-specific steroid profiles in adrenal venous (AV) and peripheral venous (PV) plasma in patients with APAs. We measured the concentrations of 15 steroids in AV and PV plasma samples by liquid chromatography-tandem mass spectrometry from 79 patients with confirmed unilateral primary aldosteronism. AV sampling lateralization ratios of steroids normalized either to cortisol or to DHEA+androstenedione were also calculated. The hybrid steroid 18-oxocortisol exhibited 18- and 16-fold higher concentrations in lateralized AV and PV plasma, respectively, from APA with KCNJ5 mutations compared with all other APA combined together (P<0.001). Lateralization ratios for the KCNJ5 group were also generally higher. Strikingly, we demonstrate that a distinct steroid signature can differentiate APA genotype in AV and PV plasma. Notably, a 7-steroid fingerprint in PV plasma correctly classified 92% of the APA according to genotype. Prospective studies are necessary to translate these findings into clinical practice and determine if steroid fingerprinting could be of value to select patients with primary aldosteronism who are particularly suitable candidates for adrenal venous sampling because of a high probability of having an APA.
    No preview · Article · Nov 2015 · Hypertension
  • A Prejbisz · E Warchoł-Celińska · J. W. M. Lenders · A Januszewicz
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    ABSTRACT: After the first cases of primary aldosteronism were described and characterized by Conn, a substantial body of experimental and clinical evidence about the long-term effects of excess aldosterone on the cardiovascular system was gathered over the last 5 decades. The prevalence of primary aldosteronism varies considerably between different studies among hypertensive patients, depending on patient selection, the used diagnostic methods, and the severity of hypertension. Prevalence rates vary from 4.6 to 16.6% in those studies in which confirmatory tests to diagnose primary aldosteronism were used. There is also growing evidence indicating that prolonged exposure to elevated aldosterone concentrations is associated with target organ damage in the heart, kidney, and arterial wall, and high cardiovascular risk in patients with primary aldosteronism. Therefore, the aim of treatment should not be confined to BP normalization and hypokalemia correction, but rather should focus on restoring the deleterious effects of excess aldosterone on the cardiovascular system. Current evidence convincingly demonstrates that both surgical and medical treatment strategies beneficially affect cardiovascular outcomes and mortality in the long term. Further studies can be expected to provide better insight into the relationship between cardiovascular risk and complications and the genetic background of primary aldosteronism.
    No preview · Article · Nov 2015 · Hormone and Metabolic Research
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    ABSTRACT: Context: Patients with pheochromocytomas and paragangliomas (PGLs) may have brown adipose tissue (BAT) activation induced by catecholamine excess. (18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT can be used for the localization of both PGLs and BAT. It is unknown whether BAT is specifically affected by altered cellular energy metabolism in patients with SDHx and VHL-related PGLs. Objective: To determine endocrine and paracrine effects of catecholamine excess on BAT activation in patients with PGLS as detected by (18)F-FDG PET/CT, taking into account genetic variation. Design: Patients with PGLs who were fully genetically characterized underwent pre-surgical (18)F-FDG PET/CT imaging for tumor localization and to quantify BAT activation. Setting: Single Dutch tertiary referral centre. Patients and intervention: 73 patients, age 52.4 ± 15.4 yr, BMI 25.2 ± 4.1 kg/m(2), mean ± SD, were grouped into sporadic, cluster 1 (SDHx, VHL) and cluster 2 (RET, NF1, MAX) mutations. Main outcome measures: (18)F-FDG mean standard uptake values (SUVmean) were assessed in predefined BAT locations, including perirenal fat. Results: 21/73 (28.8%) patients exhibited BAT activation. BAT activation was absent in all six patients with non-secreting PGLs. No difference in (18)F-FDG uptake by perirenal fat on the side of the pheochromocytoma and the contralateral side was observed (SUVmean 0.80 vs. 0.78 respectively, P=0.42). The prevalence of BAT activation did not differ between sporadic (28.9%), cluster 1 (40.0%) and cluster 2 patients (15.4%), P=0.36. Conclusion: Patients with PGLs exhibit a high prevalence of BAT activation on (18)F-FDG PET/CT. This is likely due to systemic catecholamine excess. BAT activation is not associated with specific germline mutations.
    No preview · Article · Nov 2015 · The Journal of Clinical Endocrinology and Metabolism
  • T A Williams · J W M Lenders · J. Burrello · F. Beuschlein · M. Reincke
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    ABSTRACT: Somatic mutations have been identified in the KCNJ5 gene (encoding the potassium channel GIRK4) in aldosterone-producing adenomas (APA). Most of these mutations are located in or near the selectivity filter of the GIRK4 channel pore and several have been shown to lead to the constitutive overproduction of aldosterone. KCNJ5 mutations in APA are more frequent in women; however, this gender dimorphism is a reported phenomenon of Western but not East Asian populations. In this review we discuss some of the issues that could potentially underlie this observation.
    No preview · Article · Nov 2015 · Hormone and Metabolic Research
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    ABSTRACT: The thiazide-sensitive NaCl cotransporter (NCC) is an important pharmacological target in the treatment of hypertension. Human SLC12A3 gene, encoding NCC, gives rise to three isoforms. Only the 3(rd) isoform has been extensively investigated. The aim of the present study was, therefore, to establish the abundance and localization of the almost identical isoforms 1 and 2 (NCC1/2) in the human kidney and to determine their functional properties and regulation in physiological conditions. Immunohistochemical analysis of NCC1/2 in the human kidney revealed that NCC1/2 localizes to the apical plasma membrane of the distal convoluted tubule. Importantly, NCC1/2 mRNA constitutes approximately 44% of all NCC isoforms in the human kidney. Functional analysis performed in the Xenopus laevis oocyte revealed that thiazide-sensitive (22)Na(+) transport of NCC1 was significantly increased in comparison to NCC3. Mimicking a constitutively active phosphorylation site at residue 811 (S811D) in NCC1 further augmented Na(+) transport, while a non-phosphorylatable variant (S811A) of NCC1 prevented this enhanced response. Analysis of human urinary exosomes demonstrated that water loading in human subjects significantly reduces the abundance of NCC1/2 in urinary exosomes. The present study highlights that previously underrepresented NCC1/2 is a fully functional thiazide-sensitive NaCl-transporting protein. Being significantly expressed in the kidney it may constitute a unique route of renal NaCl reabsorption and could, therefore, play an important role in blood pressure regulation.
    Preview · Article · Nov 2015 · AJP Renal Physiology

  • No preview · Article · Oct 2015
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    Full-text · Article · Oct 2015
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    ABSTRACT: Adrenal steroid hormones, which regulate a plethora of physiological functions, are produced via tightly controlled pathways. Investigations of these pathways, based on experimental data, can be facilitated by computational modeling for calculations of metabolic rate alterations. We therefore used a model system, based on mass balance and mass reaction equations, to kinetically evaluate adrenal steroidogenesis in human adrenal cortex-derived NCI H295R cells. For this purpose a panel of 10 steroids was measured by liquid chromatographic-tandem mass spectrometry. Time-dependent changes in cell incubate concentrations of steroids - including cortisol, aldosterone, dehydroepiandrosterone and their precursors - were measured after incubation with angiotensin II, forskolin and abiraterone. Model parameters were estimated based on experimental data using weighted least square fitting. Time-dependent angiotensin II- and forskolin-induced changes were observed for incubate concentrations of precursor steroids with peaks that preceded maximal increases in aldosterone and cortisol. Inhibition of 17-alpha-hydroxylase/17,20-lyase with abiraterone resulted in increases in upstream precursor steroids and decreases in downstream products. Derived model parameters, including rate constants of enzymatic processes, appropriately quantified observed and expected changes in metabolic pathways at multiple conversion steps. Our data demonstrate limitations of single time point measurements and the importance of assessing pathway dynamics in studies of adrenal cortical cell line steroidogenesis. Our analysis provides a framework for evaluation of steroidogenesis in adrenal cortical cell culture systems and demonstrates that computational modeling-derived estimates of kinetic parameters are an effective tool for describing perturbations in associated metabolic pathways.
    No preview · Article · Oct 2015 · The Journal of steroid biochemistry and molecular biology
  • Jaap Deinum · Niels P Riksen · Jacques W M Lenders
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    ABSTRACT: Primary aldosteronism, caused by autonomous secretion of aldosterone by the adrenals, is estimated to account for at least 5% of hypertension cases. Hypertension explains the considerable cardiovascular morbidity caused by aldosteronism only partly, calling for specific anti-aldosterone drugs. The pharmacology of aldosterone is complex due to high homology with other steroids, the resemblance of steroid receptors, and the common pathways of steroid synthesis. Classically, pharmacological treatment of aldosteronism relied on the mineralocorticoid receptor (MR) antagonist spironolactone, which is highly effective, but causes considerable, mainly sexual side-effects due to limited selectivity for the MR. New agents have been developed or are being developed that aim at higher selectivity for MR antagonists (eplerenone, dihydropyridine-derived calcium channel blockers (CCB)), or inhibition of aldosterone synthesis. Eplerenone is less potent than spironolactone, but causes fewer adverse effects due to its selectivity for the MR. Non-steroidal MR antagonists have been developed from dihydropyridine CCBs, having lost their CCB activity and being highly selective for the MR. The first clinical studies with these drugs are underway. Aldosterone synthase inhibitors are an attractive alternative, but are prone to interference with cortisol synthesis due to the inhibition of 11-β-hydroxylation, an essential step in both cortisol and aldosterone synthesis, and accumulation of mineralocorticoid precursors. In coming years clinical research will provide the answers as to which drugs and strategies to treat high-aldosterone states are the most effective. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Jul 2015 · Pharmacology [?] Therapeutics
  • Theo Thien · Eveline B M Keltjens · Jacques W M Lenders · Jaap Deinum
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    ABSTRACT: To establish whether the results of blood pressure (BP) measurements are affected by wearing clothing underneath the BP cuff during measurement. Normotensive and hypertensive patients (n=133; 65 men) of an outpatient clinic participated in this study. BP was measured according to a rigorous protocol with a validated oscillometric device under three conditions: with one layer of own clothing (OC) underneath the cuff, with one layer of standardized clothing (SC) underneath the cuff, and with the cuff on a bare arm (BA), in a randomized order. Patients were seated on a chair with their right arm on the table and their feet flat on the floor during BP measurement. The mean BP values (±SEM) measured during BA, OC, and SC were, respectively, 132.8±1.3, 132.3±1.4, and 133.2±1.4 mmHg for systolic blood pressure (SBP), 78.3±0.9, 78.3±0.9, and 78.5±0.9 mmHg for diastolic blood pressure (DBP), and 90.3±1.0, 90.0±1.0, and 91.5±1.0 mmHg for mean arterial blood pressure (MAP). The differences in SBP, DBP, and MAP between BA, OC, and SC measurements were not statistically significant, but there was considerable intraindividual variation in SBP deviations of more than 5 mmHg between BA versus OC and SC. There was no significant order effect of the three conditions. The absence of differences between BA, OC, and SC was not determined by age, sex, BMI, and arm circumference. We could not find differences in MAP, SBP, and DBP between the bare and clothed arms, but intraindividual variation of SBP between the three conditions is not negligible. Despite this caveat, these data suggest that in an outpatient clinic, BP can be measured reliably with one layer of clothing underneath the cuff. This is timesaving and more comfortable for patients.
    No preview · Article · Jul 2015 · Blood pressure monitoring

  • No preview · Article · Jun 2015
  • Article: PP.32.13
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    ABSTRACT: Objective: Adrenal venous sampling (AVS) is the preferred method to distinguish excess unilateral from bilateral aldosterone secretion in patients with primary aldosteronism. Although it is invasive and expensive conventional CT adrenal imaging is considered to be inferior to AVS. To examine whether 128-slice dual-source CT using strict standardized radiological diagnostic criteria may approach the diagnostic performance of AVS. Design and method: From May 2012 to August 2014 we performed both AVS and 128-slice dual-source CT in 50 consecutive patients with PA. AVS was pursued after correction of hypokalemia and adjustment of antihypertensive therapy, under continuous ACTH infusion. Blood samples were taken from both adrenal veins (AV) and the lower caval vein (LCV). Selective cannulation was defined as an AV/LCV ratio for cortisol of >=3. Lateralization was defined as a dominant/non-dominant ratio for aldosterone-to-cortisol of >=4. In addition suppression of the contralateral side was required. Computer tomography imaging was performed using 128-slice dual-source CT with a 1mm-thickness slice. As a diagnostic criterion of adrenal nodule on CT-scan a focal change > 7 mm was used. A diffuse thickening of adrenal limbs > 5 mm was thought to fit with adrenal hyperplasia. A unilateral change (adenoma/hyperplasia) was defined as a change within one single adrenal gland with normal contralateral gland. Bilateral abnormalities included bilateral adenomas and/or bilateral adrenal hyperplasia. Results: The cannulation failed in 2 (4%) subjects. No complications were observed during and after procedures. Twentythree patients (48%) demonstrated unilateral aldosterone production (14 left-sided, 9 right-sided), and 25 (48%) patients were characterized by bilateral aldosterone production. In 43,8% of the patients there was disagreement between results of AVS vs CT. In 11 subjects (22.9%) a unilateral change was found on CT-scan, while there was no lateralization on AVS. In 7 patients (14,6%) CT-scan revealed bilateral abnormalities or symmetrical normal adrenal glands whereas in AVS unilateral aldosterone secretion was observed. In 2 cases there was complete discordance between the affected sides as diagnosed by CT and AVS. Conclusions: Despite adopting strict radiological criteria to differentiate uni- from bilateral disease, the diagnostic performance of 128-slice dual-source CT-scan is inferior to that of AVS. Copyright
    No preview · Article · Jun 2015 · Journal of Hypertension
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    ABSTRACT: (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy plays an important role in the diagnostic evaluation of patients with pheochromocytoma and paraganglioma (PPGL). MIBG targets cell membrane and vesicular catecholamine transporters of chromaffin cells and facilitates localization of the primary tumor and metastatic lesions. Its specificity for the diagnosis of adrenomedullary chromaffin cell tumors can be jeopardized by physiological uptake by the normal adrenal medulla. The aim of this study was to distinguish between PPGLs and normal adrenal glands by evaluating semi-quantitative (123)I-MIBG uptake and to examine genotype-specific differences in correlation with expression of catecholamine transporter systems. Sixty-two PPGLs collected from 57 patients with hereditary mutations in SDHA (n = 1), SDHB (n = 2), SDHD (n = 4), VHL (n = 2), RET (n = 12), NF1 (n = 2), MAX (n = 1) and with sporadic PPGLs (n = 33) were investigated. Pre-operative planar and single-photon emission computed tomographic (SPECT) images were semi-quantitatively analyzed using uptake measurements. Tumor-to-liver (T/L) and normal-adrenal-to-liver (NA/L) ratios were calculated and correlated with clinical characteristics including genotype, tumor size and plasma metanephrines concentrations. The expression of norepinephrine transporter (NET) and vesicular monoamine transporter (VMAT-1) was evaluated immunohistochemically in paraffin-embedded tumor tissues. Mean T/L ratios of PPGL lesions were significantly higher than NA/L ratios (p<0.001). Cut-off values to distinguish between physiological and pathological adrenal uptake were established at 0.7 (100% sensitivity, 10.3% specificity) and 4.3 (100% specificity, 66.1% sensitivity). No statistically significant differences in (123)I-MIBG uptake were found across PPGLs of different genotypes. Mean NET expression in hereditary cluster 2 (RET, NF1, MAX) and apparently sporadic tumors was significantly higher than for hereditary cluster 1 (SDHx, VHL) PPGLs (P = 0.011 and P = 0.006, respectively). Mean VMAT-1 expression in hereditary cluster 1 PPGLs was significantly higher than for cluster 2 tumors (P = 0.010). (123)I-MIBG uptake significantly correlated with maximum tumor diameter (P = 0.002). MIBG uptake, however, did not correlate with either NET or VMAT-1 expression. Liver normalized semi-quantitative (123)I-MIBG uptake may be helpful to distinguish between pheochromocytoma and physiological adrenal uptake. Genotype-specific differences in expression of NET and VMAT-1 do not translate into differences in (123)I-MIBG uptake. Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    Full-text · Article · Apr 2015 · Journal of Nuclear Medicine

  • No preview · Article · Mar 2015 · Experimental and Clinical Endocrinology & Diabetes

  • No preview · Article · Mar 2015 · Experimental and Clinical Endocrinology & Diabetes
  • J Lenders
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    ABSTRACT: The possibility that a patient with newly diagnosed hypertension has an underlying cause that is directly.sponsible for the increased blood pressure deserves more attention from clinicians than is currently the case. This limited attention and consideration is responsible for delaying and yen missing the diagnosis and proper treatment of secondary hypertension. The reasons are manifold, varying from minimal knowledge of diagnostic tests to easy and low threshold in rescription of antihypertensive drugs. In addition there is the misconception that the prevalence of secondary hypertension; so low that it hardly needs any consideration. However, some forms of secondary hypertension are much more revalent than previously thought and this applies in particular endocrine hypertension. In addition, in recent years there re emerging new scientific developments in the field of endocrine hypertension, varying from pathogenesis, genetics, and therapeutics. It is therefore quite remarkable that endocrinologists seem to have hardly any interest in endocrine hypertension, unless there is a clear cut case such as a patient with an already diagnosed pheochromocytoma. They leave the analysis of hypertension to other specialists who have hardly any expertise a for instance the analysis of patients suspected to have primary or pseudo-aldosteronism. The contribution of endocrinology is however essential, not only for detecting more patients with concealed endocrine hypertension but also for optimizing he understanding of the pathogenesis and treatment of high blood pressure in the larger group of patients with primary hypertension.
    No preview · Article · Jan 2015 · Choroid Plexus - Pineal Gland Correlations Medical Anthropology - Computed Tomography Studies Intracranial Physiological Calcification
  • J.W.M. Lenders · G. Eisenhofer
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    ABSTRACT: The metanephrines normetanephrine and metanephrine are O-methylated metabolites of the parent catecholamines norepinephrine and epinephrine. They are biologically inactive markers of extraneuronal and intra-adrenal metabolism of catecholamines and they can be measured in the free and conjugated forms in both plasma and urine. The main utility of measurement of metanephrines is for the diagnosis of chromaffin cell tumors such as pheochromocytoma and paraganglioma. Due to their continuous production and secretion by tumoral tissue, measurements of metanephrines offer the best test with the highest accuracy for the diagnosis of these tumors.
    No preview · Article · Dec 2014
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    ABSTRACT: Objective: Testing for succinate dehydrogenase subunit B (SDHB) mutations is recommended in all patients with metastatic phaeochromocytomas and paragangliomas (PPGLs), but may not be required when metastatic disease is accompanied by adrenaline production. This retrospective cohort study aimed to establish the prevalence of SDHB mutations among patients with metastatic PPGLs, characterised by production of adrenaline compared with those without production of adrenaline, and to establish genotype–phenotype features of metastatic PPGLs according to underlying gene mutations. Design and methods: Presence of SDHB mutations or deletions was tested in 205 patients (114 males) aged 42+/-16 years (range 9–86 years) at diagnosis of metastatic PPGLs with and without adrenaline production. Results: Twenty-three of the 205 patients (11%) with metastatic PPGLs had disease characterised by production of adrenaline, as defined by increased plasma concentrations of metanephrine larger than 5% of the combined increase in both normetanephrine and metanephrine. None of these 23 patients had SDHB mutations. Of the other 182 patients with no tumoural adrenaline production, 51% had SDHB mutations. Metastases in bone were 36–41% more prevalent among patients with SDHB mutations or extra-adrenal primary tumours than those without mutations or with adrenal primary tumours. Liver metastases were 81% more prevalent among patients with adrenal than extra-adrenal primary tumours. Conclusion: SDHB mutation testing has no utility among patients with adrenaline-producing metastatic PPGLs, but is indicated in other patients with metastatic disease. Our study also reveals novel associations of metastatic spread with primary tumour location and presence of SDHB mutations.
    Full-text · Article · Nov 2014 · European Journal of Endocrinology

Publication Stats

8k Citations
1,508.08 Total Impact Points

Institutions

  • 2010-2015
    • Technische Universität Dresden
      • • Faculty of Medicine Carl Gustav Carus
      • • Institut für Chemie und Laboratoriumsmedizin
      Dresden, Saxony, Germany
  • 1984-2015
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
  • 1983-2015
    • Radboud University Nijmegen
      • Department of General Internal Medicine
      Nymegen, Gelderland, Netherlands
  • 2009-2012
    • Carl Gustav Carus-Institut
      Pforzheim, Baden-Württemberg, Germany
  • 2003-2008
    • Maastricht University
      • Department of Internal Medicine
      Maestricht, Limburg, Netherlands
  • 1992-2008
    • National Institutes of Health
      • Branch of Behavioral Neuroscience
      베서스다, Maryland, United States
  • 2007
    • University of Groningen
      • Department of General Practice
      Groningen, Groningen, Netherlands
  • 2002-2005
    • University of Florence
      Florens, Tuscany, Italy
    • The University of Edinburgh
      Edinburgh, Scotland, United Kingdom
  • 1996
    • University of Amsterdam
      Amsterdamo, North Holland, Netherlands