Publications by authors named "Markus Mohaupt"

92 Publications

Testosterone/Epitestosterone Ratios-Further Hints to Explain Hyperandrogenemia in Children with Autism.

Diseases 2021 Feb 1;9(1). Epub 2021 Feb 1.

Teaching Hospital Internal Medicine, Lindenhofgruppe, 3006 Berne, Switzerland.

Background: Epitestosterone [E] has for a long time been considered as a biologically inactive androgen. However, recently a distinct antiandrogenic activity of this naturally occurring endogenous epimer of Testosterone has been demonstrated. Especially the ratios of testosterone/epitestosterone (T/E) seem to be key as inhibition of epitestosterone on androgen activity was postulated. As in autism, a higher androgen activity was implied. We, therefore, suggested higher levels of T/E ratios of children with autism versus children with typical development.

Methods: Urine probes of 22 girls with autism (BMI 18.7 ± 4.3; average age 12.3 ± 3.8 years) and a sample of 51 controls (BMI 17.0 ± 2.6; average age 11.9 ± 4 years), as well as 61 boys with autism (BMI 17.04 ± 2. average age 11.9 ± 2.5 years) and 61 control boys (BMI 17.0 ± 2.6; average age 11.1 ± 3.0 years), were analyzed with gas chromatography mass spectrometry.

Results: The average T/E ratio of all boys with autism was 2.5 ± 1.8 versus 2.4 ± 1.3 in boys with typical development, respectively. No significant difference between boys with autism versus boys with typical development could be detected ( = 0.977). In girls with autism, the average T/E ratio was 1.4 ± 0.9 versus 2.0 ± 1.4 in girls with typical development, whereby a significant difference could be detected ( = 0.0285). Further, polynomial analysis of the third degree were conducted, showing a dependence from age with reasonable coefficients of determination (0.075 < R < 0.22, all samples).

Discussion: As encompassing steroid hormone analysis are expensive and work-intensive, we hoped to find an easily applicable biomarker to support diagnostics in autism. However, as a relatively small sample of only 22 girls with autism were analyzed and menstrual cycle and pubertal status were only partly controllable through the matching of BMI and age, the question arises if it was an incidental finding. Nevertheless, one suggestion might be that epitestosterone has the effect of a competitive inhibition on the androgen receptor, which would probably help to explain the higher prevalence of autism in boys as compared to girls. Presumably, as no significant difference was detected in boys, this effect might not be as relevant from a steroid hormone perspective, and other effects such as altered 17/20-hydroxylase activity as previously shown in boys and girls with autism seem to have more relevance. Analysis of larger samples, including plenty of metabolites and enzymatic cascades, as well as the role of backdoor pathway activity of androgen synthesis of girls with autism, are demanded in order to validate current findings of altered steroid hormones in autism.
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http://dx.doi.org/10.3390/diseases9010013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931062PMC
February 2021

Stress-induced alterations of social behavior are reversible by antagonism of steroid hormones in C57/BL6 mice.

Naunyn Schmiedebergs Arch Pharmacol 2021 01 7;394(1):127-135. Epub 2020 Sep 7.

Department of Clinical Research, University of Bern, 3010, Berne, Switzerland.

Various disturbances of social behavior, such as autism, depression, or posttraumatic stress disorder, have been associated with an altered steroid hormone homeostasis and a dysregulation of the hypothalamus-pituitary-adrenal axis. A link between steroid hormone antagonists and the treatment of stress-related conditions has been suggested. We evaluated the effects of stress induction on social behavior in the three chambers and its potential reversibility upon specific steroid hormone antagonism in mice. C57BL/6 mice were stressed twice daily for 8 days by chronic swim testing. Social behavior was evaluated by measuring, first, the preference for sociability and, second, the preference for social novelty in the three-chamber approach before and after the chronic swim test. The reversibility of behavior upon stress induction was analyzed after applying steroid hormone antagonists targeting glucocorticoids with etomidate, mineralocorticoids with potassium canrenoate, and androgens with cyproterone acetate and metformin. In the chronic swim test, increased floating time from 0.8 ± 0.2 min up to 4.8 ± 0.25 min was detected (p < 0.01). In the three-chamber approach, increased preference for sociability and decreased preference for social novelty was detected pre- versus post-stress induction. These alterations of social behavior were barely affected by etomidate and potassium canrenoate, whereas the two androgen antagonists metformin and cyproterone acetate restored social behavior even beyond baseline conditions. The alteration of social behavior was better reversed by the androgen as compared with the glucocorticoid and mineralocorticoid antagonists. This suggests that social behavior is primarily controlled by androgen rather than by glucocorticoid or mineralocorticoid action. The stress-induced changes in preference for sociability are incompletely explained by steroid hormone action alone. As the best response was related to metformin, an effect via glucose levels might confound the results and should be subject to future research.
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http://dx.doi.org/10.1007/s00210-020-01970-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778626PMC
January 2021

Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy.

EBioMedicine 2020 Aug 21;58:102899. Epub 2020 Jul 21.

Transplantační laboratoř, Institut klinické a experimentální medicíny (IKEM), Vídeňská 1958/9, 140 21 Praha 4, Czech Republic.

Background: Kidney transplant recipients (KTRs) with "operational tolerance" (OT) maintain a functioning graft without immunosuppressive (IS) drugs, thus avoiding treatment complications. Nevertheless, IS drugs can influence gene-expression signatures aiming to identify OT among treated KTRs.

Methods: We compared five published signatures of OT in peripheral blood samples from 18 tolerant, 183 stable, and 34 chronic rejector KTRs, using gene-expression levels with and without adjustment for IS drugs and regularised logistic regression.

Findings: IS drugs explained up to 50% of the variability in gene-expression and 20-30% of the variability in the probability of OT predicted by signatures without drug adjustment. We present a parsimonious consensus gene-set to identify OT, derived from joint analysis of IS-drug-adjusted expression of five published signature gene-sets. This signature, including CD40, CTLA4, HSD11B1, IGKV4-1, MZB1, NR3C2, and RAB40C genes, showed an area under the curve 0⋅92 (95% confidence interval 0⋅88-0⋅94) in cross-validation and 0⋅97 (0⋅93-1⋅00) in six months follow-up samples.

Interpretation: We advocate including adjustment for IS drug therapy in the development stage of gene-expression signatures of OT to reduce the risk of capturing features of treatment, which could be lost following IS drug minimisation or withdrawal. Our signature, however, would require further validation in an independent dataset and a biomarker-led trial.

Funding: FP7-HEALTH-2012-INNOVATION-1 [305147:BIO-DrIM] (SC,IR-M,PM,DSt); MRC [G0801537/ID:88245] (MPH-F); MRC [MR/J006742/1] (IR-M); Guy's&StThomas' Charity [R080530]&[R090782]; CONICYT-Bicentennial-Becas-Chile (EN-L); EU:FP7/2007-2013 [HEALTH-F5-2010-260687: The ONE Study] (MPH-F); Czech Ministry of Health [NV19-06-00031] (OV); NIHR-BRC Guy's&StThomas' NHS Foundation Trust and KCL (SC); UK Clinical Research Networks [portfolio:7521].
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http://dx.doi.org/10.1016/j.ebiom.2020.102899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374249PMC
August 2020

Does the 6-minute walk test in hospitalized COPD patients exclusively correlate with lung function parameters or should psychological factors also be taken into account?

PLoS One 2020 4;15(5):e0232587. Epub 2020 May 4.

Department of Behavioral Therapy and Psychosomatic Medicine, Rehabilitation Center Seehof, Federal German Pension Agency, Teltow, Germany.

The 6-minute walk test is generally considered a standard test for the evaluation of short-term maximal physical performance. It has not been evaluated whether psychological factors, such as anxiety or depression, affect the performance or the results of the test. The main aim of this study was to investigate whether a correlation exists between psychological factors and the data from the 6-minute walking test. The study cohort consisted of 85 (♀ = 34 and ♂ = 51) 66 ± 10 (mean ± SD) year-old patients with chronic obstructive pulmonary disease (COPD) hospitalized for disease exacerbation. Forced Expiratory Volume in the first second (FEV1) (% predicted) as predictor for lung function, as well as anxiety and depression symptoms assessed using the Hospital Anxiety and Depression Scale (HADS) as psychological predictors were collected. Bivariate correlations and hierarchical linear regression models were used to analyse the correlations. Walking distance was on average 260m ± 107m and ranged from 64m to 480m. HADS was negatively correlated with 6-min walking distance (r = 0.441, p = .0009, r = -.523, p = 00006). Hierarchical linear regression showed that FEV1 alone explained 33%, and together with the psychological variables anxiety and depression explained 42% of the variance of results from the 6-minute walking test. These findings demonstrated that 11% of the data correlated with the psychological variables alone (p = .011). The effect size for lung function (f2 = .717) and psychological variables (f2 = .352) were high, whereas the socio-demographic variables sex, age, educational level and BMI could not explain any additional variance in our cohort. In conclusion, our study indicates that psychological factors such as symptoms of depression and anxiety are associated with lower physical functional performance in the 6-minute walking test. As such, these factors should also be assessed. Future research is needed to show if treatments of anxiety and depression can improve the walking distance in COPD patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232587PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197854PMC
August 2020

Are Steroid Hormones Dysregulated in Autistic Girls?

Diseases 2020 Mar 14;8(1). Epub 2020 Mar 14.

Teaching Hospital Internal Medicine, Lindenhofgruppe, 3006 Berne, Switzerland.

Evidence of altered cholesterol and steroid hormones in autism is increasing. However, as boys are more often affected, evidence mainly relates to autistic males, whereas evidence for affected autistic girls is sparse. Therefore, a comprehensive gas chromatography mass spectrometry-based steroid hormone metabolite analysis was conducted from autistic girls. Results show increased levels of several steroid hormones, especially in the class of androgens in autistic girls such as testosterone or androstenediol. The increase of the majority of steroid hormones in autistic girls is probably best explained multifactorially by a higher substrate provision in line with the previously developed cholesterol hypothesis of autism.
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http://dx.doi.org/10.3390/diseases8010006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151154PMC
March 2020

Responses of the renin-angiotensin-aldosterone system in pregnant chronic kidney disease patients with and without superimposed pre-eclampsia.

Clin Kidney J 2019 Dec 25;12(6):847-854. Epub 2019 Mar 25.

Division of Child Health, Obstetrics & Gynaecology, University of Nottingham, Nottingham, UK.

Background: Women with chronic kidney disease (CKD) are at increased risk of superimposed pre-eclampsia (SPE). Accurate identification of SPE is challenging. We hypothesized that specific components of the renin-angiotensin-aldosterone system (RAAS) would discriminate between CKD and SPE. The aim of the study was to establish differences in circulating and intrarenal RAAS in women with CKD with and without SPE and compare these to normotensive controls (NCs) and women with pre-eclampsia (PE).

Methods: White European NC women ( = 20), women with PE ( = 9), normotensive CKD without SPE ( = 8) and with SPE ( = 11) were recruited in the third trimester. Plasma renin, plasma and urine total angiotensinogen (AGT) concentrations were quantified by enzyme-linked immunosorbent assay, urinary tetrahydroaldosterone (TH-aldo) concentration by gas chromatography-mass spectrometry and placental growth factor (PlGF) by immunoassay.

Results: Urinary TH-aldo:creatinine ratios were lower in women with PE or SPE compared with NC or women with CKD (P< 0.05 for all). The same group differences were observed for plasma active renin and PlGF concentrations (P< 0.05 for all). Urine total AGT was higher in women with PE compared with NC (P<0.05) and urine TH-aldo:urine AGT was lower (P< 0.05). However, women with SPE had lower urinary AGT concentrations compared with women with PE (P< 0.05). No differences in plasma total AGT were observed between groups.

Conclusions: Women with SPE have a lower urinary TH-aldo:creatinine ratio, lower plasma active renin and lower PlGF concentrations than women with CKD, comparable to women with PE without pre-existing disease, suggestive of similar pathophysiology. These data suggest disruption of the RAAS pathway in SPE similar to PE. Exploration of the predictive value of RAAS components for adverse pregnancy events in women with CKD is required.
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http://dx.doi.org/10.1093/ckj/sfz025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885683PMC
December 2019

Steroid Metabolites Support Evidence of Autism as a Spectrum.

Behav Sci (Basel) 2019 May 9;9(5). Epub 2019 May 9.

Department of Clinical Research, University of Bern, 3010 Berne, Switzerland.

: It is common nowadays to refer to autism as a spectrum. Increased evidence of the involvement of steroid metabolites has been shown by the presence of stronger alterations in Kanner's syndrome compared with Asperger syndrome. : 24 h urine samples were collected from 20 boys with Asperger syndrome, 21 boys with Kanner's syndrome, and identically sized control groups, each matched for age, weight, and height for comprehensive steroid hormone metabolite analysis via gas chromatography-mass spectrometry. : Higher levels of most steroid metabolites were detected in boys with Kanner's syndrome and Asperger syndrome compared to their matched controls. These differences were more pronounced in affected individuals with Kanner's syndrome versus Asperger syndrome. Furthermore, a specific and unique pattern of alteration of androsterone, etiocholanolone, progesterone, tetrahydrocortisone, and tetrahydrocortisol was identified in boys with Kanner's syndrome and Asperger syndrome. Interestingly, in both matched samples, only androsterone, etiocholanolone, progesterone, tetrahydrocortisone, tetrahydrocortisol, and 5a-tetrahydrocortisol groups were positively correlated. In the Asperger syndrome group, all metabolites showed a positive correlation. In the Kanner's syndrome group, 5-a tetrahydrocortisol with androsterone showed a positive correlation. : Due to differences in the level of alteration, the premise that Asperger syndrome is on the mild side of the autism spectrum and that Kanner's syndrome is on the severe side is supported, but alteration patterns yield different phenotypic expressions.
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http://dx.doi.org/10.3390/bs9050052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562465PMC
May 2019

Shrunken pore syndrome, preeclampsia, and markers of NO metabolism in pregnant women during the first trimester.

Scand J Clin Lab Invest 2019 Feb - Apr;79(1-2):91-98. Epub 2019 Feb 20.

i Kantonsspital Graubünden , Zentrallabor , Chur , Switzerland.

Shrunken pore syndrome (SPS) is a condition that manifests itself as the decreased renal clearance of low-molecular-weight proteins but normal clearance of creatinine. Pregnant women with evidence of SPS during the first trimester have an increased risk of developing preeclampsia (PE). The nitric oxide (NO) metabolism markers arginine and ADMA, especially their ratio (Arg/ADMA), are recognized markers of endothelial dysfunction. The aim of this nested case-control study was to establish first-trimester reference intervals (RI) for markers of NO metabolism and to study these markers in women with evidence of SPS at the end of the first trimester. Seventy-four women were stratified in the first trimester according to evidence of SPS (SPS + or SPS-) and the occurrence of PE during subsequent pregnancy (PE + or PE-), as follows: SPS-/PE-, SPS+/PE-, SPS-/PE+, and SPS+/PE+. RIs were determined according to the CLSI EP28-A3c guidelines. Serum Arg and ADMA levels were analyzed. The Arg and ADMA concentrations did not differ among the four groups. However, women in the SPS+/PE + group had a significantly lower Arg/ADMA ratio than those in the other 3 groups (p = .02). In conclusion, we defined the first-trimester RI of Arg, ADMA and the Arg/ADMA ratio as markers of NO metabolism. Our results suggest that SPS in the first trimester predicts a pathophysiological hallmark of subsequent PE, i.e. lower NO production leading to increased vessel tone. Early identification of women at risk for later PE could lead to adaptive prophylactic interventions, such as supplementation with Arg or an NO-donor drug in order to mitigate the risk of developing PE.
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http://dx.doi.org/10.1080/00365513.2019.1568150DOI Listing
August 2019

Physiological and Molecular Responses to Altered Sodium Intake in Rat Pregnancy.

J Am Heart Assoc 2018 08;7(15):e008363

2 Department of BioMedical Research University of Bern Switzerland.

Background In pregnancy, a high plasma volume maintains uteroplacental perfusion and prevents placental ischemia, a condition linked to elevated maternal blood pressure ( BP ). Reducing BP by increasing Na intake via plasma volume expansion appears contra-intuitive. We hypothesize that an appropriate Na intake in pregnancy reduces maternal BP and adapts the renin-angiotensin system in a pregnancy-specific manner. Methods and Results BP was measured by implanted telemetry in Sprague-Dawley rats before and throughout pregnancy. Pregnant and nonpregnant animals received either a normal-salt (0.4%; NS ), high-salt (8%; HS ), or low-salt (0.01%; LS ) diet, or HS (days 1-14) followed by LS (days 14-20) diet ( HS / LS ). Before delivery (day 20), animals were euthanized and organs collected. Food, water, and Na intake were monitored in metabolic cages, and urinary creatinine and Na were analyzed. Na intake and retention increased in pregnancy ( NS , LS ), leading to a positive Na balance ( NS , LS ). BP was stable during LS , but reduced in HS conditions in pregnancy. The renin-angiotensin system was adapted as expected. Activating cleavage of α- and γ-subunits of the renal epithelial Na channel and expression of-full length medullary β-subunits, accentuated further in all LS conditions, were upregulated in pregnancy. Conclusions Pregnancy led to Na retention adapted to dietary changes. HS exposure paradoxically reduced BP . Na uptake while only modestly linked to the renin-angiotensin system is enhanced in the presence of posttranslational renal epithelial Na channel modifications. This suggests (1) storage of Na in pregnancy upon HS exposure, bridging periods of LS availability; and (2) that potentially non-renin-angiotensin-related mechanisms participate in EN aC activation and consecutive Na retention.
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http://dx.doi.org/10.1161/JAHA.117.008363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201473PMC
August 2018

Association of 24-Hour Blood Pressure With Urinary Sodium Excretion in Healthy Adults.

Am J Hypertens 2018 06;31(7):784-791

Department of Medicine, University Hospital Basel, University of Basel, Basel, Switzerland.

Background: While the positive relationship between urinary sodium excretion and blood pressure (BP) is well established for middle-aged to elderly individuals using office BP, data are limited for younger individuals and ambulatory BP measurements.

Methods: Our analysis included 2,899 individuals aged 18 to 90 years from 2 population-based studies (GAPP, Swiss Kidney Project on Genes in Hypertension [SKIPOGH]). Participants with prevalent cardiovascular disease, diabetes, or on BP-lowering treatment were excluded. In SKIPOGH, 24-hour urinary sodium excretion was used as a measure of sodium intake, while in GAPP it was calculated from fasting morning urinary samples using the Kawasaki formula. Multivariable linear regression models were used to assess the relationships of 24-hour urinary salt excretion with office and ambulatory BP measurements.

Results: Mean age, ambulatory BP, sodium excretion, and estimated glomerular filtration rate in GAPP and SKIPOGH were 35 and 44 years, 123/78 and 118/77 mm Hg, 4.2 and 3.3 g/d, and 110 and 99 ml/min/1.73 m2, respectively. A weak linear association was observed between 24-hour ambulatory systolic BP and urinary sodium excretion (β (95% confidence interval [CI]) per 1 g increase in sodium excretion (0.33 % (0.09; 0.57); P = 0.008). No significant relationships were observed for 24-hour ambulatory diastolic BP (β (95% CI) (0.13 % (-0.15; 0.40) P = 0.37). When repeating the analyses in different age groups, all BP indices appeared to have stronger relationships in the older age groups (>40 years).

Conclusions: In these large cohorts of healthy adults, urinary sodium excretion was only weakly associated with systolic 24-hour ambulatory BP.
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http://dx.doi.org/10.1093/ajh/hpy031DOI Listing
June 2018

Steroid regulation: An overlooked aspect of tolerance and chronic rejection in kidney transplantation.

Mol Cell Endocrinol 2018 09 7;473:205-216. Epub 2018 Feb 7.

MRC Centre for Transplantation, King's College London, Great Maze Pond, London SE1 9RT, UK; NIHR Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, Great Maze Pond, London SE1 9RT, UK; Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London SE1 9RT, UK.

Steroid conversion (HSD11B1, HSD11B2, H6PD) and receptor genes (NR3C1, NR3C2) were examined in kidney-transplant recipients with "operational tolerance" and chronic rejection (CR), independently and within the context of 88 tolerance-associated genes. Associations with cellular types were explored. Peripheral whole-blood gene-expression levels (RT-qPCR-based) and cell counts were adjusted for immunosuppressant drug intake. Tolerant (n = 17), stable (n = 190) and CR patients (n = 37) were compared. Healthy controls (n = 14) were used as reference. The anti-inflammatory glucocorticoid receptor (NR3C1) and the cortisol-activating HSD11B1 and H6PD genes were up-regulated in CR and were lowest in tolerant patients. The pro-inflammatory mineralocorticoid gene (NR3C2) was downregulated in stable and CR patients. NR3C1 was associated with neutrophils and NR3C2 with T-cells. Steroid conversion and receptor genes, alone, enabled classification of tolerant patients and were major contributors to gene-expression signatures of both, tolerance and CR, alongside known tolerance-associated genes, revealing a key role of steroid regulation and response in kidney transplantation.
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http://dx.doi.org/10.1016/j.mce.2018.01.021DOI Listing
September 2018

Cytokine-Ion Channel Interactions in Pulmonary Inflammation.

Front Immunol 2017 4;8:1644. Epub 2018 Jan 4.

Lungen- und Atmungsstiftung Bern, Bern, Switzerland.

The lungs conceptually represent a sponge that is interposed in series in the bodies' systemic circulation to take up oxygen and eliminate carbon dioxide. As such, it matches the huge surface areas of the alveolar epithelium to the pulmonary blood capillaries. The lung's constant exposure to the exterior necessitates a competent immune system, as evidenced by the association of clinical immunodeficiencies with pulmonary infections. From the to the postnatal and adult situation, there is an inherent vital need to manage alveolar fluid reabsorption, be it postnatally, or in case of hydrostatic or permeability edema. Whereas a wealth of literature exists on the physiological basis of fluid and solute reabsorption by ion channels and water pores, only sparse knowledge is available so far on pathological situations, such as in microbial infection, acute lung injury or acute respiratory distress syndrome, and in the pulmonary reimplantation response in transplanted lungs. The aim of this review is to discuss alveolar liquid clearance in a selection of lung injury models, thereby especially focusing on cytokines and mediators that modulate ion channels. Inflammation is characterized by complex and probably time-dependent co-signaling, interactions between the involved cell types, as well as by cell demise and barrier dysfunction, which may not uniquely determine a clinical picture. This review, therefore, aims to give integrative thoughts and wants to foster the unraveling of unmet needs in future research.
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http://dx.doi.org/10.3389/fimmu.2017.01644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758508PMC
January 2018

Urinary Cadmium Excretion Is Associated With Increased Synthesis of Cortico- and Sex Steroids in a Population Study.

J Clin Endocrinol Metab 2018 02;103(2):748-758

Department for Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Context: Urinary cadmium (Cd) excretion is associated with cancer and cardiovascular morbidity. A potential mechanism could be disturbance of steroidogenesis in gonads and adrenal glands.

Objective: We tested whether urinary excretion of Cd is correlated with that of cortico- and sex steroid metabolites in the general adult population.

Setting: The Swiss Kidney Project on Genes in Hypertension is a multicentric, family-based population study.

Measures: Urinary excretions of steroid hormone metabolites and Cd were measured with separate day and night collections. Associations were analyzed by mixed linear models.

Results: Urinary Cd and testosterone excretions in men were significantly correlated (respective day and night β values [standard error (SE)], 1.378 [0.242], P < 0.0005; and 1.440 [0.333], P < 0.0005), but not in women [0.333(0.257), P = 0.2; and 0.674 (0.361), P = 0.06]. Urinary Cd and cortisol excretions were positively associated in both sexes [day: β = 0.475 (SE, 0.157), P = 0.0025, and 0.877 (SE, 0.194), P < 0.0005, respectively; night: β = 0.875 (SE, 0.253), P < 0.0005 and 1.183 (SE, 0.277), P = 0.00002, respectively]. Cd excretion was correlated with mineralocorticoid metabolites excretion, except tetrahydroaldosterone, in both sexes (P < 0.01). There was an independent effect of Cd on sex hormone and corticosteroid synthesis and an interdependent effect on gluco- and mineralcorticoid production.

Conclusion: Our findings provide evidence for a global stimulating effect on steroid synthesis already at low-dose Cd exposure. These findings might explain the association of Cd with diseases such as steroid-sensitive cancers or metabolic disorders.
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http://dx.doi.org/10.1210/jc.2017-01540DOI Listing
February 2018

High first-trimester maternal blood cystatin C levels despite normal serum creatinine predict pre-eclampsia in singleton pregnancies.

Scand J Clin Lab Invest 2017 Dec 25;77(8):634-643. Epub 2017 Oct 25.

b Labormedizinisches Zentrum Dr. Risch , Department of Clinical Chemistry , Vaduz , Liechtenstein.

Early biochemical identification of women at high risk for the development of pre-eclampsia (PE) is still unsatisfactory. Renal markers measured during the first trimester were analysed to predict later occurrence of PE. A nested case-control study was conducted within the prospective predictive markers for the diagnosis of preeclampsia study. Pregnant women were included at the end of the first trimester and followed up until birth. Controls were matched to PE cases. Renal markers [i.e. creatinine, cystatin C (CysC), β microglobulin (B2M), β-trace protein (BTP), glomerular filtration rate estimations (eGFR) of the aforementioned markers, uric acid (UA), urea, and serum uromodulin (sUMOD)] were compared to placental growth factor (PlGF), a marker known to predict PE later in pregnancy. Reference intervals were determined for the different markers. In the 183 women (PE, n = 39; controls, n = 144), CysC, the CysC/PlGF ratio (p < .01) and UA were higher, whereas the eGFR/eGFR ratio (a marker of glomerular endothelial integrity and shrunken pore syndrome) and PlGF were lower in women who developed PE (p < .05 for all). Compromised filtration of the larger molecule CysC together with a normal creatinine, in a subset of PE cases (15.3%) was a unique, strong and independent predictor of later PE if the baseline CysC concentration was >0.85 mg/l. In conclusion, CysC and its derivatives as well as UA, indicating volume expansion, measured at the end of the first trimester are predictive of PE. Thus, women can be easily identified and followed as an early reduction in glomerular filtration quality poses a high risk for a subsequent development of PE.
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http://dx.doi.org/10.1080/00365513.2017.1393692DOI Listing
December 2017

Vertebral alveolar echinococcosis-a case report, systematic analysis, and review of the literature.

Lancet Infect Dis 2018 03 11;18(3):e87-e98. Epub 2017 Aug 11.

Department of Internal Medicine, Sonnenhofspital, Bern, Switzerland. Electronic address:

Alveolar echinococcosis caused by Echinococcus multilocularis is an infrequent zoonosis with a high degree of disability, morbidity, and mortality, especially in disease clusters of the northern hemisphere. The diagnosis is complicated by extended incubation time, diverse clinical manifestations, and mimicking of differential diagnoses. The primary organ affected is the liver, but extrahepatic disease is possible, with vertebral involvement in only a few dozen cases described worldwide. Although vertebral alveolar echinococcosis seems to be rare, it might be under diagnosed, and it might be seen more often as the number of people with immunocompromised conditions increases. Recognition of this syndrome is crucial, because advances in medical and surgical management strategies since the introduction of benzimidazole in 1976 have controlled and relieved symptoms in most cases. In this Grand Round, we present the case of a 75-year-old woman who was referred for biopsy of a lumbar lesion 3 months after she was diagnosed with chronic myeloid leukaemia. The diagnosis of hepatic alveolar echinococcosis with metastasis to the lumbar spine and paravertebral region as well as the brain was confirmed by biopsy, PCR, and serology. The patient was given albendazole and referred for palliative surgery with the aim of pain control. Clinical features of the case are presented and discussed in the context of the literature. This case and review illustrate the complexity of extrahepatic alveolar echinococcosis manifestations and the necessity of an interdisciplinary approach.
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http://dx.doi.org/10.1016/S1473-3099(17)30335-3DOI Listing
March 2018

Increased maternal and fetal cholesterol efflux capacity and placental CYP27A1 expression in preeclampsia.

J Lipid Res 2017 06 10;58(6):1186-1195. Epub 2017 Apr 10.

Department of Nephrology, Hypertension, Clinical Pharmacology, and Clinical Research, University of Bern, Bern, Switzerland.

Preeclampsia is a pregnancy-specific condition that leads to increased cardiovascular risk in later life. A decrease in cholesterol efflux capacity is linked to CVD. We hypothesized that in preeclampsia there would be a disruption of maternal/fetal plasma to efflux cholesterol, as well as differences in the concentrations of both placental sterol 27-hydroxylase (CYP27A1) and apoA1 binding protein (AIBP). Total, HDL-, and ABCA1-mediated cholesterol effluxes were performed with maternal and fetal plasma from women with preeclampsia and normotensive controls (both n = 17). apoA1 and apoE were quantified by chemiluminescence, and 27-hydroxycholesterol (27-OHC) by GC-MS. Immunohistochemistry was used to determine placental expression/localization of CYP27A1, AIBP, apoA1, apoE, and SRB1. Maternal and fetal total and HDL-mediated cholesterol efflux capacities were increased in preeclampsia (by 10-20%), but ABCA1-mediated efflux was decreased (by 20-35%; 0.05). Maternal and fetal apoE concentrations were higher in preeclampsia. Fetal plasma 27-OHC levels were decreased in preeclamptic samples ( < 0.05). Placental protein expression of both CYP27A1 and AIBP were localized around fetal vessels and significantly increased in preeclampsia ( = 0.04). Placental 27-OHC concentrations were also raised in preeclampsia ( < 0.05). Increased HDL-mediated cholesterol efflux capacity and placental CYP27A1/27-OHC could be a rescue mechanism in preeclampsia, to remove cholesterol from cells to limit lipid peroxidation and increase placental angiogenesis.
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http://dx.doi.org/10.1194/jlr.M071985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454503PMC
June 2017

Maternal 27-hydroxycholesterol concentrations during the course of pregnancy and in pregnancy pathologies.

BMC Pregnancy Childbirth 2017 04 4;17(1):106. Epub 2017 Apr 4.

Department of Nephrology, Hypertension and Clinical Pharmacology, Inselspital, Department of Clinical Research, University of Bern, Freiburgstrasse, 3010, Berne, Switzerland.

Background: The oxysterol 27-hydroxycholesterol (27-OHC) plays an important role in the regulation of cholesterol homeostasis. Pregnancy pathologies like preeclampsia (PE), HELLP-syndrome (HELLP), intrauterine growth restriction (IUGR) and intrahepatic cholestasis in pregnancy (ICP) are linked to disturbances in lipid metabolism. In the present study, we hypothesized a specific gestational regulation of 27-OHC and compromised 27-OHC levels due to placental and hepatic diseases in pregnancy resulting in a dysregulation of lipid metabolism.

Methods: The 27-OHC was measured by gas-chromatography-mass spectrometry (GC-MS) and related to cholesterol concentrations. In the longitudinal cohort, a complete set of samples of healthy patients (n = 33) obtained at three different time points throughout gestation and once post-partum was analyzed. In the cross sectional cohort, patients with pregnancy pathologies (IUGR n = 14, PE n = 14, HELLP n = 7, ICP n = 7) were matched to a control group (CTRL) of equal gestational ages.

Results: The 27-OHC levels already increased in the first trimester despite lower TC concentrations (p < 0.05). During the course of pregnancy, a subtle rise in 27-OHC concentrations results in an overall decrease of 27-OHC/TC ratio in between the first (p < 0.05) and second trimester. The ratio remains stable thereafter including the post-partum period. No significant differences have been observed in pregnancy pathologies as compared to the CTRL group.

Conclusion: In conclusion, 27-OHC may have a compensatory role in cholesterol metabolism early in pregnancy. The conserved 27-OHC/TC ratio in pregnancy pathologies suggest that neither the placenta nor the liver is majorly involved in the regulation of 27-OHC metabolism.
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http://dx.doi.org/10.1186/s12884-017-1287-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381014PMC
April 2017

Serum cholesterol acceptor capacity in intrauterine growth restricted fetuses.

J Perinat Med 2017 Oct;45(7):829-835

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Aim: Intrauterine growth restriction (IUGR) is an independent risk factor for the development of cardiovascular diseases later in life. The mechanisms whereby slowed intrauterine growth confers vascular risk are not clearly established. In general, a disturbed cholesterol efflux has been linked to atherosclerosis. The capacity of serum to accept cholesterol has been repeatedly evaluated in clinical studies by the use of macrophage-based cholesterol efflux assays and, if disturbed, precedes atherosclerotic diseases years before the clinical diagnosis. We now hypothesized that circulating cholesterol acceptors in IUGR sera specifically interfere with cholesterol transport mechanisms leading to diminished cholesterol efflux.

Methods: RAW264.7 cells were used to determine efflux of [3H]-cholesterol in response to [umbilical cord serum (IUGR), n=20; controls (CTRL), n=20].

Results: Cholesterol efflux was lower in IUGR as compared to controls [controls: mean 7.7% fractional [3H]-cholesterol efflux, standard deviation (SD)=0.98; IUGR: mean 6.3%, SD=0.79; P<0.0001]. Values strongly correlated to HDL (ρ=0.655, P<0.0001) and apoE (ρ=0.510, P=0.0008), and mildly to apoA1 (ρ=0.3926, P=0.0122) concentrations.

Conclusions: Reduced cholesterol efflux in IUGR could account for the enhanced risk of developing cardiovascular diseases later in life.
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http://dx.doi.org/10.1515/jpm-2016-0270DOI Listing
October 2017

Salt, aldosterone and extrarenal Na - sensitive responses in pregnancy.

Placenta 2017 Aug 10;56:53-58. Epub 2017 Jan 10.

Department of Clinical Research, University of Bern, Switzerland, 3Sonnenhof Hospital, Berne, Switzerland. Electronic address:

Outside of pregnancy excessive salt consumption is known to be harmful being linked to increased blood pressure and cardiovascular disease. However, pregnancy represents a major change to a woman's physiology resulting in an intimate adaptation to environmental conditions. It is now becoming apparent that salt is essential for a number of these changes during pregnancy including haematological, cardiac adaptations as well as directly influencing placental development and the uteroplacental immune environment. The present review discusses the important role that salt has during normal pregnancy and evidence will also be presented to show how the placenta may act as a salt sensing organ temporarily, yet substantially regulating maternal blood pressure.
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http://dx.doi.org/10.1016/j.placenta.2017.01.100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526786PMC
August 2017

Window of opportunity.

Authors:
Markus G Mohaupt

Ther Umsch 2016;73(7):431-435

1 Universitätsklinik für Nephrologie, Hypertonie und Klinische Pharmakologie, Inselspital Bern.

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http://dx.doi.org/10.1024/0040-5930/a000814DOI Listing
February 2017

Relation of 24-hour urinary caffeine and caffeine metabolite excretions with self-reported consumption of coffee and other caffeinated beverages in the general population.

Nutr Metab (Lond) 2016 17;13:81. Epub 2016 Nov 17.

Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Route de la corniche 10, Lausanne, 1010 Switzerland ; Unit of Population Epidemiology, Division of Primary Care Medicine, Department of Community Medicine and Primary Care and Emergency Medicine, University Hospital of Geneva (HUG), Rue Gabrielle Perret-Gentil 4, Geneva, 1205 Switzerland ; Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, USA ; Lausanne University Outpatient Clinic, Rue du Bugnon 44, Lausanne, 1011 Switzerland ; Unit of Population Epidemiology, University Hospital of Geneva (HUG), Rue Gabrielle Perret-Gentil 4, Geneva, 1205 Switzerland.

Background: Caffeine intake is generally estimated by self-reported consumption, but it remains unclear how well self-report associates with metabolite urinary excretion. We investigated the associations of self-reported consumption of caffeinated drinks with urinary excretion of caffeine and its major metabolites in an adult population.

Methods: We used data from the population-based Swiss Kidney Project on Genes in Hypertension (SKIPOGH) study. Consumption of caffeinated coffee, decaffeinated coffee and other caffeinated beverages was assessed by self-administered questionnaire. Quantification of caffeine, paraxanthine, theobromine and theophylline was performed by ultra-high performance liquid chromatography tandem mass spectrometry in 24-h urine. Association of reported consumption of caffeinated drinks with urinary caffeine derived metabolites was determined by quantile regression. We then explored the association between urinary metabolite excretion and dichotomized weekly consumption frequency of caffeinated coffee, with Receiver Operator Characteristic (ROC) analysis.

Results: In the present analysis, we included 598 individuals (52% women, mean age =46 ± 17 years). Self-reported caffeinated coffee intake was positively associated with 24-h urinary excretions of paraxanthine, theophylline and caffeine ( < 0.001), whereas reported intakes of decaffeinated coffee and other caffeinated beverages showed no association. In ROC analysis, optimal discrimination between individuals consuming vs. was obtained for 24-h urinary paraxanthine (Area Under Curve (AUC) = 0.868, 95% Confidence Interval (CI) [0.830;0.906]), with slightly lower performance for theophylline and caffeine, whereas theobromine did not allow any discrimination.

Conclusion: Our results suggest that reported consumption of caffeinated coffee is positively associated with 24-h urinary excretion of caffeine, paraxanthine, and theophylline, and may be used as a marker of caffeine intake for epidemiological studies.
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http://dx.doi.org/10.1186/s12986-016-0144-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112879PMC
November 2016

Orteronel Switch Maintenance Therapy in Metastatic Castration Resistant Prostate Cancer After First-Line Docetaxel: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial (SAKK 08/11).

Prostate 2016 12 25;76(16):1519-1527. Epub 2016 Jul 25.

Department of Oncology/Hematology, Kantonsspital St. Gallen, St. Gallen, Switzerland.

Background: We tested whether a switch maintenance treatment with orteronel, an oral inhibitor of androgen biosynthesis, prolongs disease control in men with metastatic castration-resistant prostate cancer (mCRPC) after documented disease stabilization with docetaxel.

Methods: Men with mCRPC and non-progressive disease after a cumulative dose of ≥300 mg/m docetaxel for first line treatment were randomized 1:1 to receive orteronel 300 mg twice daily or placebo. The primary endpoint was event-free survival (EFS) defined as the time from randomization to death or the combination of at least two of radiographic, clinical, or PSA progression. Ninety-six patients per arm were planned to demonstrate an improvement of median EFS from 4 months on placebo to 6.7 months on orteronel (hazard ratio (HR) 0.6; type I error 5% and power 90%).

Results: Forty-seven patients (23 orteronel, 24 placebo) were randomized before premature closure of the trial because of discontinuation of clinical development of orteronel. Median EFS was 8.5 months with orteronel and 2.9 months with placebo (P = 0.001; HR 0.32; 95%CI 0.15-0.65). Median radiographic progression-free survival (rPFS) was 8.5 and 2.8 months (P = 0.02; HR 0.42; 95%CI 0.20-0.91) in the orteronel and placebo arm, respectively. PSA decline ≥50% was seen in 57% on orteronel and 4% on placebo. Toxicity was mainly mild, one patient on orteronel developed transient grade 3 adrenal insufficiency and one grade 4 pneumonitis.

Conclusions: Orteronel significantly prolongs EFS in men with mCRPC who achieve disease stabilization with docetaxel. The concept of switch maintenance therapy in mCRPC warrants further research. Prostate 76:1519-1527, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/pros.23236DOI Listing
December 2016

Comments and extensions to EFSUMB guidelines on renal interventional ultrasound (INVUS).

Med Ultrason 2016 Sep;18(3):351-61

Department of Internal Medicine, Caritas Hospital, Bad Mergentheim, Germany;Sino-German Research Center of Ultrasound in Medicine, The first affiliated Hospital of Zhengzhou University, China.

The substantial evidence base for interventional ultrasound approaches to renal diagnostic sampling and therapeutic access exists. This review comments on the evidence-based recommendations on ultrasound-guided renal access which have been published recently within the framework of Guidelines on Interventional Ultrasound (InVUS) of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) from a clinical practice point of view. Specific aspects of tissue handling and workup, procedural approach and patient interaction are discussed. Indications, contraindications, risk factors and methods to reduce these risks are considered.
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http://dx.doi.org/10.11152/mu.2013.2066.183.mohDOI Listing
September 2016

Lipid lowering: PCSK9 inhibitors - new kids on the block target their breakthrough.

Authors:
Markus Mohaupt

Swiss Med Wkly 2016 3;146:w14345. Epub 2016 Aug 3.

Department of Nephrology, Hypertension and Clinical Pharmacology; Department of Clinical Research; both University of Bern, Switzerland.

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http://dx.doi.org/10.4414/smw.2016.14345DOI Listing
March 2017

Fibroblast growth factor 23 and markers of mineral metabolism in individuals with preserved renal function.

Kidney Int 2016 09 28;90(3):648-57. Epub 2016 Jun 28.

Department of Nephrology, Hypertension, and Clinical Pharmacology, Bern University Hospital, University of Bern, Bern, Switzerland; Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland; Department of Clinical Research, University of Bern, Bern, Switzerland. Electronic address:

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates phosphate homeostasis. Circulating FGF23 is elevated in chronic kidney disease (CKD) and independently associated with poor renal and cardiovascular outcomes and mortality. Because the study of FGF23 in individuals with normal renal function has received little attention, we examined in a large, population-based study of 1128 participants the associations of FGF23 with markers of mineral metabolism and renal function. The median estimated glomerular filtration rate (eGFR) of the cohort was 105 ml/min per 1.73 m(2), and the median plasma FGF23 was 78.5 RU/ml. FGF23 increased and plasma 1,25-dihydroxyvitamin D3 decreased significantly below an eGFR threshold of 102 and 99 ml/min per 1.73 m(2), respectively. In contrast, plasma parathyroid hormone increased continuously with decreasing eGFR and was first significantly elevated at an eGFR of 126 ml/min per 1.73 m(2). On multivariable analysis adjusting for sex, age, body mass index, and GFR, FGF23 was negatively associated with 1,25-dihydroxyvitamin D3, and urinary absolute and fractional calcium excretion but not with serum calcium or parathyroid hormone. We found a positive association of FGF23 with plasma phosphate, but no association with urinary absolute or fractional phosphate excretion and, unexpectedly, a positive association with tubular maximum phosphate reabsorption/GFR. Thus, in the absence of CKD, parathyroid hormone increases earlier than FGF23 when the eGFR decreases. The increase in FGF23 occurs at a higher eGFR threshold than previously reported and is closely associated with a decrease in 1,25-dihydroxyvitamin D3. We speculate that the main demonstrable effect of FGF23 in the setting of preserved renal function is suppression of 1,25-dihydroxyvitamin D3 rather than stimulation of renal phosphate excretion.
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http://dx.doi.org/10.1016/j.kint.2016.04.024DOI Listing
September 2016

Placental expression of the angiogenic placental growth factor is stimulated by both aldosterone and simulated starvation.

Placenta 2016 Apr 9;40:18-24. Epub 2016 Feb 9.

Department of Nephrology, Hypertension and Clinical Pharmacology, University of Bern, 3010 Berne, Switzerland; Department of Clinical Research, University of Bern, 3010 Berne, Switzerland.

Aldosterone is an important factor supporting placental growth and fetal development. Recently, expression of placental growth factor (PlGF) has been observed in response to aldosterone exposure in different models of atherosclerosis. Thus, we hypothesized that aldosterone up-regulates growth-adaptive angiogenesis in pregnancy, via increased placental PlGF expression. We followed normotensive pregnant women (n = 24) throughout pregnancy and confirmed these results in a second independent first trimester cohort (n = 36). Urinary tetrahydroaldosterone was measured by gas chromatography-mass spectrometry and corrected for creatinine. Circulating PlGF concentrations were determined by ELISA. Additionally, cultured cell lines, adrenocortical H295R and choriocarcinoma BeWo cells, as well as primary human third trimester trophoblasts were tested in vitro. PlGF serum concentrations positively correlated with urinary tetrahydroaldosterone corrected for creatinine in these two independent cohorts. This observation was not due to PlGF, which did not induce aldosterone production in cultured H295R cells. On the other hand, PlGF expression was specifically enhanced by aldosterone in the presence of forskolin (p < 0.01) in trophoblasts. A pronounced stimulation of PlGF expression was observed with reduced glucose concentrations simulating starvation (p < 0.001). In conclusion, aldosterone stimulates placental PlGF production, enhancing its availability during human pregnancy, a response amplified by reduced glucose supply. Given the crucial role of PlGF in maintaining a healthy pregnancy, these data support a key role of aldosterone for a healthy pregnancy outcome.
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http://dx.doi.org/10.1016/j.placenta.2016.02.004DOI Listing
April 2016

Sociodemographic, behavioral and genetic determinants of allostatic load in a Swiss population-based study.

Psychoneuroendocrinology 2016 May 13;67:76-85. Epub 2016 Feb 13.

Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Route de la corniche 10, 1010 Lausanne, Switzerland. Electronic address:

Allostatic load (AL) is a marker of physiological dysregulation which reflects exposure to chronic stress. High AL has been related to poorer health outcomes including mortality. We examine here the association of socioeconomic and lifestyle factors with AL. Additionally, we investigate the extent to which AL is genetically determined. We included 803 participants (52% women, mean age 48±16years) from a population and family-based Swiss study. We computed an AL index aggregating 14 markers from cardiovascular, metabolic, lipidic, oxidative, hypothalamus-pituitary-adrenal and inflammatory homeostatic axes. Education and occupational position were used as indicators of socioeconomic status. Marital status, stress, alcohol intake, smoking, dietary patterns and physical activity were considered as lifestyle factors. Heritability of AL was estimated by maximum likelihood. Women with a low occupational position had higher AL (low vs. high OR=3.99, 95%CI [1.22;13.05]), while the opposite was observed for men (middle vs. high OR=0.48, 95%CI [0.23;0.99]). Education tended to be inversely associated with AL in both sexes(low vs. high OR=3.54, 95%CI [1.69;7.4]/OR=1.59, 95%CI [0.88;2.90] in women/men). Heavy drinking men as well as women abstaining from alcohol had higher AL than moderate drinkers. Physical activity was protective against AL while high salt intake was related to increased AL risk. The heritability of AL was estimated to be 29.5% ±7.9%. Our results suggest that generalized physiological dysregulation, as measured by AL, is determined by both environmental and genetic factors. The genetic contribution to AL remains modest when compared to the environmental component, which explains approximately 70% of the phenotypic variance.
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http://dx.doi.org/10.1016/j.psyneuen.2016.02.003DOI Listing
May 2016

Associations of Urinary Uromodulin with Clinical Characteristics and Markers of Tubular Function in the General Population.

Clin J Am Soc Nephrol 2016 Jan 18;11(1):70-80. Epub 2015 Dec 18.

Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.

Background And Objectives: Allelic variants in UMOD, the gene coding for uromodulin, are associated with rare tubulointerstitial kidney disorders and risk of CKD and hypertension in the general population. The factors associated with uromodulin excretion in the normal population remain largely unknown, and were therefore explored in this study.

Design, Setting, Participants, & Measurements: Urinary uromodulin excretion was measured using a validated ELISA in two population-based cohorts that included more than 6500 individuals. The Swiss Kidney Project on Genes in Hypertension study (SKIPOGH) included 817 adults (mean age±SD, 45±17 years) who underwent renal ultrasonography and performed a 24-hour urine collection. The Cohorte Lausannoise study included 5706 adults (mean age, 53±11 years) with fresh spot morning urine samples. We calculated eGFRs using the CKD-Epidemiology Collaboration formula and by 24-hour creatinine clearance.

Results: In both studies, positive associations were found between uromodulin and urinary sodium, chloride, and potassium excretion and osmolality. In SKIPOGH, 24-hour uromodulin excretion (median, 41 [interquartile range, 29-57] mg/24 h) was positively associated with kidney length and volume and with creatinine excretion and urine volume. It was negatively associated with age and diabetes. Both spot uromodulin concentration and 24-hour uromodulin excretion were linearly and positively associated (multivariate analyses) with eGFR<90 ml/min per 1.73 m(2).

Conclusion: Age, creatinine excretion, diabetes, and urinary volume are independent clinical correlates of urinary uromodulin excretion. The associations of uromodulin excretion with markers of tubular functions and kidney dimensions suggest that it may reflect tubule activity in the general population.
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http://dx.doi.org/10.2215/CJN.04230415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702229PMC
January 2016