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Valentina Forni, Grégoire Wuerzner, Menno Pruijm, Michel BurnierService of Nephrology and Hypertension, Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, SwitzerlandAbstract: In this review, we discuss the pharmacological and clinical properties of irbesartan, a noncompetitive angiotensin II receptor type 1 antagonist, successfully used for more than a decade in the treatment of essential hypertension. Irbesartan exerts its antihypertensive effect through an inhibitory effect on the pressure response to angiotensin II. Irbesartan 150–300 mg once daily confers a lasting effect over 24 hours, and its antihypertensive efficacy is further enhanced by the coadministration of hydrochlorothiazide. Additionally and partially beyond its blood pressure-lowering effect, irbesartan reduces left ventricular hypertrophy, favors right atrial remodeling in atrial fibrillation, and increases the likelihood of maintenance of sinus rhythm after cardioversion in atrial fibrillation. In addition, the renoprotective effects of irbesartan are well documented in the early and later stages of renal disease in type 2 diabetics. Furthermore, both the therapeutic effectiveness and the placebo-like side effect profile contribute to a high adherence rate to the drug. Currently, irbesartan in monotherapy or combination therapy with hydrochlorothiazide represent a rationale pharmacologic approach for arterial hypertension and early-stage and late-stage diabetic nephropathy in hypertensive type II diabetics.Keywords: AT1 receptor blockers, renin-angiotensin-aldosterone system, heart, renal, arterial, hypertension

Background and Aim: Blood pressure displays a seasonal pattern. Whether this pattern is related to high sodium and/or low potassium intakes has not been investigated. We assessed if sodium and potassium consumption present a seasonal pattern. We also simulated the impact of seasonality of sodium consumption on systolic blood pressure levels.Methods and Results: Data from three Swiss population-based studies (n = 2845). Sodium and potassium consumption were assessed by urinary excretion using 24 h urine collection. Seasonality was assessed using the cosinor model and was adjusted for study, gender, age, body mass index, antihypertensive drug treatment, urinary creatinine and atmospheric relative humidity. The effect of sodium variation on blood pressure levels was estimated using data from a recent meta-analysis. Both sodium and potassium excretions showed a seasonal pattern. For sodium, the nadir occurred between August and October, and the peak between February and April, with a multivariate-adjusted seasonal variation (difference between peak and nadir) of 9.2 mmol. For potassium, the nadir occurred in October and the peak in April, with a multivariate-adjusted seasonal variation of 4.0 mmol. Excluding participants on antihypertensive drug treatment or stratifying the analysis by gender cancelled the seasonality of sodium consumption. The maximum impact of the seasonal variation in sodium consumption on systolic blood pressure ranged from 0.4 to 1.1 mm Hg, depending on the model considered.Conclusion: Sodium and potassium consumptions present specific seasonal variations. These variations do not explain the seasonal variations in blood pressure levels. [ABSTRACT FROM AUTHOR]

Reported here is the case of a 22-year-old man who developed pneumonia with unusual pathogens after a near-drowning incident. On day 7 following admission,Rhizopusspp. andAspergillus fumigatuswere cultured from the patient’s bronchoalveolar lavage fluid. One week later, sputum cultures revealedN. cyriacigeorgicias well asN. farcinica. The patient recovered fully after prolonged therapy with liposomal amphotericin B, amikacin, meropenem and cotrimoxazole. [ABSTRACT FROM AUTHOR]

Background: Arterial hypertension is characterized by microvasculature changes and reduced tissue perfusion. It is unknown whether a sexual dimorphism of renal microcirculation is present in patients with arterial hypertension. We aimed to compare the cortical microcirculation in women and men with hypertension and to evaluate their response to sympathetic stimulation with a cold pressor test (CPT)., Methods: The cortical perfusion index (PI) measured by contrast-enhanced ultrasonography was used as a proxy of renal microcirculation. We measured the PI at rest and during a 2-minute CPT in patients with arterial hypertension. We used a linear mixed-model analysis to study the effect of sex, the CPT, and their interaction on the PI., Results: Thirty-two participants were included (34% women). Age and body mass index were similar in both groups. Median PI was higher in women (2344 [interquartile range, 1553-2685 arbitrary units]) than men (1285 [interquartile range, 591-1741 arbitrary units], P =0.009). The CPT increased the PI in both groups; however, the magnitude of the response to CPT was similar in both sexes., Conclusions: Women with arterial hypertension have a higher cortical microperfusion than men, while their microvascular reactivity to a CPT appears to be similar. This sexual dimorphism may have an impact on renal function decline, which needs further investigation.

From immunoglobulin A nephropathy to primary focal segmental glomerulosclerosis, sparsentan expands its indications. Complement inhibitors offer new hope for patients with certain poor-prognosis glomerulonephritides. Semaglutide enjoys great success, promising nephro- and cardioprotection for type 2 diabetics. The renal safety of proton pump inhibitors is questioned. Quality of life benefits of hemodiafiltration are confirmed. Vadadustat represents an oral alternative for the treatment of renal anemia. Xenotransplantation offers a glimpse of a future without organ shortages., Competing Interests: les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Objective: Adrenomedullin (ADM) is a potent vasodilator. The association between plasma ADM levels and blood pressure (BP) remains unclear. We assessed the association between mid-regional-pro-ADM (MR-proADM) and BP in a multicenter population- and family-based cohort., Methods: We used data from the Swiss Kidney Project on Genes in Hypertension (SKIPOGH). We included participants present at both baseline and 3-year follow-up (N = 843). We examined the association of baseline MR-proADM with baseline office and 24 h ambulatory BP as well as the 3-year change in office BP. In secondary analyses, we studied the association between baseline MR-proADM and 3-year changes in pulse wave velocity (PWV), renal resistive index (RRI) and augmentation index (AI). Mixed-effects linear regression models were used., Results: In cross-sectional analyses, MR-proADM was negatively associated with office, 24-h and daytime diastolic BP (DBP). MR-proADM was positively associated with nighttime systolic BP (SBP). In longitudinal analyses, baseline MR-proADM was associated with an increase in office SBP and pulse pressure (PP) over 3 years [β (95% CI): 8.2 (0.4, 15.9) and β (95% CI): 6.4 (0.3, 12.4), respectively] but not with changes in PWV, RRI and AI., Conclusions: The cross-sectional negative association of MR-proADM with DBP is in line with known vasodilatory properties of ADM. The positive association between MR-proADM and nighttime SBP at baseline may reflect endothelial dysfunction believed to be part of the pathogenesis of nocturnal hypertension. The association of higher baseline MR-proADM levels with increased SBP and PP at 3-year follow-up suggests that ADM levels could be a marker of cardiovascular risk., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Importance and Objective: Self-reported caffeine consumption has been widely used in research while it may be subject to bias. We sought to investigate the associations between self-reported caffeine consumption and plasma levels of caffeine and its two main metabolites (paraxanthine and theophylline) in the community., Methods: Data from two population-based studies (SKIPOGH1 and 2 (N = 1246) and CoLaus|PsyCoLaus (N = 4461)) conducted in Switzerland were used. Self-reported caffeine consumption was assessed using questionnaires. Plasma levels of caffeine and its metabolites were quantified by ultra-high performance liquid chromatography coupled to a tandem quadrupole mass spectrometer., Results: In both studies, mean log plasma levels of caffeine and its two metabolites were over 6.48 (plasma levels = 652 ng/ml) when no caffeine consumption was reported. Subsequently, nonlinear associations between log plasma levels and self-reported caffeine consumption were observed in SKIPOGH, with a change of the slope at 3-5 cups of espresso per day in SKIPOGH1 but not SKIPOGH2. In CoLaus|PsyCoLaus, increased daily consumption of caffeinated beverages was associated with increased log plasma levels with a change of the slope at 3 cups. In both studies, declared caffeine consumption higher than 3-5 cups per day was not associated with higher plasma levels of caffeine and its metabolites., Conclusion: Self-reports of no or low caffeine consumption and consumption of more than 3-5 cups of coffee should be interpreted with caution, with possible under- or over-estimation. Quantifying plasma levels of caffeine and its metabolites may contribute to a better estimation of caffeine intake., (© 2024. The Author(s).)

Introduction: The gut barrier, comprising gut microbiota, plays a pivotal role in chronic kidney disease (CKD) progression and nutritional status. This study aimed to explore gut barrier alterations in hemodialyzed (HD) patients, non-HD (NHD) CKD patients, and healthy volunteers., Methods: Our cross-sectional study enrolled 22 HD patients, 11 NHD patients, and 11 healthy volunteers. We evaluated fecal microbiota composition (assessed via bacterial 16S rRNA gene sequencing), fecal IgA levels, surrogate markers of gut permeability, serum cytokines, appetite mediators, nutritional status, physical activity, and quality of life., Results: HD patients exhibited significant alterations in fecal microbiota composition compared to healthy volunteers, with observed shifts in taxa known to be associated with dietary patterns or producing metabolites acting on human host. In comparison to healthy volunteers, individuals with HD patients exhibited elevated levels of inflammatory markers (CRP, IL-6 and TNF-α), glucagon-like peptide-2, and potential anorexigenic markers (including leptin and peptide YY). NHD patients had increased levels of CRP and peptide YY. Overall fecal microbiota composition was associated with height, soft lean mass, resting energy expenditure, handgrip strength, bone mineral content and plasma albumin and TNF-α., Discussion: Compared to healthy volunteers, HD patients have an altered fecal microbiota composition, a higher systemic inflammation, and a modification in plasma levels of appetite mediators. While some differences align with previous findings, heterogeneity exists likely due to various factors including lifestyle and comorbidities. Despite limitations such as sample size, our study underscores the multifaceted interplay between gut microbiota, physiological markers, and kidney function, warranting further investigation in larger cohorts., Competing Interests: PC is the research director at Fonds de la Recherche Scientifique (FNRS) and is a recipient of grants from FNRS. PC is an inventor on patent applications related to the use of bacteria in addressing metabolic disorders. PC was a co-founder of the Akkermansia Company SA and Enterosys. Fresenius Kabi Deutschland GmbH had no authority over the purpose, methodology, and results of this investigator-initiated study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lazarevic, Teta, Pruijm, Stoermann, Marangon, Mareschal, Solano, Wurzner-Ghajarzadeh, Gaïa, Cani, Dizdar, Herrmann, Schrenzel and Genton.)

The health-care system and particularly renal replacement therapy has a significant carbon footprint adding to global warming and extreme weather conditions. Improving sustainability has become the focus of national and international working groups. Many reviews underline the need for improvement of sustainability in nephrology, in particular dialysis, and provide recommendations on how to reduce waste, energy, and water consumption. However, how to implement these recommendations, and where to start, is not always clear. This paper summarizes discussions within the 'working group on sustainable nephrology' of the Swiss Society of Nephrology. We do not provide a detailed review of the topic but instead present a practical 10-point action plan to help health-care workers in nephrology make a start and improve the carbon footprint of their dialysis centres. We emphasize the importance of ongoing research, cooperation, and dialogue, and welcome additional ideas from the wider renal community., Competing Interests: A.W. is member of the Clinical Kidney Journal editorial board., (© Crown copyright 2024.)

Artificial intelligence (AI) is increasingly used in forensic anthropology and genetics to identify the victim and the cause of death. The large autopsy samples from persons with traumatic causes of death but without comorbidities also offer possibilities to analyze normal histology with AI. We propose a new deep learning-based method to rapidly count glomerular number and measure glomerular density (GD) and volume in post-mortem kidney samples obtained in a forensic population. We assessed whether this new method detects glomerular differences between men and women without known kidney disease. Autopsies performed between 2009 and 2015 were analyzed if subjects were aged ≥ 18 years and had no known kidney disease, diabetes mellitus, or hypertension. A large biopsy was taken from each kidney, stained with hematoxylin and eosin, and scanned. An in-house developed deep learning-based algorithm counted the glomerular density (GD), number, and size. Out of 1165 forensic autopsies, 86 met all inclusion criteria (54 men). Mean (± SD) age was 43.5 ± 14.6; 786 ± 277 glomeruli were analyzed per individual. There was no significant difference in GD between men and women (2.18 ± 0.49 vs. 2.30 ± 0.57 glomeruli/mm 2 , p = 0.71); glomerular diameter, area, and volume also did not differ. GD correlated inversely with age, kidney weight, and glomerular area. Glomerular area and volume increased significantly with age. In this study, there were no sex differences in glomerular density or size. Considering the size of the kidney samples, the use of the presented deep learning method can help to analyze large renal autopsy biopsies and opens perspectives for the histological study of other organs., (© 2023. The Author(s).)

The application of mammalian target of rapamycin inhibition (mTORi) as primary prophylactic therapy to optimize T cell effector function while preserving allograft tolerance remains challenging. Here, we present a comprehensive two-step therapeutic approach in a male patient with metastatic cutaneous squamous cell carcinoma and heart transplantation followed with concomitant longitudinal analysis of systemic immunologic changes. In the first step, calcineurin inhibitor/ mycophenolic acid is replaced by the mTORi everolimus to achieve an improved effector T cell status with increased cytotoxic activity (perforin, granzyme), enhanced proliferation (Ki67) and upregulated activation markers (CD38, CD69). In the second step, talimogene laherparepvec (T-VEC) injection further enhances effector function by switching CD4 and CD8 cells from central memory to effector memory profiles, enhancing Th1 responses, and boosting cytotoxic and proliferative activities. In addition, cytokine release (IL-6, IL-18, sCD25, CCL-2, CCL-4) is enhanced and the frequency of circulating regulatory T cells is increased. Notably, no histologic signs of allograft rejection are observed in consecutive end-myocardial biopsies. These findings provide valuable insights into the dynamics of T cell activation and differentiation and suggest that timely initiation of mTORi-based primary prophylaxis may provide a dual benefit of revitalizing T cell function while maintaining allograft tolerance., (© 2024. The Author(s).)

Objectives: Trace elements (TEs) are ubiquitous. TE concentrations vary among individuals and countries, depending on factors such as living area, workplaces and diet. Deficit or excessive TEs concentrations have consequences on the proper functioning of human organism so their biomonitoring is important. The aim of this project was to provide reference values for TEs concentrations in the Swiss population., Methods: The 1,078 participants to the SKiPOGH cohort included in this study were aged 18-90 years. Their 24-h urine and/or plasma samples were analyzed by inductively coupled plasma mass spectrometry (ICP-MS) to determine 24 TEs concentrations: Ag, Al, As, Be, Bi, Cd, Co, Cr, Cu, Hg, I, Li, Mn, Mo, Ni, Pb, Pd, Pt, Sb, Se, Sn, Tl, V and Zn. Statistical tests were performed to evaluate the influence of covariates (sex, age, BMI, smoking) on these results. Reference intervals for the Swiss adult population were also defined., Results: TEs concentrations were obtained for respectively 994 and 903 persons in plasma and urine matrices. It was possible to define percentiles of interest (P50 and P95) for almost all the TEs. Differences in TEs distribution between men and women were noticed in both matrices; age was also a cofactor., Conclusions: This first Swiss biomonitoring of a large TEs-panel offers reference values in plasma and in urine for the Swiss population. The results obtained in this study were generally in line with clinical recommendations and comparable to levels reported in other population-based surveys., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Microvascular structural alteration and dysfunction is a hallmark of arterial hypertension. So far, the visualization and the quantification of renal microcirculation in humans has been hampered by the lack of non-nephrotoxic and non-invasive radiologic techniques. Contrast-enhanced ultrasonography (CEUS) is an appealing method to investigate renal microcirculation and has not been investigated in this setting. We aimed to compare renal microcirculation in normotensive (NT) and hypertensive (HT) participants using CEUS at rest and during a sympathetic stress test., Methods: We measured the renal perfusion index (PI, primary outcome), the renal resistive index (RRI), beat-to-beat systemic hemodynamics and plasma catecholamines before and during a 2-min cold pressor test (CPT) in NT and HT participants. Linear mixed model analysis was used to compare the effect of the CPT on the variables of interest., Results: Seventy-three participants (32 HT) with normal kidney function were included. HT participants had a lower baseline PI compared with NT participants [median (interquartile range) 1476 (959-2155) arbitrary units (a.u.) vs 2062 (1438-3318) a.u., P < .001]. The CPT increased blood pressure, heart rate and catecholamines in all participants. The increase in PI observed in NT during the CPT was blunted in HT [+504 (117-920) a.u. vs +1159 (678-2352) a.u in NT, interaction P = .013]. Age, sex and body mass index did not modify these results., Conclusions: HT patients had a lower basal renal cortical perfusion. During the cold pressor test, HT participants had a smaller increase in the PI, suggesting that renal cortical flow reserve is impaired., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background: For every 100 patients with diabetes, 40 will develop diabetic kidney disease (DKD) over time. This diabetes complication may be partly due to poor adherence to their prescribed medications. In this study, we aimed to evaluate the differential impact of a 6- versus 12-month pharmacist-led interprofessional medication adherence program (IMAP) on the components of adherence (i.e., implementation and discontinuation) in patients with DKD, during and after the intervention. Methods: All included patients benefited from the IMAP, which consists in face-to-face regular motivational interviews between the patient and the pharmacist based on the adherence feedback from electronic monitors (EMs), in which the prescribed treatments were delivered. Adherence reports were available to prescribers during the intervention period. Patients were randomized 1:1 into two parallel arms: a 12-month IMAP intervention in group A versus a 6-month intervention in group B. Adherence was monitored continuously for 24 months post-inclusion during the consecutive intervention and follow-up phases. In the follow-up phase post-intervention, EM data were blinded. Blood pressure was measured by the pharmacist at each visit. The repeated measures of daily patient medication intake outcomes (1/0) to antidiabetics, antihypertensive drugs, and statins were modeled longitudinally using the generalized estimated equation in both groups and in both the intervention and the follow-up phases. Results: EM data of 72 patients were analyzed (34 in group A and 38 in group B). Patient implementation to antidiabetics and antihypertensive drugs increased during the IMAP intervention phase and decreased progressively during the follow-up period. At 12 months, implementation to antidiabetics was statistically higher in group A versus group B (93.8% versus 86.8%; Δ 7.0%, 95% CI: 5.7%; 8.3%); implementation to antihypertensive drugs was also higher in group A versus B (97.9% versus 92.1%; Δ 5.8%, 95% CI: 4.8%; 6.7%). At 24 months, implementation to antidiabetics and antihypertensive drugs remained higher in group A versus B (for antidiabetics: 88.6% versus 85.6%; Δ 3.0%, 95% CI: 1.7%; 4.4% and for antihypertensive drugs: 94.4% versus 85.9%; Δ 8.5%, 95% CI: 6.6%; 10.7%). No difference in pharmacy-based blood pressure was observed between groups. Implementation to statins was comparable at each time point between groups. Three patients discontinued at least one treatment; they were all in group B. In total, 46% (16/35) of patients in the 12-month intervention versus 37% (14/38) of patients in the 6-month intervention left the study during the intervention phase, mainly due to personal reasons. Conclusion: The IMAP improves adherence to chronic medications in patients with DKD. The longer the patients benefit from the intervention, the more the implementation increases over time, and the more the effect lasts after the end of the intervention. These data suggest that a 12-month rather than a 6-month program should be provided as a standard of care to support medication adherence in this population. The impact on clinical outcomes needs to be demonstrated. Clinical Trial Registration: Clinicaltrials.gov, identifier NCT04190251&#95;PANDIA IRIS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bandiera, Dotta-Celio, Locatelli, Nobre, Wuerzner, Pruijm, Lamine, Burnier, Zanchi and Schneider.)

Background: Evaluation of renal function and of factors associated with its decline are important public health issues. Besides markers of glomerular function [e.g. glomerular filtration rate (GFR)], those of tubular functions are rarely evaluated. Urea, the most abundant urinary solute, is markedly concentrated in urine when compared with plasma. We explored the urine-to-plasma ratio of urea concentrations (U/P urea ratio) as a marker of tubular functions., Methods: We evaluated the relationship of the U/P urea ratio with eGFR at baseline in 1043 participants (48 ± 17 years) from the Swiss Kidney Project on Genes in Hypertension (SKIPOGH) population-based cohort, using mixed regression. In 898 participants, we assessed the relation between U/P urea ratio and renal function decline between two study waves 3 years apart. We studied U/P ratios for osmolarity, Na, K and uric acid for comparison., Results: In a transversal study at baseline, estimated GFR (eGFR) was positively associated with U/P-urea ratio [βscaled = 0.08, 95% CI (0.04; 0.13)] but not with the U/P ratio of osmolarity. Considering separately participants with renal function >90 or ≤90 mL/min × 1.73 m2, this association was observed only in those with reduced renal function. In the longitudinal study, eGFR declined at a mean rate of 1.2 mL/min per year. A significant association was observed between baseline U/P urea ratio and eGFR decline [βscaled = 0.08, 95% CI (0.01; 0.15)]. A lower baseline U/P urea ratio was associated with a greater eGFR decline., Conclusion: This study provides evidence that the U/P urea ratio is an early marker of kidney function decline in the general adult population. Urea is easy to measure with well-standardized techniques and at low cost. Thus, the U/P urea ratio could become an easily available tubular marker for evaluating renal function decline., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

An accurate assessment of renal function is crucial for the diagnosis and follow up of kidney diseases. However, there is currently no clear consensus on the optimal method on how to measure renal function in older individuals (>65 years of age). The Cockcroft-Gault formula, the MDRD equation, and the CKD-EPI equation are among the most used equations. However, they have several limitations when applied to the older population. Other formulas specifically developed for the older, such as the Berlin Initiative Study (BIS) and the Full Age Spectrum (FAS) equation, demonstrated conflicting results and require more external validation. This article provides an overview of the currently available methods to assess renal function in the older persons and summarizes their shortcomings., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Objective: In patients with type 2 diabetes and diabetic kidney disease (DKD), explore the relationship between estimated glomerular filtration rate decline (eGFR-d) and simultaneously assessed vascular risk markers including office, ambulatory or central blood pressure, pulse pressure, carotid-femoral pulse wave velocity (PWV), carotid intima-media thickness (IMT) and renal resistive indexes (RRI)., Research Design and Methods: At baseline, vascular risk markers were measured in addition to the routine clinical workup. The eGFR-d was based on 2000-2019 creatinine values. Parameters were compared by eGFR-d quartiles. Regression models of eGFR-d and vascular markers were assessed., Results: In total, 135 patients were included. Mean age was 63.8 ± 10.8y, baseline eGFR 60.2 ± 26.4 ml/min/1.73 m 2 and urine albumin-creatinine ratio (ACR) 49 ± 108 mg/mmol. Mean eGFR-d was based on 43 ± 39 creatinine values within a time span of 7.0 ± 1.9y. The average yearly eGFR decline was -1.8 ± 3.0 ml/min/1.73 m 2 ranging from -5.8 ± 2.3 in the first quartile to +1.4 ± 1.7 in the fourth quartile. Mean 24 h systolic (SBP) and diastolic (DBP) blood pressure were 126 ± 17 and 74 ± 9 mmHg. Mean PWV was 11.8 ± 2.8 m/s, RRI 0.76 ± 0.07 and IMT 0.77 ± 0.21 mm. SBP and pulse pressure correlated with eGFR-d but not DBP. 24 h SBP stood out as a stronger predictor of eGFR-d than office or central SBP. PWV and RRI correlated with eGFR decline in univariate, but not multivariate regression models including 24 SBP and ACR., Conclusions: In this study, eGFR decline was highly variable in patients with type 2 diabetes and DKD. Twenty-four hour SBP provided an added value to the routine measurement of ACR in predicting eGFR decline, whereas PWV and RRI did not., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Truscello, Nobre, Sabaratnam, Bonny, Wuerzner, Burnier, Fakhouri, Pruijm and Zanchi.)

(1) Background: The renal microcirculation is essential to maintain the renal function, but its determinants in humans have been poorly studied. Contrast-enhanced ultrasound (CEUS) allows the non-invasive quantification of the cortical micro-perfusion at the bedside using the perfusion index (PI). The aims of this study were to assess whether differences exist in PI between healthy males and females and to identify clinical determinants associated with cortical micro-perfusion. (2) Methods: Healthy, normotensive volunteers (eGFR > 60 mL/min/1.73 m 2 , no albuminuria) underwent CEUS under standardized conditions with the destruction-reperfusion (DR) technique. The mean PI of four DR sequences was reported as the primary outcome measure (3) Results: A total of 115 subjects (77 females and 38 males) completed the study; the mean ± SD age was, respectively, 37.1 ± 12.2 and 37.1 ± 12.7 years in females and males, and the mean eGFR was 105.9 ± 15.1 and 91.0 ± 17.4 mL/min/1.73 m 2 . The PI (median) was higher in females than in males, i.e., 2705 (IQR 1641-3777) vs. 1965 (IQR 1294-3346) arbitrary units (a.u), p = 0.02). A correlation analysis showed positive associations between PI and eGFR, female sex, heart rate, plasma renin activity (PRA) and plasma aldosterone concentrations (PAC), negative associations with potassium, bicarbonate and systolic blood pressure, and no associations with age, body mass index and renal resistive index (RRI). In a multivariate linear regression analysis, only PRA remained significantly associated with PI. (4) Conclusions: Although the PI was higher among females, this association was no longer significant after adjustment for covariates. There was no difference in females tested during the follicular or the luteal phases. In conclusion, the PI was only weakly influenced by classic clinical variables, but was positively associated with PRA, suggesting that the renin-angiotensin system plays a role in the regulation of the cortical micro-perfusion in humans. Identifying which other factors contribute to the large variations in micro-perfusion across individuals needs further study.

Intravenous drug use (IVDU) is a major public health issue, associated with high mortality rates. The risk of overdose, cardiovascular and infectious complications are well known, but IVDU can also lead to different types of kidney disease. Patients can develop acute or chronic kidney injury due to direct nephrotoxicity of the drugs, or present with different types of glomerulonephritis, interstitial nephritis, and bacterial or viral infection-related nephropathy. Diagnosis can be difficult but is essential to prevent irreversible kidney damage. The number of persons with IVDU that develop end-stage kidney disease is increasing and poses challenges for dialysis and transplantation centers. This article summarizes the renal manifestations that clinicians may encounter in persons with IVDU, especially of heroin and cocaine., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Adverse socioeconomic circumstances negatively affect the functioning of biological systems, but the underlying mechanisms remain only partially understood. Here, we explore the associations between life-course socioeconomic factors and four markers of epigenetic aging in a population-based setting. We included 684 participants (52 % women, mean age 52.6 ± 15.5 years) from a population and family-based Swiss study. We used nine life-course socioeconomic indicators as the main exposure variables, and four blood-derived, second generation markers of epigenetic aging as the outcome variables (Levine's DNAmPhenoAge, DunedinPoAm38, GrimAge epigenetic age acceleration (EAA), and the mortality risk score (MS)). First, we investigated the associations between socioeconomic indicators and markers of epigenetic aging via mixed-effect linear regression models, adjusting for age, sex, participant's recruitment center, familial structure (random-effect covariate), seasonality of blood sampling, and technical covariates. Second, we implemented counterfactual mediation analysis to investigate life-course and intermediate mechanisms underlying the socioeconomic gradient in epigenetic aging. Effect-size estimates were assessed using regression coefficients and counterfactual mediation parameters, along with their respective 95 % confidence intervals. Individuals reporting a low father's occupation, adverse financial conditions in childhood, a low income, having financial difficulties, or experiencing unfavorable socioeconomic trajectories were epigenetically older and had a higher mortality risk score than their more advantaged counterparts. Specifically, this corresponded to an average increase of 1.1-1.5 years for Levine's epigenetic age (β and 95 %CI range, β (minimum and maximum): 1.1-1.5 95 %CI[0.0-0.2; 2.3-3.0]), 1.1-1.5 additional years for GrimAge (β: 1.1-1.5 95 %CI[0.2-0.6; 1.9-3.0]), a 1-3 % higher DunedinPoAm38 age acceleration (β: 0.01-0.03 95 %CI[0.00; 0.03-0.04]), and a 10-50 % higher MS score (β: 0.1-0.4 95 %CI[0.0-0.2; 0.3-0.4]) for the aforementioned socioeconomic indicators. By exploring the life-course mechanisms underlying the socioeconomic gradient in epigenetic aging, we found that both childhood and adulthood socioeconomic factors contributed to epigenetic aging, and that detrimental lifestyle factors mediated the relation between socioeconomic circumstances in adulthood and EAA (31-89 % mediated proportion). This study provides emerging evidence for an association between disadvantaged life-course socioeconomic circumstances and detrimental epigenetic aging patterns, supporting the "sensitive-period" life-course model. Counterfactual mediation analyses further indicated that the effect of socioeconomic factors in adulthood operates through detrimental lifestyle factors, whereas associations involving early-life socioeconomic factors were less clear., Competing Interests: Conflicts of interest The authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The recent advent of high-throughput sequencing technologies has allowed exploring the contribution of thousands of genomic, epigenomic, transcriptomic, or proteomic variants to complex phenotypic traits. Here, we sought to conduct large-scale (Epi)Genome-Wide Association Studies (GWAS/EWAS) to investigate the associations between genomic (Single Nucleotide Polymorphism; SNP) and epigenomic (Cytosine-Phospho-Guanine; CpG) markers, with multiple phenotypic traits in a population-based context. We used data from SKIPOGH, a family- and population-based cohort conducted in the cities of Lausanne, Geneva, and Bern (N=1100). We used 7,577,572 SNPs, 420,444 CpGs, and 825 phenotypes, including anthropometric, clinical, blood, urine, metabolite, and metal measures. GWAS analyses assessed the associations between SNPs and metabolites and metals (N=279), using regression models adjusted for age, sex, recruitment center, and familial structure, whereas EWAS analyses explored the relations between CpGs and 825 phenotypes, additionally adjusting for the seasonality of blood sampling and technical nuisance. Following the implementation of GWAS and EWAS analyses, we developed a web-based platform, PhenoExplorer, aimed at providing an open access to the obtained results. Of the 279 phenotypes included in GWAS, 103 displayed significant associations with 2804 SNPs (2091 unique SNPs) at Bonferroni threshold, whereas 109 of the 825 phenotypes included in EWAS analyses were associated with 4893 CpGs (2578 unique CpGs). All of the obtained GWAS and EWAS results were eventually made available using the in-house built web-based PhenoExplorer platform, with the purpose of providing an open-access to the tested associations. In conclusion, we provide a comprehensive outline of GWAS and EWAS associations performed in a Swiss population-based study. Further, we set up a web-based PhenoExplorer platform with the purpose of contributing to the overall understanding of the role of molecular variants in regulating complex phenotypes., Competing Interests: None to declare., (Copyright 2022 Jean-Pierre Ghobril, Dusan Petrovic, Georg Ehret, Belén Ponte, Menno Pruijm, Daniel Ackermann, Bruno Vogt, Silvia Stringhini, Aurélien Thomas, Jonviea Chamberlain, Semira Gonseth-Nusslé, Murielle Bochud. License: This work is licensed under a Creative Commons Attribution 4.0 International License.)