Gut microbiota associations with chronic kidney disease: insights into nutritional and inflammatory parameters.

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.

Self-reported caffeine consumption miss-matched consumption measured by plasma levels of caffeine and its metabolites: results from two population-based studies.

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.

Primary prophylaxis with mTOR inhibitor enhances T cell effector function and prevents heart transplant rejection during talimogene laherparepvec therapy of squamous cell carcinoma.

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.

Reference values for plasma and urine trace elements in a Swiss population-based cohort.

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.

The differential impact of a 6-versus 12-month pharmacist-led interprofessional medication adherence program on medication adherence in patients with diabetic kidney disease: the randomized PANDIA-IRIS study.

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_PANDIA IRIS.

A new, deep learning-based method for the analysis of autopsy kidney samples used to study sex differences in glomerular density and size in a forensic population.

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/mm2, 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.

Contrast-enhanced ultrasonography reveals a lower cortical perfusion and a decreased renal flow reserve in hypertensive patients.

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.

[Estimating renal function in older patients : which is the best formula?] / Estimation de la fonction rénale chez la personne âgée : quelle formule utiliser ?

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.

Une évaluation correcte de la fonction rénale est essentielle pour diagnostiquer et prendre des décisions cliniques importantes. Cependant, il n'y a pas de consensus clair sur la meilleure méthode pour mesurer la fonction rénale chez les personnes âgées. Les équations les plus couramment utilisées sont la formule de Cockcroft-Gault et les équations MDRD et CKD-EPI, mais elles présentent des limitations dans cette population. D'autres formules spécifiquement développées pour les aînés, telles que l'étude de l'initiative de Berlin (BIS) et l'équation du spectre complet de l'âge (FAS), ont montré des résultats contradictoires et nécessitent des études de validation externe. En conclusion, les médecins doivent être conscients des différentes options disponibles et des limitations de chaque méthode pour prendre des décisions cliniques éclairées.

Blood pressure and vascular determinants of glomerular filtration rate decline in diabetic kidney disease.

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 m2 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 m2 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.

The urine-to-plasma urea concentration ratio is associated with eGFR and eGFR decline over time in a population cohort.

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 [ßscaled = 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 [ßscaled = 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.

Determinants of Renal Micro-Perfusion as Assessed with Contrast-Enhanced Ultrasound in Healthy Males and Females.

(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 m2, 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 m2. 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 and kidney disease]. / Consommation de drogues par voie itraveineuse et maladies rénales.

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.

La consommation de drogues par voie intraveineuse (CDVI) constitue un problème majeur de santé publique. Les risques d'overdose, de complications cardiovasculaires et infectieuses sont bien connus, mais la CDVI peut aussi mener à différentes atteintes rénales. Les patients peuvent développer une insuffisance rénale aiguë ou chronique due à la toxicité directe des drogues, mais aussi une glomérulonéphrite, une néphrite interstitielle ou une néphropathie secondaire à une infection virale ou bactérienne. Le nombre de personnes avec CDVI développant une insuffisance rénale terminale est à la hausse et représente un défi pour les centres de dialyse et de transplantation. Cet article passe en revue les manifestations rénales que les cliniciens peuvent rencontrer lors de la prise en charge de patients avec CDVI, notamment d'héroïne et de cocaïne.

Life-course socioeconomic factors are associated with markers of epigenetic aging in a population-based study.

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 (ß and 95 %CI range, ß (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 (ß: 1.1-1.5 95 %CI[0.2-0.6; 1.9-3.0]), a 1-3 % higher DunedinPoAm38 age acceleration (ß: 0.01-0.03 95 %CI[0.00; 0.03-0.04]), and a 10-50 % higher MS score (ß: 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.

Contrast-Enhanced Ultrasound and Protein Shakes Are No Alternatives for Inulin Clearance and Meat to Assess Renal Functional Reserve in Humans.

INTRODUCTION: The measurement of renal functional reserve (RFR) can unmask glomerular hyperfiltration in residual nephrons, but its determination is time-consuming. In this study, we assessed whether contrast-enhanced ultrasound (CEUS) is a valuable alternative to the gold standard inulin clearance and whether L-arginine or protein shakes lead to similar changes in glomerular filtration rate (GFR) as animal proteins in men and women. METHODS: Changes in GFR and renal microperfusion were studied in 25 healthy subjects (8 men, 17 women) by simultaneously performing inulin clearance and CEUS (perfusion index, PI) before and 1 and 2 h after different protein loads (L-arginine, protein shake or meat). The Doppler parameters - renal resistive index (RRI) and pulsatility index (PuI) - were also measured. RESULTS: None of the oral protein loads induced significant changes in CEUS-assessed PI. Only meat increased inulin clearance (from 111.2 ± 16.0 to 149.8 ± 27.2 mL/min, p < 0.05) and mobilized RFR, while L-arginine decreased GFR (106.7 ± 45.3 to 86.3 ± 42.6 mL/min, p < 0.05). Protein shakes had a neutral effect. There were no correlations between changes in inulin clearance and PI. At Doppler, RRI and PuI increased after meat intake (from 0.647 ± 0.029 to 0.694 ± 0.050 a.u., p < 0.05 and from 1.130 ± 0.087 to 1.318 ± 0.163 a.u., p < 0.05, respectively), but their changes also did not correlate with changes in inulin clearance. Results were similar in both sexes. CONCLUSIONS: CEUS is not a valuable alternative for inulin clearance to measure RFR. Meat ingestion leads to modest changes in renal Doppler parameters and to glomerular hyperfiltration in both women and men, while protein shakes and L-arginine do not.

Understanding reasons and factors for participation and non-participation to a medication adherence program for patients with diabetic kidney disease in Switzerland: a mixed methods study.

BACKGROUND: An interprofessional medication adherence intervention led by pharmacists, combining motivational interviews and feedback with electronic monitor (EM) drug assessment, was offered to all consecutive patients with diabetic kidney disease (DKD) (estimated glomerular filtration rate < 60 mL/min/1.73 m2) visiting their nephrologist or endocrinologist. Approximately 73% (202/275) of eligible patients declined to participate, and the factors and reasons for refusal were investigated. METHODS: Sociodemographic and clinical data of included patients and those who refused were collected retrospectively for those who had previously signed the general consent form. Multivariate logistic regression analysis was performed to identify independent variables associated with non-participation. Patients who refused or accepted the adherence study were invited to participate in semi-structured interviews. Verbatim transcription, thematic analysis, and inductive coding were performed. RESULTS: Patients who refused to participate were older (n = 123, mean age 67.7 years, SD:10.4) than those who accepted (n = 57, mean age 64.0 years, SD:10.0, p = 0.027) and the proportion of women was higher among them than among patients who accepted it (30.9% vs 12.3%, p = 0.007). The time from diabetes diagnosis was longer in patients who refused than in those who accepted (median 14.2 years IQR 6.9-22.7 vs. 8.6 years, IQR 4.5-15.9, p = 0.003). Factors associated with an increased risk of non-participation were female sex (OR 3.8, 95% CI 1.4-10.0, p = 0.007) and the time from diabetes diagnosis (OR 1.05, 95% CI 1.01-1.09, p = 0.019). The included patients who were interviewed (n = 14) found the interprofessional intervention useful to improve their medication management, support medication literacy, and motivation. Patients who refused to participate and who were interviewed (n = 16) explained no perceived need, did not agree to use EM, and perceived the study as a burden and shared that the study would have been beneficial if introduced earlier in their therapeutic journey. Other barriers emerged as difficult relationships with healthcare providers, lack of awareness of the pharmacist's role, and negative perception of clinical research. CONCLUSIONS: Investigating the factors and reasons for participation and non-participation in a study helps tailor intervention designs to the needs of polypharmacy patients. Patients who refused the adherence intervention may not be aware of the benefits of medication management and medication literacy. There is an urgent need to advocate for interprofessional outpatient collaborations to support medication adherence in patients with DKD. Trial registration Clinicaltrials.gov NCT04190251_PANDIA IRIS.

COVID-19 Pandemic in Dialysis Patients: The Swiss Experience.

Background: Chronic dialysis patients are classified as patients with increased risk for COVID-19. Knowledge about the incidence and survival of chronic dialysis patients infected with SARS-CoV-2 in Switzerland - a high-income country with high density of relatively small dialysis centers - is scarce. We present the findings regarding incidence, survival and regional differences, compared to those of the general population in Switzerland. Methods: Information on chronic dialysis patients who tested positive for SARS-CoV-2 between February 24, 2020 and February 28, 2022 were reported to the Swiss dialysis registry by all 94 Swiss dialysis centers. Hereafter, these results were linked with clinical characteristics from the Swiss dialysis registry. Results: Throughout the study period 1,120 out of ~4,700 dialysis patients tested positive for SARS-CoV-2 in Switzerland: 96 cases occurred in the first wave, 472 in the second wave and 5 in between. During the first wave, Italian-speaking Ticino was most severely affected, with a 7-fold higher incidence of dialysis patients compared to the general Swiss population. In the second wave, the majority of cases were found in the French-speaking part of Switzerland, with a 2.5 times higher incidence vs. non-dialysis patients. A total of 123 deaths were recorded in the first two waves, of which COVID-19 was the main cause of death in 100 patients. This corresponds to a highly increased overall mortality rate of 17.5% compared to 1.7% in the general population. Age was identified as the only risk factor for mortality in dialysis patients. During the third, fourth and fifth wave, 61, 43 and 443 cases, respectively, were recorded, resulting in 6 (mortality rate 9.8%), 1 (mortality rate 2.3%) and 13 deaths (mortality rate 2.9%). Conclusion: Chronic dialysis patients in Switzerland were more likely to be infected by SARS-CoV-2 during the first and second wave than the rest of the population, but an inverse trend was observed during the third, fourth and fifth wave, probably thanks to vaccination. In addition, mortality is significantly increased compared to non-dialysis patients. In Swiss dialysis patients, age is the strongest risk factor for death.

Contrast-Enhanced Ultrasonography Enables the Detection of a Cold Pressor Test-Induced Increase in Renal Microcirculation in Healthy Participants.

Background: Renal microcirculation is essential for regulation of the glomerular filtration rate, the reabsorption of salt and water from the interstitium, and hence the blood pressure. Renal ultrasonography coupled to Doppler analysis and contrast-enhanced ultrasound enables the study of renal perfusion. So far, physiologic interventions have rarely been performed to assess the renal perfusion. The objective of our study was to measure the renal perfusion in response to a cold pressor test (CPT). Methods: Healthy adult participants were exposed to a 2 min CPT or a sham exposure (body temperature). Systemic hemodynamics, renal resistive index (RRI) and renal perfusion index (PI) were measured before and during the CPT or the sham exposure. Renal responses were compared using a paired Student's t-test or Wilcoxon signed rank test. Pearson correlation test was used to test association of variables of interest. Results: Forty-one normotensive participants (21 women) were included in the study. Mean blood pressure and heart rate both increased with the CPT. The RRI decreased from 0.60 ± 0.05 arbitrary units (AU) to 0.58 ± 0.05 AU (p < 0.05) and the PI increased from 2,074 AU (1,358-3,346) to 3,800 AU (2,118-6,399) (p < 0.05) (+66% (24-106%)). Compared to the sham exposure, the increase in PI with the CPT was more marked. There was a negative association between the increase in heart rate and mean blood pressure with the RRI (r: -0.550, p = 0.002 and r: -0.395, P = 0.016), respectively. Conclusion: Doppler Ultrasound and CEUS enable the detection of physiological changes within the macro- and microvascular renal circulation. The CPT decreases the RRI and increases the PI. Whether these changes are present in pathological states such as diabetes or hypertension will need additional studies.

Increased glucocorticoid metabolism in diabetic kidney disease.

AIMS: Glomerular damage indicated by proteinuria is a main symptom in diabetic nephropathy. Mineralocorticoid receptor (MR) antagonists (MRAs) are beneficial irrespective of aldosterone availability. Thus, we hypothesized an alternatively activated MR to promote glomerular damage in proteinuric diabetic nephropathy. Specifically, we aimed first to demonstrate the presence of steroid hormones serving as alternative MR targets in type II diabetic patients with proteinuric kidney disease, second whether MR selectivity was modified, third to characterize MR and glucocorticoid receptor (GR) expression and activity in glomerular cell types exposed to eu- and hyperglycemic conditions, fourth to characterize the pro-fibrotic potential of primary human renal mesangial cells (HRMC) upon stimulation with aldosterone and cortisol, and fifth to specify the involvement of the MR and/or GR in pro-fibrotic signaling. MATERIALS AND METHODS: Urinary steroid hormone profiles of patients with diabetic kidney disease were analyzed by gas chromatography-mass spectrometry and compared to an age and gender matched healthy control group taken out of a population study. In both cohorts, the activity of the MR pre-receptor enzyme 11ß-hydroxysteroid dehydrogenase type 2 (HSD11B2), which inactivates cortisol to prevent it from binding to the MR, was assessed to define a change in MR selectivity. Expression of HSD11B2, MR and GR was quantified in HRMC and primary human renal glomerular endothelial cells (HRGEC). Activity of MR and GR was explored in HRMC by measuring the MR/GR down-stream signal SGK1 and the pro-fibrotic genes TGFB1, FN1 and COL1A1 in normal and high glucose conditions with the MR/GR agonists aldosterone/cortisol and the MR/GR antagonists spironolactone/RU486. RESULTS: Patients with diabetic kidney disease excreted more tetrahydroaldosterone than the control group reaching significance in men. The excretion of MR-agonistic steroid hormones was only increased for 18-hydroxytetrahydrocorticosterone in diabetic women. The excretion of most glucocorticoids was higher in the diabetic cohort. Higher apparent systemic HSD11B2 activity suggested less activation of the MR by cortisol in diabetic patients. Both cell types, HRMC and HRGEC, lacked expression of HSD11B2. Hyperglycemic conditions did not change MR and GR expression and activity. Stimulation with both aldosterone and cortisol promoted upregulation of pro-fibrotic genes in HRMC. This effect of MR and/or GR activation was more pronounced in high glucose conditions and partially inhibited by MRAs and GR antagonists. CONCLUSIONS: In patients with diabetic kidney disease alternative MR activation is conceivable as cortisol and cortisone metabolites are increased. Systemic availability of active metabolites is counteracted via an increased HSD11B2 activity. As this cortisol deactivation is absent in HRMC and HRGEC, cortisol binding to the MR is enabled. Both, cortisol and aldosterone stimulation led to an increased expression of pro-fibrotic genes in HRMC. This mechanism was related to the MR as well as the GR and more marked in high glucose conditions linking the benefit of MRAs in diabetic kidney disease to these findings.

Metformin versus SGLT-2 inhibitors: how low can we go?

The progression of chronic kidney disease is difficult to stop once established. Metformin and sodium-glucose cotransporter 2 inhibitors show promise, but clinical trials with a head-to-head comparison in patients with more advanced (stage 3b-4) chronic kidney disease are largely lacking, partly for safety reasons. In this issue, Corremans et al. compare the effects of metformin and canagliflozin in rats with adenine-induced moderate (stage 2-4) chronic kidney disease. Metformin halted progression, whereas canagliflozin did not. This commentary puts the results in a wider clinical context.