Salivary Aldosterone, Central and Peripheral Mineralocorticoid Receptor Function and Their Impact on the Course of Depression

Background: Aldosterone and mineralocorticoid receptor (MR) function appear to play a role in depression. Central and peripheral biomarker parameters of MR function at baseline, their early (change within two weeks) and late (change within six weeks) plasticity were examined with regard to their relationship to clinical treatment outcome after six weeks in patients with acute major depression. Methods: Twenty-four patients with major depression were examined three times during six weeks. Aldosterone and cortisol salvia samples were taken at 7:00 am before patients got out of bed. Easy to use e-devices were used to measure markers of central MR function, i.e. slow wave sleep (SWS) and heart rate variability (HRV). A newly developed scale determined salt taste intensity (STI) and salt pleasantness (SP) of a 0.9% salt solution. In addition, systolic blood pressure (SBP) and plasma electrolytes (Mg2+, Na+, K+) were determined as markers of peripheral MR activity. The relationship between the levels of these biomarkers at baseline, their early and late plasticity and the relative change in clinical outcome parameters (Hamilton Depression Rating Scale with 6 and 21 items, QIDS-SR-16 and BDI) after six weeks of treatment was investigated. Results: By trend a higher baseline aldosterone to cortisol ratio (aldo/cort) (p < 0.1) and lower baseline SBP (p < 0.05) predicted poor outcome, independent of gender. Only in male patients lower baseline SP, lower SWS and higher HRV predicted beneficial outcome (p < 0.05). Likewise, in male patients low baseline Na+ appeared to be by trend predictive for a poor outcome (p = 0.050). Independent of gender an early cortisol reduction (p < 0.05) did predict clinical improvement, whereas by trend an early SWS increase was associated with better outcome (p < 0.1). Only in female patients an early Na+/K+ ratio increase appeared to be related to a better outcome (p < 0.05). By trend only in male patients a late HRV reduction was associated with beneficial outcome (p < 0.1). Conclusion: Correlates of higher baseline central MR activation were associated with poorer clinical improvement, particularly in men. This contrasted with a lower sensitivity of peripheral MR function at baseline in more refractory patients. As one potential mechanism to consider, Na+ loss on the basis of dysfunctional peripheral MR function and additional environmental factors may trigger increased aldosterone secretion and consequently lead to a less favorable outcome. Results for the parameter plasticity were heterogeneous. In the course of depression markers of increasing central as well as peripheral MR activation were found to be related to a favorable outcome. These makers were: decreasing cortisol (independent of aldosterone), increasing SWS, decreasing HRV and increasing Na+ plasma concentrations. Of note gender differences may exist in terms of MR function. This study showcases the usefulness of biological markers, which can be obtained at bedside, to achieve individualized medicine in therapy refractory depression

Renal and Skeletal Anomalies in a Cohort of Individuals With Clinically Presumed Hereditary Nephropathy Analyzed by Molecular Genetic Testing

Background: Chronic kidney disease (CKD) in childhood and adolescence occurs with a median incidence of 9 per million of the age-related population. Over 70% of CKD cases under the age of 25 years can be attributed to a hereditary kidney disease. Among these are hereditary podocytopathies, ciliopathies and (monogenic) congenital anomalies of the kidney and urinary tract (CAKUT). These disease entities can present with a vast variety of extrarenal manifestations. So far, skeletal anomalies (SA) have been infrequently described as extrarenal manifestation in these entities. The aim of this study was to retrospectively investigate a cohort of individuals with hereditary podocytopathies, ciliopathies or CAKUT, in which molecular genetic testing had been performed, for the extrarenal manifestation of SA. Material and Methods: A cohort of 65 unrelated individuals with a clinically presumed hereditary podocytopathy (focal segmental glomerulosclerosis, steroid resistant nephrotic syndrome), ciliopathy (nephronophthisis, Bardet-Biedl syndrome, autosomal recessive/dominant polycystic kidney disease), or CAKUT was screened for SA. Data was acquired using a standardized questionnaire and medical reports. 57/65 (88%) of the index cases were analyzed using exome sequencing (ES). Results: 8/65 (12%) index individuals presented with a hereditary podocytopathy, ciliopathy, or CAKUT and an additional skeletal phenotype. In 5/8 families (63%), pathogenic variants in known disease-associated genes (1x BBS1, 1x MAFB, 2x PBX1, 1x SIX2) could be identified. Conclusions: This study highlights the genetic heterogeneity and clinical variability of hereditary nephropathies in respect of skeletal anomalies as extrarenal manifestation

Cardiovascular Mortality Can Be Predicted by Heart Rate Turbulence in Hemodialysis Patients

Background: Excess mortality in hemodialysis patients is mostly of cardiovascular origin. We examined the association of heart rate turbulence (HRT), a marker of baroreflex sensitivity, with cardiovascular mortality in hemodialysis patients. Methods: A population of 290 prevalent hemodialysis patients was followed up for a median of 3 years. HRT categories 0 (both turbulence onset [TO] and slope [TS] normal), 1 (TO or TS abnormal), and 2 (both TO and TS abnormal) were obtained from 24 h Holter recordings. The primary end-point was cardiovascular mortality. Associations of HRT categories with the endpoints were analyzed by multivariable Cox regression models including HRT, age, albumin, and the improved Charlson Comorbidity Index for hemodialysis patients. Multivariable linear regression analysis identified factors associated with TO and TS. Results: During the follow-up period, 20 patients died from cardiovascular causes. In patients with HRT categories 0, 1 and 2, cardiovascular mortality was 1, 10, and 22%, respectively. HRT category 2 showed the strongest independent association with cardiovascular mortality with a hazard ratio of 19.3 (95% confidence interval: 3.69-92.03;P < 0.001). Age, calcium phosphate product, and smoking status were associated with TO and TS. Diabetes mellitus and diastolic blood pressure were only associated with TS. Conclusion: Independent of known risk factors, HRT assessment allows identification of hemodialysis patients with low, intermediate, and high risk of cardiovascular mortality. Future prospective studies are needed to translate risk prediction into risk reduction in hemodialysis patients

Comparable cellular and humoral immunity upon homologous and heterologous COVID-19 vaccination regimens in kidney transplant recipients

BackgroundKidney transplant recipients (KTRs) are at high risk for a severe course of coronavirus disease 2019 (COVID-19); thus, effective vaccination is critical. However, the achievement of protective immunogenicity is hampered by immunosuppressive therapies. We assessed cellular and humoral immunity and breakthrough infection rates in KTRs vaccinated with homologous and heterologous COVID-19 vaccination regimens.MethodWe performed a comparative in-depth analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–specific T-cell responses using multiplex Fluorospot assays and SARS-CoV-2-specific neutralizing antibodies (NAbs) between three-times homologously (n = 18) and heterologously (n = 8) vaccinated KTRs.ResultsWe detected SARS-CoV-2-reactive T cells in 100% of KTRs upon third vaccination, with comparable frequencies, T-cell expression profiles, and relative interferon γ and interleukin 2 production per single cell between homologously and heterologously vaccinated KTRs. SARS-CoV-2-specific NAb positivity rates were significantly higher in heterologously (87.5%) compared to homologously vaccinated (50.0%) KTRs (P &lt; 0.0001), whereas the magnitudes of NAb titers were comparable between both subcohorts after third vaccination. SARS-CoV-2 breakthrough infections occurred in equal numbers in homologously (38.9%) and heterologously (37.5%) vaccinated KTRs with mild-to-moderate courses of COVID-19.ConclusionOur data support a more comprehensive assessment of not only humoral but also cellular SARS-CoV-2-specific immunity in KTRs to provide an in-depth understanding about the COVID-19 vaccine–induced immune response in a transplant setting

Salivary Aldosterone, Central and Peripheral Mineralocorticoid Receptor Function and Their Impact on the Course of Depression

Background: Aldosterone and mineralocorticoid receptor (MR) function appear to play a role in depression. Central and peripheral biomarker parameters of MR function at baseline, their early (change within two weeks) and late (change within six weeks) plasticity were examined with regard to their relationship to clinical treatment outcome after six weeks in patients with acute major depression. Methods: Twenty-four patients with major depression were examined three times during six weeks. Aldosterone and cortisol salvia samples were taken at 7:00 am before patients got out of bed. Easy to use e-devices were used to measure markers of central MR function, i.e. slow wave sleep (SWS) and heart rate variability (HRV). A newly developed scale determined salt taste intensity (STI) and salt pleasantness (SP) of a 0.9% salt solution. In addition, systolic blood pressure (SBP) and plasma electrolytes (Mg2+, Na+, K+) were determined as markers of peripheral MR activity. The relationship between the levels of these biomarkers at baseline, their early and late plasticity and the relative change in clinical outcome parameters (Hamilton Depression Rating Scale with 6 and 21 items, QIDS-SR-16 and BDI) after six weeks of treatment was investigated. Results: By trend a higher baseline aldosterone to cortisol ratio (aldo/cort) (p < 0.1) and lower baseline SBP (p < 0.05) predicted poor outcome, independent of gender. Only in male patients lower baseline SP, lower SWS and higher HRV predicted beneficial outcome (p < 0.05). Likewise, in male patients low baseline Na+ appeared to be by trend predictive for a poor outcome (p = 0.050). Independent of gender an early cortisol reduction (p < 0.05) did predict clinical improvement, whereas by trend an early SWS increase was associated with better outcome (p < 0.1). Only in female patients an early Na+/K+ ratio increase appeared to be related to a better outcome (p < 0.05). By trend only in male patients a late HRV reduction was associated with beneficial outcome (p < 0.1). Conclusion: Correlates of higher baseline central MR activation were associated with poorer clinical improvement, particularly in men. This contrasted with a lower sensitivity of peripheral MR function at baseline in more refractory patients. As one potential mechanism to consider, Na+ loss on the basis of dysfunctional peripheral MR function and additional environmental factors may trigger increased aldosterone secretion and consequently lead to a less favorable outcome. Results for the parameter plasticity were heterogeneous. In the course of depression markers of increasing central as well as peripheral MR activation were found to be related to a favorable outcome. These makers were: decreasing cortisol (independent of aldosterone), increasing SWS, decreasing HRV and increasing Na+ plasma concentrations. Of note gender differences may exist in terms of MR function. This study showcases the usefulness of biological markers, which can be obtained at bedside, to achieve individualized medicine in therapy refractory depression

Heterozygous COL4A3 Variants in Histologically Diagnosed Focal Segmental Glomerulosclerosis

Introduction: Steroid-resistant nephrotic syndrome (SRNS) is one of the most frequent causes for chronic kidney disease in childhood. In ~30% of these cases a genetic cause can be identified. The histological finding in SRNS is often focal segmental glomerulosclerosis (FSGS). In rare cases, however, pathogenic variants in genes associated with Alport syndrome can be identified in patients with the histological finding of FSGS.Materials and Methods: Clinical information was collected out of clinical reports and medical history. Focused molecular genetic analysis included sequencing of COL4A5 and COL4A3 in the index patient. Segregation analysis of identified variants was performed in the parents and children of the index patient.Results: The female index patient developed mild proteinuria and microscopic hematuria in childhood (12 years of age). The histological examination of the kidney biopsies performed at the age of 21, 28, and 32 years showed findings partly compatible with FSGS. However, immunosuppressive treatment of the index patient did not lead to a sufficient reduction of in part nephrotic-range proteinuria. After the patient developed hearing impairment at the age of 34 years and her daughter was diagnosed with microscopic hematuria at the age of 6 years, re-examination of the index's kidney biopsies by electron microscopy revealed textural changes of glomerular basement membrane compatible with Alport syndrome. Molecular genetic analysis identified two missense variants in COL4A3 in a compound heterozygous state with maternal and paternal inheritance. One of them is a novel variant that was also found in the 6 year old daughter of the index patient who presented with microscopic hematuria.Discussion: We were able to show that a novel variant combined with a previously described variant in compound heterozygous state resulted in a phenotype that was histologically associated with FSGS. Molecular genetic analysis therefore can be essential to solve difficult cases that show an unusual appearance and therefore improve diagnostic accuracy. Additionally, unnecessary and inefficient treatment with multiple side effects can be avoided

COVID-19 vaccination acceptance and hesitancy among healthcare workers in germany

Vaccination hesitancy is a threat to herd immunity. Healthcare workers (HCWs) play a key role in promoting Coronavirus disease 2019 (COVID-19) vaccination in the general population. We therefore aimed to provide data on COVID-19 vaccination acceptance/hesitancy among German HCWs. For this exploratory, cross-sectional study, an online survey was conducted in February 2021. The survey included 54 items on demographics; previous vaccination behavior; trust in vaccines, physicians, the pharmaceutical industry and health politics; fear of adverse effects; assumptions regarding the consequences of COVID-19; knowledge about vaccines; and information seeking behavior. Odds ratios with 95% confidence intervals were calculated and chi-square tests were performed. Four thousand five hundred surveys were analyzed. The overall vaccination acceptance was 91.7%. The age group ≤20 years showed the lowest vaccination acceptance. Factors associated with vaccination hesitancy were lack of trust in authorities and pharmaceutical companies. Attitudes among acquaintances were associated with vaccination hesitancy too. Participants with vaccination hesitancy more often obtained information about COVID-19 vaccines via messenger services or online video platforms and underperformed in the knowledge test. We found high acceptance amongst German HCWs. Several factors associated with vaccination hesitancy were identified which could be targeted in HCW vaccination campaigns

Challenging Recently Published Parameter Sets for Entropy Measures in Risk Prediction for End-Stage Renal Disease Patients

Heart rate variability (HRV) analysis is a non-invasive tool for assessing cardiac health. Entropy measures quantify the chaotic properties of HRV, but they are sensitive to the choice of their required parameters. Previous studies therefore have performed parameter optimization, targeting solely their particular patient cohort. In contrast, this work aimed to challenge entropy measures with recently published parameter sets, without time-consuming optimization, for risk prediction in end-stage renal disease patients. Approximate entropy, sample entropy, fuzzy entropy, fuzzy measure entropy, and corrected approximate entropy were examined. In total, 265 hemodialysis patients from the ISAR (rISk strAtification in end-stage Renal disease) study were analyzed. Throughout a median follow-up time of 43 months, 70 patients died. Fuzzy entropy and corrected approximate entropy (CApEn) provided significant hazard ratios, which remained significant after adjustment for clinical risk factors from literature if an entropy maximizing threshold parameter was chosen. Revealing results were seen in the subgroup of patients with heart disease (HD) when setting the radius to a multiple of the data’s standard deviation ( r = 0.2 · σ ); all entropies, except CApEn, predicted mortality significantly and remained significant after adjustment. Therefore, these two parameter settings seem to reflect different cardiac properties. This work shows the potential of entropy measures for cardiovascular risk stratification in cohorts the parameters were not optimized for, and it provides additional insights into the parameter choice

Reduced Mortality in Maintenance Haemodialysis Patients on High versus Low Dialysate Magnesium: A Pilot Study

Background: Although low magnesium levels have been associated with an increased mortality in dialysis patients, they are kept low by routinely-used dialysates containing 0.50 mmol/L magnesium. Thus, we investigated the impact of a higher dialysate magnesium concentration on mortality. Methods: 25 patients on high dialysate magnesium (HDM) of 0.75 mmol/L were 1:2 matched to 50 patients on low dialysate magnesium (LDM) of 0.50 mmol/L and followed up for 3 years with regards to all-cause and cardiovascular mortality. Patients were matched according to age, gender, a modified version of the Charlson Comorbidity Index (CCI), and smoking status. Results: During the follow-up period, five patients died in the HDM and 18 patients in the LDM group. Patients in the HDM group had significantly higher ionized serum magnesium levels than matched controls (0.64 ± 0.12 mmol/L vs. 0.57 ± 0.10 mmol/L, p = 0.034). Log rank test showed no difference between treatment groups for all-cause mortality. After adjustment for age and CCI, Cox proportional hazards regression showed that HDM independently predicted a 65% risk reduction for all-cause mortality (hazard ratio 0.35, 95% confidence interval [CI]: 0.13, 0.97). Estimated 3-year probability of death from a cardiovascular event was 14.5% (95% CI: 7.9, 25.8) in the LDM group vs. 0% in the HDM group. Log rank test found a significant group difference for cardiovascular mortality (χ2 = 4.15, p = 0.042). Conclusions: Our data suggests that there might be a beneficial effect of an increased dialysate magnesium on cardiovascular mortality in chronic dialysis patients