Search

Fabry disease (FD) is a rare X chromosomally transmitted lysosomal storage disorders with an absence or deficiency of the enzyme alpha-galactosidase. The deposition of globotriaosylceramide (Gb3) may cause damage to all organs, particularly brain, heart and kidney. While acroparaesthesia, hypo- or anhydrosis and diarrhoea are the main symptoms in childhood, cardiac involvement with left ventricular hypertrophy (LVH), renal insufficiency, diffuse pain attacks and apoplexy are the main symptoms in adulthood. Regular examinations are necessary to record organ involvement and its progression. A major challenge is therefore to make a diagnosis at an early disease stage. This is the only way that treatment can be started if there is an indication. If FD is suspected, alpha-galactosidase should be tested in male patients and genetic testing should be performed in females to confirm the diagnosis. Since 2001, enzyme replacement therapy (ERT) has been available as a causal therapy. In 2016, chaperone therapy with the drug Migalastat was approved in the European Union, which leads to stabilisation of the defective alpha-galactosidase. Studies on gene therapy to cure FD in phase I/II. This review summarizes which patient should be screened, how to confirm the diagnosis and which examinations should be performed in FD patients during the course of the disease.

Zusammenfassung Hintergrund Im März 2020 breitete sich die SARS-CoV-2-Pandemie initial v. a. in Bayern aus. Zu diesem Zeitpunkt war weitgehend unklar, wie mit der immunmodulatorischen Therapie bei Rheumapatienten umzugehen ist. Ziel der Arbeit Das Ziel war es, den Einfluss der Pandemie auf klinische Entscheidungen zu erfassen. Material und Methoden Es wurden zwischen dem 16.03. und 31.07.2020 Patienten eingeschlossen, die sich in der Rheumaambulanz des Klinikums rechts der Isar vorstellten. Anpassungen der Therapie erfolgten nach klinischem Ermessen und in Anlehnung an die Handlungsempfehlungen der DGRh. Ergebnisse Es wurden 322 Patienten eingeschlossen. Die häufigsten Diagnosen waren die rheumatoide Arthritis mit 17 %, die ANCA-assoziierte Vaskulitis (AAV) mit 14 % sowie der SLE mit 12 %; 262 Patienten erhielten eine DMARD-Therapie und 77 Patienten orale Glukokortikoide. Es lagen 5 SARS-CoV-2-Verdachtsfälle vor. Kein Patient erkrankte nachweislich an COVID-19. Eine Therapieänderung erfolgte aufgrund der Pandemie bei 40 Patienten. Dabei kam es bei 3 Patienten zu einem Flare der Grunderkrankung. Eine Therapiedeeskalation erfolgte am häufigsten bei AAV, IgG4-assoziierter Erkrankung sowie bei gleichzeitig bestehenden Malignomen und beim Einsatz von Rituximab. Diskussion In dieser Single-Center-Kohorte legt das gänzliche Fehlen von nachweislichen SARS-CoV-2-Infektionen in einer sonst relativ stark betroffenen Region den Schluss nahe, dass kein überproportional erhöhtes Infektionsrisiko für Patienten mit entzündlich rheumatischen Erkrankungen zu bestehen scheint. Eine Fortführung der meisten immunsuppressiven Therapien erscheint daher sinnvoll.

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.

Rationale : Patients with end-stage renal disease are characterized by increased cardiovascular and all-cause mortality because of advanced remodeling of the macrovascular and microvascular beds. Objective : The aim of this study was to determine whether retinal microvascular function can predict all-cause and cardiovascular mortality in patients with end-stage renal disease. Methods and Results : In the multicenter prospective observational ISAR study (Risk Stratification in End-Stage Renal Disease), data on dynamic retinal vessel analysis were available in a subcohort of 214 dialysis patients (mean age, 62.6±15.0; 32% women). Microvascular dysfunction was quantified by measuring maximum arteriolar dilation and maximum venular dilation (vMax) of retinal vessels in response to flicker light stimulation. During a mean follow-up of 44 months, 55 patients died, including 25 cardiovascular and 30 noncardiovascular fatal events. vMax emerged as a strong independent predictor for all-cause mortality. In the Kaplan-Meier analysis, individuals within the lowest tertile of vMax showed significantly shorter 3-year survival rates than those within the highest tertile (66.9±5.8% versus 92.4±3.3%). Univariate and multivariate hazard ratios for all-cause mortality per SD increase of vMax were 0.62 (0.47–0.82) and 0.65 (0.47–0.91), respectively. Maximum arteriolar dilation and vMax were able to significantly predict nonfatal and fatal cardiovascular events (hazard ratio, 0.74 [0.57–0.97] and 0.78 [0.61–0.99], respectively). Conclusions : Our results provide the first evidence that impaired retinal venular dilation is a strong and independent predictor of all-cause mortality in hemodialyzed end-stage renal disease patients. Dynamic retinal vessel analysis provides added value for prediction of all-cause mortality and may be a novel diagnostic tool to optimize cardiovascular risk stratification in end-stage renal disease and other high-risk cardiovascular cohorts. Clinical Trial Registration : URL: http://www.clinicaltrials.gov . Unique identifier: NCT01152892.

BACKGROUND: The prevalence of cognitive impairment in hemodialysis patients is notably high. In previous studises performed in the general population, cognitive impairment has been associated with increased mortality. OBJECTIVE: We evaluated the relationship between global cognitive function tested by a short screening instrument and mortality in hemodialysis patients. METHODS: Cognitive testing was performed in 242 maintenance hemodialysis patients under standardized conditions at baseline using the Montreal Cognitive Assessment (MoCA).Cognitive impairment was defined as a MoCA test score \textless/=24 points, as published previously. All-cause mortality was monitored during a median follow-up of 3.54 years. Kaplan-Meier plot and Cox regression model adjusted for known risk factors for mortality in hemodialysis patients were used to examine a possible association between global cognitive function and all-cause mortality. RESULTS: A MoCA test score \textless/=24 points resulted in a significant almost 3-fold higher hazard for all-cause mortality (unadjusted hazard ratio HR: 2.812; 95{\%} confidence interval 95{\%} CI: 1.683-4.698; p {\textless} 0.001). After adjustment, this association was attenuated but remained significant (adjusted HR: 1.749; 95{\%} CI: 1.007-3.038; p = 0.047). CONCLUSION: Impairment of global cognitive function measured by a short screening instrument was identified for the first time as an independent predictor of all-cause mortality in hemodialysis patients. Thus, implementing the MoCA test in clinical routine could contribute to a better risk stratification of this patient population.

BackgroundVaccination hesitancy is a serious threat to achieve herd immunity in a global and rapidly changing pandemic situation. Health care workers play a key role in the treatment of patients with Coronavirus disease 2019 (COVID-19) and in promoting vaccination in the general population. The aim of the study was to provide data on COVID-19 vaccination acceptance and barriers among healthcare workers in Germany to support health policymakers choosing specific vaccination campaign strategies.MethodsAn online survey was conducted among health care workers in Germany in February 2021. The survey included 55 items on demographics, previous vaccination behavior, trust in vaccines, physicians, pharma industry, and health politics as well as fear of adverse effects, assumptions on disease consequences, knowledge about vaccines, information seeking behavior and a short COVID-19 vaccine knowledge test.ResultsA total of 4500 surveys could be analyzed. The overall vaccination acceptance was 91.7%. The age group ≤20 years showed the lowest vaccination acceptance of all age groups. Regarding professional groups, residents showed the highest vaccination acceptance. Main factors for vaccination hesitancy were lack of trust in authorities and pharmaceutical companies. Personal and professional environment influenced the attitude towards a vaccination too. Participants with vaccination hesitancy were more likely to obtain information about COVID-19 vaccines via messenger services or online video platforms and underperformed in the knowledge test.ConclusionsIn conclusion, we found a high acceptance rate amongst German health care workers. Furthermore, several factors associated with vaccination hesitancy were identified which could be targeted in vaccination campaigns.

In about 30% of infantile, juvenile, or adolescent patients with steroid-resistant nephrotic syndrome (SRNS), a monogenic cause can be identified. The histological finding in SRNS is often focal segmental glomerulosclerosis (FSGS). Genetic data on adult patients are scarce with low diagnostic yields. Exome sequencing (ES) was performed in patients with adult disease onset and a high likelihood for hereditary FSGS. A high likelihood was defined if at least one of the following criteria was present: absence of a secondary cause, ≤25 years of age at initial manifestation, kidney biopsy with suspicion of a hereditary cause, extrarenal manifestations, and/or positive familial history/reported consanguinity. Patients were excluded if age at disease onset was

Mineralocorticoid-receptor (MR) dysfunction as expressed by low systolic blood pressure and a high salivary aldosterone/cortisol ratio predicts less favorable antidepressant treatment outcome. Inhibition of peripheral 11-beta-hydroxysteroid-dehydrogenase type 2 (11betaHSD2) reverses these markers. We therefore tested the hypothesis that the 11betaHSD2 inhibitor glycyrrhizin affects treatment outcome via this mechanism. We administered Glycyrrhiza glabra (GG) extract containing 7–8 % of glycyrrhizin at a dose of 2 × 700 mg daily adjunct to standard antidepressants in hospitalized patients with major depression. These subjects were compared in an open-label fashion with patients, who did not receive GG (treatment as usual, TAU). Assessments were done at baseline and approximately 2 weeks after. Twelve subjects were treated with GG and compared to 55 subjects with TAU. At week 2, the Hamilton Depression Rating Scale (HAMD-21) change from baseline as well as the CGI-S change showed a significant time × treatment interaction (p < 0.03), indicating a possible therapeutic benefit of GG. Clinical benefit seems to be more pronounced in subjects with lower systolic blood pressure and significantly correlated with reduced sleep duration in the GG group. Our preliminary data show that treatment with the 11betaHSD2 inhibitor glycyrrhizin may possess a beneficial effect on antidepressant response, which may be specific to a defined depression subtype.

Background In hemodialysis patients, left ventricular hypertrophy (LVH) contributes to high cardiovascular mortality. We examined cardiovascular mortality prediction by the recently proposed Peguero-Lo Presti voltage since it identifies more patients with electrocardiographic (ECG) LVH than Cornell or Sokolow-Lyon voltages. Methods A total of 308 patients on hemodialysis underwent 24 h ECG recordings. LVH parameters were measured before and after dialysis. The primary endpoint of cardiovascular mortality was recorded during a median 3-year follow up. Risk prediction was assessed by Cox regression, both unadjusted and adjusted for the Charlson Comorbidity Index and the Cardiovascular Mortality Risk Score. Results The Peguero-Lo Presti voltage identified with 21% the most patients with positive LVH criteria. All voltages significantly increased during dialysis. Factors such as ultrafiltration rate, Kt/V, body mass index, sex, and phosphate were the most relevant for these changes. During follow-up, 26 cardiovascular deaths occurred. Post-dialysis Peguero-Lo Presti cut-off as well as the Peguero-Lo Presti and Cornell voltages were independently associated with cardiovascular mortality in unadjusted and adjusted analysis. The Sokolow-Lyon voltage was not significantly associated with mortality. An optimal cut-off for the prediction of cardiovascular mortality was estimated at 1.38 mV for the Peguero-Lo Presti. Conclusions The post-dialysis Peguero-Lo Presti cut-off as well as the Peguero-Lo Presti and Cornell voltages allowed independent risk prediction of cardiovascular mortality in hemodialysis patients. Measuring the ECG LVH parameters after dialysis might allow a standardized interpretation as dialysis-specific factors influence the voltages. Graphical abstract

Heart failure (HF), hypertension, and abnormal nocturnal blood pressure dipping are highly prevalent in hemodialysis patients. Atrial fibrillation (AF) and HF might be important mediators for the association of abnormal dipping patterns with worse prognosis. Thus, the aim of this study is to investigate the association of dipping with mortality in hemodialysis patients and to assess the influence of AF and HF. In total, 525 hemodialysis patients underwent 24-hour ambulatory blood pressure monitoring. All-cause and cardiovascular mortality served as end points. Patients were categorized according to their systolic dipping pattern (dipper, nondipper, and reverse dipper). Cox regression analysis was performed to determine the association between dipping pattern and study end points with dipping as reference. Subgroup analysis was performed for patients with and without AF or HF. In total, 185 patients with AF or HF and 340 patients without AF or HF were included. During a median follow-up of 37.8 months, 177 patients died; 81 from cardiovascular causes. Nondipping and reverse dipping were significantly associated with all-cause mortality in the whole cohort (nondipper: hazard ratio, 1.95 [1.22–3.14]; P =0.006; reverse dipper: hazard ratio, 2.31 [1.42–3.76]; P P =0.02; reverse dipper: hazard ratio, 4.48 [1.87–10.71]; P

OBJECTIVES Brain morphology and its relation to endocrine parameters were examined, in order to determine the link of these parameters to treatment outcome to psychopharmacological treatment in depressed patients. METHODS We examined the potentially predictive value of Magnetic Resonance Imaging (MRI) parameters related to mineralocorticoid receptor (MR) function on the treatment outcome of depression. 16 inpatients with a major depressive episode (MDE) were studied at baseline and 14 of them approximately six weeks later. Physiological biomarkers and 3-T-structural MRI based volume measures, using FreeSurfer 6.0 software, were determined. RESULTS Non-responders (

Introduction Platelet dysfunction is not uncommon in patients with end-stage renal disease (ESRD). Type of renal replacement therapy may have an effect on platelet functions, which has not been well investigated. We evaluated in vitro closure time (CT) differences between peritoneal dialysis (PD) and hemodialysis (HD) patients using platelet function analyzer (PFA-100)and observed a significant difference between these renal replacement therapies.Methods Patients with ESRD undergoing PD (n = 24) or HD (n = 23) for more than 6 months were included. Blood samples for collagen/epinephrine (Col/EPI) and collagen/adenosine diphosphate (Col/ADP) measurements were obtained before HD at a mid-week session for HD patients and at an outpatient control time for PD patients.Results Three of 24 (12.5%) PD patients and 16 of 23 (69.5%) HD patients had prolonged PFA-100 Col/EPI, p< 0.001. Likewise, 4.2% of PD patients and 87.0% of HD patients had prolonged PFA-100 Col/ADP, p< 0.001. Moreover, the median times of PFA-Col/EPI and PFA-100 Col/ADP were significantly lower in PD patients compared with those of HD patients (p< 0.001). Multivariate analysis showed that the type of renal replacement was a risk factor for both elevated PFA-100 Col/ADP and PFA-100 Col/EPI after adjusted for platelets, hematocrit, and urea (p< 0.001).Conclusions The type of renal replacement therapy may have an effect on in vitro CTs; therefore, studies including more patients with long-term follow-up are needed to investigate if the difference has any impact on clinical outcomes.

Background Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic PRUNE1 mutations. Methods Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms. Results We identified bi-allelic PRUNE1 mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reported missense mutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the PRUNE1 gene and part of the neighboring BNIPL gene. Conclusions PRUNE1 deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature.

A novel in vitro test (T50 test) assesses ex vivo serum calcification propensity and predicts mortality in chronic kidney disease and haemodialysis (HD) patients. For the latter, a time-dependent decline of T50 was shown to relate to mortality. Here we assessed whether a 3-month switch to acetate-free, citrate-acidified, standard bicarbonate HD (CiaHD) sustainably improves calcification propensity.T50 values were assessed in paired midweek pre-dialysis sera collected before and 3 months after CiaHD in 78 prevalent European HD patients. In all, 44 were then switched back to acetate. Partial correlation was used to study associations of changing T50 and changing covariates. Linear mixed effect models were built to assess the association of CiaHD and covariates with changing T50.A significant intra-individual increase of serum calcification resilience was found after 3 months on CiaHD (206 ± 56 to 242 ± 56 min; P 0.001), but not after switching back to acetate (252 ± 63 to 243 ± 64 min; n = 44; P = 0.29). CiaHD, Δ serum phosphate and Δ albumin but not Δ ionized calcium and magnesium were the strongest determinants of changing T50. Beneath T50, only serum albumin but not phosphate changed significantly during 3 months of CiaHD.CiaHD dialysis favourably affected calcification propensity as measured by the T50 test. Whether this treatment, beyond established phosphate-directed treatments, has the potential to sustainably tip the balance towards a more anti-calcific serum milieu needs to be further investigated.

Rationale & Objective Hereditary nephropathies are clinically and genetically heterogeneous disorders. For some patients, the clinical phenotype corresponds to a specific hereditary disease but genetic testing reveals that the expected genotype is not present (phenocopy). The aim of this study was to evaluate the spectrum and frequency of phenocopies identified by using exome sequencing in a cohort of patients who were clinically suspected to have hereditary kidney disorders. Study Design Cross-sectional cohort study. Setting & Participants 174 unrelated patients were recruited for exome sequencing and categorized into 7 disease groups according to their clinical presentation. They included autosomal dominant tubulointerstitial kidney disease, Alport syndrome, congenital anomalies of the kidney and urinary tract, ciliopathy, focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome, VACTERL association, and “other.” Results A genetic diagnosis (either likely pathogenic or pathogenic variant according to the guidelines of the American College of Medical Genetics) was established using exome sequencing in 52 of 174 (30%) cases. A phenocopy was identified for 10 of the 52 exome sequencing–solved cases (19%), representing 6% of the total cohort. The most frequent phenocopies (n = 5) were associated with genetic Alport syndrome presenting clinically as focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome. Strictly targeted gene panels ( Limitations The spectrum of described phenocopies is small. Selection bias may have altered the diagnostic yield within disease groups in our study population. The study cohort was predominantly of non-Finnish European descent, limiting generalizability. Certain hereditary kidney diseases cannot be diagnosed by using exome sequencing (eg, MUC1-autosomal dominant tubulointerstitial kidney disease). Conclusions Phenocopies led to the recategorization of disease and altered clinical management. This study highlights that exome sequencing can detect otherwise occult genetic heterogeneity of kidney diseases.

Background: Mortality in hemodialysis patients still remains unacceptably high. Enhanced arterial stiffness is a known cardiovascular risk factor, and pulse wave velocity (PWV) has proven to be a valid parameter to quantify risk. Recent studies showed controversial results regarding the prognostic significance of PWV for mortality in hemodialysis patients, which may be due to methodological issues, such as assessment of PWV in the office setting (Office-PWV). Method: This study cohort contains patients from the “Risk stratification in end-stage renal disease – the ISAR study,” a multicenter prospective longitudinal observatory cohort study. We examined and compared the predictive value of ambulatory 24-hour PWV (24 h-PWV) and Office-PWV on mortality in a total of 344 hemodialysis patients. The endpoints of the study were all-cause and cardiovascular mortality. Survival analysis included Kaplan-Meier estimates and Cox regression analysis. Results: During a follow-up of 36 months, a total of 89 patients died, 35 patients due to cardiovascular cause. Kaplan-Meier estimates for tertiles of 24 h-PWV and Office-PWV were similarly associated with mortality. In univariate Cox regression analysis, 24 h-PWV and Office-PWV were equivalent predictors for all-cause and cardiovascular mortality. After adjustment for common risk factors, only 24 h-PWV remained solely predictive for all-cause mortality (hazard ratio 2.51 [95% CI 1.31–4.81]; p = 0.004). Conclusions: Comparing both measurements, 24 h-PWV is an independent predictor for all-cause-mortality in hemodialysis patients beyond Office-PWV.

The renin-angiotensin-aldosterone system and its hormone receptors, i.e. the angiotensin and mineralocorticoid receptor (MR), have emerged as important targets for central nervous system disorders and in particular for major depression. We have recently characterized baseline MR function as a predictor for treatment outcome with standard antidepressants. The aims of this study are (i) to characterize how strongly an early biomarker change (after 2 weeks) is related to outcome and (ii) whether these biomarker changes are related to the final outcome, that is, could serve as surrogate markers for response. Twenty-four of 30 patients with unipolar major depression completed the observational trial. MR-related biomarkers were assessed at baseline, 2 weeks, and 6 weeks of standard antidepressant treatment. These biomarkers included slow wave sleep (SWS), salivary cortisol and aldosterone after awakening, heart rate variability measured as respiratory sinus arrhythmia (RSA), systolic blood pressure, salt taste intensity (STI), salt pleasantness (SP), and plasma electrolytes. The Hamilton depression rating scale with 21 items was primarily used to determine depression severity. In the overall sample, STI increased and SP decreased significantly with treatment without a clear relationship with treatment outcome. No other significant changes were observed. Reductions in cortisol and aldosterone after 2 weeks of treatment were significantly related to improvement after 6 weeks (P

Background Evidence on the utility of ambulatory BP monitoring for risk prediction has been scarce and inconclusive in patients on hemodialysis. In addition, in cardiac diseases such as heart failure and atrial fibrillation (common among patients on hemodialysis), studies have found that parameters such as systolic BP (SBP) and pulse pressure (PP) have inverse or nonlinear (U-shaped) associations with mortality. Methods In total, 344 patients on hemodialysis (105 with atrial fibrillation, heart failure, or both) underwent ambulatory BP monitoring for 24 hours, starting before a dialysis session. The primary end point was all-cause mortality; the prespecified secondary end point was cardiovascular mortality. We performed linear and nonlinear Cox regression analyses for risk prediction to determine the associations between BP and study end points. Results During the mean 37.6-month follow-up, 115 patients died (47 from a cardiovascular cause). SBP and PP showed a U-shaped association with all-cause and cardiovascular mortality in the cohort. In linear subgroup analysis, SBP and PP were independent risk predictors and showed a significant inverse relationship to all-cause and cardiovascular mortality in patients with atrial fibrillation or heart failure. In patients without these conditions, these associations were in the opposite direction. SBP and PP were significant independent risk predictors for cardiovascular mortality; PP was a significant independent risk predictor for all-cause mortality. Conclusions This study provides evidence for the U-shaped association between peripheral ambulatory SBP or PP and mortality in patients on hemodialysis. Furthermore, it suggests that underlying cardiac disease can explain the opposite direction of associations.

Biallelic mutations in SLC25A46, encoding a modified solute transporter involved in mitochondrial dynamics, have been identified in a wide range of conditions such as hereditary motor and sensory neuropathy with optic atrophy type VIB (OMIM: *610826) and congenital lethal pontocerebellar hypoplasia (PCH). To date, 18 patients from 13 families have been reported, presenting with the key clinical features of optic atrophy, peripheral neuropathy, and cerebellar atrophy. The course of the disease was highly variable ranging from severe muscular hypotonia at birth and early death to first manifestations in late childhood and survival into the fifties. Here we report on 4 patients from 2 families diagnosed with PCH who died within the first month of life from respiratory insufficiency. Patients from 1 family had pathoanatomically proven spinal motor neuron degeneration (PCH1). Using exome sequencing, we identified biallelic disease-segregating loss-of-function mutations in SLC25A46 in both families. Our study adds to the definition of the SLC25A46-associated phenotypic spectrum that includes neonatal fatalities due to PCH as the severe extreme.

Objective:The prevalence of non- and reverse-dipping is very high in hemodialysis patients. Evidence for the association of abnormal dipping patterns with worse prognosis has been reported previously. In hemodialysis, evidence is scarce and cardiac function might be an important mediator as has rece

Background: Association of Ambulatory Blood Pressure Monitoring (ABPM) with mortality depends on cardiac function in hemodialysis patients. Evidence for the predictive power of central Systolic Pressure (cSBP) is inconclusive. Thus, this study aimed to investigate the additional information of ambulatory cSBP in risk prediction in a cohort of hemodialysis patients. Methods: Within the ISAR-study cohort, 344 hemodialysis patients underwent 24 h ABPM on the dialysis day. All-cause and cardiovascular mortality served as endpoints. Risk prediction was performed using Cox regression in patients with or without atrial fibrillation (AF) or heart failure (HF) for peripheral (pSBP) and central systolic pressure calibrated with peripheral systolic and diastolic pressure (cSBP1) or peripheral mean and diastolic pressure (cSBP2). Results: During a mean follow-up of 37.6 (17.5 SD) months, 115 patients died, of whom 47 due to cardiovascular reasons. In patients with AF or HF, a negative association to mortality could be observed, independent of pressure location and calibration (see Table). In patients without AF or HF, these associations were to the opposite directions and cSBP2 was superior to pSBP and cSBP1 for all-cause (pSBP: HR = 1.01, p = 0.30; cSBP1: HR = 1.00, p = 0.77; cSBP2: HR = 1.01, p = 0.06) and cardiovascular (pSBP: HR =1.03, p = 0.02; cSBP1: HR = 1.02, p = 0.06; cSBP2: HR = 1.03, p = 0.003) mortality. This circumstance was confirmed in multivariable analysis combining pSBP and differences between pSBP and cSBP (see Table). Conclusions: This study provides evidence for the additional information of central systolic blood pressure and its dependency on calibration in risk prediction in hemodialysis patients. Further studies are needed to confirm these findings.

Objectives: Mortality rate in end-stage renal disease (ESRD) are still at a high level. Sarafidis et al. showed the predictive value of 48h PWV in patients undergoing hemodialysis [1], although recent studies using office measurement showed controversial predictive results. Aim of the present study was to confirm the predictive value of a novel oscillometric measurement of pulse wave velocity on mortality in an elderly cohort of patients with ESRD. Methods: The ISAR study is a prospective and longitudinal study targeting patients with ESRD undergoing hemodialysis. Oscillometric measurement of 24-hour PWV was performed at baseline. Survival analysis included Kaplan-Meier analysis, logrank test and Cox regression. Results: A total of 350 patients had a median age of 69.3 [55.8; 77.3] years. Mean PWV was 9.6 (2.2) m/s and 120 patients died during the mean follow-up of 45 months. PWV was significantly higher in the deceased (10.6 +/− 1.9 m/s) than in surviving patients (9.0 +/− 2.2 m/s). Kaplan-Meier analysis showed differences in dichotomized PWV (cut-off 10 m/s [2]; Logrank test: p = 0.001). For results of univariate Cox regression, see Figure. Adjusted Cox regression analysis showed a significant risk prediction for all-cause mortality (HR 2.322; p = 0.011). Patients older than 50 years showed even higher predictive values (HR 2.442; p = 0.008) as well as patients with PWV values of at least 10 m/s (HR 3.300; p = 0.006). Figure.Univariate hazard-ratios and their 95% confidence intervals for continuous PWV and PWV quartiles (Q1 as reference; ** p = 0.002; *** p < 0.001). Ql: 11.23 m/s. Conclusion: Oscillometric measurement of 24-hour pulse wave velocity is a simple and valid method and has an additional predictive value for all-cause mortality in elderly patients with end-stage renal disease.

Introduction: Heart rate variability (HRV) analysis is a non-invasive tool for assessing the cardiac health. There is evidence that the cardiac autonomic system and central hemodynamics respond to hemodialysis. The aim of this work is to compare HRV parameters and augmentation index (AIx) between intra- and interdialytic periods in patients with end-stage renal disease. Methods: All 24-h electrocardiogram data were obtained using the Lifecard CF digital Holter recorder (Delmar Reynolds/Spacelabs, Germany) and 24-h pulse wave analysis (PWA) measurements were taken with the Mobil-O-Graph 24h PWA (I.E.M. GmbH, Germany) within the ISAR hemodialysis study. Two-hundred patients (132 men / 68 women: 61+−16 years) were included. HRV was analyzed in the time- and frequency-domain in 5-min segments. AIx values and HRV parameters were averaged for intra- and interdialytic periods. Results: The low to high frequency ratio (LF/HF) as a representative of sympathovagal balance (2.85 vs 3.36, p

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.