Calreticulin Shortage Results in Disturbance of Calcium Storage, Mitochondrial Disease, and Kidney Injury.

Renal Ca2+ reabsorption plays a central role in the fine-tuning of whole-body Ca2+ homeostasis. Here, we identified calreticulin (Calr) as a missing link in Ca2+ handling in the kidney and showed that a shortage of Calr results in mitochondrial disease and kidney pathogenesis. We demonstrated that Calr+/- mice displayed a chronic physiological low level of Calr and that this was associated with progressive renal injury manifested in glomerulosclerosis and tubulointerstitial damage. We found that Calr+/- kidney cells suffer from a disturbance in functionally active calcium stores and decrease in Ca2+ storage capacity. Consequently, the kidney cells displayed an abnormal activation of Ca2+ signaling and NF-κB pathways, resulting in inflammation and wide progressive kidney injury. Interestingly, the disturbance in the Ca2+ homeostasis and signaling in Calr+/- kidney mice cells triggered severe mitochondrial disease and aberrant mitophagy, resulting in a high level of oxidative stress and energy shortage. These findings provide novel mechanistic insight into the role of Calr in kidney calcium handling, function, and pathogenesis.

Calreticulin Deficiency Disturbs Ribosome Biogenesis and Results in Retardation in Embryonic Kidney Development.

Nephrogenesis is driven by complex signaling pathways that control cell growth and differentiation. The endoplasmic reticulum chaperone calreticulin (Calr) is well known for its function in calcium storage and in the folding of glycoproteins. Its role in kidney development is still not understood. We provide evidence for a pivotal role of Calr in nephrogenesis in this investigation. We show that Calr deficiency results in the disrupted formation of an intact nephrogenic zone and in retardation of nephrogenesis, as evidenced by the disturbance in the formation of comma-shaped and s-shaped bodies. Using proteomics and transcriptomics approaches, we demonstrated that in addition to an alteration in Wnt-signaling key proteins, embryonic kidneys from Calr-/- showed an overall impairment in expression of ribosomal proteins which reveals disturbances in protein synthesis and nephrogenesis. CRISPR/cas9 mediated knockout confirmed that Calr deficiency is associated with a deficiency of several ribosomal proteins and key proteins in ribosome biogenesis. Our data highlights a direct link between Calr expression and the ribosome biogenesis.

Severely destructive unilateral wrist arthritis as a rare variant of rheumatoid arthritis: analysis of clinical and imaging features.

OBJECTIVES: Rheumatoid arthritis (RA) is a common autoimmune disease typically affecting joints symmetrically. A small number of patients develop unilateral and severely destructive wrist arthritis (DWA). The objective of our study was to characterise patients with this type of affection. METHODS: This was a retrospective cohort study of RA patients with positive RF/anti-CCP antibodies. Clinical characteristics, including, age, gender, disease duration, dexterity, occupational history, smoking status, and the number of prescribed DMARDs were recorded. Conventional radiographs were evaluated using the modified Sharp/van der Heijde scoring (mSS) method. RESULTS: We analysed our laboratory database of 1247 patients and identified 559 patients with a clinical diagnosis of RA. For 395 of the patients, radiographs of the hands were available for evaluation. 25 patients had extensive unilateral DWA, corresponding to a prevalence of 6.3% (25 of 395 patients). 11 patients were excluded due to incomplete data. Of the remaining 14 patients, 13 were female with a median age of 61 (33-83) years, and median disease duration of 18 (1-33) years. 8 of 11 (72.7%) patients were smokers; in three, smoking status was not known. 80% with known dexterity developed unilateral DWA in the dominant hand. Total mSS was significantly higher on the affected side (39, interquartile range 35.25-46.25) versus non-affected (13, IQR 3-23). MSS were not different if the carpal bones were excluded from scoring. Side of involvement (left vs. right), or dominant versus non-dominant hand, did not result in a different mSS. CONCLUSIONS: Unilateral DWA is a rare variant of RA which predominantly affects women who smoke.

The Secretome Analysis of Activated Human Renal Fibroblasts Revealed Beneficial Effect of the Modulation of the Secreted Peptidyl-Prolyl Cis-Trans Isomerase A in Kidney Fibrosis.

The secretome is an important mediator in the permanent process of reciprocity between cells and their environment. Components of secretome are involved in a large number of physiological mechanisms including differentiation, migration, and extracellular matrix modulation. Alteration in secretome composition may therefore trigger cell transformation, inflammation, and diseases. In the kidney, aberrant protein secretion plays a central role in cell activation and transition and in promoting renal fibrosis onset and progression. Using comparative proteomic analyses, we investigated in the present study the impact of cell transition on renal fibroblast cells secretome. Human renal cell lines were stimulated with profibrotic hormones and cytokines, and alterations in secretome were investigated using proteomic approaches. We identified protein signatures specific for the fibrotic phenotype and investigated the impact of modeling secretome proteins on extra cellular matrix accumulation. The secretion of peptidyl-prolyl cis-trans isomerase A (PPIA) was demonstrated to be associated with fibrosis phenotype. We showed that the in-vitro inhibition of PPIA with ciclosporin A (CsA) resulted in downregulation of PPIA and fibronectin (FN1) expression and significantly reduced their secretion. Knockdown studies of PPIA in a three-dimensional (3D) cell culture model significantly impaired the secretion and accumulation of the extracellular matrix (ECM), suggesting a positive therapeutic effect on renal fibrosis progression.

Oral health-related quality of life in different rheumatic diseases.

OBJECTIVES: Aim of this cross-sectional study was to investigate oral health-related quality of life (OHRQoL) of patients with different rheumatic diseases. SUBJECTS AND METHODS: Patients with rheumatic disease, including rheumatoid arthritis (RA), systemic lupus erythematodes (SLE), systemic sclerosis (SSc), ankylosing spondylitis (AS), psoriatic arthritis (PsA) and vasculitis were included. OHRQoL was assessed with the German short form of oral health impact profile (OHIP G14). Age, disease duration, leukocytes, c-reactive protein (CRP) and haemoglobin counts were considered as disease related parameters. RESULTS: A total of 356 patients, assigned to the groups RA (n = 218), SLE (n = 36), AS (n = 36), PsA (n = 33), vasculitis (n = 19) and SSc (n = 14) were included. The OHIP G14 sub-scale psychosocial impact differed significantly between groups (p = .02). The OHIP G14 sum score was also significantly different between groups (p < .01). A medium-sized correlation was found for CRP with OHIP G14 sum score within SLE group (r = .344, p = .04). A large correlation was detected for leukocytes within PsA group (r = .525, p < .01). The reliability of the applied OHIP G14 was high. CONCLUSION: Patients with rheumatic disease show a reduced OHRQoL, with several differences between the entities. Psychosocial aspects appear to be of relevance and should be considered in multidisciplinary dental care of these patients.

Clinical Efficacy of Routinely Administered Belimumab on Proteinuria and Neuropsychiatric Lupus.

Background and Objectives: Belimumab (BEL) is a monoclonal antibody approved for the treatment of active systemic lupus erythematosus (SLE) but not for lupus nephritis (LN) and neuropsychiatric systemic lupus erythematosus (NPSLE). We aimed to assess BEL's effects on these severe, potentially life-threatening manifestations. Methods: Retrospective observational cohort study using routine clinical data in a case series of patients with SLE receiving BEL. Results: Sixteen patients received BEL therapy for active SLE. Nine were excluded because they had no LN or NPSLE. Six suffered from LN, and one patient had NPSLE. All LN patients received BEL in addition to standard therapy including glucocorticoids, hydroxychloroquine, and mycophenolate mofetil in five cases, and tacrolimus in one case. Three patients with proteinuria >1,000 mg/g creatinine responded well (one complete, two partial renal responses); all other patients had decreasing proteinuria and a reduction in anti-dsDNA levels. The patient with NPSLE who had failed previous therapies had persistent clinical improvement of cutaneous and neuropsychiatric manifestations. There was one mild allergic reaction and one lower respiratory tract infection, but no other adverse events. One patient discontinued therapy due to a lack of improvement in clinical symptoms, another because of clinical remission. Conclusions: In our series, BEL led to a decrease of proteinuria in patients with proteinuria of more than 1,000 mg/g creatinine despite standard of care treatment, and led to a marked clinical improvement in one patient with NPSLE. No adverse events were observed. Routinely administered BEL shows clinical efficacy on non-approved manifestations, but careful patient selection is warranted.

Disease activity, morning stiffness and missing teeth are associated with oral health-related quality of life in individuals with rheumatoid arthritis.

OBJECTIVES: The aim of this cross-sectional study was to assess oral health-related quality of life (OHRQoL) in patients with rheumatoid arthritis (RA) and its relation to specific RA characteristics. MATERIAL AND METHODS: Within the oral examination, the need for dental (carious teeth showing cavitation) and periodontal treatment (presence of a probing depth ≥ 3.5 mm) and the number of missing teeth (M-T) were recorded. OHRQoL was assessed with the German short version of the Oral Health Impact Profile (OHIP G14). The disease activity score (DAS28-ESR), disease duration, number of swollen/painful joints and duration of morning stiffness were retrieved from the patient records. RESULTS: A total of 176 patients with a mean age of 62.5 ± 10.2 years were included. The overall OHIP G14 sum score was 5.4 ± 7.1. The M-T showed a significant correlation with the dimensions of oral function (r = 0.25, p = 0.001) and psychosocial impact (r = 0.20, p = 0.009) and the sum score (r = 0.26, p = 0.001). The DAS28-ESR showed a significant correlation with psychosocial impact (r = 0.19, p = 0.012) and the sum score (r = 0.16, p = 0.041). The duration of morning stiffness was correlated with oral function (r = 0.19, p = 0.019), psychosocial impact (r = 0.18, p = 0.024) and the sum score (r = 0.22, p = 0.006). The effect size of these correlations was interpreted as small. CONCLUSION: Disease activity, morning stiffness and missing teeth are associated to OHRQoL of patients with RA. Accordingly, multidisciplinary dental care appears necessary for these patients. CLINICAL RELEVANCE: The prevention of tooth loss as well as the consideration of psychosocial and disease-specific parameters in the multidisciplinary dental care of RA patients is necessary.

Prevalence of affective disorders and dementia in inflammatory polyarthropathies.

Comorbid disorders are common in psychiatric diseases and understanding the risk of secondary diseases can aid successful clinical treatment. The objective of this study was to compare the frequency of comorbid dementia, affective disorders, and inflammatory polyarthropathies. Healthcare data obtained via the German Hospital Fees Act from two independent databases with more than 7.4 million cases were analyzed to compare the prevalence of comorbid disorders. Comorbid inflammatory polyarthropathy was observed in 2.27% of patients diagnosed with affective disorders and 1.35% of patients with dementia (p < 0.001). Among patients with a primary diagnosis of inflammatory polyarthropathy, 1.27% of patients were diagnosed with dementia, whereas 4.55% of age-matched patients without inflammatory polyarthropathies had comorbid dementia (p < 0.001). The opposite effect was demonstrated for affective disorders, as 5.77% of patients with a primary diagnosis of inflammatory polyarthropathy also had comorbid affective disorders, while 4.87% of age-matched patients without inflammatory polyarthropathy had an accompanying affective disease (p < 0.001). These findings show an association between the occurrence of inflammatory polyarthropathies, dementia, and affective disorders. This correlation might improve diagnosis and treatment for patients with comorbidities. Moreover, further exploration of the molecular pathophysiology underlying these relationships could be relevant for the development of novel treatment options.

Long-term effects of baroreflex activation therapy: 2-year follow-up data of the BAT Neo system.

OBJECTIVE: Baroreflex activation therapy (BAT) reduces office blood pressure (BP) in patients with resistant hypertension (HTN). Whereas sustained effects from the BAT Rheos device have already been reported, no long-term data on 24-h ambulatory BP (ABP) are currently available for the unilateral BAT Neo device. METHODS: Patients treated with the BAT neo device for resistant hypertension were prospectively included into this observational study. Office and ABP measurements were performed before BAT implantation as well as 6, 12 and 24 months after initiation of BAT. RESULTS: A total of 60 patients with resistant HTN (office BP 172 ± 25/90 ± 17 mmHg, 24-h ABP 150 ± 16/80 ± 12 mmHg, median of antihypertensive drugs 7 (IQR 6-8)) were included. After 24 months, there was a significant reduction of - 25 ± 33/- 9 ± 18 mmHg (n = 50, both p < 0.01) in office BP and - 8 ± 23/- 5 ± 13 mmHg (n = 46, both p = 0.02) in 24-h ABP, while the number of antihypertensive medications was reduced to a median of 5 (4-6) drugs (p < 0.01). Patients with isolated systolic HTN (ISH) experienced a BP-lowering effect in office BP, but not in ABPM at month 24. Using unadjusted BP values, BAT seems to be more effective in combined hypertension (CH) than in ISH. After adjustment for baseline BP values, there was no significant difference in BP reduction between ISH and CH patients. Ambulatory SBP at baseline was the only independent correlate of BP response at month 24. CONCLUSION: BAT reduced office BP and improved relevant parameters of ABP, which is associated with a high cardiovascular risk, in patients with resistant HTN, whereas, after adjustment for baseline BP, BP reduction was not different in patients with CH compared with patients with ISH. However, randomized controlled trials are needed to confirm the effects of BAT on 24-h ABP.

Rheopheresis for Digital Ulcers and Raynaud's Phenomenon in Systemic Sclerosis Refractory to Conventional Treatments.

Raynaud's phenomenon (RP) is almost universally present in patients with Systemic Sclerosis (SSc). RP represents a generalized vasculopathy and potentially lead to digital ulcers (DU), which may be complicated by superinfection, tissue necrosis, and limb loss. We report the analysis of an extracorporeal procedure in a 36-year-old female patient with diffuse SSc with refractory RP and DU despite treatment with diltiazem, candesartan, sildenafil, and intravenous iloprost. We performed rheopheresis (RheoP), a variant of double-filtration plasmapheresis, as a potential new treatment option for refractory patients despite optimal medical therapy. We performed two RheoP per week every 4 weeks for a total of 3 months. Clinical improvement in DU healing occurred with no adverse events directly related to the treatment. While there was no reduction in the number of Raynaud attacks with RheoP, a significant reduction of the duration of attacks from a median of 15 (5-45, 95% CI 10-15) to 7 (3-30, 95% CI 6-10) minutes with an improvement of the Raynaud Condition Score (RCS) improved from 4 to 2. In conclusion, RheoP is a feasible and potentially beneficial treatment modality in patients with refractory RP and DU. We propose that RheoP should be investigated in a larger number of patients in a clinical trial setting.

Thrombophilic risk factors in hemodialysis: Association with early vascular access occlusion and patient survival in long-term follow-up.

OBJECTIVE: Thrombophilic risk factors (TRFs) occur rather frequently in hemodialysis (HD) patients. However, little is known about their significance in HD patients, besides their potential impact on arteriovenous (AV) access failure, with varying results. We examined the effects of a wide variety of TRFs on both early AV fistula occlusion and survival among HD patients in long-term follow-up. METHODS: In this single-center, observational study, 70 consecutive HD patients from our dialysis center were examined with respect to shunt occlusion within the first 2 years after fistula creation and patient survival in a long-term follow-up (at least 16 years). We examined the presence of factor V, prothrombin, and MTHFR mutations using real-time fluorescence polymerase chain reaction. Furthermore, antithrombin (AT), protein C, protein S, and antiphospholipid antibodies (APL-Abs) were assessed. RESULTS: Among the 70 patients, 32 had MTHFR mutations, 10 had heterozygous factor V Leiden mutations, 4 had prothrombin mutations, 4 had protein S deficiency, 2 had protein C deficiency, 9 had AT deficiency, and 14 had APL-Abs. 40 patients had shunt occlusion. TRFs were associated with a significantly increased risk for shunt thrombosis (P<0.02). Kaplan-Meier analysis with a log-rank test revealed significantly shorter survival in HD patients with TRFs (P<0.02). Cox regression analysis showed that the presence of TRFs (P<0.05; hazard ratio, 1.94; 95% CI: 1.07-3.56), but not early shunt occlusion, was associated with short patient survival. CONCLUSIONS: TRFs in hemodialysis patients have a strong impact on patient survival and early AV fistula failure; however, patient survival is not significantly affected by early shunt occlusion.

Risk factors for catheter-related infections in patients receiving permanent dialysis catheter.

BACKGROUND: Due to rising vascular comorbidities of patients undergoing dialysis, the prevalence of permanent hemodialysis catheters as hemodialysis access is increasing. However, infection is a major complication of these catheters. Therefore, identification of potential predicting risk factors leading to early infection related complications is valuable, in particular the significance the CRP (C-reactive protein)-value is of interest. METHODS: In this retrospective study 151 permanent hemodialysis catheters implanted in 130 patients were examined. The following data were collected at the time of catheter implantation: CRP-value, history of catheter-related infection, microbiological status, immunosuppression and diabetes mellitus. The primary outcomes were recorded over the 3 months following the implantation: catheter-related infection, days of hospital stay and death. Catheter removal or revision, rehospitalization and use of antibiotics were identified as secondary outcomes. RESULTS: We identified a total of 27 (17.9%) infections (systemic infection: 2.26 episodes/ 1000 catheter days, local infection: 0.6 episodes/ 1000 catheter days). The development of an infection was independent of the CRP-value (p = 0.66) as well as the presence of diabetes mellitus (p = 0.64) or immunosuppression (p = 0.71). Univariate analysis revealed that infection was more frequent in patients with MRSA-carriage (p < 0.001), in case of previous catheter-related infection (p < 0.05) and of bacteremia or bacteriuria in the period of 3 months before catheter implantation (p < 0.001). Catheter removal or revision (p = 0.002), rehospitalization (p = 0.001) and use of antibiotics (p = 0.02) were also more often observed in patients with MRSA-carriage. CONCLUSIONS: The CRP-value at the time of implantation of a permanent hemodialysis catheter is not associated with the development of early catheter related infections, but an individual history of catheter-related infection, MRSA-carriage and bacteremia or bacteriuria in the period of 3 months prior to catheter implantation are significant risk factors.

Effect of baroreflex activation therapy on renal sodium excretion in patients with resistant hypertension.

OBJECTIVE: Activation of the sympathetic nervous system increases sodium retention in resistant hypertension. Baroreflex activation therapy (BAT) is an interventional method to reduce sympathetic overactivity in patients with resistant hypertension. This study aimed to assess the effect of BAT on urinary sodium excretion. METHODS: From 2012 to 2015, consecutive patients with resistant hypertension and blood pressure (BP) above target despite polypharmacy strategies were consecutively included in this observational study. BAT was provided with the individual adaption of programmed parameters over the first months. 24-h urinary sodium excretion (UNa) was estimated at baseline and after 6 months using the Kawasaki formula in patients undergoing BAT. Additionally, the fractional sodium excretion, plasma renin activity, and aldosterone levels were assessed. RESULTS: Forty-two patients completed the 6-month follow-up period. Office systolic and ambulatory 24-h systolic BP at baseline were 169 ± 27 mmHg and 148 ± 16 mmHg despite a median intake of 7(3-9) antihypertensive drugs. After 6 months of BAT, systolic office BP decreased to 150 ± 29 mmHg (p < 0.01), 24-h systolic BP to 142 ± 22 mmHg (p = 0.04) and 24-h UNa increased by 37% compared to baseline (128 ± 66 vs. 155 ± 83 mmol/day, p < 0.01). These findings were accompanied by a significant increase in fractional sodium excretion (0.74% [0.43-1.47] to 0.92% [0.61-1.92]; p = 0.02). However, in contrast to the significant BP reduction, eGFR, plasma sodium, renin activity and aldosterone levels did not change during BAT. The increase in sodium excretion was correlated with the change in eGFR (r = 0.371; p = 0.015). CONCLUSION: The present study revealed a significant increase of estimated 24-h UNa which may contribute to the long-term BP-lowering effects of this interventional method.

Immunoadsorption or plasma exchange in steroid-refractory multiple sclerosis and neuromyelitis optica.

BACKGROUND: Plasma exchange (PE) and immunoadsorption (IA) are alternative treatments of steroid-refractory relapses of multiple sclerosis (MS) or neuromyelitis optica (NMO). METHODS: Adverse events and neurological follow-ups in 127 MS- (62 PE, 65 IA) and 13 NMO- (11 PE, 2 IA) patients were retrospectively analyzed. Response was defined by improvements in either expanded disability status scale (EDSS) by at least 1.0 or visual acuity (VA) to 0.5, confirmed after 3 and/or 6 months. RESULTS: Hundred and forty patients were included in safety analysis, 102 patients provided sufficient neurological follow-up-data. There were no significant differences between IA and PE in side effects (3.9% vs 3.6%, P = .96) or response-rate (P = .65). Responders showed significant lower age (P = .02) and earlier apheresis-initiation (P = .01). Subgroup-analysis confirmed significant lower age in patients with relapsing-remitting MS (RRMS) /clinical isolated syndrome (CIS). CONCLUSION: IA and PE seem equally safe and effective in steroid-resistant MS- or NMO-relapses. Early apheresis and low patient age are additional prognostic factors.

Dickkopf-3 in aberrant endothelial secretome triggers renal fibroblast activation and endothelial-mesenchymal transition.

Background: Our laboratory has previously demonstrated that Sirt1endo-/- mice show endothelial dysfunction and exaggerated renal fibrosis, whereas mice with silenced endothelial transforming growth factor beta (TGF-ß) signaling are resistant to fibrogenic signals. Considering the fact that the only difference between these mutant mice is confined to the vascular endothelium, this indicates that secreted substances contribute to these contrasting responses. Methods: We performed an unbiased proteomic analysis of the secretome of renal microvascular endothelial cells (RMVECs) isolated from these two mutants. We cultured renal fibroblasts and RMVECs and used microfluidic devices for coculturing. Results: Dickkopf-3 (DKK3), a putative ligand of the Wnt/ß-catenin pathway, was present exclusively in the fibrogenic secretome. In cultured fibroblasts, DKK3 potently induced myofibroblast activation. In addition, DKK3 antagonized effects of DKK1, a known inhibitor of the Wnt pathway, in conversion of fibroblasts to myofibroblasts. In RMVECs, DKK3 induced endothelial-mesenchymal transition and impaired their angiogenic competence. The inhibition of endothelial outgrowth, enhanced myofibroblast formation and endothelial-mesenchymal transition were confirmed in coculture. In reporter DKK3-eGFP × Col3.6-GFPcyan mice, DKK3 was marginally expressed under basal conditions. Adriamycin-induced nephropathy resulted in upregulation of DKK3 expression in tubular and, to a lesser degree, endothelial compartments. Sulindac sulfide was found to exhibit superior Wnt pathway-suppressive action and decreased DKK3 signals and the extent of renal fibrosis. Conclusions: In conclusion, this unbiased proteomic screen of the profibrogenic endothelial secretome revealed DKK3 acting as an agonist of the Wnt pathway, enhancing formation of myofibroblasts and endothelial-mesenchymal transition and impairing angiogenesis. A potent inhibitor of the Wnt pathway, sulindac sulfide, suppressed nephropathy-induced DKK3 expression and renal fibrosis.

Direct assessment of adherence and drug interactions in patients with hypertensive crisis-A cross-sectional study in the Emergency Department.

Though drug adherence is supposed to be low in hypertensive crisis (HTN-C), there are no data available from direct adherence assessments. The aim of the present study was to evaluate adherence to prescribed antihypertensives and potential interactions of concomitant drugs and foods with prescribed antihypertensives in patients with HTN-C by a direct evaluation via biochemical urine analysis. In the present cross-sectional study, 100 patients with HTN-C, admitted to the emergency department (ED), were included. A biochemical urine analysis using gas chromatography-tandem mass spectrometry was performed. Out of 100 patients, 86 received antihypertensives. Urine analyses could be evaluated unambiguously in 62 patients. In 15 of these 62 patients (24%), a nonadherence could be demonstrated, and in 21 patients (34%), a partial nonadherence could be demonstrated. Patients with nonadherence or partial nonadherence showed a longer hypertension history (15[5-22] vs 10[3-15] years, P = 0.04) were prescribed more general medication (number 7.1 ± 3.4 vs 3.4 ± 1.8; P < 0.01) as well as antihypertensive drugs (number 2.8 ± 1.1 vs 1.5 ± 0.7, P < 0.01). A potential BP-raising trigger by medications or food interaction was frequently detectable, predominantly with nonsteroidal anti-inflammatory drugs (NSAIDs; n = 38), glucocorticoids (n = 8), antidepressants (n = 10), and licorice (n = 10). Nonadherence and partial nonadherence to prescribed antihypertensives might play a crucial role for the occurrence of HTN-C. However, further case-controlled studies are needed to confirm the present findings. Ingestion of concurrent over-the-counter drugs such as NSAIDs but also prescribed drugs as well as aliments may lead to critical BP elevation. In order to prevent HTN-C, the present findings emphasize the importance for clinicians to pay attention to the issue of adherence and co-medication.

Dialysis vintage time has the strongest correlation to psychosocial pattern of oral health-related quality of life - a multicentre cross-sectional study

BACKGROUND: Aim of this cross-sectional, multicentre study was to investigate associations of dialysis vintage time in haemodialysis (CKD5D) patients with oral health-related quality of life (OHRQoL) and dental and periodontal treatment need. MATERIAL AND METHODS: CKD5D patients were divided into subgroups according to dialysis vintage time in different dialysis centres in Germany. OHRQoL was assessed with oral health impact profile (OHIP-G14). Dental treatment need was classified as presence of carious lesions. Periodontal treatment need was defined as periodontal screening index score (PSI) 3-4. RESULTS: In total, 190 participants were divided into the subgroups according to the time on CKD5D: 0 - 2 (n = 29), 3 - 5 (n = 35), 6 - 8 (n = 34), 9 - 12 (n = 29), 13 - 20 (n = 34) and >20 years (n = 29). The overall treatment need in the total cohort was 92% (dental 56%, periodontal 88%) with a total OHIP-G14 sum score of 4.17 [2; 0-5] without a significant correlation. Time on CKD5D was inversely correlated with the OHIP G14 score (p < 0.01, R = -0.201). The pattern psychosocial impact was significantly associated with the dialysis duration (p < 0.01) and showed a negative correlation to the OHIP-G14 (R = -0.283, Spearman's rho test p < 0.01). For oral function also a negative correlation with OHIP-G14 was detected (Spearman's rho: -0.183). CONCLUSIONS: Patients with a prolonged dialysis vintage time show an improved OHRQoL, which might be mainly caused by the positive development of psychosocial pattern of OHRQoL. The oral health situation of HD patients seems unsatisfying, independently of dialysis vintage time and OHRQoL. Accordingly, an improvement in oral health situation of CKD5D patients is mandatory necessary. Thereby, consideration of psychosocial aspects especially at the beginning of CKD5D therapy and a sensitization regarding oral health issues with increasing vintage time might be recommendable

Fibrogenic Secretome of Sirtuin 1-Deficient Endothelial Cells: Wnt, Notch and Glycocalyx Rheostat.

Sirtuins (SIRT) are ubiquitous histone and protein deacetylases and a member of this family, SIRT1, is the best-studied one. Its functions in endothelial cells encompass branching angiogenesis, activation of endothelial nitric oxide synthase, regulation of proapoptotic and proinflammatory pathways, among others. Defective SIRT1 activity has been described in various cardiovascular, renal diseases and in aging-associated conditions. Therefore, understanding of SIRT1-deficient, endothelial dysfunctional phenotype has much to offer clinically. Here, we summarize recent studies by several investigative teams of the characteristics of models of global endothelial SIRT1 deficiency, the causes of facilitative development of fibrosis in these conditions, dissect the protein composition of the aberrant secretome of SIRT1-deficient endothelial cells and present several components of this aberrant secretome that are involved in fibrogenesis via activation of fibroblasts to myofibroblasts. These include ligands of Wnt and Notch pathways, as well as proteolytic fragments of glycocalyx core protein, syndecan-4. The latter finding is crucial for understanding the degradation of glycocalyx that accompanies SIRT1 deficiency. This spectrum of abnormalities associated with SIRT1 deficiency in endothelial cells is essential for understanding the origins and features of endothelial dysfunction in a host of cardiovascular and renal diseases.

Kidney protective effects of baroreflex activation therapy in patients with resistant hypertension.

Baroreflex activation therapy (BAT) is approved for the treatment of resistant hypertension. In addition to blood pressure (BP) reduction, pilot studies suggested several organoprotective effects of BAT. Thirty-two patients with resistant hypertension were prospectively treated with BAT. Besides office BP and 24-hour ambulatory BP (ABP) measurements, detection of a urinary proteome-based classifier (CKD273), which has been shown to predict chronic kidney disease (CKD) progression, was carried out at baseline and after 6 months of BAT. Office BP significantly decreased from 170 ± 25/90 ± 18 to 149 ± 29/82 ± 18 mm Hg. Analysis of CKD273 score and eGFR with CKD-EPI equation at baseline revealed strong correlation (r = 0.568, P < 0.001). After 6 months of BAT, there was no significant change in CKD273 score (-0.061 [95% CI: -0.262 to 0.140], P = 0.601). However, by stratification of the data regarding ABP response, there was a statistically significant (P = 0.0113) reduction in the CKD273 score from a mean of 0.161 [95% CI: -0.093 to 0.414] to -0.346 [95% CI: -0.632 to -0.060] after BAT in patients with systolic ABP decrease of ≥5 mm Hg. These data emphasized potential nephroprotective effects of BAT in patients with sufficient BP response.

The "rapid atrial swirl sign" for assessing central venous catheters: Performance by medical residents after limited training.

RATIONALE: Central venous catheter (CVC) placement is a standard procedure in critical care. Ultrasound guidance during placement is recommended by current guidelines, but there is no consensus on the best method for evaluating the correct CVC tip position. Recently, the "rapid atrial swirl sign" (RASS) has been investigated in a limited number of studies. OBJECTIVES: We performed a prospective diagnostic accuracy study of focused echocardiography for the evaluation of CVC tip position in our medical ICU and IMC units. METHODS: We performed a prospective diagnostic accuracy study in 100 patients admitted to the Intensive Care Unit and Intermediate Care Unit at our center. The first 10 subjects were assessed by one staff physician investigator (reference cohort), the remaining 90 patients by different residents (test cohort). All patients received a post-procedural chest radiograph (CXR) as gold standard. CVC placement was assessed with focused echocardiography performed by residents after a short training session. A rapid opacification of the right atrium (RASS) after injection of 10 mL of normal saline was regarded as "positive", flush after more than two seconds was defined as "delayed", no flush was a "negative" test result. MEASUREMENTS AND MAIN RESULTS: Overall sensitivity of the RASS was 100% (95% CI 73.54-100%), specificity was 94.32% (CI 87.24-98.13%). Positive and negative predictive values were 70.59% (CI 44.04-89.09%) and 100% (CI 95.65-100%), respectively. Median time for echocardiographic testing was 5 minutes (1-28) in the whole cohort, CXRs were available after 49.5 minutes (13-254). Interrater agreement of the RASS was 0.77 (Cohen's kappa), Measurement of CVC tip position was not different between two observers. Test characteristics were similar among differently experienced residents. CONCLUSIONS: Presence of the RASS by focused echocardiography showed excellent sensitivity and specificity and was equally performed by residents after minimal training. In patients with a positive RASS, routine CXR can be safely omitted, reducing time, costs and radiation exposure. A negative RASS should lead to a search for misplaced catheters. CLINICAL TRIAL REGISTRATION: The study was registered with www.clinicaltrials.gov (NCT02661607).