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.

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.

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.

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.

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.

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.

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.

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.

Endothelial dysfunction is a superinducer of syndecan-4: fibrogenic role of its ectodomain.

Syndecan-4 (Synd4) is a member of the membrane-spanning, glycocalyx-forming proteoglycan family. It has been suggested that Synd4 participates in renal fibrosis. We compared wild-type and fibrosis-prone endothelial sirtuin 1-deficient (Sirt1endo-/-) mice, the latter being a model of global endothelial dysfunction. We performed mass spectrometry analysis, which revealed that Synd4 was highly enriched in the secretome of renal microvascular endothelial cells obtained from Sirt1endo-/- mice upon stimulation with transforming growth factor-ß1; notably, all detectable peptides were confined to the ectodomain of Synd4. Elevated Synd4 was due to enhanced NF-κB signaling in Sirt1endo-/- mice, while its shedding occurred as a result of oxidative stress in Sirt1 deficiency. Synd4 expression was significantly enhanced after unilateral ureteral obstruction compared with contralateral kidneys. Furthermore, hyperplasia of renal myofibroblasts accompanied by microvascular rarefaction and overexpression of Synd4 were detected in Sirt1endo-/- mice. The ectodomain of Synd4 acted as a chemoattractant for monocytes with higher levels of macrophages and higher expression levels of Synd4 in the extracellular matrix of Sirt1endo-/- mice. In vitro, ectodomain application resulted in generation of myofibroblasts from cultured renal fibroblasts, while in vivo, subcapsular injection of ectodomain increased interstitial fibrosis. Moreover, the endothelial glycocalyx was reduced in Sirt1endo-/- mice, highlighting the induction of Synd4 occurring in parallel with the depletion of its intact form and accumulation of its ectodomain in Sirt1endo-/- mice. On the basis of our experimental results, we propose that it is the Synd4 ectodomain per se that is partially responsible for fibrosis in unilateral ureteral obstruction, especially when it is combined with endothelial dysfunction. NEW & NOTEWORTHY Our findings suggest that endothelial dysfunction induces the expression of syndecan-4 via activation of the NF-κB pathway. Furthermore, we show that syndecan-4 is shed to a greater amount because of increased oxidative stress in dysfunctional endothelial cells and that the release of the syndecan-4 ectodomain leads to tubulointerstitial fibrosis.

Periodontal condition is associated with disease duration and motoric disabilities in patients with ankylosing spondylitis: results of a cross-sectional study.

OBJECTIVE: Recent literature reveals worse periodontal health condition in ankylosing spondylitis (AS). However, roles of AS-related parameters, periodontal condition, and their association appear unclear. This cross-sectional study aimed at investigating dental and periodontal health as well as potentially periodontal pathogenic bacteria in patients with AS compared to healthy control subjects (HC). METHODS: Dental examination comprised dental findings (DMF-T), periodontal probing depth (PPD), bleeding on probing, clinical attachment loss (CAL), papillary bleeding index, and microbiological analysis based on polymerase chain reaction of selected potentially periodontal pathogenic bacteria. Classification of periodontitis severity was based on PPD and/or CAL and divided into no/mild, moderate, and severe periodontitis. RESULTS: 52 participants with AS and 52 HC were included. 96% of the AS group and 75% of HC had moderate to severe periodontitis (moderate: AS = 26, HC = 34; severe: AS = 23, HC = 5; p < 0.01). Furthermore, a higher number of decayed teeth (D-T) were found in AS compared to HC (p = 0.02). A significant difference between AS und HC was detected for the prevalences of Parvimonas micra (AS = 92%, HC = 71%; p = 0.01), Eubacterium nodatum (AS = 35%, HC = 17%; p = 0.05), and Eikenella corrodens (AS = 96%, HC = 77%; p = 0.01). Bath Ankylosing Spondylitis Metrology Index (BASMI) and disease duration showed significant associations to PPD and CAL (p < 0.01). CONCLUSION: Patients with AS show worse dental and periodontal conditions compared to HC. Thereby, prevalence of bacteria related to insufficient oral hygiene was higher in AS. BASMI and duration of AS affect periodontal burden. Accordingly, particular attention considering dental care and oral hygiene in AS patients seems to be reasonable.

Oral health-related quality of life is associated with disease specific parameters in patients with ankylosing spondylitis.

BACKGROUND: The aim of this cross-sectional study was to investigate oral health-related quality of life (OHRQoL) in patients with ankylosing spondylitis (AS) and its association to oral health as well as AS specific parameters. METHODS: Patients with AS and a healthy control group (HC) were included and examined. The oral examination included decayed-, missing-, and filled-teeth index (DMF-T) as well as assessment of periodontal probing depth and clinical attachment loss to classify patients into healthy/mild, moderate, or severe periodontitis. Furthermore, the German short form of the oral health impact profile (OHIP G14) was used. RESULTS: A total of 50 patients each group (age: AS, 47.18 ± 15.67; HC, 55.82 ± 10.56; p < 0.01, gender male: AS, 52%; HC, 46%; p = 0.69) was included. AS patients showed worse D-T (p < 0.01) and periodontal condition (p = 0.01). The OHIP G14 score was clinically relevant and statistically significant higher in AS compared to HC (AS, 6.2 [2; 0-10.75]; HC, 1.7 [0; 0-2.0]; < 0.01). Only in HC, an association of OHIP G14 to DMF-T (p = 0.01) and M-T (p = 0.01) was found, while the OHIP G14 in AS group was not associated to oral health parameters. Within the AS group, the majority of investigated AS specific parameters were statistically significant and clinically relevant associated to OHIP G14 scores (pi < 0.05). CONCLUSION: Patients with AS show worse OHRQoL compared to HC, irrespective of oral status. The high general disease burden might affect OHRQoL, making an increased attention of these patients in dental care, especially considering psychological aspects, necessary. CLINICAL RELEVANCE: Increased consideration of psychosocial and disease related aspects in dental care of AS patients appear recommendable.

Low-dose hydralazine prevents fibrosis in a murine model of acute kidney injury-to-chronic kidney disease progression.

Acute kidney injury (AKI) and progressive chronic kidney disease (CKD) are intrinsically tied syndromes. In this regard, the acutely injured kidney often does not achieve its full regenerative capacity and AKI directly transitions into progressive CKD associated with tubulointerstitial fibrosis. Underlying mechanisms of such AKI-to-CKD progression are still incompletely understood and specific therapeutic interventions are still elusive. Because epigenetic modifications play a role in maintaining tissue fibrosis, we used a murine model of ischemia-reperfusion injury to determine whether aberrant promoter methylation of RASAL1 contributes causally to the switch between physiological regeneration and tubulointerstitial fibrogenesis, a hallmark of AKI-to-CKD progression. It is known that the antihypertensive drug hydralazine has demethylating activity, and that its optimum demethylating activity occurs at concentrations below blood pressure-lowering doses. Administration of low-dose hydralazine effectively induced expression of hydroxylase TET3, which catalyzed RASAL1 hydroxymethylation and subsequent RASAL1 promoter demethylation. Hydralazine-induced CpG promoter demethylation subsequently attenuated renal fibrosis and preserved excretory renal function independent of its blood pressure-lowering effects. In comparison, RASAL1 demethylation and inhibition of tubulointerstitial fibrosis was not detected upon administration of the angiotensin-converting enzyme inhibitor Ramipril in this model. Thus, RASAL1 promoter methylation and subsequent transcriptional RASAL1 suppression plays a causal role in AKI-to-CKD progression.

Urinary free light chains may help to identify infection in patients with elevated systemic inflammation due to rheumatic disease.

The risk of infection in patients with rheumatic diseases is elevated, but a clear marker to differentiate the cause of the systemic inflammation is missing. We assessed the ability urinary immunoglobulin free light chains (FLCs) to indicate the presence of infection in patients with rheumatic disease. We performed a retrospective analysis of patients with rheumatic disease attending the Georg-August University Hospital in Goettingen, Germany, from January 2011 to December 2013. Subjects were included if they had urine levels of κ and λ FLCs available. A reference group of patients without autoimmune disease, but with documented infection, was constructed. A total of 1500 patients had their urinary FLCs quantified during the study period. Of the 382 patients with rheumatic disease, 172 (45%) displayed no systemic inflammation, 162 (42%) had inflammation due to the underlying disease activity, and 48 (13%) had inflammation due to a confirmed infection. Urinary FLC concentrations were much higher in patients with rheumatic diseases and infection (κ 68.8 ± 81.8 mg/L, λ 31.4 ± 53.5 mg/L) compared to those with inflammation due to rheumatic disease activity (κ 22.7 ± 26.3 mg/L, λ 8.1 ± 9.1 mg/L, κ p < 0.001, λ p = 0.004). Urinary κ FLCs demonstrated good ability to predict infection, with a sensitivity of 63% and specificity of 84%. Urinary λ FLCs gave similar values, with a sensitivity of 65% and specificity of 81%. FLCs may be useful for distinguishing inflammation due to rheumatic disease activity from that due to the additional presence of infection. The ability to quantify these proteins in urine provides a simple alternative to the use of blood.

Anti-Leukemic Activity of Shikonin: Role of ERP57 in Shikonin Induced Apoptosis in Acute Myeloid Leukemia.

BACKGROUND/AIMS: ER-Stress and activation of unfolded protein response belong to the major factors involved in chemoresistance in cancer cells. In this study we investigated the effect of shikonin on the survival of acute myeloid leukemia cells and the role of ER-stress protein ERP57, a protein disulfide isomerase, in improvement of chemotherapy. METHODS: Using MTT assay we studied cytotoxic effects of shikonin on HL-60 cells. The flow cytometry was adopted to examine the shikonin induced mode of cell death in HL-60 cells. The overall protein expression alteration resulting from shikonin treatment was investigated using proteomics methods. Western blotting was performed to quantify the alteration in protein expression in HL-60 after shikonin treatment. Silencing and overexpression studies were carried out to highlight the therapeutic role of ERP57 in shikonin effect on AML cells. RESULTS: Shikonin induces apoptosis in HL-60 cells without significant effect on Primary cells from healthy volunteers. The apoptotic effect was dose and time dependent and was accompanied by strong alteration in cell proteome. Among the proteins targeted by shikonin, ERP57 was significantly downregulated in HL-60 after treatment. Compared to healthy control ERP57 was found to be highly expressed in AML cell line HL60 and was downregulated after shikonin treatment. Overexpression of ERP57 protected HL-60 from shikonin induced apoptosis, whereas knockdown of ERP57 expression resulted in increase in shikonin induced apoptosis. CONCLUSIONS: Our results demonstrate that ERP57 plays a crucial role in resistance towards shikonin induced apoptosis in AML cells. Targeting of ERP57 might offer a new therapeutic option for the treatment of acute myeloid leukemia.

Vimentin fragments are potential markers of rheumatoid synovial fibroblasts.

OBJECTIVES: To study the protein expression differences between primary fibroblasts explanted from synovial membranes of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: Fibroblast cultures were obtained from 10 patients with RA and 5 patients with OA. After two-dimensional gel electrophoresis, proteins were excised and identified using peptide mass fingerprint. Expression of selected proteins was subsequently examined by immunoblot. Furthermore, we examined the cellular lysates for the presence of citrullinated proteins. RESULTS: The study was designed to compare expression changes of the common proteins detected in all studied fibroblast cultures (i.e. detected in all patients samples). We totally identified 191 shared proteins between RA and OA fibroblasts. A significant difference was defined as at least 2-fold upregulation or 0.6-fold downregulation of protein expression. The most obvious alteration observed in RA was the appearance of several vimentin fragments not present in OA. We did not detect citrullinated proteins in lysates from RA fibroblasts. This corroborates the current assumption that fibroblasts are not able to citrullinate proteins by themselves and that invading macrophages play a central role in this process. CONCLUSIONS: We demonstrated that fibroblasts from patients with RA, despite being grown under identical conditions, preserve a particular feature and generate vimentin fragments not present in fibroblasts from OA. Elevated levels of different vimentin fragments have been recently reported in several rheumatic conditions. Further studies are needed to elucidate the pathogenic mechanisms induced by vimentin fragments in RA.

FABP1 and FABP3 Have High Predictive Values for Renal Replacement Therapy in Patients with Acute Kidney Injury.

BACKGROUND/AIMS: Early initiation of renal replacement therapy (RRT) is recommended in order to improve the clinical outcome of patients who develop an acute kidney injury (AKI). However, markers that guide an early RRT initiation do not really exist currently. METHODS: Urine and serum samples were prospectively collected from 120 AKI patients. Depending on the necessity of initiating RRT, patients were divided into 2 different groups: dialysis (n = 52) and non-dialysis (n = 68). RESULTS: Comparative urinary proteomic analyses identified 4 different proteins (fatty acid binding proteins 1 and 3 (FABP1 and FABP3), ß-2-microglobulin (B2M), cystatin-M (CST6)) that discriminate AKI patients with high risk for RRT. Western blot analysis confirmed the proteomics data for FABP1 and FABP3 but not for B2M and CST6. Validation analysis confirmed that the FABP1 and FABP3 fulfilled the requirement of functioning as markers for AKI patients with risk to dialysis (p < 0.001). CONCLUSION: The release of high amounts of FABP1 and FABP3 in urine of AKI patients could serve as a diagnostic/prognosis marker for RRT initiation in these patients.

Oral behavior, dental, periodontal and microbiological findings in patients undergoing hemodialysis and after kidney transplantation.

BACKGROUND: Aim of this single center cross-sectional study was to investigate oral behavior, dental, periodontal and microbiological findings in patients undergoing hemodialysis (HD) and after kidney transplantation (KT). METHODS: Patients undergoing HD for end-stage renal failure and after KT were investigated. Oral health behavior was recorded using a standardized questionnaire, e.g. dental behavior, tooth brushing, oral hygiene aids. Oral investigation included screening of oral mucosa, dental findings (DMF-T) and periodontal situation (Papilla bleeding index [PBI] periodontal probing depth [PPD] and clinical attachment loss [CAL]). Additionally, microbiological analysis of subgingival biofilm samples (PCR) was performed. STATISTICAL ANALYSIS: Student's t-test or Mann-Whitney-U-test, Fisher's exact test (α = 5 %). RESULTS: A total of 70 patients (HD: n = 35, KT: n = 35) with a mean age of 56.4 ± 11.1 (HD) and 55.8 ± 10.9 (KT) years were included. Lack in use of additional oral hygiene (dental floss, inter-dental brush) was found. KT group presented significantly more gingivial overgrowth (p = 0.01). DMF-T was 19.47 ± 5.84 (HD) and 17.61 ± 5.81 (KT; p = 0.21). Majority of patients had clinically moderate and severe periodontitis; showing a need for periodontal treatment of 57 % (HD) and 71 % (KT; p = 0.30). Significantly higher prevalence of Parvimonas micra and Capnocytophaga species in the HD group were found (p < 0.01). CONCLUSION: Periodontal treatment need and lack in oral behavior for both groups indicate the necessity of an improved early treatment and prevention of dental and periodontal disease, e.g. in form of special care programs. Regarding microbiological findings, no major differences between KT and HD patients were found.

Tet3-mediated hydroxymethylation of epigenetically silenced genes contributes to bone morphogenic protein 7-induced reversal of kidney fibrosis.

Methylation of CpG island promoters is an epigenetic event that can effectively silence transcription over multiple cell generations. Hypermethylation of the Rasal1 promoter contributes to activation of fibroblasts and progression of kidney fibrosis. Here, we explored whether such causative hypermethylation could be reversed through endogenous mechanisms and whether such reversal of hypermethylation is a constituent of the antifibrotic activity of bone morphogenic protein 7 (BMP7). We show that successful inhibition of experimental kidney fibrosis through administration of BMP7 associates with normalization of Rasal1 promoter hypermethylation. Furthermore, this reversal of pathologic hypermethylation was achieved specifically through Tet3-mediated hydroxymethylation. Collectively, our findings reveal a new mechanism that may be exploited to facilitate therapeutic DNA demethylation to reverse kidney fibrosis.

Cellulose membranes are more effective in holding back vital proteins and exhibit less interaction with plasma proteins during hemodialysis.

The vast majority of patients with end-stage renal disease are treated with intermittent hemodialysis as a form of renal replacement therapy. To investigate the impact of hemodialysis membrane material on vital protein removal, dialysates from 26 well-characterized hemodialysis patients were collected 5 min after beginning, during 5h of treatment, as well as 5 min before ending of the dialysis sessions. Dialysis sessions were performed using either modified cellulose (n=12) (low-flux and high flux) or synthetic Polyflux (n=14) (low-flux and high-flux) dialyzer. Protein removal during hemodialysis was quantified and the dialysate proteome patterns were analyzed by 2-DE, MS and Western blot. There was a clear correlation between the type of membrane material and the amount of protein removed. Synthetic Polyflux membranes exhibit strong interaction with plasma proteins resulting in a significantly higher protein loss compared to modified cellulosic membrane. Moreover, the proteomics analysis showed that the removed proteins represented different molecular weight range and different functional groups: transport proteins, protease inhibitors, proteins with role in immune response and regulations, constructive proteins and as a part of HLA immune complex. The effect of this protein removal on hemodialysis treatment outcome should be investigated in further studies.

Impact of baroreflex activation therapy on renal function--a pilot study.

BACKGROUND/AIMS: Resistant hypertension and chronic kidney disease (CKD) are interlinked via sympathetic overdrive. Baroreflex activation therapy (BAT) has been shown to chronically reduce blood pressure (BP) in patients with resistant hypertension. The effect of BAT on renal function in CKD patients with resistant hypertension has not been reported. The aim of this study was to investigate the effect of sympathetic inhibition on renal function in CKD patients. METHODS: 23 CKD patients with resistant hypertension were prospectively treated with BAT. Analyses were performed before and 6 months after the start of BAT. The renal function was analyzed by creatinine, cystatin C, glomerular filtration rate (GFR), renin, aldosterone, fractioned and 24-hour sodium excretion and analyses of urine marker proteins. The purpose of the control group was to investigate the influence of treating patients in a center for hypertension and regression to the mean on investigated variables. RESULTS: The office mean BP decreased from 116.9 ± 20.9 mm Hg to 104.2 ± 22.2 mm Hg (p < 0.01), while the number of prescribed antihypertensive classes decreased from 6.6 ± 1.6 to 6.1 ± 1.7 (p = 0.02). Proteinuria and albuminuria decreased from a median of 283.9 and 47.7 to 136.5 (p = 0.01) and 45.0 mg/g creatinine (p = 0.01) with pronounced effects in higher CKD stage III + IV compared to I + II (p < 0.01). CKD-EPI cystatin C equation improved from 53.6 ± 22.7 to 60.4 ± 26.1 ml/min (p = 0.02). While creatinine and GFR were impaired after a period of 6 months, no changes of proteinuria, albuminuria, or BP were obtained in control patients. CONCLUSION: The data of this prospective trial demonstrate potential nephroprotective effects of BAT in therapy-resistant hypertension in CKD patients by a reduction of BP, proteinuria and moreover, a stabilization of estimated GFR.