Effects of a single phosphate-enriched test meal on inflammasome activity and postprandial inflammatory markers in healthy subjects.

PURPOSE: The consumption of highly processed food is often associated with a high intake of inorganic phosphate. Hyperphosphatemia is accompanied by an inflammatory status in patients with chronic kidney disease. However, the immune response to high phosphorus intake in healthy individuals is largely unknown. Therefore, the aim of the present study was to evaluate the effect of a single phosphate-enriched meal on inflammasome activity and plasma levels of inflammatory markers. METHODS: The analysis included 28 participants who received a single dose of either 700 mg phosphorus or a placebo with a test meal. At baseline, 4 and 8 h post-meal, plasma interleukin (IL)-6, IL-1ß, IL-10, c-reactive protein (CRP), soluble IL-6 receptor (sIL-6R) and glycoprotein 130 (sgp130) levels were determined. At baseline and 4 h post-meal, peripheral blood mononuclear cells were isolated to assess inflammasome activity. Subsequently, the effect of phosphate with or without glucose on IL-6 and IL-1ß gene expression and secretion in U937 monocytes was examined. RESULTS: While both groups showed a marked postprandial increase in IL-6 plasma levels, neither plasma levels of IL-6, IL-1ß, CRP, IL-10, sIL-6R, and sgp130 nor inflammasome activity were affected by phosphate compared to placebo. In U937 cells, there was also no effect of phosphate on IL-6 expression, but the addition of glucose increased it. Phosphate, however, reduced the IL-1ß secretion of these cells. CONCLUSION: Postprandial inflammatory markers were not affected by dietary phosphate. However, IL-6 plasma levels were markedly increased post-meal, which appears to be a metabolic rather than a pro-inflammatory phenomenon. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT03771924, date of registration: 11th December 2018, retrospectively registered.

Hypervolemia in Dialysis Patients Impairs STAT3 Signaling and Upregulates miR-142-3p: Effects on IL-10 and IL-6.

Fluid overload in hemodialysis patients (HD) has been proven to be associated with inflammation. Elevated levels of the pro-inflammatory cytokine interleukin-6 (IL-6) appear to be inadequately counterbalanced by the anti-inflammatory cytokine interleukin-10 (IL-10). We initiated a cross-sectional study enrolling 40 HD patients who were categorized by a bioimpedance measurement in normovolemic (N; 23) and hypervolemic (H; 17) groups to test whether IL-10- and IL-6-related signal transduction pathways (signal transducer of transcript 3: STAT3) and/or a post-transcriptional regulating mechanism (miR-142) are impaired by hypervolemia. IL-10/IL-6 transcript and protein production by PBMCs (peripheral blood mononuclear cells) were determined. Phospho-flow cytometry was used to detect the phosphorylated forms of STAT3 (pY705 and pS727). miR-142-3p/5p levels were detected by qPCR. Hypervolemic patients were older, more frequently had diabetes, and showed higher CRP levels. IL-10 transcripts were elevated in H patients but not IL-10 protein levels. In spite of the elevated mRNA expression of the suppressor of cytokine expression 3 (SOCS3), IL-6 mRNA and protein expression were increased in immune cells of H patients. The percentage of cells staining positive for STAT3 (pY705) were comparable in both groups; in STAT3 (pS727), however, the signal needed for full transactivation was decreased in H patients. miR-142-3p, a proven target of IL-10 and IL-6, was significantly elevated in H patients. Insufficient phosphorylation of STAT3 may impair inflammatory and anti-inflammatory cytokine signaling. How far degradative mechanisms induced by elevated miR-142-3p levels contribute to an inefficient anti-inflammatory IL-10 signaling remains elusive.

Liquid biomarkers of macrophage dysregulation and circulating spike protein illustrate the biological heterogeneity in patients with post-acute sequelae of COVID-19.

Post-acute sequelae of COVID-19 (PASC) are long-term consequences of SARS-CoV-2 infection that can substantially impair the quality of life. Underlying mechanisms ranging from persistent viruses to innate and adaptive immune dysregulation have been discussed. Here, we profiled the plasma of 181 individuals from the cohort study for digital health research in Germany (DigiHero), including individuals after mild to moderate COVID-19 with or without PASC and uninfected controls. We focused on soluble factors related to monocyte/macrophage biology and on circulating SARS-CoV-2 spike (S1) protein as a potential biomarker for persistent viral reservoirs. At a median time of 8 months after infection, we found pronounced dysregulation in almost all tested soluble factors, including both pro-inflammatory and pro-fibrotic cytokines. These immunological perturbations were remarkably independent of ongoing PASC symptoms per se, but further correlation and regression analyses suggested PASC-specific patterns involving CCL2/MCP-1 and IL-8 that either correlated with sCD162, sCD206/MMR, IFN-α2, IL-17A and IL-33, or IL-18 and IL-23. None of the analyzed factors correlated with the detectability or levels of circulating S1, indicating that this represents an independent subset of patients with PASC. These data confirm prior evidence of immune dysregulation and persistence of viral protein in PASC and illustrate its biological heterogeneity that still awaits correlation with clinically defined PASC subtypes.

Subclinical cognitive impairment in chronic kidney disease is associated with frailty and reduced quality of life.

BACKGROUND: Cognitive impairment (CI) in chronic kidney disease (CKD) is highly prevalent and is associated with multiple limitations to patients as well as a higher mortality, more days of hospitalisation and a lower quality of life. Frailty in CKD is associated with adverse health outcomes and is also highly prevalent. The aim of our study was to determine the prevalence and characteristics of CI and relate the findings to frailty, mobility, muscle strength and health-related quality of life (HRQOL). METHODS: Non-dialysis patients with CKD stages 3-5 were prospectively evaluated for inclusion. Excluded were patients with other cognitive disorders, signs of overt uraemic encephalopathy, severe infection and hyponatraemia. All patients underwent psychometric testing (five different tests): assessments of mobility, strength and frailty and an evaluation of HRQOL. Based on the number of pathological psychometric test results, we established two different definitions of CI: subclinical uraemic encephalopathy 1 (SUE1: one pathological test) and subclinical uraemic encephalopathy 2 (SUE2: two or more pathological test results). RESULTS: Sixty-two patients were included [median age 66 years (interquartile range 57-75), male 55%]. Most patients had CKD stage 3 (48%; stage 4: 32%; stage 5: 19%). CI was highly prevalent (SUE1: 60%; SUE2: 42%) and associated with a higher risk of falls (pathological tandem gait test; SUE1: 50% versus 16%, P = .023; SUE2: 69% versus 15%, P = .001), lower muscle strength (SUE2-pathological: 39% versus 7%, P = .008), frailty (SUE1: 59% versus 28%, P = .038; SUE2: 67% versus 33%, P = .028) and HRQOL. CONCLUSION: CI is highly prevalent in non-dialysis CKD patients. Even mild CI is associated with decreased mobility, muscle strength and HRQOL and increased frailty.

Inflammation in Hypervolemic Hemodialysis Patients: The Roles of RelB and Caspase-4.

Hypervolemia is associated with inflammation in hemodialysis (HD) patients. How hypervolemia triggers inflammation is not entirely known. We initiated a cross-sectional study enrolling 40 hemodialysis patients who were categorized into normovolemic (N; 23) and hypervolemic (H; 17) groups by bioimpedance measurement. A caspase activity assay in combination with a specific caspase-4 inhibitor was used to detect caspase-4 activity in isolated peripheral blood mononuclear cells (PBMCs). Transcription factors RelA (pS529) and RelB (pS552) were analyzed by phospho-flow cytometry. Serum endotoxins were detected by an amebocyte lysate-based assay, and IL-6 (interleukin-6) and TNF-α (Tumor necrosis factor-α) gene expression were detected using the ELISA technique. Hypervolemic patients were older, more frequently had diabetes and showed increased CRP and IL-6 levels. Caspase-4 activity, which is linked to intracellular endotoxin detection, was significantly elevated in H patients. While the frequency of RelA-expressing immune cells and the expression density in these cells did not differ, the monocytic frequency of cells positively stained for RelB (pS552) was significantly decreased in H patients. Increased caspase-4 activity in H patients may indicate a cause of inflammation in H patients. The post-translational modification of RelB (pS552) is linked to downregulation of NF-kB activity and may indicate the resolution of inflammation, which is more distinct in N patients compared to H patients. Therefore, both higher inflammatory loads and lower inflammatory resolution capacities are characteristics of H patients.

Risk of overanticoagulation during acute kidney injury in patients treated with vitamin K antagonists.

BACKGROUND: Vitamin K antagonists (VKAs) are still in use for oral anticoagulation, but not all indications allow their replacement by direct oral anticoagulants. Although formal dose reduction is not required in patients with impaired kidney function, case reports indicate that acute kidney injury (AKI) might be associated with derailment of VKA therapy. METHODS: The study retrospectively collected patients from a tertiary nephrology care centre who experienced AKI while being treated with VKA. In these individuals, the international normalized ratio (INR) as a measure of anticoagulant effect during renal failure was compared with a reference time point with stable kidney function. RESULTS: A total of 100 patients with AKI and ongoing VKA therapy met the inclusion criteria. The majority (76%) of patients had AKI with CKD. Volume depletion (n = 43), septic renal failure (n = 22), decompensated heart failure (n = 18) and toxic renal damage (n = 11) were the most important causes of AKI. The average INR values at the time of AKI were higher than at the reference time point [median 3.17 (range 1.10-13.0) versus 2.24 (1.07-5.17); P < 0.0001]. Fifty-four patients had INR values above the recommended therapeutic range for their indication at the time point of AKI. Bleeding complications occurred in 24 patients during AKI and the VKA dose had to be reduced in 55. Women, patients with low body mass index and patients with diabetes were predisposed to overanticoagulation during AKI. CONCLUSIONS: The effect of AKI on anticoagulation by VKA has not been systematically described. This risk should be considered in patients at high risk for AKI.

Efficacy and safety of systemic, high-dose glucocorticoid therapy for idiopathic sudden sensorineural hearing loss : Study protocol for a three-armed, randomized, triple-blind, multicenter trial (HODOKORT).

BACKGROUND: Systemic glucocorticosteroids ("steroids") are widely used worldwide as a standard of care for primary therapy of idiopathic sudden sensorineural hearing loss (ISSHL). The German ISSHL guideline recommends high-dose steroids without evidence from randomized controlled trials (RCTs) and refers solely to retrospective cohort studies. This RCT aims to assess the efficacy (improvement in hearing) and safety (especially systemic side effects) of high-dose steroids versus standard of care (standard dose systemic steroids) for the treatment of unilateral ISSHL, when given as a primary therapy. METHODS: The study is designed as a multicenter (approximately 40 centers), randomized, triple-blind, three-armed, parallel group, clinical trial with 312 adult patients. The interventions consist of 5 days of 250 mg/day intravenous prednisolone (intervention 1) + oral placebo, or 5 days of 40 mg/day oral dexamethasone (intervention 2) + intravenous placebo. The control intervention consists of 60 mg oral prednisolone for 5 days followed by five tapering doses + intravenous placebo. The primary efficacy endpoint is the change in hearing threshold in the three most affected contiguous frequencies between 0.25 and 8 kHz 1 month after ISSHL. Secondary endpoints include further measures of hearing improvement including speech audiometry, tinnitus, quality of life, blood pressure, and altered glucose tolerance. DISCUSSION: There is an unmet medical need for an effective medical therapy of ISSHL. Although sensorineural hearing impairment can be partially compensated by hearing aids or cochlear implants (CI), generic hearing is better than using hearing aids or CIs. Since adverse effects of a short course of high-dose systemic corticosteroids have not been documented with good evidence, the trial will improve knowledge on possible side effects in the different treatment arms with a focus on hyperglycemia and hypertension. TRIAL REGISTRATION: EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) Nr. 2015-002602-36; Sponsor code: KKSH-127.

Minimally invasive robotic versus conventional open living donor kidney transplantation.

PURPOSE: First robotic-assisted kidney transplants (RAKT) were performed in Germany in 2016. To introduce and establish this method as a routine procedure for patients in transplantation medicine, our 2-year experiences are presented. METHODS: Non-randomized open-label cohort study to compare functional and operative results as well as complication rates between RAKT and standard open transplantation. Collected data are part of ERUS RAKT Group Registry. RESULTS: Since initiation of the RAKT program 21/27 transplantations after living kidney donations have been performed as RAKT. This represents the largest series of RAKT in Germany. Patient survival, transplant survival, and primary function rate are 100% (mean follow-up 12.9 ± 8.6 month). Mean incision to closure time was 306.1 ± 45.5, mean handling time 70.8 ± 13.1 min compared to 212.1 ± 40.6 min and 51.7 ± 9.9 min, respectively, in the standard group. Despite extended operating times using the robotic approach, comparable complication rates and graft function with significant reduction in median length of hospital stay (14 vs. 20 days) were observed. CONCLUSIONS: RAKT extends the options for recipients towards minimally invasive techniques. Compared to classic open surgery, RAKT appears to be safe in selected patients without influencing graft outcome or higher complication rates. However, RAKT till today is not suitable for all patients but seems to be one of the upcoming new standard techniques in kidney transplantation.

Diabetes prevalence and outcomes in hospitalized cardiorenal-syndrome patients with and without hyponatremia.

BACKGROUND: Hyponatremia is known to be associated with a worse patient outcome in heart failure. In cardiorenal syndrome (CRS), the prognostic role of concomitant hyponatremia is unclear. We sought to evaluate potential risk factors for hyponatremia in patients with CRS presenting with or without hyponatremia on hospital admission. METHODS: In a retrospective study, we investigated 262 CRS patients without sepsis admitted to the University Hospital Halle over a course of 4 years. CRS diagnosis was derived from an electronic search of concomitant diagnoses of acute or chronic (NYHA 3-4) heart failure and acute kidney injury (AKIN 1-3) or chronic kidney disease (KDIGO G3-G5nonD). A verification of CRS diagnosis was done based on patient records. Depending on the presence (Na < 135 mmol/L) or absence (Na ≥ 135 mmol/L) of hyponatremia on admission, the CRS patients were analyzed for comorbidities such as diabetes, presence of hypovolemia on admission, need for renal replacement therapy and prognostic factors such as in-hospital and one-year mortality. RESULTS: Two hundred sixty-two CRS patients were included in this study, thereof, 90 CRS patients (34.4%) with hyponatremia (Na < 135 mmol/L). The diabetes prevalence among CRS patients was high (> 65%) and not related to the serum sodium concentration on admission. In comparison to non-hyponatremic CRS patients, the hyponatremic patients had a lower serum osmolality, hypovolemia was more prevalent (41.1% versus 16.3%, p < 0.001). As possible causes of hypovolemia, diarrhea, a higher number of diuretic drug classes and higher diuretic dosages were found. Hyponatremic and non-hyponatremic CRS patients had a comparable need for renal-replacement therapy (36.7% versus 31.4%) during the hospital stay. However, after discharge, relatively more hyponatremic CRS patients on renal replacement therapy switched to a non-dialysis therapy regimen (50.0% versus 22.2%). Hyponatremic CRS patients showed a trend for a higher in-hospital mortality (15.6% versus 7.6%, p = 0.054), but no difference in the one-year mortality (43.3% versus 40.1%, p = 0.692). CONCLUSIONS: All CRS patients showed a high prevalence of diabetes mellitus and a high one-year mortality. In comparison to non-hyponatremic CRS patients, hyponatremic ones were more likely to have hypovolemia, and had a higher likelihood for temporary renal replacement therapy.

Peritoneal dialysis is associated with better cognitive function than hemodialysis over a one-year course.

Impaired cognitive functioning in patients with end-stage renal disease may reduce their capabilities to adhere to complex medical or dietary regimens and to fully participate in medical decisions. With decreasing renal function, cognitive abilities are likely to decline, with cognitive dysfunction improving after initiation of dialysis and even being generally reversible after successful renal transplantation. However, little is known about cognitive changes particularly regarding different treatment modalities. To gain further insight into this, we focused on a one-year course of cognitive functions, comparing peritoneal to hemodialysis patients. Within the CORETH-project, two validated neurocognitive tests, assessing executive functioning (Trail Making Test-B) and attention (d2-Revision-Test) and the self-reported Kidney Disease Quality of Life Short Form Cognitive Function-subscale, were administered to 271 patients at baseline and after one year. Subsamples were matched by propensity score, adjusting for age, comorbidity, education, and employment status for 96 hemodialysis and 101 peritoneal dialysis patients. The effects of time and treatment modality were investigated, controlling for well-known confounders. Both tests revealed improvement over one year. Peritoneal dialysis was associated with better outcomes than hemodialysis at baseline and follow-up, but comparability between groups may be limited. The opposite pattern applied to self-reporting. Hemodialysis patients had to be excluded from cognitive testing more often than peritoneal dialysis patients. As such, the number of exclusions may have biased the findings, limiting generalizability. Thus, our findings suggest an improvement of cognitive functioning and support previous indications for peritoneal dialysis being associated with better cognitive functions during a one-year course than hemodialysis.

Social relationships and their impact on health-related outcomes in peritoneal versus haemodialysis patients: a prospective cohort study.

Background: Social relationships are important determinants of health-related outcomes for patients with chronic conditions. However, the effects of social networks and social support on health outcomes of dialysis patients in different treatment modalities have been under studied. Methods: We surveyed peritoneal dialysis (PD) and haemodialysis (HD) patients in the Choice of Renal Replacement Therapy project about their social relationships and health-care outcomes at baseline and 1-year follow-up. Two propensity score-matched groups (n = 353; HD = 200, PD = 153) with similar age, comorbidity level, education and employment status were compared. We used an ego-centred Network Generator to assess quantitative and qualitative aspects of social networks and the Berlin Social Support Scales to evaluate dimensions of social support, and analysed the effects of the social variables on anxiety, depression, autonomy preferences, and physical and psychological quality of life. Results: Over time, the non-family networks (e.g. friends) of both groups decreased (P = 0.04) and the absolute number of types of relationships increased (P = 0.01). The family-network size, quality of relationships and social support remained stable. Larger social networks were associated with higher participation-seeking preferences (B = 1.39, P = 0.002) and lower anxiety (B = -0.11, P = 0.03). Closer and more satisfying relationships were associated with better psychological well-being (B = 3.41, P = 0.003). PD patients had larger networks, more types of relationships and received more social support than HD patients (P ≤ 0.05). Conclusions: These differences may reflect the degree of autonomy and self-care associated with the different treatment modalities. In practice, our findings suggest that the early identification and inclusion of persons providing social support for patients may have a positive effect on different aspects of their care and quality of life.

Modulation of leucocytic angiotensin-converting enzymes expression in patients maintained on high-permeable haemodialysis.

BACKGROUND: High mortality of haemodialysis patients is associated with systemic chronic inflammation and overactivation of the renin-angiotensin system (RAS). Insufficient elimination of pro-inflammatory immune mediators, especially in the molecular weight range of 15-45 kDa, may be one of the reasons for this. Employment of haemodialysis membranes with increased permeability was shown to ameliorate the inflammatory response and might modulate the effects of local RAS. In this study, we tested the impact of high cut-off (HCO), medium cut-off (MCO) and high-flux (HF) dialysis on leucocytic transcripts of angiotensin-converting enzymes (ACE and ACE2). Additionally, the impact of HCO, MCO and HF sera and dialysates on local ACEs and inflammation markers was tested in THP-1 monocytes. METHODS: Patients' leucocytes were obtained from our recent clinical studies comparing HCO and MCO dialysers with HF. The cells were subjected to quantitaive polymerase chain reaction (qPCR) analyses with TaqMan probes specific for ACE, ACE2 and angiotensin II (AngII) and Ang1-7 receptors. Sera and dialysates from the clinical trials as well as samples from in vitro dialysis were tested on THP-1 monocytic cells. The cells were subjected to qPCR analyses with TaqMan probes specific for ACE, ACE2, interleukin-6 and tumour necrosis factor α and immunocytochemistry with ACE and ACE2 antibodies. RESULTS: Leucocytes obtained from patients treated with HCO or MCO demonstrated decreased transcript expression of ACE, while ACE2 was significantly upregulated as compared with HF. Receptors for AngII and Ang1-7 remained unchanged. THP-1 monocytes preconditioned with HCO and MCO patients' or in vitro dialysis sera reflected the same expressional regulation of ACE and ACE2 as those observed in HCO and MCO leucocytes. As a complementary finding, treatment with HCO and MCO in vitro dialysates induced a pro-inflammatory response of the cells as demonstrated by elevated messenger RNA expression of tumour necrosis factor α and interleukin-6, as well as upregulation of ACE and decreased levels of ACE2. CONCLUSIONS: Taken together, these data demonstrate that employment of membranes with high permeability eliminates a spectrum of mediators from circulation that affect the RAS components in leucocytes, especially ACE/ACE2.

Tumour necrosis factor-alpha in uraemic serum promotes osteoblastic transition and calcification of vascular smooth muscle cells via extracellular signal-regulated kinases and activator protein 1/c-FOS-mediated induction of interleukin 6 expression.

Background: Vascular calcification is enhanced in uraemic chronic haemodialysis patients, likely due to the accumulation of midsize uraemic toxins, such as interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Here we have assessed the impact of uraemia on vascular smooth muscle cell (VSMC) calcification and examined the role of IL-6 and TNF-α as possible mediators and, most importantly, its underlying signalling pathway in VSMCs. Methods: VSMCs were incubated with samples of uraemic serum obtained from patients treated with haemodialysis for renal failure in the Permeability Enhancement to Reduce Chronic Inflammation-I clinical trial. The VSMCs were assessed for IL-6 gene regulation and promoter activation in response to uraemic serum and TNF-α with reporter assays and electrophoretic mobility shift assay and for osteoblastic transition, cellular calcification and cell viability upon osteogenic differentiation. Results: Uraemic serum contained higher levels of TNF-α and IL-6 compared with serum from healthy individuals. Exposure of VSMCs to uraemic serum or recombinant TNF-α lead to a strong upregulation of IL-6 mRNA expression and protein secretion, which was mediated by activator protein 1 (AP-1)/c-FOS-pathway signalling. Uraemic serum induced osteoblastic transition and calcification of VSMCs could be strongly attenuated by blocking TNF-α, IL-6 or AP-1/c-FOS signalling, which was accompanied by improved cell viability. Conclusion: These results demonstrate that uraemic serum contains higher levels of uraemic toxins TNF-α and IL-6 and that uraemia promotes vascular calcification through a signalling pathway involving TNF-α, IL-6 and the AP-1/c-FOS cytokine-signalling axis. Thus treatment modalities aiming to reduce systemic TNF-α and IL-6 levels in chronic haemodialysis patients should be evaluated in future clinical trials.

Hyperglycemia-related central pontine demyelinization after a binge-eating attack in a patient with type-2 diabetes: a case report.

BACKGROUND: Here, we report a case of central pontine demyelinization in a type-2 diabetes patient with hyperglycemia after a binge-eating attack in the absence of a relevant hyponatremia. CASE PRESENTATION: A 55-year-old, male type-2 diabetic patient with liver cirrhosis stage Child-Pugh B was admitted due to dysmetria of his right arm, gait disturbance, dizziness, vertigo, and polyuria, polydipsia after a binge-eating attack of sweets (a whole fruit cake and 2 Liters of soft drinks). A recently initiated insulin therapy had been discontinued for 8 months. A serum glucose measurement obtained 5 days prior to hospitalisation was 38.5 mmol/l (694 mg/dl). The patient graved for sweets since stopping alcohol consumption 8 months earlier. On admission, venous-blood glucose was 29.1 mmol/l (523.8 mg/dl), glycated hemoglobin was 168.0 mmol/mol or 17.6%. No supplementation of sodium chloride was reported. Laboratory exams revealed an elevated serum ammonia level (127.1 µmol/l), rendering a hepatic encephalopathy very likely. After initiation of insulin therapy, capillary glucose normalized, and serum sodium rose from 133 on admission to 144 mmol/l during the hospital stay. In retrospect, the mild hyponatremia on admission was classified as pseudohyponatremia due to hyperglycemia. The patient had an insulin resistance (HOMA-IR 7.8 (normal range < 2.5)). A T2-weighted magnetic resonance imaging (MRI) of the head and a cranial computed tomography scan were obtained demonstrating a symmetric central pontine demyelinization. After 26 days in hospital, the patient was discharged with an inkretin-mimetic therapy (dulaglutide SC, 1.5 mg/week) and an intensified conventional insulin therapy (insulin aspart: 14 units/d in euglycemia, insulin glargin 20 units/d). CONCLUSIONS: Central pontine and/or cerebellar myelinolysis can be caused by sudden, severe, and sustained hyperglycemia, especially when another risk factor (in this case, liver cirrhosis) is present. Functional neurological deficits in the context of hyperglycemia should prompt for the consideration of this differential diagnosis in all diabetes patients.

Influence of SPRINT Study Type Automated Office Blood Pressure Measurements on Hypertension Diagnosis in Kidney Transplant Patients.

BACKGROUND/AIMS: We compare conventional office blood pressure measurements with automated SPRINT-study type readings in kidney transplant recipients in order to determine the impact of the white coat effect in a prospective observational study. METHODS: Adult patients with a functional renal transplant not dependent on dialysis were eligible. Readings were taken in the office in presence of the physician with an oscillometric method. Afterwards, readings were repeated with the patients resting alone in a quiet examination room with an automated blood pressure monitor. After 5 minutes of rest, 3 readings were taken at 1 minute intervals, with an average of these 3 readings calculated by the monitor. RESULTS: 120 patients with an average age of 58.5±12.2 years were included. Mean time since transplantation was 7.95±6.48 years. Mean eGFR (CKD-EPI) was 48.5±18.3 ml/min. SPRINT-study type readings were significantly lower than office readings (139.01±18.45 vs. 149.00±21.02 mmHg systolic, p<0.001; 80.88±11.63 mmHg vs. 84.35±12.41 mmHg diastolic, p <0.001). Correlation analysis for many potentially influencing factors (diabetes mellitus, transplant vintage, proteinuria, age, immunosuppression, donor type) was not significant but obese women were significantly more prone to white coat hypertension. CONCLUSION: Automated office blood pressure measurements should be considered the method of choice in kidney transplant recipients.

Expanded Haemodialysis Therapy of Chronic Haemodialysis Patients Prevents Calcification and Apoptosis of Vascular Smooth Muscle Cells in vitro.

BACKGROUND: Vascular calcification is a common phenomenon in patients with chronic kidney disease and strongly associated with increased cardiovascular mortality. Vascular calcification is an active process mediated in part by inflammatory processes in vascular smooth muscle cells (VSMC). These could be modified by the insufficient removal of proinflammatory cytokines through conventional high-flux (HF) membranes. Recent trials demonstrated a reduction of inflammation in VSMC by use of dialysis membranes with a higher and steeper cut-off. These membranes caused significant albumin loss. Therefore, the effect of high retention Onset (HRO) dialysis membranes on vascular calcification and its implications in vitro was evaluated. METHODS: In the PERCI II trial, 48 chronic dialysis patients were dialyzed using HF and HRO dialyzers and serum samples were collected. Calcifying VSMC were incubated with the serum samples. Calcification was determined using alizarin red staining (AZR) and determination of alkaline phosphatase (ALP) activity. Furthermore, apoptosis was evaluated, and release of matrix Gla protein (MGP), osteopontin (OPN) and growth differentiation factor 15 (GDF-15) were measured in cell supernatants. RESULTS: Vascular calcification in vitro was significantly reduced by 24% (ALP) and 36% (AZR) after 4 weeks of HRO dialysis and by 33% (ALP) and 48% (AZR) after 12 weeks of dialysis using HRO membranes compared to HF dialysis. Apoptosis was significantly lower in the HRO group. The concentrations of MGP and OPN were significantly elevated after incubation with HF serum compared to HRO serum and healthy controls. Similarly, GDF-15 release in the supernatant was elevated after incubation with HF serum, an effect significantly ameliorated after treatment with HRO medium. CONCLUSIONS: Expanded haemodialysis therapy reduces the pro-calcific potential of serum from dialysis patients in vitro. With a markedly reduced albumin filtration compared to high cut-off dialysis, use of the HRO dialyzers may possibly provide a treatment option for chronic dialysis patients to reduce the progression of vascular calcification.

The Choice of Renal Replacement Therapy (CORETH) project: dialysis patients' psychosocial characteristics and treatment satisfaction.

Background: Until today, research has underestimated the role of psychosocial conditions as contributing factors to dialysis modality choice. The novelty within the Choice of Renal Replacement Therapy (CORETH) project (German Clinical Trials Register #DRKS00006350) is its focus on the multivariate associations between these aspects and their consecutive significance regarding treatment satisfaction (TS) in peritoneal dialysis (PD) versus haemodialysis (HD) patients. In this article, we present the baseline results of a multicentre study, which is supported by a grant from the German Ministry for Education and Research. Methods: Six to 24 months after initiation of dialysis, 780 patients from 55 dialysis centres all over Germany were surveyed. The questionnaire addressed psychosocial, physical, socio-demographic and shared decision-making (SDM) aspects. Furthermore, cognitive functioning was tested. After indexing the measures, two propensity score-matched groups (n = 482) were compared in a first step, after having chosen PD or HD. In a second step, a moderated multiple regression (n = 445) was conducted to initially investigate the multivariate impact of patient characteristics on TS. Results: In comparison with HD patients, PD patients were more satisfied with their treatment (P < 0.001), had a more autonomy-seeking personality (P = 0.04), had better cognitive functioning (P = 0.001), indicated more satisfying SDM (P < 0.001) and had a larger living space (P < 0.001). All patients were more satisfied when they had a good psychological state and received SDM. Especially in HD patients, TS was higher when the patient had a less autonomous personality, lower cognitive functioning, more social support, a poorer physical state and poorer socio-demographic conditions (R2 = 0.26). Conclusions: Psychosocial characteristics play a major role in TS in dialysis patients. Within a multivariate approach, these factors are even more important than physical or environment-related factors. In practice, focusing on SDM and screening patient characteristics at an early stage can foster patients' TS. Changes will be examined in a 1-year follow-up.

Monocytic angiotensin-converting enzyme 2 relates to atherosclerosis in patients with chronic kidney disease.

Background: Increased levels of monocytic angiotensin-converting enzyme (ACE) found in haemodialysis (HD) patients may directly participate in the pathogenesis of atherosclerosis. We demonstrated recently that uremia triggers the development of highly pro-atherogenic monocytes via an angiotensin II (AngII)­dependent mechanism. Opposing actions of the AngII-degrading ACE2 remain largely unknown. We examined the status of both ACEs and related receptors in circulating leukocytes of HD, not-dialyzed CKD and healthy individuals. Furthermore, we tested the possible impact of monocytic ACEs on atherogenesis and behaviour of the cells under conditions mimicking chronic renal failure. Methods: Expression of ACE, ACE2, AT1R, AT2R and MASR was investigated on circulating leukocytes from 71 HD (62 ± 14 years), 24 CKD stage 3­5 (74 ± 10 years) patients and 37 healthy control subjects (53 ± 6 years) and isolated healthy monocytes treated with normal and uremic serum. Analyses of ACE, ACE2, ICAM-1, VCAM-1, MCSF and endothelial adhesion were tested on ACE-overexpressing THP-1 monocytes treated with captopril or losartan. ACE2-overexpressing monocytes were subjected to transmigration and adhesion assays and investigated for MCP-1, ICAM-1, VCAM-1, MCSF, AT1R and AT2R expression. Results: The ACE mRNA level was significantly increased in HD and CKD stage 3­5 leukocytes. Correspondingly, ACE2 was downregulated and AngII as well as MAS receptor expression was upregulated in these cells. Healthy monocytes preconditioned with uremic serum reflected the same expressional regulation of ACE/ACE2, MAS and AngII receptors as those observed in HD and CKD stage 3­5 leukocytes. Overexpression of monocytic ACE dramatically decreased levels of ACE2 and induced a pro-atherogenic phenotype, partly reversed by AngII-modifying treatments, leading to an increase in ACE2. Overexpression of ACE2 in monocytes led to reduced endothelial adhesion, transmigration and downregulation of adhesion-related molecules. Conclusions: HD and not-dialyzed CKD stage 3­5 patients show enhanced ACE and decreased ACE2 expression on monocytes. This constellation renders the cells endothelial adhesive and likely supports the development of atherosclerosis.

Vitamin D3 supplementation does not modify cardiovascular risk profile of adults with inadequate vitamin D status.

PURPOSE: The Nutrition Societies in Germany, Austria, and Switzerland recommend a daily intake of 20 µg vitamin D3 for adults when endogenous synthesis is absent. The current study aimed to elucidate whether this vitamin D3 dose impacts cardiovascular risk markers of adults during the winter months. METHODS: The study was conducted in Halle (Saale), Germany (51o northern latitude) as a placebo-controlled, double-blinded, randomised trial (from January to April). A total of 105 apparently healthy subjects (male and female, 20-71 years old) were included. Subjects were randomly allocated to two groups. One group received a daily 20-µg vitamin D3 dose (n = 54), and the other group received a placebo (n = 51) for 12 weeks. Outcome measures included blood pressure, heart rate, concentrations of renin, aldosterone, serum lipids and vascular calcification markers, and haematologic variables such as pro-inflammatory monocytes. RESULTS: Blood pressure and systemic cardiovascular risk markers remained unchanged by vitamin D3 supplementation, although serum 25-hydroxyvitamin D3 increased from 38 ± 14 to 73 ± 16 nmol/L at week 12. The placebo and vitamin D groups did not differ in their final cardiovascular risk profile. CONCLUSION: Daily supplementation of 20 µg vitamin D3 during winter is unlikely to change cardiovascular risk profile.

Serum klotho levels in acute kidney injury
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AIMS: Klotho is a co-receptor for FGF-23 and key regulator of phosphate excretion. Soluble klotho modulates ion-channel expression and growth factor sensitivity. In chronic kidney disease (CKD), impaired klotho expression has been demonstrated. Likewise, reduced soluble klotho levels in serum and urine have been established in rodents in experimental acute kidney injury (AKI). In contrast, no data on soluble serum klotho levels in human AKI has been presented to date. MATERIAL AND METHODS: A cross-sectional case-control study of klotho serum levels in 30 subjects with AKI and 126 control subjects with kidney functions ranging from normal to end-stage renal disease (ESRD). RESULTS: Klotho levels were higher in AKI patients (567.6 ± 294.4 pg/mL, vs. 403.5 ± 152.5 pg/mL, p < 0.01) and females (463.0 ± 202.6 pg/mL vs. 387.6 ± 132.0 pg/mL, p < 0.01) and lower in ESRD patients than in healthy adults and patients with moderate CKD (368.3 ± 99.0 pg/mL vs. 468.1 ± 205.8, p < 0.01 and 368.3 ± 99.0 pg/mL vs. 498.7 ± 221.9, p < 0.01). There was a correlation with estimated glomerular filtration rate (eGFR) in CKD (p < 0.0001, r = 0.34). CONCLUSIONS: In AKI, serum klotho levels are not associated with kidney function whereas in CKD, impaired klotho levels may be observed and are significantly correlated to eGFR.
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