Transient Receptor Potential Vanilloid 4 and Serum Glucocorticoid-regulated Kinase 1 Are Critical Mediators of Lung Injury in Overventilated Mice In Vivo.

BACKGROUND: Mechanical ventilation can cause lung endothelial barrier failure and inflammation cumulating in ventilator-induced lung injury. Yet, underlying mechanotransduction mechanisms remain unclear. Here, the authors tested the hypothesis that activation of the mechanosensitive Ca channel transient receptor potential vanilloid (TRPV4) by serum glucocorticoid-regulated kinase (SGK) 1 may drive the development of ventilator-induced lung injury. METHODS: Mice (total n = 54) were ventilated for 2 h with low (7 ml/kg) or high (20 ml/kg) tidal volumes and assessed for signs of ventilator-induced lung injury. Isolated-perfused lungs were inflated with continuous positive airway pressures of 5 or 15 cm H2O (n = 7 each), and endothelial calcium concentration was quantified by real-time imaging. RESULTS: Genetic deficiency or pharmacologic inhibition of TRPV4 or SGK1 protected mice from overventilation-induced vascular leakage (reduction in alveolar protein concentration from 0.84 ± 0.18 [mean ± SD] to 0.46 ± 0.16 mg/ml by TRPV4 antagonization), reduced lung inflammation (macrophage inflammatory protein 2 levels of 193 ± 163 in Trpv4 vs. 544 ± 358 pmol/ml in wild-type mice), and attenuated endothelial calcium responses to lung overdistension. Functional coupling of TRPV4 and SGK1 in lung endothelial mechanotransduction was confirmed by proximity ligation assay demonstrating enhanced TRPV4 phosphorylation at serine 824 at 18% as compared to 5% cyclic stretch, which was prevented by SGK1 inhibition. CONCLUSIONS: Lung overventilation promotes endothelial calcium influx and barrier failure through a mechanism that involves activation of TRPV4, presumably due to phosphorylation at its serine 824 residue by SGK1. TRPV4 and SGK1 may present promising new targets for prevention or treatment of ventilator-induced lung injury.

Oscillometric assessment of arterial stiffness in everyday clinical practice.

Measurement of carotid-femoral pulse wave velocity (cfPWV) is considered the gold standard for assessing arterial stiffness. Although widely used in clinical and observational studies, the detection of cfPWV has not yet been applied in everyday clinical practice due to technical and procedural difficulties. We, therefore, evaluated the applicability of oscillometric cfPWV assessment for everyday clinical practice. Eighty-nine patients were prospectively included in the study. Oscillometric calculations of cfPWV were performed with Tel-O-GRAPH and tonometric calculations with Sphygmocor. The accuracy, reproducibility, reliability and robustness of Tel-O-GRAPH calculations in different clinical situations were evalu??ated. The mean study population age was 48.8±19.1 years. More than half (59.6%) of the patients were male, and 15.1% were smokers. The mean difference of PWV between devices was 0.49±1.26 m s-1 (P<0.0001), and the Pearson correlation index was 0.86 (P<0.0001). The coefficient of variation and intraclass correlation coefficients between three single measured PWV values with the Tel-O-GRAPH and Sphygmocor were 2.38±6.13% vs. 6.3±4.33% (P<0.05) and 0.99; 0.99; and 0.99 vs. 0.78; 0.84; and 0.71, respectively. For Tel-O-GRAPH, there was no statistically significant difference between PWV in seated vs. supine positions or by experienced or inexperienced users. High reproducibility and reliability of the calculated single PWV values with Tel-O-GRAPH and considerable performance accuracy compared with Sphygmocor were observed. The reported evidence suggests that oscillometry might evolve as a favored method for the assessment of the PWV in everyday clinical practice and in clinical studies due to its ease of use, accuracy and robustness.

Cystatin C standardization decreases assay variation and improves assessment of glomerular filtration rate.

BACKGROUND: Cystatin C is increasingly used in glomerular filtration rate (GFR) estimation equations. The dependence of cystatin C results upon the analytical method has been a major source of controversy. METHODS: Cystatin C was measured with non-standardized turbidimetric Roche Generation 1 and standardized nephelometric Siemens assays in 3666 and additionally with standardized Roche Generation 2 and Siemens in 567 blood samples of the Berlin Initiative Study. Cystatin C-based GFR was assessed with CKD-EPIcys (Chronic Kidney Disease Epidemiology) and CAPA (Caucasian, Asian, Pediatric, Adult) equations and the impact of the assays on GFR estimation was determined. Equation performance compared to measured GFR was evaluated. RESULTS: Concordance of Roche Gen2 and Siemens was high with median difference of 0.003 ± 0.13 mg/L (limits of agreement: -0.12 to 0.12) and Passing Bablok correlation was essentially perfect. Roche Gen1 assay showed worse concordance with Siemens: median difference was 0.08 ± 0.13 mg/L (limits of agreement: -0.18 to 0.34) and correlation was inferior. Mean difference (± SD) of estimated GFRCKD-EPIcys was 0 ± 4 mL/min/1.73 m(2) for Gen2 and Siemens compared to -5 ± 8 with Gen1. Performance of GFR estimating equations was not influenced by the choice of Siemens or Gen2 assays. CONCLUSIONS: Standardization of Roche Gen2 assay improved accuracy of cystatin C measurement compared to Siemens. It suggests only negligible method bias and results in equal performance of both assays when estimating GFR indicating that successful calibration has led to major progress in cystatin C analysis.

High-urgency kidney transplantation in the Eurotransplant Kidney Allocation System: success or waste of organs? The Eurotransplant 15-year all-centre survey.

BACKGROUND: In the Eurotransplant Kidney Allocation System (ETKAS), transplant candidates can be considered for high-urgency (HU) status in case of life-threatening inability to undergo renal replacement therapy. Data on the outcomes of HU transplantation are sparse and the benefit is controversial. METHODS: We systematically analysed data from 898 ET HU kidney transplant recipients from 61 transplant centres between 1996 and 2010 and investigated the 5-year patient and graft outcomes and differences between relevant subgroups. RESULTS: Kidney recipients with an HU status were younger (median 43 versus 55 years) and spent less time on the waiting list compared with non-HU recipients (34 versus 54 months). They received grafts with significantly more mismatches (mean 3.79 versus 2.42; P < 0.001) and the percentage of retransplantations was remarkably higher (37.5 versus 16.7%). Patient survival (P = 0.0053) and death with a functioning graft (DwFG; P < 0.0001) after HU transplantation were significantly worse than in non-HU recipients, whereas graft outcome was comparable (P = 0.094). Analysis according to the different HU indications revealed that recipients listed HU because of an imminent lack of access for dialysis had a significantly worse patient survival (P = 0.0053) and DwFG (P = 0.0462) compared with recipients with psychological problems and suicidality because of dialysis. In addition, retransplantation had a negative impact on patient and graft outcome. CONCLUSIONS: Facing organ shortages, increasing wait times and considerable mortality on dialysis, we question the current policy of HU allocation and propose more restrictive criteria with regard to individuals with vascular complications or repeated retransplantations in order to support patients on the non-HU waiting list with a much better long-term prognosis.

Arteriosclerosis and vascular calcification: causes, clinical assessment and therapy.

BACKGROUND: Arteriosclerosis is a pathological, structural (media vascular calcification) and physiological (modified vascular smooth vessel cells; increased arterial stiffness) alteration of the vessel wall. Through improved assessment methods (functional and imaging), it has become a well-known phenomenon in recent decades. However, its clinical importance was underestimated until recently. MATERIALS AND METHODS: Currently available English-speaking data about conditions/diseases associated with arteriosclerosis, its clinical sequels, available diagnostic procedures and therapeutic modalities were reviewed and summarized. RESULTS: In recent decades, emerging data have brought about a better understanding of causes and consequences of arteriosclerosis and highlight its growing clinical impact. CONCLUSION: Although arteriosclerosis showed an independent clinical impact on cardiovascular morbidity and mortality, especially in patients with chronic kidney disease/end-stage renal disease (CKD/ESRD) and diabetes mellitus, convincing clinical therapy concepts are not available until now. The establishment of novel therapeutic strategies derived from basic research is strongly needed.

An efficient approach for glomerular filtration rate assessment in older adults.

AIMS: Assessment of glomerular filtration rate (GFR) is crucial because the GFR value defines the stage of chronic kidney disease and determines the adjustment of drug dosage. The aim was to investigate a new method for the accurate determination of GFR in older adults based on the combination of an exogenous filtration marker, iohexol, and an endogenous marker, serum creatinine or cystatin C. METHODS: We combined variables for the estimation of GFR with a reduced set of measurements of the marker iohexol. In a population-based sample of 570 subjects (≥70 years old) from the Berlin Initiative Study (BIS), we investigated the following: (i) the BIS1 and BIS2 equations based on age, gender and serum creatinine with or without serum cystatin C; (ii) equations based on one or two iohexol measurements; and (iii) equations based on the combination of variables from BIS1 or BIS2 with iohexol measurements. The reference standard was based on eight iohexol measurements. The cut-off value of 60 ml min(-1) (1.73 m)(-2) was chosen to assess accuracy. Equations were constructed using a learning sample (n = 285) and an independent validation sample (n = 285). RESULTS: Misclassification rates were 17.2% (BIS1), 11.6% (BIS2), 14.7% [iohexol measurement at 240 min (iohexol240 )], 7.0% (iohexol240 combined with variables included in BIS1) and 6.7% (iohexol240 combined with variables included in BIS2). Misclassification rates did not decrease significantly after inclusion of two or three iohexol measurements. CONCLUSIONS: Combined strategies for the determination of GFR lead to a relevant increase of diagnostic validity.

Diabetes mellitus type 2 in urban Ghana: characteristics and associated factors.

BACKGROUND: Sub-Saharan Africa faces a rapid spread of diabetes mellitus type 2 (DM2) but its potentially specific characteristics are inadequately defined. In this hospital-based study in Kumasi, Ghana, we aimed at characterizing clinical, anthropometric, socio-economic, nutritional and behavioural parameters of DM2 patients and at identifying associated factors. METHODS: Between August 2007 and June 2008, 1466 individuals were recruited from diabetes and hypertension clinics, outpatients, community, and hospital staff. Fasting plasma glucose (FPG), serum lipids and urinary albumin were measured. Physical examination, anthropometry, and interviews on medical history, socio-economic status (SES), physical activity and nutritional behaviour were performed. RESULTS: The majority of the 675 DM2 patients (mean FPG, 8.31 mmol/L) was female (75%) and aged 40-60 years (mean, 55 years). DM2 was known in 97% of patients, almost all were on medication. Many had hypertension (63%) and microalbuminuria (43%); diabetic complications occurred in 20%. Overweight (body mass index > 25 kg/m2), increased body fat (> 20% (male), > 33% (female)), and central adiposity (waist-to-hip ratio > 0.90 (male), > 0.85 (female)) were frequent occurring in 53%, 56%, and 75%, respectively. Triglycerides were increased (≥ 1.695 mmol/L) in 31% and cholesterol (≥ 5.17 mmol/L) in 65%. Illiteracy (46%) was high and SES indicators generally low. Factors independently associated with DM2 included a diabetes family history (adjusted odds ratio (aOR), 3.8; 95% confidence interval (95%CI), 2.6-5.5), abdominal adiposity (aOR, 2.6; 95%CI, 1.8-3.9), increased triglycerides (aOR, 1.8; 95%CI, 1.1-3.0), and also several indicators of low SES. CONCLUSIONS: In this study from urban Ghana, DM2 affects predominantly obese patients of rather low socio-economic status and frequently is accompanied by hypertension and hyperlipidaemia. Prevention and management need to account for a specific risk profile in this population.