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1.  Prognostic Value and Link to Atrial Fibrillation of Soluble Klotho and FGF23 in Hemodialysis Patients 
PLoS ONE  2014;9(7):e100688.
Deranged calcium-phosphate metabolism contributes to the burden of morbidity and mortality in dialysis patients. This study aimed to assess the association of the phosphaturic hormone fibroblast growth factor 23 (FGF23) and soluble Klotho with all-cause mortality. We measured soluble Klotho and FGF23 levels at enrolment and two weeks later in 239 prevalent hemodialysis patients. The primary hypothesis was that low Klotho and high FGF23 are associated with increased mortality. The association between Klotho and atrial fibrillation (AF) at baseline was explored as secondary outcome. AF was defined as presence of paroxysmal, persistent or permanent AF. During a median follow-up of 924 days, 59 (25%) patients died from any cause. Lower Klotho levels were not associated with mortality in a multivariable adjusted analysis when examined either on a continuous scale (HR 1.25 per SD increase, 95% CI 0.84–1.86) or in tertiles, with tertile 1 as the reference category (HR for tertile two 0.65, 95% CI 0.26–1.64; HR for tertile three 2.18, 95% CI 0.91–2.23). Higher Klotho levels were associated with the absence of AF in a muItivariable logistic regression analysis (OR 0.66 per SD increase, 95% CI 0.41–1.00). Higher FGF23 levels were associated with mortality risk in a multivariable adjusted analysis when examined either on a continuous scale (HR 1.45 per SD increase, 95% CI 1.05–1.99) or in tertiles, with the tertile 1 as the reference category (HR for tertile two 1.63, 95% CI 0.64–4.14; HR for tertile three 3.91, 95% CI 1.28–12.20). FGF23 but not Klotho levels are associated with mortality in hemodialysis patients. Klotho may be protective against AF.
PMCID: PMC4084634  PMID: 24991914
2.  Plasma Concentrations of the Vasoactive Peptide Fragments Mid-Regional Pro-Adrenomedullin, C-Terminal Pro-Endothelin 1 and Copeptin in Hemodialysis Patients: Associated Factors and Prediction of Mortality 
PLoS ONE  2014;9(1):e86148.
Vasopressin, endothelin and adrenomedullin are vasoactive peptides that regulate vascular tone and might play a role in hypertensive diseases. Recently, laboratory assays have been developed to measure stable fragments of vasopressin, endothelin and adrenomedullin. Little is known about their diagnostic and prognostic value in hemodialysis patients. In this study, we measured the plasma concentration of copeptin, mid-regional-pro-adrenomedullin (MR-pro-ADM) and C-terminal pro-endothelin 1 (CT-pro-ET1) in stable ambulatory hemodialysis patients (n = 239) and investigated their associations with clinical factors and mortality. In all patients enrolled, the plasma concentrations of copeptin, MR-pro-ADM and CT-pro-ET1 were largely elevated with a median concentration of 132 pmol/L (interquartile range [IQR] 78–192) for copeptin, 1.26 nmol/L (IQR 1.02–1.80) for MR-pro-ADM and 149 pmol/L (IQR 121–181) for CT-pro-ET1. The plasma concentrations of all vasoactive peptide fragments correlated with time on dialysis and plasma β2-microglobulin concentration and were negatively correlated to residual diuresis. The plasma concentration of MR-pro-ADM was a strong predictor of all-cause (univariate hazard ratio for a 10-fold increase 9.94 [3.14;32], p<0.0001) and cardiovascular mortality (hazard ratio 34.87 [5.58;217], p = 0.0001) within a 3.8-year follow-up. The associations remained stable in models adjusted for dialysis specific factors and were attenuated in a full model adjusted for all prognostic factors. Plasma copeptin concentration was weakly associated with cardiovascular mortality (only in univariate analysis) and CT-pro-ET1 was not associated with mortality at all. In conclusion, vasoactive peptide fragments are elevated in hemodialysis patients because of accumulation and, most likely, increased release. Increased concentrations of MR-pro-ADM are predictive of mortality.
PMCID: PMC3899212  PMID: 24465926
3.  Sensitive Troponins – Which Suits Better for Hemodialysis Patients? Associated Factors and Prediction of Mortality 
PLoS ONE  2012;7(10):e47610.
In hemodialysis patients, elevated plasma troponin concentrations are a common finding that has even increased with the advent of newly developed sensitive assays. However, the interpretation and relevance of this is still under debate.
In this cross-sectional study, we analyzed plasma concentrations of sensitive troponin I (TnI) and troponin T (TnT) in stable ambulatory hemodialysis patients (n = 239) and investigated their associations with clinical factors and mortality.
In all of the enrolled patients, plasma TnI or TnT was detectable at a median concentration of 14 pg/ml (interquartile range: 7–29) using the Siemens TnI ultra assay and 49 pg/ml (31–74) using the Roche Elecsys high sensitive TnT assay. Markedly more patients exceeded the 99th percentile for TnT than for TnI (95% vs. 14%, p<0.0001). In a multivariate linear regression model, TnT was independently associated with age, gender, systolic dysfunction, time on dialysis, residual diuresis and systolic blood pressure, whereas TnI was independently associated with age, systolic dysfunction, pulse pressure, time on dialysis and duration of a HD session. During a follow-up period of nearly two years, TnT concentration above 38 pg/mL was associated with a 5-fold risk of death, whereas elevation of TnI had a gradual association to mortality.
In hemodialysis patients, elevations of plasma troponin concentrations are explained by cardiac function and dialysis-related parameters, which contribute to cardiac strain. Both are highly predictive of increased risk of death.
PMCID: PMC3471860  PMID: 23077650
4.  Impact of mannose-binding lectin deficiency on radiocontrast-induced renal dysfunction: a post-hoc analysis of a multicenter randomized controlled trial 
BMC Nephrology  2012;13:99.
Local renal ischemia is regarded as an important factor in the development of contrast-induced nephropathy (CIN). Mannose-binding lectin (MBL) is involved in the tissue damage during experimental ischemia/reperfusion injury of the kidneys. The aim of the present study was to investigate the association of MBL deficiency with radiocontrast-induced renal dysfunction in a large prospective cohort.
246 patients with advanced non–dialysis-dependent renal dysfunction who underwent radiographic contrast procedures were included in the study. Baseline serum MBL levels were analyzed according to the occurrence of a creatinine-based (increase of ≥0.5 mg/dL or ≥25% within 48 hours) or cystatin C-based (increase of ≥10% within 24 hours) CIN.
The incidence of creatinine-based and cystatin C-based CIN was 6.5% and 24%, respectively. MBL levels were not associated with the occurrence of creatinine-based CIN. However, patients that experienced a cystatin C increase of ≥10% showed significantly higher MBL levels than patients with a rise of <10% (median 2885 (IQR 1193–4471) vs. 1997 (IQR 439–3504)ng/mL, p = 0.01). In logistic regression analysis MBL deficiency (MBL levels≤500 ng/ml) was identified as an inverse predictor of a cystatin C increase ≥10% (OR 0.34, 95% CI 0.15-0.8, p = 0.01).
MBL deficiency was associated with a reduced radiocontrast-induced renal dysfunction as reflected by the course of cystatin C. Our findings support a possible role of MBL in the pathogenesis of CIN.
PMCID: PMC3471006  PMID: 22938690
Complement; Mannose-binding lectin; Contrast-induced nephropathy; Ischemia/reperfusion injury; Acute kidney injury
5.  Plasma neutrophil gelatinase-associated lipocalin for the prediction of acute kidney injury in acute heart failure 
Critical Care  2012;16(1):R2.
The accurate prediction of acute kidney injury (AKI) in patients with acute heart failure (AHF) is an unmet clinical need. Neutrophil gelatinase-associated lipocalin (NGAL) is a novel sensitive and specific marker of AKI.
A total of 207 consecutive patients presenting to the emergency department with AHF were enrolled. Plasma NGAL was measured in a blinded fashion at presentation and serially thereafter. The potential of plasma NGAL levels to predict AKI was assessed as the primary endpoint. We defined AKI according to the AKI Network classification.
Overall 60 patients (29%) experienced AKI. These patients were more likely to suffer from pre-existing chronic cardiac or kidney disease. At presentation, creatinine (median 140 (interquartile range (IQR), 91 to 203) umol/L versus 97 (76 to 132) umol/L, P < 0.01) and NGAL (114.5 (IQR, 67.1 to 201.5) ng/ml versus 74.5 (60 to 113.9) ng/ml, P < 0.01) levels were significantly higher in AKI compared to non-AKI patients. The prognostic accuracy for measurements obtained at presentation, as quantified by the area under the receiver operating characteristic curve was mediocre and comparable for the two markers (creatinine 0.69; 95%CI 0.59 to 0.79 versus NGAL 0.67; 95%CI 0.57 to 0.77). Serial measurements of NGAL did not further increase the prognostic accuracy for AKI. Creatinine, but not NGAL, remained an independent predictor of AKI (hazard ratio (HR) 1.12; 95%CI 1.00 to 1.25; P = 0.04) in multivariable regression analysis.
Plasma NGAL levels do not adequately predict AKI in patients with AHF.
PMCID: PMC3396227  PMID: 22226205
6.  Value of arterial blood gas analysis in patients with acute dyspnea: an observational study 
Critical Care  2011;15(3):R145.
The diagnostic and prognostic value of arterial blood gas analysis (ABGA) parameters in unselected patients presenting with acute dyspnea to the Emergency Department (ED) is largely unknown.
We performed a post-hoc analysis of two different prospective studies to investigate the diagnostic and prognostic value of ABGA parameters in patients presenting to the ED with acute dyspnea.
We enrolled 530 patients (median age 74 years). ABGA parameters were neither useful to distinguish between patients with pulmonary disorders and other causes of dyspnea nor to identify specific disorders responsible for dyspnea. Only in patients with hyperventilation from anxiety disorder, the diagnostic accuracy of pH and hypoxemia rendered valuable with an area under the receiver operating characteristics curve (AUC) of 0.86. Patients in the lowest pH tertile more often required admission to intensive care unit (28% vs 12% in the first tertile, P < 0.001) and had higher in-hospital (14% vs 5%, P = 0.003) and 30-day mortality (17% vs 7%, P = 0.002). Cumulative mortality rate was higher in the first (37%), than in the second (28%), and the third tertile (23%, P = 0.005) during 12 months follow-up. pH at presentation was an independent predictor of 12-month mortality in multivariable Cox proportional hazard analysis both for patients with pulmonary (P = 0.043) and non-pulmonary disorders (P = 0.038).
ABGA parameters provide limited diagnostic value in patients with acute dyspnea, but pH is an independent predictor of 12 months mortality.
PMCID: PMC3219017  PMID: 21663600
7.  Direct comparison of serial B-type natriuretic peptide and NT-proBNP levels for prediction of short- and long-term outcome in acute decompensated heart failure 
Critical Care  2011;15(1):R1.
Monitoring treatment efficacy and assessing outcome by serial measurements of natriuretic peptides in acute decompensated heart failure (ADHF) patients may help to improve outcome.
This was a prospective multi-center study of 171 consecutive patients (mean age 80 73-85 years) presenting to the emergency department with ADHF. Measurement of BNP and NT-proBNP was performed at presentation, 24 hours, 48 hours and at discharge. The primary endpoint was one-year all-cause mortality; secondary endpoints were 30-days all-cause mortality and one-year heart failure (HF) readmission.
During one-year follow-up, a total of 60 (35%) patients died. BNP and NT-proBNP levels were higher in non-survivors at all time points (all P < 0.001). In survivors, treatment reduced BNP and NT-proBNP levels by more than 50% (P < 0.001), while in non-survivors treatment did not lower BNP and NT-proBNP levels. The area under the ROC curve (AUC) for the prediction of one-year mortality increased during the course of hospitalization for BNP (AUC presentation: 0.67; AUC 24 h: 0.77; AUC 48 h: 0.78; AUC discharge: 0.78) and NT-proBNP (AUC presentation: 0.67; AUC 24 h: 0.73; AUC 48 h: 0.75; AUC discharge: 0.77). In multivariate analysis, BNP at 24 h (1.02 [1.01-1.04], P = 0.003), 48 h (1.04 [1.02-1.06], P < 0.001) and discharge (1.02 [1.01-1.03], P < 0.001) independently predicted one-year mortality, while only pre-discharge NT-proBNP was predictive (1.07 [1.01-1.13], P = 0.016). Comparable results could be obtained for the secondary endpoint 30-days mortality but not for one-year HF readmissions.
BNP and NT-proBNP reliably predict one-year mortality in patients with ADHF. Prognostic accuracy of both biomarker increases during the course of hospitalization. In survivors BNP levels decline more rapidly than NT-proBNP levels and thus seem to allow earlier assessment of treatment efficacy. Ability to predict one-year HF readmission was poor for BNP and NT-proBNP.
Trial registration identifier: NCT00514384.
PMCID: PMC3222028  PMID: 21208408
8.  Copeptin and risk stratification in patients with acute dyspnea 
Critical Care  2010;14(6):R213.
The identification of patients at highest risk for adverse outcome who are presenting with acute dyspnea to the emergency department remains a challenge. This study investigates the prognostic value of Copeptin, the C-terminal part of the vasopressin prohormone alone and combined to N-terminal pro B-type natriuretic peptide (NT-proBNP) in patients with acute dyspnea.
We conducted a prospective, observational cohort study in the emergency department of a university hospital and enrolled 287 patients with acute dyspnea.
Copeptin levels were elevated in non-survivors (n = 29) compared to survivors at 30 days (108 pmol/l, interquartile range (IQR) 37 to 197 pmol/l) vs. 18 pmol/l, IQR 7 to 43 pmol/l; P < 0.0001). The areas under the receiver operating characteristic curve (AUC) to predict 30-day mortality were 0.83 (95% confidence interval (CI) 0.76 to 0.90), 0.76 (95% CI 0.67 to 0.84) and 0.63 (95% CI 0.53 to 0.74) for Copeptin, NT-proBNP and BNP, respectively (Copeptin vs. NTproBNP P = 0.21; Copeptin vs. BNP P = 0.002). When adjusted for common cardiovascular risk factors and NT-proBNP, Copeptin was the strongest independent predictor for short-term mortality in all patients (HR 3.88 (1.94 to 7.77); P < 0.001) and especially in patients with acute decompensated heart failure (ADHF) (HR 5.99 (2.55 to 14.07); P < 0.0001). With the inclusion of Copeptin to the adjusted model including NTproBNP, the net reclassification improvement (NRI) was 0.37 (P < 0.001). An additional 30% of those who experienced events were reclassified as high risk, and an additional 26% without events were reclassified as low risk.
Copeptin is a new promising prognostic marker for short-term mortality independently and additive to natriuretic peptide levels in patients with acute dyspnea.
PMCID: PMC3220005  PMID: 21106053
9.  Effect of oral beta-blocker on short and long-term mortality in patients with acute respiratory failure: results from the BASEL-II-ICU study 
Critical Care  2010;14(6):R198.
Acute respiratory failure (ARF) is responsible for about one-third of intensive care unit (ICU) admissions and is associated with adverse outcomes. Predictors of short- and long-term outcomes in unselected ICU-patients with ARF are ill-defined. The purpose of this analysis was to determine predictors of in-hospital and one-year mortality and assess the effects of oral beta-blockers in unselected ICU patients with ARF included in the BASEL-II-ICU study.
The BASEL II-ICU study was a prospective, multicenter, randomized, single-blinded, controlled trial of 314 (mean age 70 (62 to 79) years) ICU patients with ARF evaluating impact of a B-type natriuretic peptide- (BNP) guided management strategy on short-term outcomes.
In-hospital mortality was 16% (51 patients) and one-year mortality 41% (128 patients). Multivariate analysis assessed that oral beta-blockers at admission were associated with a lower risk of both in-hospital (HR 0.33 (0.14 to 0.74) P = 0.007) and one-year mortality (HR 0.29 (0.16 to 0.51) P = 0.0003). Kaplan-Meier analysis confirmed the lower mortality in ARF patients when admitted with oral beta-blocker and further shows that the beneficial effect of oral beta-blockers at admission holds true in the two subgroups of patients with ARF related to cardiac or non-cardiac causes. Kaplan-Meier analysis also shows that administration of oral beta-blockers before hospital discharge gives striking additional beneficial effects on one-year mortality.
Established beta-blocker therapy appears to be associated with a reduced mortality in ICU patients with acute respiratory failure. Cessation of established therapy appears to be hazardous. Initiation of therapy prior to discharge appears to confer benefit. This finding was seen regardless of the cardiac or non-cardiac etiology of respiratory failure.
Trial registration Identifier: NCT00130559
PMCID: PMC3219994  PMID: 21047406
10.  QRS and QTc interval prolongation in the prediction of long‐term mortality of patients with acute destabilised heart failure 
Heart  2007;93(9):1093-1097.
To quantify the prognostic utility of QRS and QTc interval prolongation in patients presenting with acute destabilised heart failure (ADHF) to the emergency department (ED).
Prospective cohort study among patients enrolled in the B‐Type Natriuretic Peptide for Acute Shortness of Breath Evaluation (BASEL) study. QRS and QT intervals were measured in 173 consecutive patients with ADHF. QT interval was corrected using the Bazett formula. The primary end point was all‐cause mortality during the 720‐day follow‐up.
QRS interval was prolonged (⩾120 ms) in 27% of patients, and QTc interval was prolonged (⩾440 ms) in 72% of patients. Baseline demographic and clinical characteristics were comparable in patients with normal and prolonged QRS or QTc intervals. A total of 78 patients died during follow‐up. Interestingly, the 720‐day mortality was similar in patients with prolonged and normal QTc (44% vs 42%, p = 0.546), but was significantly higher in patients with prolonged QRS interval than in those with normal QRS (59% vs 37%, p = 0.004). In Cox proportional hazards analysis, prolonged QRS interval was associated with a nearly twofold increase in mortality (HR 1.94, 95% CI 1.22 to 3.07; p = 0.005). This association persisted after adjustment for variables routinely available in the ED.
Prolonged QRS interval, but not prolonged QTc interval, is associated with increased long‐term mortality in patients with ADHF.
PMCID: PMC1955023  PMID: 17395674
11.  Midregional pro-Adrenomedullin in addition to b-type natriuretic peptides in the risk stratification of patients with acute dyspnea: an observational study 
Critical Care  2009;13(4):R122.
The identification of patients at highest risk for adverse outcome who are presenting with acute dyspnea to the emergency department remains a challenge. This study investigates the prognostic value of the newly described midregional fragment of the pro-Adrenomedullin molecule (MR-proADM) alone and combined to B-type natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) in patients with acute dyspnea.
We conducted a prospective, observational cohort study in the emergency department of a University Hospital and enrolled 287 unselected, consecutive patients (48% women, median age 77 (range 68 to 83) years) with acute dyspnea.
MR-proADM levels were elevated in non-survivors (n = 77) compared to survivors (median 1.9 (1.2 to 3.2) nmol/L vs. 1.1 (0.8 to 1.6) nmol/L; P < 0.001). The areas under the receiver operating characteristic curve (AUC) to predict 30-day mortality were 0.81 (95% CI 0.73 to 0.90), 0.76 (95% CI 0.67 to 0.84) and 0.63 (95% CI 0.53 to 0.74) for MR-proADM, NT-proBNP and BNP, respectively (MRproADM vs. NTproBNP P = 0.38; MRproADM vs. BNP P = 0.009). For one-year mortality the AUC were 0.75 (95% CI 0.69 to 0.81), 0.75 (95% CI 0.68 to 0.81), 0.69 (95% CI 0.62 to 0.76) for MR-proADM, NT-proBNP and BNP, respectively without any significant difference. Using multivariate linear regression analysis, MR-proADM strongly predicted one-year all-cause mortality independently of NT-proBNP and BNP levels (OR = 10.46 (1.36 to 80.50), P = 0.02 and OR = 24.86 (3.87 to 159.80) P = 0.001, respectively). Using quartile approaches, Kaplan-Meier curve analyses demonstrated a stepwise increase in one-year all-cause mortality with increasing plasma levels (P < 0.0001). Combined levels of MR-proADM and NT-proBNP did risk stratify acute dyspneic patients into a low (90% one-year survival rate), intermediate (72 to 82% one-year survival rate) or high risk group (52% one-year survival rate).
MR-proADM alone or combined to NT-proBNP has a potential to assist clinicians in risk stratifying patients presenting with acute dyspnea regardless of the underlying disease.
PMCID: PMC2750172  PMID: 19627611

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