Robert Faulhaber-Walter

Circulating miR-210 Predicts Survival in Critically Ill Patients with Acute Kidney Injury

BACKGROUND AND OBJECTIVES MicroRNAs (miRNAs) are small ribonucleotides regulating gene expression. MicroRNAs are present in the blood in a remarkably stable form. We tested whether circulating miRNAs in the plasma of critically ill patients with acute kidney injury (AKI) at the inception of renal replacement therapy are deregulated and may predict survival. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We profiled miRNAs using RNA isolated from the plasma of patients with AKI and healthy controls. The results were validated in 77 patients with acute kidney injury, 30 age-matched healthy controls, and 18 critically ill patients with acute myocardial infarction by quantitative real-time PCR. RESULTS Circulating levels of miR-16 and miR-320 were downregulated in the plasma of kidney injury AKI patients, whereas miR-210 was upregulated compared with healthy controls (all P < 0.0001) and disease controls (miR-210 and miR-16: P < 0.0001; miR-320: P = 0.03). Cox regression (P < 0.05) and Kaplan-Meier curve analysis (P = 0.03) revealed miR-210 as an independent and powerful predictor of 28-day survival. CONCLUSIONS Circulating miRNAs are altered in patients with kidney injury AKI. MiR-210 predicts mortality in this patient cohort and may serve as a novel biomarker AKI reflecting pathophysiological changes on a cellular level.

Excess circulating angiopoietin-2 is a strong predictor of mortality in critically ill medical patients

IntroductionThe endothelial specific angiopoietin (Ang)-Tie2 ligand-receptor system has been identified as a non-redundant mediator of endothelial activation in experimental sepsis. Binding of circulating Ang-1 to the Tie2 receptor protects the vasculature from inflammation and leakage, whereas binding of Ang-2 antagonises Tie2 signalling and disrupts endothelial barrier function. Here, we examine whether circulating Ang-1 and/or Ang-2 independently predict mortality in a cohort of critically ill medical patients.MethodsCirculating vascular endothelial growth factor (VEGF), Ang-1 and Ang-2 were prospectively measured in sera from 29 healthy controls and 43 medical ICU patients by immunoradiometric assay (IRMA) and ELISA, respectively. Survival after 30 days was the primary outcome studied.ResultsMedian serum Ang-2 concentrations were increasingly higher across the following groups: healthy controls, patients without sepsis, patients with sepsis and patients with septic shock. In contrast, Ang-1 and VEGF concentrations were significantly lower in all patient groups compared with healthy controls. Ang-2 correlated with partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FiO2), tissue hypoxia, Sequential Organ Failure Assessment (SOFA) and Physiology and Chronic Health Evaluation II (APACHE II) score. Multivariate Cox regression analyses confirmed a strong independent prognostic impact of high Ang-2 as a novel marker of 30-day survival.ConclusionsA marked imbalance of the Ang-Tie system in favour of Ang-2 is present in critically ill medical patients. Our findings highlight the independent prognostic impact of circulating Ang-2 in critical illness. Ang-2 may be used as a readily available powerful predictor of outcome and may open new perspectives to individualise treatment in the ICU.

The Hannover Dialysis Outcome study: comparison of standard versus intensified extended dialysis for treatment of patients with acute kidney injury in the intensive care unit

BACKGROUND Increasing the dose of renal replacement therapy has been shown to improve survival in critically ill patients with acute kidney injury (AKI) in several smaller European trials. However, a very recent large multicentre trial in the USA could not detect an effect of dose of renal replacement therapy on mortality. Based on those studies, it is not known whether a further increase in dialysis dose above and beyond the currently employed doses would improve survival in patients with AKI. We therefore aimed to assess mortality and renal recovery of patients with AKI receiving either standard (SED) or intensified extended dialysis (IED) therapy in the intensive care unit. METHODS A prospective randomized parallel group study was conducted in seven intensive care units of a tertiary university hospital. Pre-existing chronic kidney disease was an exclusion criterion. A total of 156 patients (570 screened) with AKI requiring renal replacement therapy were randomly assigned to receive standard dialysis [dosed to maintain plasma urea levels between 120 and 150 mg/dL (20-25 mmol/L)] or intensified dialysis [dosed to maintain plasma urea levels <90 mg/dL (<15 mmol/L)]. Outcome measures were survival at Day 14 (primary) and survival and renal recovery at Day 28 (secondary) after initiation of renal replacement therapy. RESULTS Treatment intensity differed significantly (P < 0.01 for plasma urea and administered dose). No differences between intensified and standard treatment were seen for survival by Day 14 (70.4% versus 70.7%) or Day 28 (55.6% versus 61.3%), or for renal recovery amongst the survivors by Day 28 (60.0% versus 63.0%). CONCLUSIONS Although this study cannot deliver a definitive answer, it suggests that increasing the dose of extended dialysis above the currently recommended dose might neither reduce mortality nor improve renal recovery in critically ill patients, mainly septic patients, with AKI.

Serum neutrophil gelatinase-associated lipocalin at inception of renal replacement therapy predicts survival in critically ill patients with acute kidney injury

IntroductionNeutrophil gelatinase-associated lipocalin (NGAL) is a promising novel biomarker that correlates with the severity and outcome of acute kidney injury (AKI). However, its prognostic utility during the late course of AKI, especially in patients that require renal replacement therapy (RRT) remains unknown. The aim of this study was to evaluate the predictive value of serum NGAL in patients with established AKI at inception of RRT in the intensive care unit (ICU).MethodsSerum NGAL (ELISA methodology) was measured in 109 critically ill patients with AKI at inception of RRT in 7 ICUs of a tertiary care university hospital. The primary outcome studied was 28-day mortality. Secondary outcome measures were ICU length of stay, ventilator-free days, and renal recovery at day 28.ResultsThere was a significant difference in serum NGAL between healthy subjects (median [interquartile range] 39.0 [37.5-42.75] ng/mL), critically ill patients with systemic inflammatory response syndrome (SIRS) (297 [184-490] ng/mL), and critically ill patients with sepsis (708 [365-1301] ng/mL; P < 0.0001), respectively. Multiple linear regression showed that NGAL levels were independently related to the severity of AKI and the extent of systemic inflammation. NGAL levels were higher in non-survivors (430 [303-942] ng/mL) compared to survivors (298 [159-506] ng/mL; P = 0.004). Consistently, Cox proportional hazards regression analysis identified NGAL as a strong independent predictor for 28-day survival (hazard ratio 1.6 (95% confidence interval [CI] 1.15 - 2.23), P = 0.005).ConclusionsThis is the first prospective evaluation of serum NGAL as an outcome-specific biomarker in critically ill patients at initiation of RRT. The results from this study indicate that serum NGAL is as an independent predictor of 28-day mortality in ICU patients with dialysis-dependent AKI.

Circulating Long Noncoding RNA TapSAKI Is a Predictor of Mortality in Critically Ill Patients with Acute Kidney Injury

BACKGROUND Long noncoding RNAs (lncRNAs) are novel intracellular noncoding ribonucleotides regulating gene expression. Intriguingly, these RNA transcripts are detectable and stable in the blood of patients with cancer and cardiovascular disease. We tested whether circulating lncRNAs in plasma of critically ill patients with acute kidney injury (AKI) at inception of renal replacement therapy were deregulated and might predict survival. METHODS We performed a global lncRNA expression analysis using RNA isolated from plasma of patients with AKI, healthy controls, and ischemic disease controls. This global screen revealed several deregulated lncRNAs in plasma samples of patients with AKI. lncRNA-array-based alterations were confirmed in kidney biopsies of patients as well as in plasma of 109 patients with AKI, 30 age-matched healthy controls, and 30 disease controls by quantitative real-time PCR. RESULTS Circulating concentrations of the novel intronic antisense lncRNA TrAnscript Predicting Survival in AKI (TapSAKI) (P < 0.0001) were detectable in kidney biopsies and upregulated in plasma of patients with AKI. Cox regression and Kaplan-Meier curve analysis revealed TapSAKI as an independent predictor of 28-day survival (P < 0.01). TapSAKI was enriched in tubular epithelial cells subjected to ATP depletion (P = 0.03). CONCLUSIONS The alteration of circulating concentrations of lncRNAs in patients with AKI supports TapSAKI as a predictor of mortality in this patient cohort.

Circulating Long Noncoding RNA TrAnscript Predicting Survival in AKI Is a Predictor of Mortality in Critically Ill Patients with Acute Kidney Injury

BACKGROUND Long noncoding RNAs (lncRNAs) are novel intracellular noncoding ribonucleotides regulating gene expression. Intriguingly, these RNA transcripts are detectable and stable in the blood of patients with cancer and cardiovascular disease. We tested whether circulating lncRNAs in plasma of critically ill patients with acute kidney injury (AKI) at inception of renal replacement therapy were deregulated and might predict survival. METHODS We performed a global lncRNA expression analysis using RNA isolated from plasma of patients with AKI, healthy controls, and ischemic disease controls. This global screen revealed several deregulated lncRNAs in plasma samples of patients with AKI. lncRNA-array-based alterations were confirmed in kidney biopsies of patients as well as in plasma of 109 patients with AKI, 30 age-matched healthy controls, and 30 disease controls by quantitative real-time PCR. RESULTS Circulating concentrations of the novel intronic antisense lncRNA TrAnscript Predicting Survival in AKI (TapSAKI) (P < 0.0001) were detectable in kidney biopsies and upregulated in plasma of patients with AKI. Cox regression and Kaplan-Meier curve analysis revealed TapSAKI as an independent predictor of 28-day survival (P < 0.01). TapSAKI was enriched in tubular epithelial cells subjected to ATP depletion (P = 0.03). CONCLUSIONS The alteration of circulating concentrations of lncRNAs in patients with AKI supports TapSAKI as a predictor of mortality in this patient cohort.

Osteopontin predicts survival in critically ill patients with acute kidney injury

BACKGROUND The cytokine osteopontin is involved in the pathophysiology of experimental acute kidney injury. We have tested the hypothesis that osteopontin levels might serve as a biomarker predicting outcome in critically ill patients requiring renal replacement therapy after acute kidney injury. METHODS We measured circulating plasma osteopontin levels in 109 critically ill patients with acute kidney injury at inception of renal replacement therapy and 4 weeks thereafter. Critically ill patients without acute kidney injury served as controls. Osteopontin was measured with ELISA. RESULTS Baseline osteopontin levels in patients with acute kidney injury were significantly higher compared with controls (P<0.0001). Baseline osteopontin levels in patients recovering from acute kidney injury were significantly elevated compared with patients with permanent loss of kidney function after acute kidney injury (P=0.01). In addition, in patients recovering from acute kidney injury without further need for renal replacement therapy, osteopontin levels were significantly lower 4 weeks after initiation of renal replacement therapy (P=0.0005). Moreover, multivariate Cox analysis revealed osteopontin levels at renal replacement therapy inception as an independent and powerful predictor of mortality (P<0.0001). In the ROC-curve analysis, an osteopontin cut-off value of 577 ng/mL separated survivors from non-survivors with a sensitivity of 100% and a specificity of 61% (AUC 0.82; 95% confidence interval: 0.74-0.89; P<0.0001). CONCLUSIONS Osteopontin may serve as a novel biomarker for both, overall survival and renal outcome in critically ill patients with acute kidney injury, that require renal replacement therapy.

Effects of chronic SDMA infusion on glomerular filtration rate, blood pressure, myocardial function and renal histology in C57BL6/J mice

BACKGROUND Symmetrical dimethylarginine (SDMA), the structural isomer of the nitric oxide synthase inhibitor asymmetrical dimethylarginine, has long been regarded as an inert substance. Recent epidemiological and preclinical data suggest that it might be involved in the pathophysiology of renal and cardiovascular diseases. Therefore, we aimed to investigate the effect of chronic SDMA infusion on renal and cardiac function in mice. METHODS Eight-week-old male C57Bl/6 mice received vehicle-controlled infusion of SDMA (250 µmol/kg/days) for 28 days using osmotic minipumps (n = 24/group). The following parameters were monitored: glomerular filtration rate (GFR; fluoresceinyl thiocarbamoyl-inulin excretion kinetic), cardiac function (echocardiography) and blood pressure (tail cuff). Blood samples for SDMA determination were obtained at baseline, 2 and 4 weeks. Mice were euthanized at 4 weeks to obtain tissue for renal histology. RESULTS Chronic SDMA infusion led to a significant increase of SDMA levels from 0.26 ± 0.10 to 3.49 ± 1.66 µmol/L (P < 0.001) at 4 weeks. Despite this SDMA increase, the GFR did not change (1224 ± 351 versus 1017 ± 345 mL/min/g body weight, n.s.) at 4 weeks, when compared with baseline. We did not find any histological changes, particularly no effect on fibrosis or endothelias nitric oxide synthase expression. There was neither an effect of SDMA on systolic blood pressure (106 ± 12 versus 111 ± 18 mmHg, n.s.) nor on ejection fraction (54.2 ± 1.7 versus 58.4 ± 1.9%, n.s.). CONCLUSIONS Based on our experiments, it seems unlikely that chronically elevated SDMA alone has an effect on renal and cardiac function in otherwise healthy mice. Future studies have to clarify the potential pathophysiological role of SDMA in cardiovascular disease.

Renal replacement therapy intensity for acute kidney injury and recovery to dialysis independence: a systematic review and individual patient data meta-analysis

Background There is no consensus whether higher intensity dose renal replacement therapy (RRT) compared with standard intensity RRT has survival benefit and achieves better renal recovery in acute kidney injury (AKI). Methods In an individual patient data meta-analysis, we merged individual patient data from randomized controlled trials (RCTs) comparing high with standard intensity RRT in intensive care unit patients with severe AKI. The primary outcome was all-cause mortality. The secondary outcome was renal recovery assessed as the proportion of patients who were RRT dependent at key trial endpoints and by time to the end of RRT dependence. Results Of the eight prospective RCTs assessing different RRT intensities, seven contributed individual patient data (n = 3682) to the analysis. Mortality was similar between the two groups at 28 days [769/1884 (40.8%) and 744/1798 (41.4%), respectively; P = 0.40] after randomization. However, more participants assigned to higher intensity therapy remained RRT dependent at the most common key study point of 28 days [e.g. 292/983 (29.7%) versus 235/943 (24.9%); relative risk 1.15 (95% confidence interval 1.00-1.33); P = 0.05]. Time to cessation of RRT through 28 days was longer in patients receiving higher intensity RRT (log-rank test P = 0.02) and when continuous renal replacement therapy was used as the initial modality of RRT (log-rank test P = 0.03). Conclusions In severe AKI patients, higher intensity RRT does not affect mortality but appears to delay renal recovery. Trial Registration Australian New Zealand Clinical Trials Registry (ANZCTR) identifier ACTRN12615000394549 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12615000394549).

Health status, renal function, and quality of life after multiorgan failure and acute kidney injury requiring renal replacement therapy

Background Critically ill patients with acute kidney injury (AKI) in need of renal replacement therapy (RRT) may have a protracted and often incomplete rehabilitation. Their long-term outcome has rarely been investigated. Study design Survivors of the HANnover Dialysis OUTcome (HANDOUT) study were evaluated after 5 years for survival, health status, renal function, and quality of life (QoL). The HANDOUT study had examinded mortality and renal recovery of patients with AKI receiving either standard extendend or intensified dialysis after multi organ failure. Results One hundred fifty-six former HANDOUT participants were analyzed. In-hospital mortality was 56.4%. Five-year survival after AKI/RRT was 40.1% (86.5% if discharged from hospital). Main causes of death were cardiovascular complications and sepsis. A total of 19 survivors presented to the outpatient department of our clinic and had good renal recovery (mean estimated glomerular filtration rate 72.5±30 mL/min/1.73 m2; mean proteinuria 89±84 mg/d). One person required maintenance dialysis. Seventy-nine percent of the patients had a pathological kidney sonomorphology. The Charlson comorbidity score was 2.2±1.4 and adjusted for age 3.3±2.1 years. Numbers of comorbid conditions averaged 2.38±1.72 per patient (heart failure [52%] > chronic kidney disease/myocardial infarction [each 29%]). Median 36-item short form health survey (SF-36™) index was 0.657 (0.69 physical health/0.66 mental health). Quality-adjusted life-years after 5 years were 3.365. Conclusion Mortality after severe AKI is higher than short-term prospective studies show, and morbidity is significant. Kidney recovery as well as general health remains incomplete. Reduction of QoL is minor, and social rehabilitation is very good. Affectivity is heterogeneous, but most patients experience emotional well-being. In summary, AKI in critically ill patients leads to incomplete rehabilitation but acceptable QoL after 5 years.