Explorative study on the value of hepcidin in predicting iron non-responsiveness in paediatric inflammatory bowel disease.

BACKGROUND: In a considerable proportion of anaemic children with inflammatory bowel disease (IBD), haemoglobin (Hb) does not normalise after iron therapy. We evaluated the added value of novel iron markers (hepcidin and soluble transferrin receptor [sTfR]) as compared to traditional iron markers (ferritin and transferrin saturation [TSAT]) to determine the best strategy for the prediction of non-responsiveness to iron suppletion. METHODS: In this secondary analysis of prospectively collected data, we measured iron markers in anaemic children (Hb Z-score < -2.0) with IBD at baseline and one month after the initiation of iron therapy. Non-responsiveness was defined as an increase in Hb Z-score of less than 1 within a month. Logistic regression analysis was used to construct multi-biomarker prognostic models. RESULTS: Of 40 anaemic paediatric IBD patients, sixteen (40%) were non-responsive to iron therapy after one month. Hb Z-score and hepcidin Z-score had the highest predictive ability (area under the ROC curve [AUROC] 0.80) providing sensitivity of 69% and specificity 92%. In a post-hoc analysis we defined hepcidin cut-off values to predict iron non-responsiveness. CONCLUSION: A diagnostic strategy that involves baseline Hb Z-score and hepcidin Z-score in anaemic children with IBD reliably identifies those who will not respond to iron therapy. IMPACT: Non-response to oral and intravenous iron suppletion therapy is high in paediatric IBD and should be identified early. Prediction models using baseline hepcidin demonstrated higher sensitivity and specificity to predict iron non-response compared to models using baseline traditional iron indicators (ferritin and transferrin saturation). In a post hoc analysis, we defined cut-off values for hepcidin to facilitate the correct timing of iron treatment in young anaemic patients with chronic inflammatory bowel disease.

Evaluation of automated microscopy sediment analysis in urinary tract infection screening: a practical insight in adjusting fixed cut-off values for urine culture.

PURPOSE: The aim of our study was to evaluate a procedure in which urine culture was only being performed based on fixed cut-off values of urine sediment analysis with intention to prevent unnecessary negative urine cultures. METHODS: From January 2018 to August 2018, all urine samples from patients visiting the urology outpatient department were analyzed. Urine culture was only performed if urine sediment contained more than 130 bacteria per microliter and/or more than 50 leukocytes per microliter. RESULTS: In total, 2821 urine cultures with accompanying urine sediments were analyzed. 2098 cultures (74.4%) were defined negative and 723 (25.6%) positive. By adjusting cut-off values of sediment analysis > 20 per microliter or bacteria more than 330 per microliter, 1051 cultures would have been saved with an estimated cost reduction of € 31.470. Eleven clinically relevant urine cultures would have been missed (1%). CONCLUSION: Using cut-offs values leads to a notable decrease of the total number of urine cultures. According to our analysis, adjusting cut-off values could result in 37% less urine cultures and almost 50% less negative cultures. Hereby, unnecessary cost can be prevented [in our department estimated €31.470 in eight months (€ 47.205/year)].

Ferric Carboxymaltose Versus Ferrous Fumarate in Anemic Children with Inflammatory Bowel Disease: The POPEYE Randomized Controlled Clinical Trial.

OBJECTIVE: To determine whether intravenous (IV) or oral iron suppletion is superior in improving physical fitness in anemic children with inflammatory bowel disease (IBD). STUDY DESIGN: We conducted a clinical trial at 11 centers. Children aged 8-18 with IBD and anemia (defined as hemoglobin [Hb] z-score < -2) were randomly assigned to a single IV dose of ferric carboxymaltose or 12 weeks of oral ferrous fumarate. Primary end point was the change in 6-minute walking distance (6MWD) from baseline, expressed as z-score. Secondary outcome was a change in Hb z-score from baseline. RESULTS: We randomized 64 patients (33 IV iron and 31 oral iron) and followed them for 6 months. One month after the start of iron therapy, the 6MWD z-score of patients in the IV group had increased by 0.71 compared with -0.11 in the oral group (P = .01). At 3- and 6-month follow-ups, no significant differences in 6MWD z-scores were observed. Hb z-scores gradually increased in both groups and the rate of increase was not different between groups at 1, 3, and 6 months after initiation of iron therapy (overall P = .97). CONCLUSION: In this trial involving anemic children with IBD, a single dose of IV ferric carboxymaltose was superior to oral ferrous fumarate with respect to quick improvement of physical fitness. At 3 and 6 months after initiation of therapy, no differences were discovered between oral and IV therapies. The increase of Hb over time was comparable in both treatment groups. TRIAL REGISTRATION: NTR4487 [Netherlands Trial Registry].

Safety of low-volume PEG-asc bowel cleansing preparation for colonoscopy: identifying patients at risk for hypokalemia in a prospective cohort study.

Background and study aims The aim of bowel cleansing preparation should be high-quality results and conformance with safety standards. Previously, we reported that hypokalemia occurred in 23.6 % of patients after bowel preparation in a high-risk population on diuretics or hospitalized and referred for colonoscopy. Here we report on a prospective study in a non-selected colonoscopy cohort to identify patients at risk of developing hypokalemia before and after bowel cleansing with low-volume polyethylene glycol with ascorbic acid (PEG-asc). Patients and methods From January 1 to July 31, 2016, we included all patients undergoing colonoscopy in our institution. Prevalences of hypokalemia before and after PEG-asc bowel cleansing for colonoscopy were calculated and risk factors for developing hypokalemia after PEG-asc bowel cleansing were identified. Results In total, 2011 patients were included in the analysis. Of these, 0.8 % had hypokalemia before bowel cleansing with PEG-asc. After bowel preparation, 5.4 % developed hypokalemia. Of the patients, 281 were considered to have "high cardiac risk." The combination of "high cardiac risk" and hypokalemia was present in 1 % of the initial colonoscopy population. Female sex, colorectal cancer diagnosis, and thiazide use were found to be significant predictors for hypokalemia after use of PEG-asc. No arrhythmias or serious adverse events due to hypokalemia occurred. Conclusions Physicians referring patients for colonoscopy should be aware that "high cardiac risk" patients and those on thiazide diuretics undergoing bowel cleansing for colonoscopy are a risk of developing post-cleansing hypokalemia but it remains to be determined whether their risk of developing life-threatening arrhythmias is truly increased.

Value of biomarkers in predicting mortality in older medical emergency department patients: a Dutch prospective study.

OBJECTIVE: Older emergency department (ED) patients are at high risk of mortality, and it is important to predict which patients are at highest risk. Biomarkers such as lactate, high-sensitivity cardiac troponin T (hs-cTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), D-dimer and procalcitonin may be able to identify those at risk. We aimed to assess the discriminatory value of these biomarkers for 30-day mortality and other adverse outcomes. DESIGN: Prospective cohort study. On arrival of patients, five biomarkers were measured. Area under the curves (AUCs) and interval likelihood ratios (LRs) were calculated to investigate the discriminatory value of the biomarkers. SETTING: ED in the Netherlands. PARTICIPANTS: Older (≥65 years) medical ED patients, referred for internal medicine or gastroenterology. PRIMARY AND SECONDARY OUTCOME MEASURES: 30-day mortality was the primary outcome measure, while other adverse outcomes (intensive care unit/medium care unit admission, prolonged length of hospital stay, loss of independent living and unplanned readmission) were the composite secondary outcome measure. RESULTS: The median age of the 450 included patients was 79 years (IQR 73-85). In total, 51 (11.3%) patients died within 30 days. The AUCs of all biomarkers for prediction of mortality were sufficient to good, with the highest AUC of 0.73 for hs-cTnT and NT-proBNP. Only for the highest lactate values, the LR was high enough (29.0) to be applicable for clinical decision making, but this applied to a minority of patients. The AUC for the composite secondary outcome (intensive and medium care admission, length of hospital stay >7 days, loss of independent living and unplanned readmission within 30 days) was lower, ranging between 0.58 and 0.67. CONCLUSIONS: Although all five biomarkers predict 30-day mortality in older medical ED patients, their individual discriminatory value was not high enough to contribute to clinical decision making. TRIAL REGISTRATION NUMBER: NCT02946398; Results.

Prevalence of pseudonatremia in a clinical laboratory - role of the water content.

BACKGROUND: Sodium concentration is a frequently used marker to discriminate between differential diagnoses or for clinical follow-up. Pseudonatremia, as a result of indirect ion-selective electrode (ISE) measurements in automated chemistry analyzers, can lead to incorrect diagnosis and treatment. We investigated whether the estimated water content, based on total protein and lipid concentrations, can be used to reduce diagnoses of pseudonatremia. METHODS: Indirect and direct ISE measurements of sodium were compared in blood samples from intensive care unit (ICU) (n = 98) and random non-ICU patients (n = 100). Differences between direct measurements using whole blood and lithium-heparin plasma were also determined. Water content, estimated by a linear combination of total protein and lipid concentrations, was used to correct indirectly measured sodium concentrations. The prevalence of pseudonatremia was evaluated in the ICU patient group. RESULTS: An absolute difference of 3 mmol/L was observed between direct measurements using lithium-heparin plasma and whole blood, with higher concentrations in plasma. Additionally, we observed that differences between indirect and direct measurements displayed a linear relationship with the estimated water content. The prevalence of pseudohypernatremia after indirect measurements (32%) was reduced when measurements were corrected for water content (19%). CONCLUSIONS: In critically ill patients, sodium concentrations should be preferably measured by direct measurements. Whole blood is the preferred material for these measurements. For routine sodium analyses in other patients, correction using the estimated water content appears promising in reducing the prevalence of pseudohypernatremia by indirect measurements.

Collection of blood specimens by venipuncture for plasma-based coagulation assays: necessity of a discard tube.

The Clinical and Laboratory Standards Institute (CLSI) recently abandoned its recommendation for drawing a discard tube when performing a prothrombin time (PT)/international normalized ratio (INR) or an activated partial thromboplastin time (APTT). Because there is currently no evidence that a discard tube is necessary for more specialized coagulation assays, we studied the need for a discard tube for some of these tests. Blood was obtained from 88 subjects in 2 subsequent citrate tubes. Platelet-free plasma was tested for PT, APTT, antithrombin, protein C, and factors II, V, VIII, IX, and X. Difference and bias between tubes were tested using the Wilcoxon signed rank test and Bland-Altman plots. For only APTT, antithrombin, and protein C was a small, statistically significant mean bias found (0.5 seconds; P = .001; -0.7%, P = .002; and -0.8%, P < .0001, respectively), but the bias of individual samples was not clinically relevant. This was also true for the other parameters tested. The recent CLSI recommendation that a discard tube is not necessary for PT/INR and APTT can be extended to include more specialized plasma-based coagulation assays as identified in this study.

The effect of paraproteins on the erythrocyte sedimentation rate: a comparison between the StarrSed and TEST 1.

BACKGROUND: The principle of the erythrocyte sedimentation rate (ESR) as assessed by TEST 1 is different from that of Westergren-based methods. This could result in different influences on the tests by paraproteins. METHODS: We investigated the effect of paraproteins on ESR readings by TEST 1 (y) and the StarrSed (x), a Westergren-based method, in 142 patients with paraproteinaemia. Agreement (Passing-Bablok) and bias (Bland-Altman) between methods was investigated and compared with that of a control population. RESULTS: A poor agreement between the two methods was found in patients with a paraprotein (y = 0.67x + 3.3) in comparison with that of the control population (y = 0.96x + 0.2). Large differences between methods were present when ESR readings were >40 mm/hour, but clinical interpretation was similar in 90% of cases. Linear regression showed a concentration dependent influence of paraproteins on ESR readings by the StarrSed, especially for immunoglobulin class IgM. CONCLUSION: ESR readings by TEST 1 result in similar clinical interpretation for most subjects, but readings are less influenced by the presence of a paraprotein than those of a Westergren-based method.

The transient increase of oxidative stress during normal pregnancy is higher and persists after delivery in women with pre-eclampsia.

OBJECTIVES: Glutathione, an intracellular tripeptide, functions in the protection of cells against free radicals and toxins of endogenous and exogenous origin. To maintain the intracellular redox status in presence of reactive oxygen species, glutathione (GSH) and other thiols are oxidized. The oxidative status of thiols is reflected by the free-to-oxidized ratio and is a real-time measure for oxidative stress. Previously, we have reported abnormal ratios for the thiols cysteine (Cys), homocysteine (Hcy) and cysteinylglycine (CysGly) in women with pre-eclampsia. The aims of this study were to confirm our previous findings in a different case-control cohort and more importantly to determine whether these differences persist postpartum. STUDY DESIGN: At onset of disease and at 6-8 weeks postpartum we analyzed whole blood of 41 women with pre-eclampsia and of 31 women with normotensive pregnancies for the free-to-oxidized ratio of thiols by the assessment of free and oxidized thiol levels using high performance liquid chromatography. Differences between values were determined using either the paired t-test (antepartum versus postpartum) or the t-test (pre-eclampsia versus normotensive pregnancy). RESULTS: Antepartum levels of free GSH as well as the free-to-oxidized ratios of Hcy were lower in pre-eclampsia and normotensive pregnancy when compared with corresponding postpartum values (P<0.0001 and P<0.01, respectively). Moreover, the free-to-oxidized ratio for Hcy was significantly lowered in pre-eclamptic compared with normotensive women, during as well as after pregnancy (both P< or =0.01). CONCLUSION: The data suggest that pregnancy is a state of higher oxidative stress when compared to the postpartum period. In women with pre-eclampsia, oxidative stress is higher and persists in the postpartum period.

A longitudinal study of antioxidant status during uncomplicated and hypertensive pregnancies.

BACKGROUND: To study the possible involvement of an (im)balance between oxidants and antioxidants in pre-eclampsia concentrations of intra- and extracellular blood antioxidants in women with uncomplicated and hypertensive pregnancies, they were studied preconceptionally and throughout pregnancy. METHODS: In uncomplicated pregnancies (n = 19) and hypertensive pregnancies (n = 6) concentrations of whole blood and plasma thiols, plasma vitamins/E and C, hemoglobin, and hematocrit were assessed at preconception, 6, 10, 20, and 37 weeks of gestational age, as well as six weeks postpartum. A repeated mixed model was used for statistical analysis. RESULTS: Vitamin C and most whole blood and plasma thiol concentrations decreased during pregnancy, while vitamin E, whole blood oxidized cysteinyl-glycine and the ratio of free to oxidized homocysteine revealed a linear increase during pregnancy. Postpartum plasma cysteine and vitamin C levels and the ratio of free to oxidized levels of cysteine, cysteinyl-glycine, and glutathione were significantly (p <0.05) lower as compared to preconceptional levels, whereas whole blood oxidized cysteine, cysteinyl-glycine and glutathione levels, and whole blood and plasma homocysteine levels were significantly (p <0.05) higher six weeks after delivery. Plasma cysteine and homocysteine, and whole blood oxidized cysteine and homocysteine levels were significantly (p <0.05) higher at 37 weeks of gestational age in the hypertensive group compared to those in the uncomplicated group. There were no other differences between the hypertensive and uncomplicated groups. CONCLUSION: In normal pregnancy there seems a balance between antioxidant and oxidant concentrations despite modest oxidative stress. In mildly hypertensive pregnancies a marginal imbalance may occur.

Oral N-acetylcysteine administration does not stabilise the process of established severe preeclampsia.

OBJECTIVE: To stabilise the disease process in women with early onset severe preeclampsia and/or HELLP syndrome by enhancing maternal antioxidants effects of glutathione. STUDY DESIGN: In a randomised, double-blind, placebo-controlled trial, women with severe preeclampsia and/or HELLP syndrome received oral N-acetylcysteine. Primary outcome measures were disease stabilisation expressed as treatment-to-delivery interval and biochemical assessment of glutathione and parameters of oxidative stress. Secondary outcome measures were maternal complications, rate of caesarean section, stay at intensive care unit, postpartum hospital stay and neonatal morbidity and mortality. Analyses were done by intention-to-treat using Wilcoxon's two-sample test and regression analysis. RESULTS: Median treatment-to-delivery interval was not significantly different between the N-acetylcysteine and placebo group. The whole blood and plasma levels of glutathione and other thiols were not affected by N-acetylcysteine administration, except for plasma homocysteine concentrations, which were lower in the N-acetylcysteine group. There were no differences found in maternal nor neonatal secondary outcome measures between both groups. CONCLUSION: Oral N-acetylcysteine administration does not stabilise the disease process of early onset severe preeclampsia and/or HELLP syndrome.

N-acetyl-transferase phenotype and risk for preeclampsia.

OBJECTIVE: This study was undertaken to determine whether the N-acetyltransferase (NAT) phenotype contributes to the susceptibility for the development of preeclampsia. STUDY DESIGN: The NAT acetylator status was determined by measuring urinary caffeine metabolites in 134 nonpregnant women with a history of preeclampsia and in 109 control women with uncomplicated pregnancy. The chi(2) and logistic regression analyses were used for statistical evaluation of differences in acetylator status. RESULTS: Significantly more fast acetylators were found among the women with a history of preeclampsia (46.3%) than among the controls (25.4%). Fast acetylators showed an odds ratio of 2.5 (95% CI 1.4-4.3) for preeclampsia. No differences in the acetylator status were found between women with a history of preeclampsia only and those with the HELLP syndrome as well. CONCLUSION: The fast NAT acetylator status, which may result in altered NAT detoxification capacity, is associated with preeclampsia.

Physical well-being in women with a history of severe preeclampsia.

OBJECTIVE: To evaluate the physical and mental health of women with a history of severe preeclampsia. METHODS: In a historical cohort study 131 former patients with a history of severe preeclampsia and 127 control patients received questionnaires about experienced physical and mental complaints after delivery. At a follow-up visit blood pressure, body mass index, and proteinuria were measured and venous blood was drawn. RESULTS: Former patients experienced significantly (p < 0.001) more frequent problems of headache (31% vs. 2%), right upper quadrant pain (16% vs. 1%), visual disturbances (21% vs. 1%), tiredness (66% vs. 27%), subjective loss of concentration (37% vs. 16%), and mental health (37% vs. 6%) compared with controls. When present, these health problems, except for tiredness, lasted significantly more often beyond six months postpartum compared to controls. Admittance to the intensive care unit was associated with headache, and subjective loss of memory and concentration over a longer period of time. The risk of recurrence of severe preeclampsia was a subject of concern in 20% of former patients. At follow-up, systolic and diastolic blood pressures were significantly higher (p < 0.001) among former patients. CONCLUSION: Patients with a history of severe preeclampsia more frequently reported physical and mental complaints, also during a longer period of time.

Maternal antioxidant concentrations after uncomplicated pregnancies.

BACKGROUND: To analyse the post-partum concentrations of intra- and extra-cellular blood antioxidants in women with uncomplicated pregnancies. METHODS: Whole blood and plasma thiols, plasma vitamin E and C, serum cholesterol and triglyceride, ferric reducing ability of plasma (FRAP) concentrations were compared between women delivered by caesarean section (n=17) or spontaneous delivery (n=10). A repeated mixed model was used for statistical analysis. RESULTS: The majority of whole blood thiols increased significantly in both groups the first days post-partum. However, within the caesarean group free cysteine, oxidised cysteine, homocysteine and glutathione and plasma cysteine and homocysteine levels dropped significantly after 24 h, while FRAP levels peaked significantly in this group. Plasma vitamin E levels decreased significantly in both groups within 24 to 48 h after delivery. Independent of the way of delivery whole blood and plasma thiols were significantly increased and vitamin E levels were significantly decreased 3 months post-partum while plasma vitamin C levels and FRAP were unchanged compared to ante-partum levels. DISCUSSION: Decreased plasma vitamin E levels shortly post-partum are associated with decreased lipid peroxidation. The 24 h post-partum drop of some plasma and whole blood thiols in the caesarean group may be due to prolonged fasting.

Low plasma levels of oxidized low density lipoprotein in preeclampsia.

BACKGROUND: Markers of lipid peroxidation are commonly used to assess oxidative stress in preeclampsia. The aim of this study was to assess the concentration of oxidized low density lipoprotein (oxLDL), a novel marker for lipid peroxidation, and that of the thiobarbituric acid reactive substances (TBARS) in the pathogenesis of severe preeclampsia and to investigate the influence of gestational age on these parameters. METHOD: Plasma levels of oxLDL and TBARS were assayed in women with severe preeclampsia (n = 40), normotensive pregnant controls matched for gestational age (n = 24) and normotensive pregnant controls at full term (n = 16). RESULTS: Women with preeclampsia showed lower oxLDL levels (mean +/- SE) than matched controls (181 +/- 12 vs. 219 +/- 14; p = 0.027), whereas no differences were found for the TBARS concentration (3.8 +/- 0.6 vs. 3.7 +/- 0.4). When women with preeclampsia were compared to control women at full term, TBARS were elevated (3.8 +/- 0.6 vs. 1.5 +/- 0.2; p = 0.01). However, in women with normotensive pregnancy TBARS were also lower in full-term control pregnancy compared to early third-trimester values (p < 0.0001). CONCLUSION: Plasma TBARS decreased during the third trimester of pregnancy, underlining the importance of matching for gestational age when studying markers of lipid peroxidation in pregnant women. Women with preeclampsia had lower plasma levels of oxLDL compared to gestational age-matched controls, indicating that oxLDL could be a marker for preeclampsia.

The Tyr113His polymorphism in exon 3 of the microsomal epoxide hydrolase gene is a risk factor for perinatal mortality.

BACKGROUND: A genetic predisposition to impaired detoxification of oxidative or chemical stress could play a role in the etiology of perinatal mortality. In this pilot study we investigated the risk of perinatal mortality in relation to genetic polymorphism in microsomal epoxide hydrolase (EPHX) and glutathione S-transferase P1 (GSTP1) in women who experienced perinatal mortality caused by placental pathology, congenital disorders and complications of premature delivery and their male partners. METHODS: Genomic DNA of couples (72 females and 46 males) with a history of perinatal mortality and control couples (71 females and 66 males) with no complications in their obstetric history were analyzed for the presence of the polymorphisms in exon 3 of EPHX (Tyr113His) and GSTP1 (Ile105Val). RESULTS: A similar distribution of the GSTP1 polymorphism was found in all subjects investigated. In women who experienced perinatal mortality, we demonstrated a higher prevalence of the EPHX His113/His113 genotype, which could result in a lower enzyme activity, compared with controls (25% vs. 9%; chi2 = 5.7 and p < 0.02), with an odds ratio (95% confidence interval) of 3.5 (1.1-12.7). CONCLUSION: Our results suggest that the maternal Tyr113His polymorphism in EPHX may be a risk factor for perinatal mortality. However, more research is needed to determine the implication of this finding.

Oxidative stress and preeclampsia: rationale for antioxidant clinical trials.

Preeclampsia remains a frequent and potentially dangerous complication of pregnancy. The cause remains largely unknown, but oxidative stress and a generalized inflammatory state are features of the maternal syndrome. The placenta appears to be the principal source of free radical synthesis but maternal leukocytes and the maternal endothelium are also likely contributors. Recent reports have suggested an important role for placental trophoblast NAD(P)H oxidase in free radical generation in preeclampsia. The antioxidant vitamin E is now known to have multiple actions in addition to prevention of lipid peroxidation (ie, inhibition of NAD(P)H oxidase activation and the inflammatory response). In view of the abnormally low plasma vitamin C concentrations in preeclampsia, a combination of vitamins C and E is a promising prophylactic strategy for prevention of preeclampsia. Several multicenter randomized clinical trials are now underway. The potential use of antioxidants and the recognized, albeit modest, benefit of low-dose aspirin prophylaxis have heightened the need for a reliable predictive test for preeclampsia. A combination test involving several relevant biomarkers is likely to provide the best predictive potential.