Reinhard Ziebig

Renal Elimination of Troponin T and Troponin I

Cardiovascular complications represent the predominant cause of death in patients in the terminal stage of renal failure. Increased concentrations of cardiac troponin T (cTnT) may be a valuable predictor of cardiac risk (1)(2). However, cardiac troponin I (cTnI), clinical symptoms, and electrocardiogram (ECG) indications may be absent in patients with a positive cTnT. This may be attributable to instability of the cTnI molecule (3) or dissimilar glomerular filtration of cTnT and cTnI (4). Positive cTnT values are of cardiac origin because the second generation of cTnT assays will not detect cTnT isoforms expressed in the skeletal muscle of hemodialysis patients (5). We therefore measured the cardiac troponins cTnT and cTnI in the plasma and urine of selected patients differing in their kidney function. We examined 24 patients with increased plasma cTnT. Patients were grouped according to their basic disease and renal function as follows: Group A included five patients (patients 1–5) who had suffered an acute myocardial infarction and three patients (patients 6–8) with cardiac damage as a result of heart surgery, all with normal or only slightly restricted glomerular filtration rate of >80 mL/min. All eight patients were male, with a mean (SD) age of 63 (11) years. Patients had clinically typical chest pain (with the exception of patient 8), and electrocardiography (ECG) showed signs of old myocardial infarction, signs of ST-segment reduction or elevation >0.1 mV with and without chest pain, or signs any arrhythmia of unknown origin. Group B included two patients (patients 9 and 10) who had suffered an acute myocardial infarction and six patients (patients 11–16) with cardiac damage as a result of heart surgery; all had a substantially restricted glomerular filtration rate (only patient 9 had values for creatinine and creatinine clearance that were within the appropriate reference intervals). All patients in …

Different Impact of Biomarkers as Mortality Predictors among Diabetic and Nondiabetic Patients Undergoing Hemodialysis

Diabetic patients undergoing hemodialysis demonstrate much worse survival rates than do nondiabetic patients undergoing hemodialysis. To search for risk predictors, a prospective cohort study was performed with 245 hemodialysis patients, including 84 with diabetes mellitus, for 2 yr. C-reactive protein, troponin T (TnT), total, HDL, LDL, and lipoprotein(a) cholesterol, apoA2, apoB, triglyceride, fibrinogen, D-dimer, albumin, and creatinine levels and clinical characteristics at the time of entry were recorded. Survival rates were compared with Kaplan-Meier and Cox regression analyses. Forty-three diabetic patients and 30 nondiabetic patients died. Among diabetic patients, oliguria (<200 ml/d) (relative risk, 3.24; 95% confidence interval, 1.63 to 6.41; P = 0.001), elevated C-reactive protein levels (relative risk, 2.57; 95% confidence interval, 1.06 to 6.18; P = 0.035), and elevated D-dimer levels (relative risk, 2.36; 95% confidence interval, 1.11 to 5.01; P = 0.025) predicted all-cause mortality rates. Oliguria was by far the most important predictor, particularly for infectious disease-related death (relative risk, 23.35; 95% confidence interval, 2.60 to 209.97; P = 0.005). Among nondiabetic patients, elevated TnT levels (relative risk, 4.00; 95% confidence interval, 1.58 to 10.10; P = 0.003), elevated D-dimer levels (relative risk, 3.45; 95% confidence interval, 1.27 to 9.33; P = 0.015), and low cholesterol levels (relative risk, 3.61; 95% confidence interval, 1.34 to 9.71; P = 0.011) predicted all-cause mortality rates. Subdivision of the causes of death among nondiabetic patients revealed that TnT levels predicted cardiovascular mortality rates (relative risk, 5.38; 95% confidence interval, 1.11 to 26.10; P = 0.037) and infectious disease-related mortality rates (relative risk, 12.02; 95% confidence interval, 1.42 to 191.96; P = 0.023). In conclusion, mortality predictors among patients undergoing hemodialysis differed substantially between diabetic and nondiabetic patients. Strategies to reduce mortality rates should consider these differences.

Relaxin Is an Independent Risk Factor Predicting Death in Male Patients With End-Stage Kidney Disease

Background—Patients with end-stage kidney disease (ESKD) have a reduced life expectancy mainly as the result of cardiovascular diseases. Relaxin has been implicated in the pathogenesis of cardiovascular diseases. We analyzed the impact of relaxin on death in patients with ESKD. Methods and Results—Patients (n = 245; 122 women, 123 men) on long-term hemodialysis were followed for 1140 days for death. Blood samples for analysis of relaxin, C-reactive protein, Troponin T, cholesterol, HDL, brain natriuretic peptide, and albumin were taken at study entry. Survival was compared by the Kaplan-Meier method and Cox regression analysis. One hundred seven patients died during the observation period; 66 died of cardiovascular diseases and 28 died of infectious diseases. Elevated serum relaxin concentrations (greater than median) predicted death in male but not in female patients with ESKD: All-cause death (men: relative risk, 2.63; 95% CI, 1.34 to 5.12; P = 0.005; women: relative risk, 0.671; 95% CI, 0.33 to 1.35; P = 0.262) and cardiovascular death (men: relative risk, 2.95; 95% CI, 1.20 to 7.21; P = 0.018; women: relative risk, 0.639; 95% CI, 0.26 to 1.56; P = 0.324). Conclusions—Relaxin is an independent risk factor predicting death in male patients with ESKD on chronic hemodialysis.

Chronic Chagas disease: from basics to laboratory medicine

Abstract Chagas disease, caused by Trypanosoma cruzi infection, is ranked as the most serious parasitic disease in Latin America and has huge potential to become a worldwide problem, due to increasing migration, and international tourism, as well as infectant transfer by blood contact and transfusion, intrauterine transfer, and organ transplantation. Nearly 30% of chronically-infected patients become symptomatic, often with a latency of 10–30 years, developing life-threatening complications. Of those, nearly 90% develop Chagas heart disease, while the others manifest gastrointestinal disease and neuronal disorders. Besides interrupting the infection cycle and chemotherapeutic infectant elimination, starting therapy early in symptomatic patients is important for counteracting the disease. This would be essentially supported by optimized patient management, involving risk assessment, early diagnosis and monitoring of the disease and its treatment. From economic and logistic viewpoints, the tools of laboratory medicine should be especially able to guarantee this. After summarizing the basics of chronic Chagas disease, such as the epidemiological data, the pathogenetic mechanisms thought to drive symptomatic Chagas disease and also treatment options, we present tools of laboratory medicine that address patient diagnosis, risk assessment for becoming symptomatic and guidance, focusing on autoantibody estimation for risk assessment and heart marker measurement for patient guidance. In addition, increases in levels of inflammation and oxidative stress markers in chronic Chagas disease are discussed.

Soluble CD154 Is a Unique Predictor of Nonfatal and Fatal Atherothrombotic Events in Patients Who Have End-Stage Renal Disease and Are on Hemodialysis

Cardiovascular mortality is remarkably high in patients who are on hemodialysis. Soluble CD154 (sCD154), a protein that belongs to the TNF receptor superfamily, has been implicated in the pathogenesis of atheromatous plaque destabilization and thrombotic events. The predictive value of sCD154 as a marker for clinical outcome in patients with ESRD was investigated. A total of 232 patients were prospectively followed for 52 mo. At study entry, clinical characteristics were documented and plasma concentrations of sCD154 and those of conventional risk predictors were analyzed. The time and cause of any hospitalization and death were documented during the entire follow-up. Survival rates were compared by Kaplan-Meier and Cox regression analyses. A total of 122 patients died, 64 of cardiovascular disease, including 20 cases of fatal atherothrombotic diseases (myocardial infarction, stroke, mesenteric ischemia). All 20 cases of fatal atherothrombotic events had high sCD154 plasma levels (cutoff >6.42 ng/ml) at study entry. The total number of fatal and nonfatal atherothrombotic events was 66. Only five atherothrombotic nonfatal events occurred in patients with sCD154 <6.42 ng/ml, whereas 61 fatal and nonfatal events were seen in patients with sCD154 > or =6.42 ng/ml (P < 0.005). This was confirmed by Kaplan-Meier curves for fatal atherothrombotic events (P = 0.0214) and the combined end point fatal and nonfatal atherothrombotic events (P = 0.0039). Cox regression analysis revealed that high sCD154 is an independent predictor (relative risk 6.80; 95% confidence interval 1.64 to 28.26; P = 0.008) for the combined end point death or hospitalization as a result of atherothrombotic events. Death or hospitalizations as a result of any other reason (arrhythmia, heart failure, infectious diseases, and cancer) were not linked to sCD154 plasma concentrations. In conclusion, sCD154 predicts nonfatal and fatal atherothrombotic events (myocardial infarction, stroke, mesenteric ischemia) but not death and hospitalization as a result of any other reason in stable patients who have ESRD and are on hemodialysis.

Gender-Dependent Impact of Risk Factors for Cardiovascular and Non-Cardiovascular Mortality in End-Stage Renal Disease Patients on Haemodialysis

We investigated whether mortality risk factors are gender dependent in haemodialysis patients. Patients (n = 230; 118 women, 112 men) on haemodialysis were followed for 52 months to assess the incidence of death due to cardiovascular or non-cardiovascular causes. Survival was compared by Cox regression analysis using age, diabetes, pre-existing coronary disease, troponin T and C-reactive protein as covariates. In total, 120 participants (52.2%) died within the 52 months of follow-up: 57 patients died of cardiovascular disease, 35 patients died of infectious diseases. Cox regression revealed that age, pre-existing coronary heart disease and troponin T were independent all-cause mortality risk factors for both sexes. Analyzing men and women separately revealed that diabetes and C-reactive protein seemed to be a stronger risk factors for all-cause mortality in women. Cardiovascular mortality was predicted by troponin T in women (relative risk = 5.16, 95% CI: 1.67–15.88; p = 0.004), but not in men (relative risk = 1.69; 95% CI: 0.72–3.96; p = 0.23). Our study showed for the first time that the impact of risk factors in predicting death due to cardiovascular disease is clearly gender dependent.

Does contrast echocardiography induce increases in markers of myocardial necrosis, inflammation and oxidative stress suggesting myocardial injury?

BackgroundContrast echocardiography is a precise tool for the non-invasive assessment of myocardial function and perfusion. Side effects of contrast echocardiography resulting from contrast-agent induced myocardial micro-lesions have been found in animals. The goal of this study is to measure markers of myocardial necrosis, inflammation and oxidative stress in humans to evaluate potential side-effects of contrast echocardiography.Methods20 patients who underwent contrast echocardiography with Optison as the contrast medium were investigated. To evaluate myocardial micro-necrosis, inflammation and oxidative stress, cardiac troponin I (cTnI), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, -8 and thiobarbituric acid reactive substances (TBARS) were measured at baseline and at 2, 4, 8 and 24 hours after contrast echocardiography.ResultsAt baseline, 50% of the patients had cTnI and TBARS values outside the reference range. TNF-α, IL-6, IL-8 levels were within the reference range. Patients with cTnI above the RR clustered to significantly higher levels of TNF-α and IL-6. After contrast echocardiography, no statistically significant increase of cTnI, cytokines and TBARS was found. However, for nearly 50% of the patients, the intra-individual cTnI kinetics crossed the critical difference (threefold of methodical variation) which indicates a marker increase. This was neither predicted by the baseline levels of the cytokines nor the markers of oxidative stress.ConclusionThere are no clinically relevant increases in serum markers for micro-necrosis, inflammation and oxidative stress in humans after contrast echocardiography. Future studies have to address whether cTnI increase in some patients represent a subset with increased risk for side effects after contrast echocardiography.

Organ siderosis and hemophagocytosis during acute graft-versus-host disease

Iron overload prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) due to blood transfusions is associated with increased non-relapse mortality (NRM) and with low overall survival.1,2 After allo-HSCT, high iron content in liver biopsies and elevated ferritin concentrations in blood, used as a surrogate parameter for iron overload, are also related to NRM.3–6 The cellular and molecular mechanisms behind this association, however, are yet to be clarified. In particular, available data on the role of ferritin and iron metabolism during the pathophysiology of acute graft-versus-host disease (GvHD), a major contributor to NRM, are scarse. To shed light on the connection between GvHD, ferritin levels, and iron metabolism, we decided to analyse the clinical data of patients undergoing allo-HSCT as well as data from preclinical murine GvHD models.

Leukocyte, neutrophil, immature granulocyte counts and interleukin-6 are superior to procalcitonin, C-reactive protein and delta-He for detection of mild inflammation: data from marathon runners producing mild systemic inflammation visible immediately after the run / Leukozyten, Neutrophile, unreife Granulozyten und Interleukin-6 sind zum Nachweis geringgradiger Entzündungen Procalcitonin, C-reaktivem Protein und Delta-He überlegen: Ergebnisse aus einer Untersuchung von Marathonläufern

Abstract Immature granulocytes (IGs) and differences between reticulocyte and erythrocyte haemoglobin content (delta-He) are now available as modern parameters on routine haematology analysers for detecting inflammation. Are these markers more suitable to detect mild inflammation when compared with traditional inflammation markers such as leukocyte count, C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6) or diverse leukocyte surface molecules mainly used in research programs? To answer this question, a marathon race was used as a model of mild inflammation. Full blood counts, CRP, PCT, IL-6, expression of surface molecules on granulocytes, monocytes and lymphocytes were measured before and immediately after the race (inflammatory state) and were compared with each other. A further blood sample was taken after a 10-day rest. In the inflammatory state leukocytes, neutrophil counts and IL-6 concentration were considerably increased compared with basic conditions. Diagnostic sensitivity and specificity came up to 100%. CRP was not increased and delta-He did not drop to negative values, as it occurs in severe inflammation. Leukocyte surface molecules were able to indicate a mild inflammatory state induced by the marathon race, but these markers did not achieve the same discriminatory power when compared with IL-6 levels or neutrophil count. In conclusion, leukocytes, neutrophils and IG counts as well as IL-6 levels are the best indicators in a mild inflammation model similar to a marathon race. Zusammenfassung Unreife Granulozyten (IG) und das delta-He werden von modernen Hämatologieautomaten bereitgestellt und werden zur Diagnostik von systemischen Entzündungen herangezogen. Sind diese Marker besser zum Nachweis einer geringgradigen Entzündung geeignet als die traditionellen Parameter Leukozytenzahl, C-reaktives Protein (CRP), Procalcitonin (PCT), Interleukin-6 (IL-6) und die üblicherweise in der Forschung eingesetzten Leukozytenoberflächenmoleküle? Zur Beantwortung dieser Frage wählten wir als Modell den Marathonlauf, von dem bekannt ist, dass sich nach Beendigung des Laufes typische Entzündungszeichen im Blut der Läufer nachweisen lassen. Blutbild mit Leukozytendifferenzierung, CRP, PCT, IL-6, und die Expression von Leukozytenoberflächenmolekülen wurden unmittelbar nach dem Lauf gemessen und mit den Werten verglichen, die unter Ruhebedingungen (vor dem Lauf, bzw. 10 Tage nach dem Marathon) bestimmt wurden. Im Vergleich zum Ruhezustand ließ sich unmittelbar nach dem Marathonlauf (Entzündungsphase) ein Anstieg von Leukozyten, Neutrophilen sowie eine Zunahme der Konzentration von IL-6 nachweisen. Die diagnostische Sensitivität und Spezifität betrug für diese Marker nahezu 100%. In dem gewählten Modell wurde keine CRP-Erhöhung beobachtet. Das delta-He fiel in der Entzündungsphase unmittelbar nach dem Lauf nicht in den negativen Bereich ab, wie es für systemische inflammatorische Prozesse charakteristisch ist. Die Leukozytenoberflächenmoleküle zeigten eine Entzündung an, waren jedoch in der Sensitivität und Spezifität den traditionellen Parametern unterlegen. Leukozyten- und Neutrophilenzahl, IGs und IL-6 sind die besten Indikatoren für eine geringgradige Entzündung, die in der vorliegenden Arbeit durch einen Marathonlauf hervorgerufen wurde.

Evaluation of the iChem® Velocity™ Urine Chemistry Analyzer in a hospital routine laboratory

Abstract Background: The novel urine chemistry analyzer iChem Velocity (IRIS Diagnostics) offers improved urinalysis automation options through integration with the well-established iQ200 urine microscopy analyzer. In the course of optimizing the workflow in our hospital routine laboratory, we evaluated the performance of the iChem Velocity. Methods: A total of 257 random urine samples were analyzed with the iChem Velocity, iQ200, Clinitek Atlas (Siemens Healthcare Diagnostics) and by manual microscopy. Results: Depending on the parameter, 93% (hemoglobin) to 100% (urobilinogen), the iChem Velocity and Clinitek Atlas results agreed within the same rank or within one level of difference. The Clinitek Atlas featured a higher sensitivity for hemoglobin (area under the curve 0.86) and leukocyte esterase (area under the curve 0.85) compared with the iChem Velocity (area under the curve for hemoglobin 0.73, leukocytes 0.78). Imprecision was highest for hemoglobin and leukocytes in a pathological sample pool. While the precision of the Clinitek Atlas for hemoglobin measurements was superior, the iChem Velocity was more precise in analyzing protein and pH. Conclusions: Through urinalysis automation with the iChem Velocity and iQ200, we achieved a reduction of hands-on time by 89%. The sensitivity of this new system should be further improved through ongoing development.