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Biomedical subjects

Thomas Metzger

Publications and source records attributed to Thomas Metzger.

8 recordsLinked to original sources
PubMed2004

Mouse amnionless, which is required for primitive streak assembly, mediates cell-surface localization and endocytic function of cubilin on visceral endoderm and kidney proximal tubules.

Impaired primitive streak assembly in the mouse amnionless (amn) mutant results in the absence of non-axial trunk mesoderm, a derivative of the middle region of the primitive streak. In addition, the epiblast of amn mutants fails to increase significantly in size after E7.0, indicating that middle primitive streak assembly is mechanistically tied to the growth of the embryo during gastrulation. Amn, a novel transmembrane protein, is expressed exclusively in an extra-embryonic tissue, visceral endoderm (VE), during the early post-implantation stages. We show that Amn is also expressed in kidney proximal tubules (KPT) and intestinal epithelium, which, like the VE, are polarized epithelia specialized for resorption and secretion. To explore whether Amn participates in the development or function of KPT and intestinal epithelia and to gain insight into the function of Amn during gastrulation, we constructed Amn(-/-) ES cell<-->+/+ blastocyst chimeras. While chimeras form anatomically normal kidneys and intestine, they exhibit variable, selective proteinuria, a sign of KPT malfunction. In humans, AMN has been genetically connected to Cubilin (CUBN), a multi-ligand scavenger receptor expressed by KPT, intestine and yolk sac. Loss of CUBN, the intestinal intrinsic factor (IF)-vitamin B12 receptor, results in hereditary megaloblastic anemia (MGA1), owing to vitamin B12 malabsorption. The recent report of MGA1 families with mutations in AMN suggests that AMN functions in the same pathway as CUBN. We demonstrate that Cubn is not properly localized to the cell surface in Amn(-/-) tissues in the embryo and adult mouse, and that adult chimeras exhibit selective proteinuria of Cubn ligands. This study demonstrates that Amn is an essential component of the Cubn receptor complex in vivo and suggests that Amn/Cubn is required for endocytosis/transcytosis of one or more ligands in the VE during gastrulation to coordinate growth and patterning of the embryo. Furthermore, as AMN is apparently not required for gastrulation in humans, the developmental requirements for Amn/Cubn function may not be evolutionarily conserved, possibly reflecting differences between species in the role and organization of extra-embryonic tissues.

Animals↗
PubMed2003

Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study.

BACKGROUND: Vascular calcification is the most prominent underlying pathological finding in patients with uraemia, and is a predictor of mortality in this population. Fetuin-A (alpha2-Heremans Schmid glycoprotein; AHSG) is an important circulating inhibitor of calcification in vivo, and is downregulated during the acute-phase response. We aimed to investigate the hypothesis that AHSG deficiency is directly related to uraemic vascular calcification. METHODS: We did a cross-sectional study in 312 stable patients on haemodialysis to analyse the inter-relation of AHSG and C-reactive protein (CRP) and their predictive effect on all-cause and cardiovascular mortality, over a period of 32 months. Subsequently, we tested the capacity of serum to inhibit CaxPO4 precipitation in patients on long-term dialysis (n=17) with apparent soft-tissue calcifications, and in those on short-term dialysis (n=8) without evidence of calcifications and cardiovascular disease. FINDINGS: AHSG concentrations in serum were significantly lower in patients on haemodialysis (mean 0.66 g/L [SD 0.28]) than in healthy controls (0.72 [0.19]). Low concentrations of the glycoprotein were associated with raised amounts of CRP and with enhanced cardiovascular (p=0.031) and all-cause mortality (p=0.0013). Sera from patients on long-term dialysis with low AHSG concentrations showed impaired ex-vivo capacity to inhibit CaxPO4 precipitation (mean IC50: 9.0 microL serum [SD 3.1] vs 7.5 [0.8] in short-term patients and 6.4 [2.6] in controls). Reconstitution of sera with purified AHSG returned this impairment to normal. Interpretation AHSG deficiency is associated with inflammation and links vascular calcification to mortality in patients on dialysis. Activated acute-phase response and AHSG deficiency might account for accelerated atherosclerosis in uraemia.

Blood Proteins↗
PubMed2003

Deficiencies of calcium-regulatory proteins in dialysis patients: a novel concept of cardiovascular calcification in uremia.

Dialysis patients suffer a manifold increase in cardiovascular mortality when compared to a nonuremic population, while this phenomenon is not sufficiently explained by an increased prevalence of traditional risk factors, such as hypercholesterolemia and hypertension. The presence of hyperphosphatemia, of an increased calcium x phosphate product, as well as the magnitude of vascular and valvular calcifications, were recently identified as specific major risk factors of cardiovascular mortality in the uremic population. Furthermore, hyperphosphatemia and an increased calcium x phosphate product could be quantitatively linked to the burden of coronary artery calcification in young dialysis patients, suggesting the correction of hyperphosphatemia as the central target for preventive therapeutic intervention. Recent studies in knockout mice, however, point to the alternative possibility that deficiencies in calcium-regulatory proteins may represent important pathomechanisms leading to extraosseous calcifications. alpha 2-Heremans Schmid glycoprotein (Ahsg/fetuin) and matrix Gla protein (MGP) are strong inhibitors of calcification in vivo. Novel evidence that deficiencies of such proteins may be involved in the pathogenesis of cardiovascular calcifications in dialysis patients will be discussed.

Animals↗
PubMed2002

Advanced glycation end products and mortality in hemodialysis patients.

BACKGROUND: Advanced glycation and oxidation end products (AGEs) cause oxidative stress and trigger cytokine driven inflammatory reactions in vitro. The net effects on markers of inflammation and acute phase proteins in vivo as well as their influence on survival in hemodialysis patients are unknown. METHODS: We conducted a cross-sectional study in 312 stable hemodialysis patients and analyzed the interrelationships of AGEs and C-reactive protein (CRP) and their predictive effect on all-cause as well as cardiovascular mortality. Mortality was monitored prospectively over a period of 32 months. AGEs were determined by measuring total serum fluorescent AGEs (AGE-fl) and Nepsilon-(carboxymethyl)-lysine (CML). RESULTS: The levels of AGE-fl, CML and CRP were 3.2-, 3.8- and 10-fold higher as compared to healthy controls. AGE-fl and CML levels correlated significantly with each other but not with CRP or serum albumin. Patients with high (above median values) AGE-fl or CML levels (109 x 103 AU and 1.4 microg/mL, respectively) had a significant better survival than those with low (below median values) AGE-fl or CML levels. Patients with high CRP levels (above 7.7 mg/L = median value) had a better survival than those with low CRP (below median value) when AGE-fl or CML levels were high in parallel. CONCLUSIONS: In contrast to in vitro data and to current hypotheses, the presence of high serum AGEs, as measured by AGE-fl and CML, were not linked to increased mortality. Statistically, high serum AGEs partly overcame the negative impact of the acute phase response on mortality in hemodialysis patients. Whether the benefit of high serum AGEs is an epiphenomenon or reflects a better nutritional support needs further studies.

Adult↗
PubMed2002

Inflammation and outcome in end-stage renal failure: does female gender constitute a survival advantage?

BACKGROUND: Elevated C-reactive protein (CRP) is a strong predictor of cardiovascular events and all-cause mortality in end-stage renal disease (ESRD) patients. However, although sex hormones may influence serum levels of inflammatory proteins, gender has not been taken into consideration in previous studies of inflammation and outcome in ESRD patients. METHODS: We included 663 (374 males) ESRD patients (59 +/- 1 year) from three European renal centers (Sweden, Germany and Italy) in which CRP levels and outcome data (follow-up 33 +/- 1 months) were available. The relation between outcome and serum levels of the soluble intercellular adhesion molecule (sICAM-1) was evaluated in 312 of the patients. RESULTS: The present study shows that elevated CRP is a strong predictor of outcome, but whereas no difference in all-cause mortality was observed between non-inflamed (CRP <or=3.4 mg/L) males and females, inflamed males had a significantly (log rank 6.1; P = 0.01) higher mortality rate than inflamed females. A strong positive correlation between CRP and sICAM-1 was found in the combined patient material (rho = 0.37; P < 0.0001) as well as in the male (rho = 0.25; P < 0.01) and female (rho = 0.52; P < 0.0001) subgroups. The Cox proportional hazard model showed that whereas both elevated sICAM-1 and log CRP predicted outcome in males, neither predicted outcome significantly in females. CONCLUSIONS: As inflamed female patients have a better outcome that inflamed males the present observation suggests that sex hormones may have important cardioprotective effects that limit the effect of inflammation on vascular injury in female ESRD patients.

Age Distribution↗
PubMed2002

Inflammation and cardiovascular risk in dialysis patients.

BACKGROUND: Chronic inflammation, as evidenced by increased levels of C-reactive protein (CRP), predicts all-cause and cardiovascular mortality in hemodialysis patients in short-term studies. Whether CRP is also predictive in the long-term follow-up is unknown. METHODS: We conducted a 4-year follow-up of a cross-sectional study in a cohort of 280 stable hemodialysis patients. CRP was determined once at the beginning of the study, and all-cause as well as cardiovascular mortality was monitored prospectively. RESULTS: During follow-up, 123 patients (43.9%) had died, mostly from cardiovascular events (58.5%) corresponding to an annual mortality rate of 11%. Overall mortality and cardiovascular mortality were significantly higher in patients with a CRP more than 8 mg/L (73% vs. 39% and 87% vs. 55%, respectively). Multivariate Cox regression analysis demonstrated that age, CRP, and preexisting cardiovascular disease were the most powerful predictors, but the presence of diabetes, albumin, and BMI also remained in the model. CONCLUSION: A single determination of CRP is a powerful indicator of all cause and cardiovascular death even after a follow-up period of 4 years in patients on hemodialysis treatment.

Acute-Phase Reaction↗
PubMed2002

C-reactive protein a marker for all-cause and cardiovascular mortality in haemodialysis patients.

Inflammation is thought to play a central role in the aetiology and outcome of atherosclerosis. C-reactive protein (CRP) is a prominent product of the inflammatory response syndrome and a marker of overall and cardiovascular death in the general population and in dialysis patients. CRP is 5- to 10-fold higher in haemodialysis patients than in healthy controls and clearly is multifactorial in origin. A number of endogenous factors have been identified in vitro [angiotensin II, lipopolysacharide, modified low-density lipoprotein (LDL), advanced glycation end-products, homocysteine, viral infections] which all are able to trigger a nuclear factor (NF)-kappaB-mediated inflammatory, interleukin-6-driven, response via the generation of oxygen free radicals (oxidative stress). In addition, exogenous factors (dialysate endotoxin, vascular access, cuprophane dialyser material) have been identified in clinical studies which are also responsible, at least in part, for high serum CRP levels. Some of these factors function by themselves as non-traditional cardiovascular risk factors. Whether CRP is simply a marker of cardiovascular disease and mortality or whether it is in the causal pathway of the disease remains an open question. Recent data are in favour of a direct involvement in the pathogenesis of disease, since binding of CRP to degraded LDL enhances complement activation and induces the expression of tissue factor.

Biomarkers↗