Fibroblast growth factor 23 and matrix-metalloproteinases in patients with chronic kidney disease: are they associated with cardiovascular disease?

BACKGROUND: High cardiovascular risk in patients with chronic kidney disease (CKD) may be related to mineral disorder and microinflammation. Fibroblast growth factor 23 (FGF-23) is a phosphatonin and inhibitor of calcitriol synthesis, which is associated with poor prognosis in CKD patients starting dialysis. Matrix-metalloproteinases (MMP-2, MMP-9) contribute to myocardial remodeling and arterial calcification. FGF-23 and MMPs levels are altered in CKD, however, little is known about their association and relation to cardiovascular (CV) disease. METHODS: Standard laboratory parameters, plasma levels of MMP-2, MMP-9, FGF-23, PAPP-A and CV disease history were assessed in 80 patients with CKD 1-5 and 44 healthy control subjects. RESULTS: FGF-23 and MMP-2 (assessed by ELISA) were higher in CKD patients compared to controls. FGF-23 increased from CKD 3, whereas MMP-2 increased only in CKD 5. FGF-23 was positively associated with MMP-2, adjusted to age, eGFR, phosphatemia, calcitriol and parathormone. FGF-23 independently correlated with parathormone and inversely with calcitriol, whereas MMP-2 was related to phosphatemia. FGF-23 was higher in subjects with a history of CV disease compared to those free of such history (559.0 vs.184.0 RU/ml), adjusted to age and eGFR. CONCLUSION: Our data suggest a possible relationship between FGF-23, MMP-2 and CV disease in CKD. Potential causality of this association remains to be elucidated.

[Advanced glycation and oxidation products in patients with atherosclerosis]. / Produkty pokrocilé glykace a oxidace u pacientu s aterosklerózou.

BACKGROUND: Oxidative stress can potentiate atherogenesis via modification of biological structures and formation of new compounds, e.g. advanced glycation end products (AGEs) and advanced oxidation protein products (AOPP). The aim of the study was to determine AGEs and AOPP in patients with atherosclerosis, effect of statin therapy and relationship to parameters of lipid metabolism. METHODS AND RESULTS: AGEs (carboxymethyllysine - ELISA and fluorescent AGEs - spectrofluorimetry) and AOPP (spectrophotometry) were assessed in 42 patients with atherosclerosis and 21 healthy controls. AGEs are significantly elevated in patients with atherosclerosis in comparison with healthy subjects (carboxymethyllysine 9.02+/-1.66 microg/g prot. vs 7.52+/-1.18 microg/g prot., p<0.001, fluorescent AGEs 4.39 x 103+/-1.15 x 103 AU/g prot. vs 3.78 x 103+/-0.52 x 103 AU/g prot., p<0.001). Mean AOPP concentrations are also slightly higher, but this elevation is not quite significant (95.0+/-42.9 micromol/l vs 79.7+/-28.2 micromol/l, p=0.096). AGEs and AOPP correlate significantly with each other and with selected lipids. Patients with atherosclerosis treated with statins have slightly lower CML, AGEs and AOPP (it did not reach the statistical significance). CONCLUSIONS: Advanced glycoxidation products are elevated in patients with atherosclerosis and are related to parameters of lipid metabolism. Glycoxidation might be possibly therapeutically influenced by statins; however, further clinical studies are required to confirm this hypothesis.

Oxidative stress, inflammation and autoimmune reaction in type 1 and type 2 diabetes mellitus.

Diabetes mellitus (DM) is associated with oxidative stress, elevation of inflammatory markers and other mechanisms, which may contribute to accelerated atherosclerosis. The aim of the study was to determine prominent factors of these pathogenic processes in patients with DM, to examine their relationship in serum, and to find out the differences between DM1 and DM2. Advanced oxidation protein products (AOPP), C-reactive protein (CRP), pregnancy-associated plasma protein-A (PAPP-A), anticardiolipin antibodies (ACA) and anti-beta2-glycoprotein-1 antibodies (anti-beta2-GPI) were determined in 27 patients with DM1, 27 patients with DM2 and 23 healthy subjects. AOPP, CRP and anti-beta2-GPI were significantly elevated in DM2 in comparison with healthy subjects (p<0.01, p<0.0001, p<0.0001, respectively). In DM1, anti-beta2-GPI were elevated (p<0.0001) as well, but there was no increase of either AOPP or CRP. There was no difference in PAPP-A levels in DM1 or DM2 and healthy subjects. In DM 1, AOPP correlate significantly with anti-beta2-GPI (r = 0.68, p<0.05). In DM2, there is a significant correlation between anti-beta2-GPI and PAPP-A (r=0.45, p<0.05). Oxidative stress and inflammation are more expressed in DM2 and they are partly related. In DM1, oxidative stress seems to be in closer link to autoimmune reaction than to inflammation.

Pregnancy-associated plasma protein A during hemodialysis with polyamide and diacetate cellulosic membranes.

Pregnancy-associated plasma protein A (PAPP-A) is a new prognostic factor of acute coronary syndrome in the general population. It is elevated in hemodialysis (HD) patients and at baseline, it was shown to be related to inflammation and oxidative stress. The aim of the study was to examine the relationship of PAPP-A and oxidative stress and inflammatory markers to HD treatment. Studied parameters were determined in 10 chronic HD patients treated with low flux polyamide (1st session) and diacetate cellulosic membranes (2nd session) at the beginning, after 15 minutes and at the end of the dialysis session. TRACE method (Time Resolved Amplified Cryptate Emission) was used for PAPP-A assessment. Results were evaluated with ANOVA. PAPP-A levels did not depend on the type of HD membrane but changed significantly with the time of the HD session. They increased significantly from the beginning of HD to 15 min and then decreased to the end of the HD session - p<0.05 15 min of HD vs start, p<0.01 end vs start, p<0.0001 end vs 15 min of HD for polyamide membrane and p=0.05 15 min of HD vs start, p<0.01 end vs start, p<0.0001 end vs 15 min of HD for diacetate cellulosic membrane. Changes in other parameters and differences between membranes were only minimal. We can conclude that PAPP-A as a marker of cardiovascular damage shows significant changes during the HD session. Its initial increase might be ascribed to its release from complexes or storage. During dialysis, it might be destroyed or cleaved and removed as free fragments. Its levels both before and after the HD session are higher than in healthy subjects.

Pregnancy-associated plasma protein A (PAPP-A): theoretical and clinical aspects.

Pregnancy-associated plasma protein A (PAPP-A) is an important pregnancy protein. PAPP-A exists in pregnancy serum as a heterotetrameric 2:2 complex with the proform of eosinophil major basic protein (proMBP), forming an approximately 500 kDa and called PAPP-A/proMBP. The gene of PAPP-A has been assigned to human chromosome 9q 33.1. PAPP-A belongs to the metzincin superfamily of metalloproteinases. It contains five short consensus repeats (SCR) and three the lin-notch repeats (LNR) and in addition a putative Zn binding site. The main site of both PAPP-A and proMBP synthesis during pregnancy is the placenta as shown by in situ hybridization. PAPP-A seems to be the predominating IGFBP-4 proteinase in pregnancy serum. In the women the levels of PAPP-A are highest during pregnancy, when plasma levels increase by a factor of about 150 as compared to the nonpregnant state. PAPP-A is the most abundant in the peripheral maternal circulation. Determination of PAPP-A in pregnancy serum has a limited value in some complication in gravidity such as a threatened abortion, ectopic gravidity, preeclampsia or diabetes mellitus. PAPP-A determination will gain increasing importance since this protein seems to be the major biochemical marker of Down syndrome in the first trimester of pregnancy. Maternal serum levels of PAPP-A in the first trimester are significantly reduced when a fetus affected by Down syndrome is present. Low first trimester maternal serum levels were found not only in trisomy 21 but also in non-Down syndrome fetal aneuploidies. Another contribution of PAPP-A determination may be in differentation of stable and unstable angina pectoris. (Tab. 3, Fig. 5, Ref. 78.)

[Advanced oxidation protein products in pregnancy]. / Produkty pokrocilé oxidace proteinu v tehotenství.

OBJECTIVE: Pregnancy and mainly its complications are associated with increased oxidative stress. Advanced oxidation protein products (AOPP) can serve as one of its markers. SETTING: First Institute of Medical Chemistry and Biochemistry and Institute for Clinical Biochemistry, First Medical Faculty, Charles University; Institute for Care of Mother and Child, Prague. METHODS: Together with parameters of prenatal screening, AOPP were measured in the serum of 23 pregnant women in the 2nd trimester of pregnancy. A group of healthy blood donors--women and men was used for comparison. AOPP were determined spectrophotometrically according to Witko-Sarsat (absorbance at 340 nm) and are expressed in chloramin units (mumol/l). RESULTS: Serum AOPP concentrations in pregnant women are significantly higher in comparison with blood donors--women (85.90 +/- 18.70 mumol/l vs 57.34 +/- 16.31 mumol/l, P < 0.0001) but there is no statistically significant difference between pregnant women and blood donors--men (85.90 +/- 18.70 mumol/l vs 78.60 +/- 44.01 mumol/l). AOPP level does not correlate either with the age of pregnant women or with the parameters of prenatal screening (human chorionic gonadotrophin--HCG, alpha-1-fetoprotein--AFP and trophoblast-specific--beta-1-glycoproteion--SP1). CONCLUSION: AOPP as a marker of oxidative stress is increased in the serum of pregnant women in comparison with women--blood donors but is similar as in men--blood donors which supports the hypothesis of hormonal influence. Nevertheless, AOPP do not correlate with the parameters of prenatal screening (HCG, AFP and SP1).

[Determination of advanced glycation end products]. / Soucasné moznosti stanovení produktu pokrocilé glykace.

Advanced glycation end products--AGEs take part in the pathogenesis of many diseases and their complications--e.g. diabetes mellitus, chronic renal failure, atherosclerosis, Alzheimer's disease. Their determination could be of importance for follow up of progression of these diseases. Determination of AGEs is very difficult due to the heterogeneity of this group of substances, lack of standards, long analytical procedures and necessity of equipment. There are several methods for determination of advanced glycation end products: immunochemical method--ELISA (enzyme linked immunosorbent assay) with the use of either polyclonal or monoclonal antibodies, fluorimetry using the characteristic fluorescence spectrum of AGEs, HPLC--high performance liquid chromatography, and MS--mass spectrometry. Mass spectrometry is the best and most precise method. When coupled with other methods, mass spectrometry is a unique research method, which can be used mainly for characterization of new AGEs. HPLC is very precise as well, but its drawback is time-consuming sample preparation. Fluorimetry and ELISA could be in the future used for the special diagnostic of complications of chronic diseases.

Antibodies against phospholipids and oxidized LDL in alcoholic patients.

Antiphospholipid antibodies (APA) are a generic term describing antibodies that recognize various phospholipids. Hepatocyte damage is a cardinal event in the course of alcoholic liver injury and autoantibodies against phospholipids could play an important role in this process. APA in alcoholic patients seem to reflect membrane lesions, impairment of immunological reactivity, liver disease progression and they correlate significantly with disease severity. LDL oxidation is supposed to be one of the most important pathogenic mechanisms of atherosclerosis and antibodies against oxidized low-density lipoprotein (oxLDL) are some kind of an epiphenomenon of this process. The scope of our study was to determine some autoantibodies (IgG-oxLDL and antiphospholipid antibodies) and their possible changes in alcoholic patients. We studied IgG-oxLDL and four APA - anticardiolipin antibodies (ACA), antiphosphatidylserine antibodies (APSA) antiphosphatidylethanolamine antibodies (APE) and antiphosphatidylcholine antibodies (APCA) in 35 alcoholic patients with mildly affected liver function at the beginning of the abuse treatment. The control group consisted of 60 healthy blood donors. In the studied group, we obtained positive results concerning total ACA in 17.1 % of alcoholic patients (8.3 % in the control group), 11.4 % IgG-ACA (6.7 %), 8.6 % IgM-ACA (3.3 %), 14.3 % total APE (6.7 %), 14.3 % total APCA (8.3 %) and 20 % total APSA (8.3 % in the control group). The IgG-oxLDL (406.4+/-52.5 vs 499.9+/-52.5 mU/ml) was not affected in alcoholic patients. We conclude that the autoantibodies against oxLDL are present in sera of alcoholics and healthy blood donors. Based on our results which revealed a wide range of IgG-oxLDL titres in the healthy population, this parameter does not appear to be very promising for the evaluation of the risk of atherosclerosis. Alcoholics with only mild affection of liver functions did not exhibit a significantly higher prevalence of all studied antiphospholipid antibodies (ACA, APSA, APE, APCA) which could lead to membrane lesions in these patients.

[Trace elements, human nutrition and health]. / Stopové prvky, lidská výziva a zdraví.

The importance of trace elements as essential dietary constituents is not sufficiently appreciated by the medical profession, although in recent years a significant increase of new finding on their essential character in nutrition occurred as well as of data on changes in the composition of the diet which can cause their deficiency and in some instances a toxic excess. The diagnosis of deficiency or excess of these substances in the organism is very complicated. because their blood level frequently does not provide sufficient information on their reserves in the organism and new laboratory methods suited for this purpose must be developed and tested. The interpretation of the assembled results is very pretentious and it will be therefore necessary to expand teaching of nutrition, where the problem of trace elements no doubt belongs, into undergraduate and postgraduate medical curricula to prevent health damage due to inadequate intake of trace elements as well as uncontrolled intake of freely available preparations sold as supplements.