Inflammatory Markers and Platelet Aggregation Tests as Predictors of Hemoglobin and Endogenous Erythropoietin Levels in Hemodialysis Patients

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Abstract

Background/Aims: Chronic inflammation is a common cause of severe anemia and hyporesponsiveness to recombinant erythropoietin (EPO) therapy in maintenance hemodialysis (HD) patients. We compared various acute-phase markers and ex vivo platelet aggregation tests in relation to clinical conditions in order to find factors predictive of hemoglobin (Hb) and endogenous EPO levels in a cross-section of clinically stable HD patients. Methods: In 100 subjects, pre-HD blood levels of C-reactive protein (CRP), α<sub>1</sub>-acid-glycoprotein (AGP), α<sub>1</sub>-antitrypsin (AT), immunoglobulin (Ig) M and G (by nephelometry), antigens of endothelial von Willebrand factor (vWF), type 1 plasminogen activator inhibitor and thrombomodulin, interleukin-6, lipoprotein(a) [Lp(a)] and EPO (by ELISA), and albumin, fibrinogen, iron metabolism indices, thyroid-stimulating hormone, phosphorus, parathormone, total cholesterol, triglycerides, viral hepatitis B/C markers, liver enzyme, and aluminium were determined. Platelet aggregations in response to ristocetin (RIPA), adenosine diphosphate, and collagen were measured in whole blood (electric impedance method) and platelet-rich plasma (optical aggregometry). Results: Hb levels inversely correlated with IgM, Lp(a), soluble vWF antigen, phosphorus, and all platelet aggregations in whole blood, but not in platelet-rich plasma. HD duration and triglycerides were positive correlates of anemia. In a multivariable analysis, increased IgM, short HD duration, increased Lp(a) and enhanced whole blood RIPA (in descending order of significance) were independent predictors of low Hb levels. In 51 patients not treated with recombinant EPO, serum levels of this hormone inversely correlated with whole blood RIPA, AT, age, vWF antigen, AGP, and positively with viral hepatitis marker. Anemia and EPO levels were not affected by gender, body mass index, cause of renal failure, residual renal function, HD dose, protein catabolic rate, use of different heparins or dialysate buffers, ACE inhibitor therapy, and parathyroid or thyroid function. In additional 10 patients, single HD session resulted in an increase in IgM levels associated with a fall in total lymphocyte counts. Conclusion: Subclinical inflammation is an important determinant of anemia in maintenance HD patients. Increased serum IgM reflecting a microinflammatory effect of HD procedures, enhanced whole blood RIPA as a surrogate of vascular endothelial damage, and Lp(a) as its promoter could be markers of such impaired erythropoiesis.

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A potential basis for the thrombotic risks associated with lipoprotein(a).

Antonio M Scanu, G Fless, Carol Levin … (1989)

Lipoprotein(a) (Lp(a)) has been strongly linked with atherosclerosis and is an independent risk factor for myocardial infarction. Distinguishing Lp(a) from other low-density lipoprotein particles is its content of a unique apoprotein, apo(a). The recently described sequence of apo(a) indicates a remarkable homology with plasminogen, the zymogen of the primary thrombolytic enzyme, plasmin. Lp(a) may contain 37 or more disulphide-looped kringle structures, which are 75-85% identical to the fourth kringle of plasminogen. Plasminogen receptors are widely distributed on blood cells and are present at extremely high density on endothelial cells. These receptors promote thrombolysis by accelerating plasminogen activation and protecting plasmin from inhibition. If, by molecular mimicry, Lp(a) competes with plasminogen for receptors, then thrombolysis would be inhibited and thrombosis promoted. Here we provide support for such a mechanism being responsible for the thrombotic risks associated with elevated Lp(a) by demonstrating that Lp(a) inhibits plasminogen binding to cells.

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Role of cytokines in the response to erythropoietin in hemodialysis patients.

V Carreño, C Caramelo, Jenny C. Martin … (1998)

Cytokines are regulatory factors of erythropoiesis, especially in pathologic conditions. Even though a relevant role for a deranged cytokine production in the pathogenesis of dialysis anemia has been suggested, no data are available that analyze the role of cytokines in the key therapeutic issue of the needs of erythropoietin. The aim of the present study in hemodialysis patients was, therefore, to examine the relationship between the dose of recombinant human erythropoietin (EPO) and the production of cytokines by peripheral blood mononuclear cells (PBMC). After the exclusion of subjects with major active causes of EPO resistance, data from 34 hemodialysis patients were available for analysis. Cytokine levels were measured in the supernatants of stimulated [with bacterial lipopolysaccharide and interferon gamma (IFN-gamma)] and unstimulated PBMC. Mean yearly values of hematocrit, hemoglobin, transferrin saturation, ferritin, parathormone (PTH) and aluminum levels and EPO doses (U/kg/week) were calculated. For analysis, the 34 patients were divided according to their cutoff requirements for EPO: patients with requirements of EPO > or = 60 U/kg/week (group A1, 26 subjects) versus EPO or = 100 U/kg/week (group A2, 18 subjects) versus <100 U/kg/week (group B2, 16 subjects). A significant direct correlation between interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-a) production values and EPO doses was found (P = 0.039 and P = 0.02 respectively). On the other hand, there was a significantly negative correlation between interleukin-12 (IL-12) production values and EPO doses (P = 0.029). Patients of groups A1 and A2 had spontaneously higher tumor necrosis factor-alpha (TNF-alpha) and lower IL-12 and IFNgamma production compared to patients from groups B1 and B2. Our data disclose a previously undescribed pattern of cytokine alteration that is relevant to determine increased needs of EPO in hemodialysis patients. The present results have potential applicability in designing strategies to improve EPO resistance.

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Influence of hematocrit on the measurement of lipoproteins demonstrated by the example of lipoprotein(a).

H Dieplinger, G Utermann, E Trenkwalder … (1998)

The measurement of many parameters of human blood is usually performed in plasma or serum. Since lipoproteins or apolipoproteins, for example, are found almost exclusively in the plasma fraction after low-speed centrifugation, these parameters can be expected to be distributed in a different plasma volume depending on the hematocrit value. Therefore, the measured plasma levels might be relatively too low or too high in comparison to the whole blood concentrations in the case of abnormal hematocrit levels. The aim of our experiments was to evaluate the extent of differences between whole blood and plasma concentrations, taking as an example lipoprotein(a) [Lp(a)] in hemodialysis patients with documented decreased hematocrit values. Lp(a) was measured in plasma as well as whole blood of 15 hemodialysis patients with low hematocrit values (0.29 +/- 0.02) in comparison to 11 control subjects (0.45 +/- 0.04). Plasma concentrations were 27% higher in patients than in controls (19.7 vs. 15.5 mg/dl). The relative difference was twice as high (59%) when measured in whole blood (13.5 vs. 8.5 mg/dl). Similar relative differences were observed when whole blood concentrations of 125 hemodialysis patients and 256 controls were calculated with the formula [Lp(a)plasma * (1-hematocrit)]. Our findings clearly demonstrate that hematocrit is a strong confounding variable of lipoprotein measurement in epidemiological studies when concentrations are measured in plasma, especially in cases of abnormal hematocrit values. Furthermore, studies investigating the longitudinal changes of lipoproteins should consider potential hematocrit changes.

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Author and article information

Journal

Journal ID (publisher-id): NEF

Journal ID (nlm-ta): Nephron

Journal ID (doi): 10.1159/issn.1660-8151

Title: Nephron

Publisher: S. Karger AG

ISSN (Print): 1660-8151

ISSN (Electronic): 2235-3186

Publication date Subscription-year: 2002

Publication date (Print): August 2002

Publication date (Electronic): 15 July 2002

Volume: 91

Issue: 4

Pages: 671-681

Affiliations

Department of Nephrology and Internal Medicine, Medical Academy, Białystok, Poland

Article

Publisher ID: 65030 Other ID: Nephron 2002;91:671–681

DOI: 10.1159/000065030

PubMed ID: 12138272

SO-VID: dedec141-755d-4fde-ada3-208a293977b0

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