Despina Kyriaki

Anaemia in systemic lupus erythematosus: aetiological profile and the role of erythropoietin

OBJECTIVE To study the prevalence of different causes of anaemia in patients with systemic lupus erythematosus (SLE) and their associations with immunological and clinical parameters and to evaluate the contribution of erythropoietin (Epo) and anti-erythropoietin (anti-Epo) autoantibodies to the development of SLE anaemia. METHODS 132 SLE patients with anaemia (defined as haemoglobin of 12 g/dl or less for women and 13.5 g/dl or less for men) from among a total of 345 consecutive SLE patients were prospectively enrolled into the study. Standard haematological and immunological tests were performed and serum Epo and anti-Epo antibodies were assayed. RESULTS The identified causes were anaemia of chronic disease (ACD) n=49 (37.1%), iron deficiency anaemia (IDA) n=47 (35.6%), autoimmune haemolytic anaemia (AHA) n=19 (14.4%) and other causes n=17 (12.9%). There was significant heterogeneity in the severity of anaemia between the four groups (p<0.01) with AHA cases being on average more severe. The proportion of patients with anticardiolipin antibodies, low complement levels and anti-dsDNA differed significantly among the four groups; these markers were particularly common in patients with AHA, and uncommon in patients with IDA. Twenty one of 100 tested patients had anti-Epo antibodies. Such antibodies were seen practically only in patients with ACD (odds ratio 3.1, p=0.041) and in patients with high lupus activity (ECLAM) scores (odds ratio 1.27 per point, p=0.055). Epo response was inadequate in 42.4% and 41.2% of patients with ACD and AHA, respectively. CONCLUSIONS Anaemia in SLE usually takes the form of ACD and IDA, however autoimmune haemolysis is not uncommon. SLE patients with different causes of anaemia differ in regard to several immunological parameters. Epo response is blunted in anaemic SLE patients, particularly those with ACD and AHA.

Circulating Autoantibodies to Erythropoietin Are Associated with Human Immunodeficiency Virus Type 1—Related Anemia

In a cohort of 204 unselected consecutive human immunodeficiency virus type 1 (HIV-1)-infected patients, the association of circulating autoantibodies to endogenous erythropoietin (EPO) with HIV-1-related anemia was studied. Circulating autoantibodies to EPO were present in 48 (23.5%) of the 204 patients studied. Circulating autoantibodies were an independent predictor of anemia (odds ratio [OR]=5.0; 95% confidence interval [CI], 2.5-9.9), as strong as other known causes of anemia. The association of anti-EPO antibodies with anemia became stronger when the analysis was limited to the group of patients without any medical condition causing anemia (OR=10.4; 95% CI, 3.2-33.9). Moreover, the effect on hemoglobin levels remained significant even after adjusting for other anemia parameters. Anti-EPO autoantibodies were associated with higher EPO levels (r=.25, P=.012) and with a more prominent EPO response to anemia. Our findings suggest that autoimmunity, among other factors, may contribute to the pathogenesis of HIV-1-related anemia.

β2-Microglobulin, pulse pressure and metabolic alterations in hemodialysis patients.

Background/Aim: Pulse pressure (PP) is a result of arterial stiffness seen in dialysis patients, but may be a consequence of fluid overload. We examined the role of β2-microglobulin (β2M) in PP in relation to metabolic alterations in patients on different hemodialysis (HD) modalities. Methods: We studied 76 hemodialyzed patients on regular HD (n = 34), predilution bagged hemodiafiltration (n = 19) and online predilution hemodiafiltration (n = 23). β2M levels were measured by radioimmunoassay, and the clearance of β2M was assessed by Kt/V for β2M. Arterial stiffness was measured as carotid-femoral pulse wave velocity, and PP was derived. Insulin levels were measured using immunoradioassay, and insulin resistance was calculated using homeostasis model assessment insulin resistance (HOMA-IR). Serum bicarbonate levels were measured using a blood gas analyzer, and percent sodium removal was calculated. Results: β2M levels predict increased PP (p = 0.02) adjusting for age, HD modalities, HD duration, HOMA-IR and percent sodium removal. β2M was positively associated with HOMA-IR (r = 0.306, p = 0.007). Serum bicarbonate levels and carotid-femoral pulse wave velocity were inversely associated (r = –0.719, p = 0.001). Conclusions: β2M levels were positively associated with PP, which was influenced mainly by dialysis modality fluid and sodium balance and less by arterial stiffness. β2M levels were positively associated with insulin resistance. Uremic acidosis may contribute to arterial stiffness.

Circulating antibodies to endogenous erythropoietin and risk for HIV-1-related anemia

OBJECTIVES In a previous retrospective study we have shown that circulating antibodies to endogenous erythropoietin (anti-EPO) are associated with HIV-1-related anemia. The present longitudinal cohort study was conducted to examine the effect of anti-EPO on the risk of developing anemia over time. METHODS The study population consisted of 113 HIV-1 seropositive patients, who were screened for the presence of anti-EPO, with a mean+/-SD follow up of 105+/-40 months, for a total of 2190 visits. Anti-EPO were detected with an ELISA assay. RESULTS Anti-EPO were detected in 41% (46/113) at enrollment and 29% (320/1094) for all visits, and were associated with higher EPO levels for all visits (45.7+/-60.4 vs. 31.8+/-31.7 IU/ml, p<0.001). After adjusting for other significant confounders, anti-EPO has been associated with increased risk of anemia both at enrollment (odds ratio [OR], 5.07; 95% confidence interval [CI], 1.25-20.49) as well as for all visits ([OR], 2.15; 95% [CI]: 1.29-3.56). During follow up, a decline in prevalence of both anti-EPO and anemia was observed as the percentage of patients receiving HAART was increasing. CONCLUSIONS Anti-EPO are an independent risk factor for anemia in HIV-1-infected patients. HAART seems to reduce both anti-EPO and anemia prevalence.

The relationship between glycemic control, beta2-microglobulin and inflammation in patients on maintenance dialysis treatment.

BackgroundHyperglycemia appears to play a significant role on the inflammatory cytokines production. Beta2-microglobulin (beta2M) is accumulated in the circulation of dialysis patients. We studied the relationship between glycemic control defined by glucose serum concentrations and insulin resistance, beta2M and markers of inflammation in patients on renal replacement therapies with or/and without diabetes mellitus.MethodsWe enrolled 96 dialyzed patients, 62 males and 34 females. The treatment modalities which were applied were : regular hemodialysis (HD, n = 34), predilution hemodiafiltration (HDF, n = 42) and peritoneal dialysis (PD, n = 20). Dialysis adequacy was defined by Kt/V for urea.Beta2M and insulin serum concentrations were measured by radioimmunoassays. hsCRP and TNF-α serum concentrations were measured by ELISA. Insulin resistance was calculated using the homeostasis model assessment of insulin resistance (HOMA-IR).We examined the association of elevated serum glucose with inflammatory factors and we built a multivariable model to investigate if glucose could be a potential determinant of beta2M serum levels.ResultsSerum glucose was positively correlated with beta2M and TNF-α (r = 0.320, p = 0.002 and r = 0.215, p = 0.03 respectively).We observed significant association between the patients with higher serum glucose concentrations and the patients with greater beta2Μ concentrations (x2 = 4.44, p = 0.03). Multivariable model showed that glucose acts as a significant independent determinant of beta2M adjusting for age, gender, dialysis modality and metabolic acidosis status.ConclusionsThe elevated glucose concentrations were positively associated with both, greater beta2M serum concentrations and up-regulated inflammatory procedure in dialysis patients with or/and without diabetes mellitus.

Association between Low Serum Bicarbonate Concentrations and Cardiovascular Disease in Patients in the End-Stage of Renal Disease

Background: Metabolic acidosis, a common condition particularly in the end-stage of renal disease patients, results in malnutrition, inflammation and oxidative stress. In this study, we focused on the association between low serum bicarbonate and cardiovascular disease in patients on intermittent dialysis. Methods: We studied 52 on-line-pre-dilution hemodiafiltration (on-l HDF) patients, 32 males and 20 females, with a mean age of 58.01 ± 15.4 years old. Metabolic acidosis was determined by serum bicarbonate concentrations less than 22 mmol/L. Residual renal function (RRF) was defined by interdialytic urine volume. Kaplan–Meier curves and Cox regression models were performed to predict coronary artery disease (CAD), defined by ejection fraction <50%, or diastolic dysfunction congestive heart failure (CHF) and peripheral vascular disease (PVD). Results: Kaplan–Meier analyses showed that a lower or higher than 22 mmol/L serum bicarbonate metabolic acidosis status was significantly associated with both PVD and diastolic dysfunction (log-rank = 5.07, p = 0.02 and log-rank = 5.84, p = 0.01, respectively). A similar prevalence of serum bicarbonate on CAD or CHF by low ejection fraction was not shown. The RRF was associated with PVD event and serum bicarbonate less than 22 mmol/L (log-rank = 5.49, p = 0.01 and log-rank = 3.9, p = 0.04, respectively). Cox regression analysis revealed that serum bicarbonate and RRF were significant risk factors for PVD after adjustment for confounders. Furthermore, RRF adjusted for covariates was shown to be a significant risk factor for diastolic dysfunction. Conclusion: Low serum bicarbonate was associated with peripheral vascular disease and diastolic dysfunction in intermittent dialysis. The residual renal function may impact patients’ outcomes through its relationship with metabolic acidosis status, particularly for peripheral vascular disease manifestation.

The relationship of residual renal function with cardiovascular morbidity in hemodialysis patients and the potential role of monocyte chemoattractant protein-1

Background: Residual renal function (RRF) provides several benefits to patients on dialysis. Monocyte chemoattractant protein-1 (MCP-1) plays an important role in atherosclerotic lesions. We considered the relationship between RRF and cardiovascular morbidity and the significant role of MCP-1 serum concentrations in hemodiafiltration (HDF) patients. Methods: We enrolled 76 patients on on-line HDF. RRF was defined by interdialytic urine output, and we studied the patients in two groups according to the preservation or not of urine output. MCP-1 levels were measured using enzyme-linked immunosorbent assay. χ2 tests were applied for the association between RRF and left ventricular hypertrophy (LVH), coronary artery disease (CAD), peripheral artery disease (PAD), and systolic and diastolic cardiac dysfunction. We built an adjusted model using logistic regression analysis for the factors which might impact on the loss of urine output. Results: χ2 tests showed a significant association between the loss of urine output and LVH, diastolic dysfunction, and PAD (χ2 = 7.4, p = 0.007; χ2 = 14.3, p = 0.001; χ2 = 4.2, p = 0.03, respectively), although the association with CAD and systolic dysfunction was found to be nonsignificant. The patients without RRF had significantly higher MCP-1, and the urine volume was inversely associated with MCP-1 (r = -465, p = 0.03). In the built adjusted model, the elevated MCP-1 was found to be a significant predictor for the loss of RRF. Conclusion: The loss of RRF was significantly associated with LVH, diastolic dysfunction, and PAD in HDF patients. The increased MCP-1, affected by the lack of urine, may act as an additional underlying factor on this relationship, reflecting a progressive inflammation/oxidative stress condition.

Oxidized Low-Density Lipoprotein Serum Concentrations and Cardiovascular Morbidity in End Stage of Renal Disease

Introduction: Oxidized low-density lipoprotein (ox-LDL) is considered a main biomarker of oxidative stress, a common characteristic in end stage renal disease. We examined the relationship between ox-LDL serum concentrations and cardiovascular disease in permanent hemodiafiltration therapy patients. Methods: Ox-LDL values were measured by ELISA and were corrected for LDL-cholesterol (LDL-C) in 96 participants and in 45 healthy control subjects. We performed chi-square tests and adjusted models for the role of ox-LDL on cardiovascular morbidity including coronary artery disease, left ventricular hypertrophy, systolic, diastolic dysfunction and peripheral arterial disease. Results: ox-LDL/LDL-C values were significantly higher in patients than in control group (p = 0.02), due to increased ox-LDL serum levels rather than to low LDL-C. The unadjusted relationship between high ox-LDL/LDL-C and low ejection fraction was found significant (x2 = 9.04, p = 0.003), although the association with the other cardiovascular manifestations was found non-significant. In the adjusted model for the prediction of systolic cardiac dysfunction, high ox-LDL/LDL-C, old age and non-administration of vitamin D supplementation during dialysis session were found to be significant predictors after adjustment to the confounder. Moreover, the association between systolic cardiac dysfunction and non-administration of vitamin D derivatives during dialysis sessions was found significant (x2 = 6.9, p = 0.008). Conclusions: This study showed a significant association between high ox-LDL and systolic cardiac dysfunction in permanent hemodiafiltration therapy patients. This relationship seems to be influenced by aging and pharmaceutical therapy during dialysis sessions, including vitamin D derivatives.

The Association between Intradialytic Hypertension and Metabolic Disorders in End Stage Renal Disease

Background Intradialytic hypertension was associated with a high mortality risk. We examined the relationship between intradialytic hypertension and metabolic disorders in hemodialysis treatment patients. Methods We studied 76 patients in online hemodiafiltration. Dialysis adequacy was defined by Kt/V for urea. Normalized protein catabolic rate (nPCR), as a marker of protein intake, was calculated. Sodium removal was determined as percent sodium removal. Metabolic acidosis was determined by serum bicarbonate less than 22 mmol/L. Interdialytic urine volume more than 100 ml was recorded. Intradialytic hypertension was defined by an increase in systolic blood pressure equal to 10 mmHg from pre- to posthemodialysis. Arterial stiffness was assessed as carotid-femoral pulse wave velocity (c-fPWV) and carotid augmentation index (AIx). Chi-square tests and logistic regression analysis were applied for intradialytic hypertension prediction. Results Patients with intradialytic hypertension were older and had significantly lower hemoglobin, nPCR, urine output, and serum bicarbonate and significantly higher c-fPWV, though similar Kt/V for urea, than patients without intradialytic hypertension. They also had increased sodium removal and pulse pressure related to less urine output. Serum bicarbonate was inversely associated with c-fPWV (r = −0.377, p = 0.001). Chi-square test showed significant association between intradialytic hypertension and serum bicarbonate < 22 mmol/L (x2 = 5.6, p = 0.01), which was supported by an adjusted model. Conclusion The intradialytic hypertension was significantly associated with metabolic disorders including malnutrition/inflammation and uncontrolled metabolic acidosis in hemodialysis treatment patients. Severe metabolic acidosis may reflect sodium imbalance and hemodynamic instability of these patients resulting in volume overload and increased vascular resistance.

Leptin and hypertension in non-obese patients in renal replacement therapy

Background: The real role of leptin on the vascular disease in end stage of renal disease patients is complicated rather than clear. We considered the relationship between leptin serum concentrations and manifested hypertension in non-obese patients in intermittent dialysis therapy. Methods: We studied 76 patients in on-line hemodiafiltration. Dialysis adequacy was defined by Kt/V for urea. Leptin and i-parathormone (i-PTH) were measured by radioimmunoassay. Metabolic acidosis was determined by serum bicarbonate concentrations less than 22mmol/L. We recorded the home blood pressure according to a standard protocol and it was verified by 24-h monitoring. Antihypertensive treatment was noted. Chi-square tests and adjusted model were performed for the role of leptin on established hypertension. Results: Chi-square tests showed significant association between hypertension and both, low leptin and low bicarbonate (x2=12.4, p=0.001 and x2=13.1, p=0.001 respectively) and it was supported by the built adjusted model. The patients with hypertension had significantly lower leptin, hemoglobin, normalized protein catabolic rate (nPCR) as a marker of protein intake and bicarbonate levels, but similar dialysis dose than the patients without hypertension. The patients with high leptin had significantly decreased blood pressure, but higher i-PTH, bicarbonate levels and liquids overload in combination with similar dialysis sufficiency comparatively to the patients with low leptin. Conclusion: Hypertension was significantly associated with low leptin in non-obese dialysis patients. In spite of apparently adequate dialysis dose, the involved factors in this relationship may be malnutrition and uncontrolled metabolic acidosis state, although the usage of antihypertensive treatment may play an additional role. Material and Methods