Ulrich Gladziwa

Uncarboxylated matrix Gla protein (ucMGP) is associated with coronary artery calcification in haemodialysis patients

Matrix gamma-carboxyglutamate (Gla) protein (MGP) is a potent local inhibitor of cardiovascular calcification and accumulates at areas of calcification in its uncarboxylated form (ucMGP). We previously found significantly lower circulating ucMGP levels in patients with a high vascular calcification burden. Here we report on the potential of circulating ucMGP to serve as a biomarker for vascular calcification in haemodialysis (HD) patients. Circulating ucMGP levels were measured with an ELISA-based assay in 40 HD patients who underwent multi-slice computed tomography (MSCT) scanning to quantify the extent of coronary artery calcification (CAC). The mean ucMGP level in HD patients (193 +/- 65 nM) was significantly lower as compared to apparently healthy subjects of the same age (441 +/- 97 nM; p < 0.001) and patients with rheumatoid arthritis (RA) without CAC (560 +/- 140 nM; p < 0.001). Additionally, ucMGP levels correlated inversely with CAC scores (r = -0.41; p = 0.009), and this correlation persisted after adjustment for age, dialysis vintage and high-sensitivity C-reactive protein (hs-CRP). Since circulating ucMGP levels are significantly and inversely correlated with the extent of CAC in HD patients, ucMGP may become a tool for identifying HD patients with a high probability of cardiovascular calcification.

Undercarboxylated Matrix GLA Protein Levels Are Decreased in Dialysis Patients and Related to Parameters of Calcium-Phosphate Metabolism and Aortic Augmentation Index

Background: Vascular calcifications are related to cardiovascular mortality and morbidity in dialysis patients. Limited data exist on the role of calcification inhibitors, such as matrix-carboxyglutamic acid protein (MGP) in dialysis patients. Methods: In 120 dialysis patients and 41 age-matched healthy controls, circulating undercarboxylated (uc) MGP levels were measured with a novel ELISA-based competitive assay. The association between ucMGP levels and determinants of bone mineral metabolism, including the calcification inhibitor fetuin-A, was studied. Moreover, the relation between ucMGP levels and arterial stiffness was investigated. Results: The ucMGP level was significantly lower in dialysis patients compared to controls (173 ± 70 vs. 424 ± 126 nmol/l; p < 0.0001). After adjustment for age, sex and duration of dialysis an independent negative association between time-averaged phosphate levels [regression coefficient β with 95% confidence interval = –64 (–107 to –21)] and a positive association between serum ucMGP and fetuin-A [131 (55–208)] was observed. Duration of dialysis was inversely correlated with ucMGP (r = –0.24, p = 0.007). ucMGP levels were not related to high-sensitivity C-reactive protein or time-averaged calcium levels. After adjustment for age, sex, cardiovascular disease, diabetes, height and mean arterial pressure, ucMGP level was negatively associated with the aortic augmentation index [–0.036 (–0.061 to –0.010)] but not with pulse wave velocity or pulse pressure. Conclusion: Significantly lower serum ucMGP levels were observed in dialysis patients compared to healthy controls. ucMGP levels were inversely associated with phosphate and positively associated with serum fetuin-A levels. Furthermore, ucMGP levels were inversely associated with the aortic augmentation index. These data suggest that low ucMGP levels may be a marker of active calcification.

Influence of Interdialytic Weight Gain on Blood Pressure in Hemodialysis Patients

The role of fluid overload in the pathogenesis of hypertension in hemodialysis patients is not clear. One problem is the lack of techniques to determine the fluid state. Recent new noninvasive techniques have become available which make it possible to accurately determine the dry weight in these patients. Therefore, we studied the influence of interdialytic weight gain on interdialytic blood pressure in 10 normotensive and 10 hypertensive hemodialysis patients without antihypertensive medication. The dry weight was determined with echography of the vena cava. The blood pressure was measured during 2-day and 3-day interdialytic periods using Spacelabs 90207 ambulatory blood pressure monitors. Mean systolic and diastolic blood pressures of the last day of the interdialytic period were compared with mean systolic and diastolic blood pressures of the 1st day of the interdialytic period. Although the interdialytic weight gain in the normotensive and hypertensive patients was greater during the 3-day than during the 2-day interdialytic period, the interdialytic systolic and diastolic blood pressure changes were not greater during the 3-day period. Also, the interdialytic blood pressure rise did not correlate significantly with weight gain, neither in the normotensive nor in hypertensive patients. No significant interdialytic blood pressure changes were found between the normotensive and the hypertensive patients. We conclude that fluid overload does not seem to play a major role in interdialytic blood pressure control in normotensive and hypertensive hemodialysis patients.

Predictors of low circulating endothelial progenitor cell numbers in haemodialysis patients

BACKGROUND End-stage renal disease (ESRD) patients exhibit increased cardiovascular mortality associated with cardiovascular calcifications and endothelial dysfunction. As circulating endothelial progenitor cells (EPCs) harbour vascular regenerative potential and are altered in uraemia, we examined clinical and biochemical factors influencing EPC levels as well as the relation between EPC numbers and function and uraemic cardiovascular calcifications. METHODS Sixty-five haemodialysis patients were investigated. Cardiovascular calcifications were assessed by multi-slice spiral CT (MSCT, n = 44) with the calculation of coronary Agatston scores and indirectly by carotid-femoral pulse wave velocity (PWV, n = 61). EPCs were quantified in peripheral blood (CD34(+)/KDR(+)) and at day 7 after ex vivo cultivation (ac-LDL(+)/lectin(+)) by flow cytometry. In addition, colony-forming units (CFUs), migratory activity, adhesion and viability of isolated EPCs were analysed. RESULTS EPC numbers were reduced (P < 0.001) compared to 27 healthy controls (-64%) or 81 patients with documented coronary artery disease and normal renal function (-58%). Coronary calcifications did not exhibit a significant association with the numbers of circulating CD34(+)/KDR(+) or isolated ac-LDL(+)/lectin(+) EPCs. No difference in EPC functions was observed between the 10 patients with the lowest Agatston scores (range 0-41) versus those with the highest scores (range 1181-3736). Multivariate analysis revealed low fetuin-A serum levels to be a positive predictor, while haematocrit and reticulocytes were negative predictors of reduced ac-LDL(+)/lectin(+) EPC numbers. CONCLUSIONS EPC numbers and function did not correlate with the degree of coronary calcifications in haemodialysis patients. Rather they appear to be related to serum fetuin-A levels, haematocrit and reticulocytes.

Determinants of Arterial Distensibility in Patients with Renal Failure

Background: An increased stiffness of the arterial system is an adverse risk factor for the outcome in patients with renal disease. Few studies have focused on the determinants of an increased arterial stiffness in patients with renal failure. As the percentage of patients with renal failure secondary to vascular disease and/or diabetes mellitus is rapidly growing, and the underlying disease per se may also influence the arterial wall properties, it may also be of interest to study the arterial wall properties in relation to the etiology of kidney disease. Methods: The distensibility coefficient (DC) of the common carotid artery was used as a marker of arterial stiffness. One hundred and seventeen patients were studied: 47 patients (aged 63 ± 10 years) with renal failure secondary to vascular disease and/or diabetes mellitus and 70 patients (aged 57 ± 13 years) with other diagnoses. The origin of the renal failure was retrieved from the patients’ charts. Results: Age, mean arterial pressure, and serum calcium level were each independent predictors of arterial stiffness (DC). The DC was significantly lower in the patients with vascular renal disease or diabetes mellitus [11.0 ± 5.5 (1/MPa)] as compared with patients with renal/urological diseases [15.4 ± 7.5 (1/MPa)]. Nevertheless, after correction for potentially confounding variables, the relation between cause of renal disease and DC lost significance in the overall group, but remained significant (p < 0.05) in the younger age groups (≤61 years; median age of the patient group). Conclusions: Age, mean arterial pressure, and serum calcium level were independent predictors of arterial stiffness in our patients with renal failure. Only in younger dialysis patients, the origin of renal failure was an independent predictor of arterial wall stiffness.