Torbjörn Linde

Blood viscosity and peripheral vascular resistance in patients with untreated essential hypertension

Objectives: The viscosity of blood is increased in patients with essential hypertension. The aim of the present study was to investigate the importance of the different variables of blood rheology to total peripheral resistance, and to elucidate whether inappropriate regulation of the formation of erythropoietin could be important. Design: Nineteen consecutive patients with untreated essential hypertension were examined and compared with a group of matched healthy volunteers. Methods: The haemorheologic variables were assessed by rotational viscometry and the haemodynamic variables by bioimpedance cardiography. The serum concentrations of erythropoietin were determined by radioimmunoassay. Results: The whole blood viscosity and peripheral resistance index were elevated in the hypertensive group. The two variables were positively correlated with each other (r=0.68, P=0.0015). The plasma viscosity and erythrocyte aggregation tendency were increased and the erythrocyte deformability, measured as fluidity, was decreased in the hypertensive patients. In the male subpopulation (n=12) the aggregation tendency was positively, and the deformability negatively, correlated with body mass index. The serum concentrations of erythropoietin were equal in the two groups. Conclusions: The increased total peripheral resistance in patients with essential hypertension may in part be explained by an increased blood viscosity, but the possibility of an opposite cause-effect relationship must also be taken into consideration. The haemorheological abnormalities observed in the present patients cannot be explained by high serum levels of erythropoietin.

Renal anaemia treatment with recombinant human erythropoietin increases cardiac output in patients with ischaemic heart disease.

An increase in blood pressure is common during treatment of renal anaemia with recombinant human erythropoietin (rhEPO). Concomitant findings of a decrease in cardiac output indicate that an increase in the peripheral flow resistance underlies the increase in blood pressure. The aim of this study was to elucidate the haemodynamic changes during rhEPO treatment in patients with ischaemic heart disease (IHD). Haemodynamic variables were assessed by impedance cardiography in 18 consecutive patients with renal anaemia before and after rhEPO treatment. IHD was found in eleven of these patients. The remaining seven served as controls. Before rhEPO treatment, the cardiac index was decreased in the group of patients with IHD, compared with controls and healthy subjects. Due to an increase in stroke index, the cardiac index increased during rhEPO treatment and reached values equal to those in the control group. The blood pressure increased and the increase in mean arterial pressure was correlated to the increase in cardiac index. Apparently the patients with IHD were unable to compensate for anaemia by increasing their cardiac index. Anaemia treatment increased cardiac index, which in turn caused an increase in blood pressure in these patients.

Impaired erythrocyte fluidity during treatment of renal anaemia with erythropoietin

Abstract. Seventeen haemodialysis patients with renal anaemia were treated with recombinant human erythropoietin (rhEPO) and observed for 30 weeks. The viscosity of whole blood and plasma, the erythrocyte aggregation tendency, and the erythrocyte deformability, measured as fluidity, were analysed every second week. All patients responded with increasing haematocrit and whole‐blood viscosity. The plasma viscosity and the erythrocyte aggregation tendency were already increased before the start of treatment, and remained unchanged during treatment. The basal erythrocyte fluidity tended to be impaired, although not significantly so. During treatment, significant impairment of fluidity was observed at the beginning of the treatment period. After 24 weeks the fluidity started to increase, and it later reached values observed before the start of treatment. Hence, the quality of the erythrocytes formed during the corrective phase of rhEPO treatment differs in some respects from that of cells formed at a normal production rate. The impaired fluidity might have important implications for the flow resistance in small vessels, and contribute to the development or aggravation of hypertension that is often seen during rhEPO treatment.

Fibroblast growth factor 23, mineral metabolism and mortality among elderly men (Swedish MrOs)

BackgroundFibroblast growth factor 23 (FGF23) is the earliest marker of disturbed mineral metabolism as renal function decreases. Its serum levels are associated with mortality in dialysis patients, persons with chronic kidney disease (CKD) and prevalent cardiovascular disease (CVD), and it is associated with atherosclerosis, endothelial dysfunction and left ventricular hypertrophy in the general population. The primary aim of this study is to examine the association between FGF23 and mortality, in relation to renal function in the community. A secondary aim is to examine the association between FGF23 and CVD related death.MethodsThe population-based cohort of MrOS Sweden included 3014 men (age 69–81 years). At inclusion intact FGF23, intact parathyroid hormone (PTH), 25 hydroxyl vitamin D (25D), calcium and phosphate were measured. Mortality data were collected after an average of 4.5 years follow-up. 352 deaths occurred, 132 of CVD. Association between FGF23 and mortality was analyzed in quartiles of FGF23. Kaplan-Meier curves and Log-rank test were used to examine time to events. Cox proportional hazards regression was used to examine the association between FGF23, in quartiles and as a continuous variable, with mortality. The associations were also analyzed in the sub-cohort with estimated glomerular filtration rate (eGFR) above 60 ml/min/1.73 m2.ResultsThere was no association between FGF23 and all-cause mortality, Hazard ratio (HR) 95% confidence interval (CI): 1.02 (0.89-1.17). For CVD death the HR (95% CI) was 1.26 (0.99 - 1.59)/(1-SD) increase in log(10)FGF23 after adjustment for eGFR, and other confounders. In the sub-cohort with eGFR > 60 ml/min/1.73 m2 the HR (95% CI) for CVD death was 55% (13–111)/(1-SD) increase in log(10)FGF23.ConclusionsFGF23 is not associated with mortality of all-cause in elderly community living men, but there is a weak association with CVD death, even after adjustment for eGFR and the other confounders. The association with CVD death is noticeable only in the sub-cohort with preserved renal function.

Anemia associated with advanced prostatic adenocarcinoma : Effects of recombinant human erythropoietin

BACKGROUND AND METHODS. Nine patients with hormone‐refractory metastatic prostatic adenocarcinoma and anemia were treated with recombinant human erythropoietin (rHuEpo) at a median dose of 150 U/kg BW 3 times a week subcutaneously. Baseline hemoglobin (Hb) ranged from 70 to 116 g/L, and the study duration was 12 weeks (median patient participation period was 8 weeks).

Erythropoietin Impairs Endothelial Vasodilatory Function in Patients with Renal Anemia and in Healthy Subjects

Background/Aim: The mechanisms underlying the aggravation or development of hypertension frequently seen during treatment of renal anemia with epoetins are not fully elucidated. The aim of the present study was to investigate the effects of epoetin alfa on endothelial vasodilatory function in patients with renal anemia and in healthy subjects. Methods: Eighteen preuremic patients with anemia (GFR 23.4 ± 11 SD ml/min, Hb 101 ± 8 g/l) and 10 healthy subjects underwent evaluation of endothelium-dependent vasodilation (EDV) and endothelium-independent vasodilation (EIDV) by means of forearm blood flow (FBF) measurements with venous occlusion plethysmography during local intra-arterial infusions of methacholine (MCh, evaluating EDV) and sodium nitroprusside (SNP, evaluating EIDV). These investigations were performed before and 30 min after an intravenous injection of epoetin alfa (10,000 IU). Ten healthy subjects underwent the same procedure with the exception that saline were given instead of epoetin. The patients were treated with epoetin alfa subcutaneously for 12–19 weeks and revaluated when Hb exceeded 120 g/l. Results: EDV was attenuated after the epoetin injection in both renal patients and healthy subjects. This impairment persisted after anemia had been treated. EDIV and blood pressure remained constant. Saline had no effect on the variables measured. Conclusion: Our results indicate that epoetin alfa impairs endothelial function in renal patients and healthy subjects which may have an impact on vascular complications.

Fibroblast growth factor-23 and mineral metabolism after unilateral nephrectomy

BACKGROUND Fibroblast growth factor -23 (FGF-23) is a key regulator of mineral metabolism. It regulates renal phosphate (Pi) reabsorption and calcitriol synthesis, and has an inhibitory effect on parathyroid hormone (PTH) secretion. FGF-23 increases early in chronic kidney disease (CKD), but the regulation of FGF-23 in mild -to -moderate renal dysfunction is not fully understood. METHODS Nine healthy kidney donors underwent unilateral nephrectomy. Estimated glomerular filtration rate (eGFR) calculated from cystatin C and parameters of mineral metabolism: (Pi, ionized calcium, biointact PTH, intact FGF-23, calcitriol, and urinary excretion of calcium and Pi) were analysed before surgery, and one day, one week and three to six months after surgery. RESULTS On the first post-operative day, PTH increased due to a decrease in the calcium level. One week after nephrectomy, the FGF-23 level increased from 31.8 ± 12.3 pg/mL to 55.8 ± 15.1 pg/mL, while PTH, Pi and calcium levels were unchanged compared towith baseline. On follow-up, eGFR improved compared with its one-week value, and PTH and FGF-23 were unchanged compared towith baseline. The calcitriol level decreased but was in the normal range at all points in time. The total amount of Pi in urine did not change, while the calcium excretion decreased significantly. CONCLUSIONS Pi homeostasis after nephrectomy is maintained by PTH on the first day. When serum calcium is stabilized and food intake resumed, FGF-23 rises, possibly in response to the Pi- load in relation to GFR.

PREOPERATIVE TUMOR LOCALIZATION BY MEANS OF VENOUS SAMPLING FOR FIBROBLAST GROWTH FACTOR-23 IN A PATIENT WITH TUMOR-INDUCED OSTEOMALACIA

OBJECTIVE To report on a novel strategy for tumor localization in a 62-year-old man with hypophosphatemic tumor-induced osteomalacia (TIO). METHODS Repeated computed tomographic and magnetic resonance imaging scans failed to localize any tumor in a patient with adult-onset hypophosphatemic osteomalacia. Therefore, venous sampling for fibroblast growth factor-23 (FGF23)--a circulating hormone that has been identified as a causative factor for TIO--in major veins was conducted. Serum FGF23 was measured from collected samples by an intact FGF23 enzyme-linked immunosorbent assay. RESULTS Venous sampling suggested a local increase in serum FGF23 in the left femoral vein; this finding prompted performance of octreotide scintigraphy restricted to the left leg. A tumor was located at the lateral condyle of the left femur, which was also confirmed by magnetic resonance imaging. Surgical resection of the tumor normalized the serum phosphorus and 1,25-dihydroxyvitamin D3 levels within 5 to 10 days, and FGF23 declined to normal levels within 24 hours. Histologic analysis supported the diagnosis of a soft-tissue giant cell tumor. CONCLUSION Our study case demonstrates the diagnostic complexity and difficulties in localizing a small tumor in a patient with TIO. Venous sampling for FGF23 may be helpful in tumor localization in sporadic cases of hypophosphatemic osteomalacia, especially when noninvasive diagnostic techniques prove insufficient.

The use of pretransplant erythropoietin to normalize hemoglobin levels has no deleterious effects on renal transplantation outcome

Background. The aim of this study was to establish the outcome of renal transplantation in patients given pretransplant erythropoietin (EPO) treatment targeted at reaching a normal hemoglobin concentration (Hb), compared to those given EPO-treatment aimed at maintaining subnormal Hb. Methods. A total of 416 patients from Scandinavian countries and with renal anaemia were enrolled to examine the effects of increasing Hb from a subnormal level (90–120 g/liter) to a normal level (135–160 g/liter) by EPO treatment. Half of the patients were randomized to have their Hb increased, with the other half randomized to maintain a subnormal Hb. Thirty-two patients from the normal Hb group and 24 patients from the subnormal group received a renal graft during the study period. The outcomes of these transplantations were examined prospectively for 6 months. Results. Preoperative Hb levels were 143±17 and 121±14 g/liter in the two groups, respectively (P <0.0001). The Hb remained higher in the normal Hb group during the first 2 weeks after transplantation. The percentage of patients requiring postoperative blood transfusions in the normal Hb group was 16%, compared with 50% in the subnormal group (P <0.01). No statistically significant difference in the proportion of functioning grafts or in the serum creatinine levels could be detected. No correlation between EPO treatment and creatinine levels after transplantation was found. The frequency of adverse events was similar in the two groups. Conclusions. EPO treatment aimed at reaching a normal Hb in renal transplant recipients reduces the postoperative requirement for blood transfusions and has no deleterious effects on kidney graft function.

Hemorheological and hemodynamic changes in predialysis patients after normalization of hemoglobin with epoetin-alpha.

Objective. Changes in blood viscosity and total peripheral resistance may contribute to increased blood pressure during partial correction of renal anemia with erythropoietin. An increase in hemoglobin level is followed by decreases in cardiac output and left ventricular mass. We examined how normalization of hemoglobin in predialysis patients affects both hemorheological and hemodynamic variables. Material and methods. Twelve moderately anemic predialysis patients (hemoglobin 115.9±7.8 g/l) received epoetin-α with the aim of achieving a normal hemoglobin level (135–160 g/l). Hemorheological variables were measured using rotational viscometry. Cardiac index was determined by means of Doppler echocardiography. Results. After 48 weeks, the hematocrit level had increased from 37.9%±3.0% to 47.0%±3.1% (p<0.0001). Blood viscosity increased from 3.84±0.33 to 4.59±0.4 mPa×s (p<0.001). Blood viscosity standardized to a hematocrit level of 45% and a plasma viscosity of 1.31 mPa×s did not change. Plasma viscosity, erythrocyte aggregation tendency and erythrocyte fluidity remained unchanged. The cardiac index decreased from 2.64±0.57 to 2.19±0.72 l/min/m2 (p<0.05). The total peripheral resistance index increased from 3270±985 to 4013±1046 (dyn×s/cm5)m2 (p<0.05). Blood pressure remained constant, but the amount of antihypertensive medication used increased by 30%. Conclusions. Hemoglobin normalization in predialysis patients raised blood viscosity and total peripheral resistance due to an increase in hematocrit level, without other consistent hemorheological changes. Antihypertensive therapy had to be increased in many patients to maintain an acceptable blood pressure. The cardiac index was reduced, which may have prevented further development of left ventricular hypertrophy.